Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet

BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.

Controversies in the management of acute pancreatitis:An update

This review summarized the current controversies in the management of acute pancreatitis(AP).The controversies in management range from issues involving fluid resuscitation,nutrition,the role of antibiotics and antifungals,which analgesic to use,role of anticoagulation and intervention for complications in AP.The interventions vary from percutaneous drainage,endoscopy or surgery.Active research and emerging data are helping to formulate better guidelines.The available evidence favors crystalloids,although the choice and type of fluid resuscitation is an area of dynamic research.The nutrition aspect does not have controversy as of now as early enteral feeding is preferred most often than not.The empirical use of antibiotics and antifungals are gray zones,and more data is needed for conclusive guidelines.The choice of analgesic is being studied,and the recommendations are still evolving.The position of using anticoagulation is still awaiting consensus.The role of intervention is well established,although the modality is constantly changing and favoring endoscopy or percutaneous drainage rather than surgery.It is evident that more multicenter randomized controlled trials are required for establishing the standard of care in these crucial management issues of AP to improve the morbidity and mortality worldwide.

Natural history and long-term clinical course of Crohn's disease

Crohn’s disease is a chronic inflammatory disease process involving different sites in the gastrointestinal tract.Occasionally,so-called metastatic disease occurs in extra-intestinal sites.Granulomatous inflammation may be detected in endoscopic biopsies or resected tissues.Genetic,epigenetic and environmental factors appear to play a role.Multiple susceptibility genes have been described in both familial and non-familial forms while the disease is phenotypically heterogeneous with a female predominance.The disorder occurs over a broad age spectrum,from early childhood to late adulthood.More than 80%are diagnosed before age 40 years usually with terminal ileal and colonic involvement.Pediatric-onset disease is more severe and more extensive,usually with a higher chance of upper gastrointestinal tract disease,compared to adult-onset disease.Long-term studies have shown that the disorder may evolve with time into more complex disease with stricture formation and penetrating disease complications(i.e.,fistula,abscess).Although prolonged remission may occur,discrete periods of symptomatic disease may re-appear over many decades suggesting recurrence or re-activation of this inflammatory process.Eventual development of a cure will likely depend on identification of an etiologic cause and a fundamental understanding of its pathogenesis.Until now,treatment has focused on removing risk factors,particularly cigarette smoking,and improving symptoms.In clinical trials,clinical remission is largely defined as improved numerical and endoscopic indices for"mucosal healing"."Deep remission"is a conceptual,more"extended"goal that may or may not alter the long-term natural history of the disease in selected patients,albeit at a significant risk for treatment complications,including serious and unusual opportunistic infections.

ABO blood type,diabetes and risk of gastrointestinal cancer in northern China

AIM:To explore the potential risk factors related to gastrointestinal cancer in northern China.METHODS:A total of 3314 cases of gastrointestinal cancer(esophageal,gastric,pancreatic and biliary) and 2223 controls(including healthy individuals,glioma and thyroid cancer) were analyzed by case-control study.Multivariable logistic regression analysis was applied to evaluate the association between different cancers and hepatitis B surface antigen,sex,age,blood type,diabetes,or family history of cancer.RESULTS:Type 2 diabetes was significantly associated with gastric,biliary and pancreatic cancer with an OR of 2.0-3.0.Blood type B was significantly associated with esophageal cancer [odd ratio(OR) = 1.53,95% confidence interval(CI) = 1.10-2.14] and biliary cancer(OR = 1.49,95% CI = 1.09-2.05).The prevalence of type 2 diabetes was significantly higher in gastric,biliary and pancreatic cancers compared with other groups,with ORs ranging between 2.0 and 3.0.Family history of cancer was strongly associated with gastrointestinal compared with other cancers.CONCLUSION:Blood type B individuals are susceptible to esophageal and biliary cancer.Type 2 diabetes is significantly associated with gastric,biliary and especially pancreatic cancer.

