Influence of interleukin polymorphisms on development of gastric cancer and peptic ulcer

Pro-inflammatory cytokines are produced in the gastric mucosa by inflammatory cells activated by chronic Helicobacter pylori (H. pylori) infection. Polymorphisms of these cytokine genes are associated with individual differences in gastric mucosal cytokine mRNA level, which result in differences in gastric mucosal inflammation, acid inhibition and gastroduodenal disease risk in response to H. pylori infection. Although polymorphisms of interleukin (IL)-1B, IL-1RN and TNF-A have been reported to relate well with gastric cancer and peptic ulcer risk, those of IL-2, IL-4, IL-6 and IL-8 genes are unclear. In combined analyses using data from previous studies, we found that the risk of gastric non-cardia cancer development was significantly associated with IL-4-168 C allele (OR: 0.81, 95% CI: 0.69-1.00) and IL-4-590 T allele carrier status (0.61, 0.53-0.73), and IL-6-174 G/G genotype (2<Abstract>Pro-inflammatory cytokines are produced in the gastric mucosa by inflammatory cells activated by chronic Helicobacter pylori (H. pylori) infection. Polymorphisms of these cytokine genes are associated with individual differences in gastric mucosal cytokine mRNA level, which result in differences in gastric mucosal inflammation, acid inhibition and gastroduodenal disease risk in response to H. pylori infection. Although polymorphisms of interleukin (IL)-1B, IL-1RN and TNF-A have been reported to relate well with gastric cancer and peptic ulcer risk, those of IL-2, IL-4, IL-6 and IL-8 genes are unclear. In combined analyses using data from previous stud- ies, we found that the risk of gastric non-cardia cancer development was significantly associated with IL-4-168 C allele (OR: 0.81, 95% CI: 0.69-1.00) and IL-4-590 T allele carrier status (0.61, 0.53-0.73), and IL-6-174 G/G genotype (2.02, 1.31-3.10). In peptic ulcer development, IL-2-330 G and IL-4-590 T allele carriers had a significantly decreased risk (0.37, 0.27-0.50 and 0.58, 0.34-0.99, respectively). Moreover, IL-2, IL-4, IL-6 and IL-8 gene genotypes prevalence differs among popula- tions. The inflammatory cytokine gene polymorphisms (e.g. IL-4 -590 and IL-6 -572 for gastric cancer, and IL-4-590, IL-6-572 and IL-8-251 for peptic ulcer) have a more potent influence on development of gastroduo- denal diseases in Western than East Asian populations. These cytokine gene polymorphisms, as well as those of IL-1B, IL-1RN and TNF-A, may be used to identify groups at higher risk of gastric cancer and peptic ulcer, and those suitable for their prevention by H. pylori eradication therapy in Western populations..02, 1.31-3.10). In peptic ulcer development, IL-2-330 G and IL-4-590 T allele carriers had a significantly decreased risk (0.37, 0.27-0.50 and 0.58, 0.34-0.99, respectively). Moreover, IL-2, IL-4, IL-6 and IL-8 gene genotypes prevalence differs among populations. The inflammatory cytokine gene polymorphisms (e.g. IL-4 -590 and IL-6 -572 for gastric cancer, and IL-4-590, IL-6-572 and IL-8-251 for peptic ulcer) have a more potent influence on development of gastroduo-denal diseases in Western than East Asian populations. These cytokine gene polymorphisms, as well as those of IL-1B, IL-1RN and TNF-A, may be used to identify groups at higher risk of gastric cancer and peptic ulcer, and those suitable for their prevention by H. pylori eradication therapy in Western populations.