Significant decrease in prevalence ofHelicobacter pylori in the Czech Republic

AIM:To study possible decrease in prevalence of Helicobacter pylori(H.pylori) infection in the Czech Republic within a 10-year period.METHODS:A total of 22 centres entered the study.The catchment areas of these centres covered cities and towns with more than 20 000 inhabitants,smaller towns(≤ 20 000 inhabitants) with surrounding villages and rural areas,and were spread over the whole country,corresponding well to the geographical distribution of the Czech population.A total of 1 837 subjects(aged 5-98 years) took part in the study,randomly selected out of 38 147 people from the general population.H.pylori infection was investigated by means of a 13 C-urea breath test.Breath samples in duplicates were analysed using isotope ratio mass spectrometry.The cut-off point was 3.5.Social and demographic characteristics were based on data from self-completed questionnaires.RESULTS:The overall prevalence of H.pylori infection was 23.5%(430/1826),and 4.8%(20/420) in children aged 15 or less.There was no statistically significant difference in prevalence between males(24.3%;208/857) and females(22.9%,222/969,P = 0.494).H.pylori infection was strongly associated with higher age,among subjects aged 55+ years,prevalence of H.pylori infection was 39.8%(252/633,P < 0.001).The highest prevalence of H.pylori infection was found among persons aged 55-64 years(43.9%,97/221) and 75+ years(37.9%,58/153).Among study subjects aged 15+ years,prevalence of H.pylori infection was significantly increased in those with lowest education(odds risk 3.19,95% CI 1.87-5.47).Compared to never married(14.1%),the prevalence of H.pylori infection was statistically significantly higher among married(35.4%,246/694,P < 0.001),divorced(36.8%,49/133,P < 0.001) and widowed study subjects(40.2%,45/112,P < 0.001),both in minimally and fully adjusted analysis.There was no significant difference in the prevalence of H.pylori infection between married and widowed subjects(35.4%,246/694 vs 40.2%,45/112,P = 0.389).There was little variation in smoking prevalence across categories of smoking and there was no evidence of an increased risk ofH.pylori infection among current or past smokers in our data(odds risk 1.04 with 95% CI 0.78-1.40 for current smokers;odds ratio 0.83 with 95% CI 0.60-1.16 for former smokers).The current prevalence of H.pylori in 2011 was significantly lower compared to the prevalence reported from identical geographical areas in 2001(23.5%vs 41.7%,P < 0.001).CONCLUSION:The overall prevalence of H.pylori infection in the general population has fallen substantially in the Czech Republic over the past 10 years.

Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis

Fundic gland polyps are now commonly recognized during endoscopy. These polyps are benign, often multiple and usually detected in the gastric body and fundus. In the past, these polyps were sometimes associated with familial adenomatous polyposis. In recent years, it has become evident that increasing numbers of these polyps are being detected during endoscopic studies, particularly in patients treated with proton pump inhibitors for prolonged periods. In some, dysplastic changes in these polyps have also been reported. Recent studies have suggested that there may be no increase in risk of colon cancer with long-term proton pump inhibitor therapy. While temporarily reassuring, ongoing vigilance, particularly in those genetically predisposed to colon cancer, is still warranted.

Endoscopic mucosal resection of colorectal adenomas > 20 mm: Risk factors for recurrence

AIM: To evaluate risk factors for local recurrence after endoscopic mucosal resection of colorectal adenomas > 20 mm.METHODS: Retrospective data analysis of 216 endoscopic mucosal resections for colorectal adenomas > 20 mm in 179 patients(40.3% female; median age 68 years; range 35-91 years). All patients had at least 1 follow-up endoscopy with a minimum control interval of 2 mo(mean follow-up 6 mo/2.0-43.4 mo). Possible factors associated with local recurrence were analyzed by univariate and multivariate analysis. RESULTS: Median size of the lesions was 30 mm(20-70 mm),69.0% were localized in the right-sided(cecum,ascending and transverse) colon. Most of the lesions(85.6%) showed a non-pedunculated morphology and the majority of resections was in piecemeal technique(78.7%). Histology showed carcinoma or high-grade intraepithelial neoplasia in 51/216(23.6%) lesions including 4 low risk carcinomas(pT1 a,L0,V0,R0- G1/G2). Histologically proven recurrence was observed in 33/216 patients(15.3%). Patient age>65 years,polyp size>30 mm,non-pedunculated morphology,localization in the right-sided colon,piecemeal resection and tubular-villous histology were found as associated factors in univariate analysis. On multivariate analysis,only localization in the rightsided colon(HR = 6.842/95%CI:1.540-30.394; P=0.011),tubular-villous histology(HR = 3.713/95%CI: 1.617-8.528;P=0.002) and polyp size>30 mm(HR=2.563/95%CI:1.179-5.570; P=0.017) were significantly associated risk factors for adenoma recurrence. CONCLUSION: Meticulous endoscopic follow-up is warranted after endoscopic mucosal resection of adenomas localized in the right-sided colon larger than > 30 mm,with tubular-villous histology.

Dimensions of hepatocellular carcinoma phenotypic diversity

Hepatocellular carcinoma(HCC) is the 3^(rd) leading cause of cancer-related death worldwide. More than 80% of HCCs arise within chronic liver disease resulting from viral hepatitis, alcohol, hemochromatosis, obesity and metabolic syndrome or genotoxins. Projections based on Western lifestyle and its metabolic consequences anticipate a further increase in incidence, despite recent breakthroughs in the management of viral hepatitis. HCCs display high heterogeneity of molecular phenotypes, which challenges clinical management. However, emerging molecular classifications of HCCs have not yet formed a unified corpus translatable to the clinical practice. Thus, patient management is currently based upon tumor number, size, vascular invasion, performance status and functional liver reserve. Nonetheless, an impressive body of molecular evidence emerged within the last 20 years and is becoming increasingly available to medical practitioners and researchers in the form of repositories. Therefore, the aim this work is to review molecular data underlying HCC classifications and to organize this corpus into the major dimensions explaining HCC phenotypic diversity. Major efforts have been recently made worldwide toward a unifying "clinically-friendly" molecular landscape. As a result, a consensus emerges on three major dimensions explaining the HCC heterogeneity. In the first dimension, tumor cell proliferation and differentiation enabled allocation of HCCs to two major classes presenting profoundly different clinical aggressiveness. In the second dimension, HCC microenvironment and tumor immunity underlie recent therapeutic breakthroughs prolonging patients' survival. In the third dimension,metabolic reprogramming, with the recent emergence of subclass-specific metabolic profiles, may lead to adaptive and combined therapeutic approaches. Therefore, here we review recent molecular evidence, their impact on tumor histopathological features and clinical behavior and highlight the remaining challenges to translate our cognitive corpus into patient diagnosis and allocation to therapeutic options.

Interaction of the major inflammatory bowel disease susceptibility alleles in Crohn’s disease patients

AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 locus in Crohn's disease(CD) patients. METHODS:A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped.Interactions and specific genotype combinations of a total of eight variants were tested.The variants of IBD5locus(IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868),CARD15(R702W rs2066845 and L1007fs rs2066847),ATG16L1(rs2241880)and IL23R (rs1004819,rs2201841)genes were genotyped by PCR-RFLP,the G908R(rs2066844)in CARD15 was determined by direct sequencing. RESULTS:The association of ATG16L1 T300A with CD was confirmed[P=0.004,odds ratio(OR)=1.69, 95%CI:1.19-2.41],and both IL23R variants were found to represent significant risk for the disease(P= 0.008,OR=2.05,95%CI:1.20-3.50 for rs1004819 AA;P<0.001,OR=2.97,95%CI:1.65-5.33 for rs2201841 CC).Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD)loci indicated that IL23R,ATG16L1,CARD15 and IBD5(IGR2198a_1)contribute independently to disease risk.We also analysed the specific combina- tions by pair of individual ATG16L1,IL23R rs1004819, rs2201841,IGR2198a_1,IGR2096a_1 and CARD15 genotypes for disease risk influence.In almost all cases,the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism.The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status(P<0.001,OR=9.15,95% CI:2.05-40.74). CONCLUSION:The present study suggests a cumulative effect of individual IBD susceptibility loci.

No association of the cytotoxic T-lymphocyte associated gene CTLA4 +49A/G polymorphisms with Crohn's disease and ulcerative colitis in Hungarian population samples

瞄准：当前的工作的目标细胞毒素的 T 淋巴细胞抗原是分析 +49A/G 的流行变体的在有 Crohn 的匈牙利病人的 4 基因(CTLA4 )?&#713;s 疾病(CD ) 和 ulcerative (UC ) 。方法：有 CD 的 130 个无关的题目的一个总数并且 150 与 UC，和 170 匹配的控制是为单个核苷酸多型性(SNP ) 的 genotyped。遗传型被使用 PCR/RFLP 测试决定。结果：G 等位基因频率和 GG 遗传型的流行在 CD 组，是 38.1% 和 12.3%40.6% 和 18.6% 在 UC 病人，并且 37.4% 和 15.9% 在控制组分别地。结论：当前的学习的结果显示出 +49G SNP 的那辆马车在异质接合或不在匈牙利人口为 CD 或为 UC 在同型结合的形式授与风险任何一个。

Metastatic breast cancer to the gastrointestinal tract:A case series and review of the literature

Metastatic breast cancer involving the hepatobiliary tract or ascites secondary to peritoneal carcinomatosis has been well described. Luminal gastrointestinal tract involvement is less common and recognition of the range of possible presentations is important for early and accurate diagnosis and treatment. We report 6 patients with a variety of presentations of metastatic breast cancer of the luminal gastrointestinal tract. These include oropharyngeal and esophageal involvement presenting as dysphagia with one case of pseudoachalasia, a linitis plastica-like picture with gastric narrowing and thickened folds, small bowel obstruction and multiple strictures mimicking Crohn’s disease, and a colonic neoplasm presenting with obstruction. Lobular carcinoma, representing only 10% of breast cancers is more likely to metastasize to the gastrointestinal tract. These patients presented with gastrointestinal manifestations after an average of 9.5 years and as long as 20 years from initial diagnosis of breast cancer. Given the increased survival of breast cancer patients with current therapeutic regimes, more unusual presentations of metastatic disease, including involvement of the gastrointestinal tract can be anticipated.