Efficacy of tailored Helicobacter pylori eradication therapy based on antibiotic susceptibility and CYP2C19 genotype

The cure rates of Helicobacter pylori(H.pylori)eradication therapy using a proton pump inhibitor(PPI)and antimicrobial agents such as amoxicillin,clarithromycin,and metronidazole are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of the inhibition of acid secretion.Annual cure rates have gradually decreased because of the increased prevalence of H.pylori strains resistant to antimicrobial agents,especially to clarithromycin.Alternative regimens have therefore been developed incorporating different antimicrobial agents.Further,standard PPI therapy(twice-daily dosing)often fails to induce a long-term increase in intragastric pH>4.0.Increasing the eradication rate requires more frequent and higher doses of PPIs.Therapeutic efficacy related to acid secretion is influenced by genetic factors such as variants of the genes encoding drug-metabolizing enzymes(e.g.,cytochrome P450 2C19,CYP2C19),drug transporters(e.g.,multidrug resistance protein-1;ABCB1),and inflammatory cytokines(e.g.,interleukin-1β).For example,quadruple daily administration of PPI therapy potently inhibits acid secretion within 24 h,irrespective of CYP2C19 genotype.Therefore,tailored H.pylori eradication regimens that address acid secretion and employ optimal antimicrobial agents based on results of antimicrobial agent-susceptibility testing may prove effective in attaining higher eradication rates.

Characteristics of non-erosive gastroesophageal reflux disease refractory to proton pump inhibitor therapy

AIM:To investigate whether potent acid inhibition is effective in non-erosive reflux disease (NERD) refractory to standard rabeprazole (RPZ) treatment. METHODS:We treated 10 Japanese patients with NERD resistant to standard dosages of RPZ:10 mg or 20 mg od,20 mg bid,or 10 mg qid for 14 d. All patients completed a frequency scale for symptoms of gastroesophageal reflux disease questionnaire frequency scale for the symptoms of GERD (FSSG); and underwent 24 h pH monitoring on day 14. RESULTS:With increased dosages and frequency of administration of RPZ,median intragastric pH significantly increased,and FSSG scores significantly decreased. With RPZ 10 mg qid,potent acid inhibition was attained throughout 24 h. However,five subjects were refractory to RPZ 10 mg qid,although the median intragastric pH in these subjects (6.6,range:6.2-7.1) was similar to that in the remaining five responsive subjects (6.5,range:5.3-7.3). With baseline RPZ 10 mg od,FSSG scores in responsive patients improved by > 30%,whereas there was no significant decrease in the resistant group. CONCLUSION:NERD patients whose FSSG score fails to decrease by > 30% after treatment with RPZ 10 mg od for 14 d are refractory to higher dosage.

Inverted Meckel's diverticulum preoperatively diagnosed using double-balloon enteroscopy

An inverted Meckel's diverticulum is a rare gastrointestinal congenital anomaly that is difficult to diagnose prior to surgery and presents with anemia, abdominal pain, or intussusception. Here, we report the case of 57-year-old men with an inverted Meckel's diverticulum, who was preoperatively diagnosed using doubleballoon enteroscopy. He had repeatedly experienced epigastric pain for 2 mo. Ultrasonography and computed tomography showed intestinal wall thickening in the pelvis. Double-balloon enteroscopy via the anal route was performed for further examination, which demonstrated an approximately 8-cm, sausage-shaped, submucosal tumor located approximately 80 cm proximal to the ileocecal valve. A small depressed erosion was observed at the tip of this lesion. Forceps biopsy revealed heterotopic gastric mucosa. Thus, the patient was diagnosed with an inverted Meckel's diverticulum, and single-incision laparoscopic surgery was performed. This case suggests that an inverted Meckel's diverticulum should be considered as a differential diagnosis for a submucosal tumor in the ileum. Balloon-assisted enteroscopy with forceps biopsy facilitate a precise diagnosis of this condition.