Antibiotics resistance rate of Helicobacter pylori in Bhutan

AIM:To survey the antibiotic resistance pattern of Helicobacter pylori(H.pylori)strains isolated from Bhutanese population.METHODS:We isolated 111 H.pylori strains from the gastric mucosa of H.pylori-infected patients in Bhutan in 2010.The Epsilometer test was used to determine the minimum inhibitory concentrations(MICs)of amoxicillin(AMX),clarithromycin(CLR),metronidazole(MNZ),levofloxacin(LVX),ciprofloxacin(CIP),and tetracycline(TET).RESULTS:Nineteen of the isolated H.pylori strains were susceptible to all antibiotics tested.The isolated strains showed the highest rate of antibiotic resistance to MNZ(92/111,82.9%).Among the 92 MNZresistant strains,74 strains(80.4%)showed high-level resistance(MIC≥256 g/mL).Three strains were resistance to LVX(2.7%).These strains were also resistance to CIP.None of the strains showed resistance to CLR,AMX and TET.CONCLUSION:CLR-based triple therapy is a more effective treatment approach over MNZ-based triple therapy for H.pylori infection in Bhutan.

Consensus of primary care in acute pancreatitis in Japan

在日本的尖锐胰腺炎的发生正在增加并且每百万张人口从 187 ～ 347 个盒子。盒子命运是 0.2% 为对温和中等，并且 9.0% 为在在 2003 的日本的严重尖锐胰腺炎。在日本的胰腺炎的专家做了与尖锐胰腺炎在病人的早管理集中于实际方面的这个文件。尖锐胰腺炎和严厉层化的正确诊断应该为尖锐胰腺炎的诊断用标准在所有病人被做并且多，因素得分系统尽早由胰的难处理的疾病的研究委员会求婚了。与尖锐胰腺炎诊断的所有病人应该在医院里被管理。血压监视，脉搏和呼吸率，体温，时时尿的体积，和血氧饱和水平在如此的病人的管理是必要的。早精力旺盛的静脉内的水和具有最前的重要性稳定循环动力学。有鸦片剂的足够的疼痛地势也是重要的。在严重尖锐胰腺炎，在一个早阶段的抗菌素的预防静脉内的管理被推荐。一旦尖锐胰腺炎的诊断被证实，朊酶禁止者的管理应该被开始。如果没有肠塞痛并且胃肠的流血的清楚的症状，从早舞台用非肠道的营养喂的肠内的联合被推荐。有严重尖锐胰腺炎的病人应该尽早被转移到 ICU 执行象朊酶的连续地区性的动脉的注入那样的特殊措施禁止者和抗菌素，和连续牙齿过敏过滤。日本政府为难处理的疾病作为关于措施的研究的工程之一为严重尖锐胰腺炎盖住医疗保健开销。

Endoscopic excision of a prolapsing malignant polyp which caused intermittent gastric outlet obstruction

A 69-year-old male with chronic lymphocytic leukemia presented with iron deficiency anemia and post-prandial abdominal fullness. Endoscopy showed a large polyp on a stalk, protruding through the pylorus into the duodenum causing intermittent gastric outlet obstruction. While prolapsing gastric antral polyps are usually benign and hyperplastic, inflammatory or regenerative in type, excisional snare polypectomy here led to complete resolution of his symptoms, but showed a malignant polyp.

Use of agents stimulating erythropoiesis in digestive diseases

Anemia is the most common complication of inflammatory bowel disease (IBD). Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron def iciency in IBD. There is also a variable component of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin (rHuEPO), which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as f irst choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit (11-12 g/dL). New formulations of intravenous iron (iron carboxymaltose) and the new generation of erythropoietic agents (darbepoetin and continuous erythropoietin receptor activator) will allow better dosing with the same eff icacy and safety.

Recent developments on the role of Clostridium difficile in inflammatory bowel disease

Clostridium difficile (CD), specifically its toxins, have been implicated as a risk factor for exacerbation of the inflammatory process in up to 5% of patients with ulcerative colitis or Crohn’s disease. Typical evidence of colonic changes with CD infection, including pseudomembranous exudate, are often not present; however, a severe clinical course may result, including precipitation of toxic colitis and toxic megacolon. Recently, hypervirulent CD strains have been reported raising concern for a more severe disease process in patients with underlying inflammatory bowel disease.Moreover, small bowel involvement or CD enteritis has been increasingly described, usually in those with a history of a prior colectomy or total proctocolectomy for prior severe and extensive inflammatory bowel disease. Finally, refractory or treatment-resistant pouchitis may occur with CD infection.

Free perforation of the small intestine in collagenous sprue

A 67-year-old man with celiac disease developed recurrent diarrhea,profound weakness and weight loss, with evidence of marked protein depletion.His clinical course was refractory to a strict gluten-free diet and steroid therapy.Postmortem studies led to definition of unrecognized collagenous sprue that caused ulceration and small intestinal perforation.Although PCR showed identical monoclonal T-cell populations in antemortem duodenal biopsies and postmortem jejunum,careful pathological evaluation demonstrated no frank lymphoma.Rarely,overt or even cryptic T-cell lymphoma may complicate collagenous sprue,however, small intestinal ulcers and perforation may also develop independently.The dramatic findings here may reflect an underlying or early molecular event in the eventual clinical appearance of overt T-cell lymphoma.

Perivascular epithelioid cell neoplasm of the colon

A 17-year-old female presented with rectal bleeding from an ulcerated sigmoid mass in 1994.Initial pathological evaluation revealed a rare clear cell neoplasm of the colon,possibly originating from kidneys,adrenals,lung or a gynecologic source as a metastatic lesion.Extensive imaging studies were negative,and over the next 15 years,she remained well with no recurrence.The original resected neoplasm was reviewed and reclassified as a perivascular epithelioid cell neoplasm (PEComa).Although the long-term natural history of PEComas requires definition,increased clinical and pathological awareness should lead to increased recognition of an apparently rare type of colonic neoplasm that likely occurs more often than is currently appreciated.

Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.

Discovery of unique African Helicobacter pylori CagAmultimerization motif in the Dominican Republic

BACKGROUND Helicobacter pylori(H.pylori)colonizes the human stomach and is a major cause of peptic ulcer disease and gastric cancer.However,although the prevalence of H.pylori is high in Africa,the incidence of gastric cancer is low,and this phenomenon is called to be African enigma.The CagA protein produced by H.pylori is the most studied virulence factor.The carcinogenic potential of CagA is associated with the Glu-Pro-Ile-Tyr-Ala(EPIYA)patterns and CagAmultimerization(CM)motifs.AIM To better understand the EPIYA patterns and CM motifs of the cagA gene.METHODS Gastric mucosal biopsy specimens were obtained from 258 patients with dyspepsia living in the Dominican Republic,from which 120 H.pylori strains were cultured.After the bacterial DNA extraction,the EPIYA pattern and CM motif genotypes were determined using a polymerase chain reaction-based sequencing.The population structure of the Dominican Republic strains was analyzed using multilocus sequence typing(MLST).Peptic ulcer disease and gastric cancer were identified via endoscopy,and gastric cancer was confirmed by histopathology.Histological scores of the gastric mucosa were evaluated using the updated Sydney system.RESULTS All CagA-positive strains carried the Western-type CagA according to the identified EPIYA patterns.Twenty-seven kinds of CM motifs were observed.Although the typical Western CM motif(FPLKRHDKVDDLSKVG)was observed most frequently,the typical East Asian CM motif(FPLRRSAAVNDLSKVG)was not observed.However,“FPLRRSAKVEDLSKVG”,similar to the typical East Asian CM motif,was found in 21 strains.Since this type was significantly more frequent in strains classified as hpAfrica1 using MLST analysis(P=0.034),we termed it Africa1-CM(Af1-CM).A few hpEurope strains carried the Af1-CM motif,but they had a significantly higher ancestral Africa1 component than that of those without the Af1-CM motif(P=0.030).In 30 cagA-positive strains,the"GKDKGPE"motif was observed immediately upstream of the EPIYA motif in the EPIYA-A segment,and there was a significant association between strains with the hpAfrica1 population and those containing the“GKDKGPE”motif(P=0.018).In contrast,there was no significant association between the CM motif patterns and histological scores and clinical outcomes.CONCLUSION We found the unique African CM motif in Western-type CagA and termed it Africa1-CM.The less toxicity of this motif could be one reason to explain the African enigma.