A case of small bowel adenocarcinoma in a patient with Crohn’s disease detected by PET/CT and double-balloon enteroscopy

Small bowel adenocarcinoma (SBA) in patients with Crohn’s disease (CD) is quite rare, difficult to diagnose without surgery, and has a poor prognosis. Here, we report a 48-year-old man with SBA and a 21-year history of CD who was diagnosed by a combination of positron emission tomography/computed tomography (PET/CT) and double-balloon enteroscopy (DBE). Since the age of 27 years, the patient had been treated for ileal CD and was referred to our hospital with persistent melena. Multiple hepatic tumors were found by CT. PET/CT detected an accumulation spot in the small bowel. DBE revealed an ulcerative tumor in the ileum about 100 cm from the ileocecal valve. An endoscopic forceps biopsy specimen showed poorly differentiated adenocarcinoma. There were some longitudinal ulcer scars near the tumor, and the chronic inflammation inthe small bowel appeared to be associated with the cancer development. Previous reports suggest the risk of SBA in patients with CD is higher than in the overall population. Since early diagnosis is extremely difficult in these cases, novel techniques, such as PET/CT and DBE, may be expected to help in making a preoperative diagnosis of the development of SBA in CD.

Tuberous sclerosis patient with neuroendocrine carcinoma of the esophagogastric junction:A case report

BACKGROUND Tuberous sclerosis complex(TSC)is a rare inherited disease with non-cancerous tumor growths in the skin,brain,kidneys,heart,and lungs.The co-occurrence of neuroendocrine neoplasm(NEN)with TSC is even rarer.There have been few reports on the relationship between TSC and neuroendocrine tumors(NETs),and fewer on the relationship between TSC and neuroendocrine carcinoma(NEC),a subtype of NEN.This is the first reported case of NEC occurring at the esophagogastric junction in a patient with TSC.CASE SUMMARY A 46-year-old woman visiting our hospital for the treatment of TSC was admitted to the emergency department with tarry stools and dizziness.Computed tomography scans revealed thickness of the gastric cardia,multiple metastatic lesions of the liver,and enlarged lymph nodes near the lesser curvature of the stomach.Esophagogastroduodenoscopy revealed a type 3 tumor located from the esophagogastric junction to the fundus,and the pathological diagnosis by biopsy was NEC.The patient was treated with seven courses of cisplatin+irinotecan,followed by eight courses of ramucirumab+nab-paclitaxel,one course of nivolumab,and two courses of S-1+oxaliplatin.Twenty-three months after the first treatment,the patient died because of disease progression and deterioration of the general condition.CONCLUSION This case of NEC occurring in a patient with TSC indicates a difference in the occurrence of NETs and NECs.

Early serum albumin changes in patients with ulcerative colitis treated with tacrolimus will predict clinical outcome

BACKGROUND Oral tacrolimus is a therapeutic agent for moderate to severe steroid-dependent or resistant ulcerative colitis(UC),but remission induction is difficult,and it is necessary to treat the patient while considering the next treatment.AIM To examine serum albumin(Alb)level as a prognostic factor for the therapeutic effect of tacrolimus in clinical practice.METHODS Forty-seven patients with UC treated with tacrolimus at our institution were divided into remission and failure groups(colectomy or switch to biologics),and the biological data at the start of observation and at weeks 1 and 2 were retrospectively examined.Kaplan-Meier and multivariate analyses were performed using Alb as a prognostic factor in UC treatment.RESULTS During the three months observed,17(36.2%)patients failed treatment with tacrolimus.A comparison between the failure and remission groups showed a significant difference only in Alb in week 2,and in the week 2/week 0 Alb ratio,which showed the rate of change in Alb.The cut-off value of the week 2/week 0 Alb ratio that predicted failure was 1,and its area under the curve was 0.751(95%CI:0.604-0.898).In the Kaplan-Meier analysis,a week 2/week 0 Alb ratio≤1 had a significantly higher failure rate than that of>1;Cox proportional hazard regression analysis also showed that a week 2/week 0 Alb ratio≤1 was an independent prognostic factor for failure within 3 mo after the start of tacrolimus treatment.CONCLUSION A week 2/week 0 Alb ratio≤1 predicts failure within 3 mo of tacrolimus administration for UC.High failure risk exists with week 2 Alb values≤1 on admission.

Relationship between ghrelin, Helicobacter pylori and gastric mucosal atrophy in hemodialysis patients

AIM To investigate the relationship between plasma ghrelin level, Helicobacter pylori(H. pylori) infection status and the severity of atrophy in hemodialysis patients.METHODS One hundred eights patients who received hemodialysis and 13 non-hemodialysis H. pylori-negative controlsunderwent gastroduodenoscopy to evaluate the severity of gastric atrophy. Serum levels of pepsinogen(PG) were measured as serum markers of gastric atrophy. H. pylori infection was evaluated by anti-H. pylori IgG antibody, rapid urease test and culture test. We classified H. pylori infection status as non-infection, present infection and past infection. In addition, plasma acyl-ghrelin and desacyl-ghrelin levels were measured by enzyme-linked immunosorbent assay. RESULTS Infection rate of H. pylori was 45.4%(49/108). Acylghrelin level in the non-infection group(39.4 ± 23.0 fmol/ml) was significantly higher than in the past(23.4 ± 19.9 fmol/ml, P = 0.005) and present infection groups(19.5 ± 14.0 fmol/ml, P < 0.001). Furthermore, desacyl-ghrelin level in the non-infection group(353.2 ± 190.2 fmol/ml) was significantly higher than those in the past(234.9 ± 137.5 fmol/ml, P = 0.008) and present infection groups(211.8 ± 124.2 fmol/ml, P < 0.001). Acyl-ghrelin was positively correlated with the PG Ⅰ level and PG Ⅰ/Ⅱ ratio(|R| = 0.484, P < 0.001 and |R| = 0.403, P < 0.001, respectively). Both ghrelins were significantly decreased in accordance with the progress of endoscopic atrophy(both P < 0.001) and acyl-ghrelin was significantly lower in patients with mild, moderate and severe atrophy(24.5 ± 23.1 fmol/ml, 20.2 ± 14.9 fmol/ml and 18.3 ± 11.8 fmol/ml) than in those with non-atrophy(39.4 ± 22.2 fmol/ml, P = 0.039, P = 0.002 and P < 0.001, respectively).CONCLUSION In hemodialysis patients, plasma ghrelin level was associated with the endoscopic and serological severity of atrophy related to H. pylori infection.

Cecal vanishing tumor associated with cytomegalovirus infection in an immunocompetent elderly adult

Gastrointestinal involvement in cytomegalovirus (CMV) infection is well documented among immunocompromised patients and is also observed in immunocompetent individuals. The presentation of this infection can sometimes mimic those of other diseases, thus making accurate diagnosis difficult. We herein report a rare case of an immunocompetent elderly adult with gastrointestinal CMV infection that presented as a vanishing tumor at the cecum. A 76-year old man initially presented with lower abdominal pain. Colonoscopy revealed a tumorous lesion with irregular ulceration observed at the ileocecal valve. Histological findings of a biopsy specimen revealed intranuclear inclusions which were positive for CMV on immunohistochemical staining. However, this tumorous lesion disappeared within 7 wk from the initialhospital visit without any further treatment. Inflammatory pseudotumors associated with CMV infection should be considered as a differential diagnosis of tumorous lesions in the colon, even in immunocompetent adults.

Evaluating mucosal healing using colon capsule endoscopy predicts outcome in patients with ulcerative colitis in clinical remission

AIM To examine whether second generation of colon capsule endoscopy(CCE-2) is acceptable for assessing the severity of mucosal inflammation and evaluating mucosal healing using CCE-2 is able to predict outcome in ulcerative colitis(UC) patients, especially in clinical remission.METHODS A total of 30 consecutive UC patients in clinical remission were enrolled to undergo CCE-2. Clinical remission was defined as clinical activity index(CAI) ≤ 4 according to Rachmilewitz index. The rate of total colon observation and colon cleansing level were evaluated. Severity of mucosal inflammation in UC was assessed according to the Mayo endoscopic subscore(MES) and Ulcerative Colitis Endoscopic Index of Severity(UCEIS). Relapsefree survival was assessed. Acceptability of CCE-2 was assessed using a questionnaire survey.RESULTS The rate of total colon observation within its battery life was 93.3%. The proportion of "excellent" plus "good" cleansing level was 73.3%. The rate of mucosal healing(MES 0, 1) assessed by CCE-2 was 77.0%. The relapse-free survival rate was significantly higher in MES 0, 1 than in MES 2, 3(P = 0.0435), and in UCEIS 0-3 than in UCEIS 4-8(P = 0.0211), whereas there was no significant difference between CAI 0 and CAI 1-4 groups. A questionnaire survey revealed an overall acceptability of CCE.CONCLUSION CCE-2 is acceptable for assessing the severity of mucosal inflammation in UC patients, especially in clinical remission. Evaluating mucosal healing using CCE-2 was able to predict outcome.

Maintenance time of sedative effects after an intravenous infusion of diazepam: A guide for endoscopy using diazepam

AIM: To examine whether the sedative effects assessed by psychomotor tests would depend on the cytochrome P450 (CYP ) 2C19 genotypes after an infusion regimen of diazepam commonly used forgastrointestinal endoscopy in Japan. METHODS: Fifteen healthy Japanese volunteers consisting of three different CYP2C19 genotype groups underwent a critical ? icker fusion test, an eye movement analysis and a postural sway test as a test for physical sedative effects, and a visual analog scale (VAS) symptom assessment method as a test for mental sedative effects during the 336 h period after the intravenous infusion of diazepam (5 mg). RESULTS: The physical sedative effects assessed by the critical flicker test continued for 1 h (t values of 5 min, 30 min and 60 min later: 4.35, 5.00 and 3.19, respectively) and those by the moving radial area of a postural sway test continued for 3 h (t values of 5 h, 30 h, 60 min and 3 h later: -4.05, -3.42, -2.17 and -2.58, respectively), which changed significantly compared with the baseline level before infusion (P < 0.05). On the other hand, the mental sedative effects by the VAS method improved within 1 h. The CYP2C19 genotype-dependent differences in the postinfusion sedative effects were not observed in any of the four psychomotor function tests. CONCLUSION: With the psychomotor tests, the objective sedative effects of diazepam continued for 1 h to 3 h irrespective of CYP2C19 genotype status and the subjective sedative symptoms improved within 1 h. Up to 3 h of clinical care appears to be required after the infusion of diazepam, although patients feel subjectively improved.

Lymphocyte-to-monocyte ratio is a short-term predictive marker of ulcerative colitis after induction of advanced therapy

Advanced therapies for patients with mild-to-severe ulcerative colitis(UC)may result in treatment failure.We examined whether the lymphocyte-to-monocyte ratio(L/M ratio)could predict the failure of advanced therapies.This retrospective,observational,cohort study included 73 patients who were treated with advanced therapies at the Hamamatsu University School of Medicine(Shizuoka,Japan)between February 2011 and November 2020.The patients were divided into the nonfailure and failure groups,and their leukocyte counts and ratios before induction were examined.Univariate and multivariate analyses were performed to identify the prognostic factors.Advanced therapies failed within 3 months in 15(20.5%)patients.Only the L/M ratio was significantly lower in the failure group than in the non-failure group(P=0.004).Receiveroperating characteristic(ROC)curve analysis revealed that an L/M ratio of ≤3.417 was predictive of treatment failure;the area under the curve(AUC)was 0.747(95%CI,0.620–0.874).Kaplan–Meier analysis revealed that the failure-free rate was significantly lower in the group with an L/M ratio of≤3.417 than in the group with an L/M ratio of>3.417(log-rank test P=0.002).Cox proportional hazard regression analysis identified an L/M ratio of≤3.417 as an independent risk factor for failure within 3 months after the induction of advanced therapies.Furthermore,ROC analysis of patients who did not receive immunomodulators also revealed that the cut-off L/M ratio was 3.417 and the AUC was 0.796(95%CI,0.666–0.925).In patients receiving advanced therapies for active UC,the L/M ratio can predict treatment failure within 3 months.L/M ratios could facilitate the transition from advanced therapies to subsequent treatments.