Causal role of Helicobacter pylori infection in gastric cancer

胃的癌症是在世界，为在亚洲的所有癌症盒子的一个大比例的财务，拉丁美洲，和在欧洲的一些国家上的第二很经常的癌症。Helicobacter pylori (H pylori ) 被认为是在萎缩性胃炎的发展起一个特定的作用，它多代表最公认的小径在走肠类型的胃的致癌作用。最近的研究建议那联合招待基因因素，细菌的毒力因素，并且环境并且生活方式因素决定胃的损坏和 H pylori 感染的最终的临床的结果的严厉。胃的癌症的领先的原因应该导致有效根除策略的 H pylori 的精液的发现。胃的癌症的预防要求更好屏蔽的策略为根除识别候选人。

Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization

AIM: To determine the role of interleukin (IL)-17 in gastric ulcerogenesis. METHODS: Thirty-six gastric ulcer (GU) patients and 29 non-ulcer (NU) patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used in in situ stimulation for 48 h in the presence of 10 μg/mL phytohemagglutinin-P (PHA), histological examination, and Helicobacter pylori(H pylori) culture. IL-17 and IL-8 protein levels in culture supernatants were assayed by ELISA. IL-17 mRNA expression was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). H pylori cagA and vacA status was assessed by reverse hybridization using a line probe assay (LiPA). IL-8 levels in culture supernatants were assayed after AGS cells were co-cultured with H pylori strain 26 695 or recombinant human (rh) IL-17. RESULTS: All 36 GU patients and 15 of 29 NU patients were found to be H pylori-positive, while 14 NU patients were H pylori-negative. All 51 H pylori strains from both GU and NU patients were cagA- and vacAs1/m1-positive. Antral mucosal tissues from H pylori-positive patients contained significantly (H pylori-positive NU patients: median 467 pg/mg/protein, range 53-2 499; H pylori-negative NU patients: median 104 pg/mg/protein, range 16-312, P<0.0005) higher levels of IL-17 than those from uninfected patients. IL-17 levels at the ulcer site were significantly (ulcer site: median 1356 pg/mg/protein, range 121-1 3730; antrum: median 761 pg/mg/protein, range 24-7 620, P<0.005) higher than those at distant sites in the antrum. Biopsies from H pylori-positive GU and NU patients showed IL-17 mRNA expression in all samples whereas those from the antrum of the H pylori-negative controls showed no detectable expression. A significant correlation was seen between IL-17 and IL-8 levels at each biopsy site (ulcer: r= 0.62, P<0.0001; antrum: r = 0.61, P<0.0001) in GU patients. RhIL-17 and H pylori strain 26 695 each stimulated IL-8 production from AGS cells. CONCLUSION: IL-17 may play an important role in the inflammatory response to H pylori colonization, and may ultimately influence the outcome of H pylori-associated diseases that arise within the context of gastritis.

Recent progress of chemotherapy and biomarkers for gastroesophageal cancer

Key cytotoxic drugs of chemotherapy for gastroesophageal cancer include fluoropyrimidine, platinum, taxanes and irinotecan. Concurrent chemoradiotherapy is one of the main treatment strategies, especially for esophageal cancer. As molecular target agents, the anti-HER2 antibody trastuzumab for HER2-positive gastric cancer and the anti-angiogenesis agent ramucirumab combined with paclitaxel have been proven to improve the survival of gastric cancer patients. Recently, anti-PD-1 antibodies have become available as second- or later-line chemotherapy. Microsatellite instability is also useful as a biomarker to select patients suitable for immunotherapy. Furthermore, genome-wide analysis has improved our understanding of the biological features and molecular mechanisms of gastroesophageal cancer and will provide optimized treatment selection.

Modified docetaxel, cisplatin and capecitabine for stage Ⅳ gastric cancer in Japanese patients: A feasibility study

AIM To evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients.METHODS We performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage Ⅳ gastric cancer. In particular, 30 or 40 mg/m^2 of docetaxel on day 1, 60 mg/m^2 of cisplatin on day 1, and 2000 mg/m^2 of capecitabine for 2 wk were administered every three weeks.RESULTS Three patients were treated with modified DCX(m DCX) with 30 mg/m^2 docetaxel, and five patients were treated with this regimen with 40 mg/m^2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes.CONCLUSION m DCX was well tolerated by Japanese patients with stage Ⅳ gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.

Azathioprine is essential following cyclosporine for patients with steroid-refractory ulcerative colitis

AIM: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders.METHODS: We retrospectively reviewed clinical records for 29 patients diagnosed with severe steroid-refractory ulcerative colitis in our hospital from August 1997 to August 2008 and treated with cyclosporine by continuous intravenous infusion.All patients were treated with intravenous corticosteroids for more than 5 d prior to cyclosporine therapy.Administration was continued for up to 21 d under serum monitoring to maintain cyclosporine levels between 400 and 600 ng/mL.Clinical activity was assessed before and after cyclosporine therapy using the clinical activity index score,with a reduction of ≥ 5 considered to indicate a response.Among responders,we defined cases not requiring surgery for more than 5 years as exhibiting long-term efficacy of cyclosporine.Factors considered to be possibly predictive of long-term efficacy of cyclosporine were sex,age,disease duration,clinical activity index score,C-reactive protein level,hemoglobin level,disease extent,endoscopic findings,and clinical course.RESULTS: Cyclosporine was not discontinued due to side effects in any patient.Nineteen(65.5%) of 29 patients were considered responders.A statistically significant(P = 0.004) inverseas sociation wa s observed between an endoscopic finding of "mucosal bleeding" and responsive cases.Fifteen(9 males,6 females) of these 19 patients were followed for 5 years or more,of whom 9(60%) exhibited long-termefficacy of cyclosporine.Of the 10 non-responders,9(90%) underwent surgery within 6 mo of cyclosporine therapy.None of the following factors had a significant impact on the long-term efficacy of cyclosporine: sex,age,duration of disease,clinical activity index score,C-reactive protein level,hemoglobin level,extent of disease,endoscopic findings,or clinical course.In contrast,a significant association was observed for maintenance therapy with azathioprine after cyclosporine therapy(P = 0.0014).CONCLUSION: Maintenance therapy with azathioprine might improve the long-term efficacy of continuously infused cyclosporine for severe steroid-refractory ulcerative colitis patients.

Magnifying chromoscopy, a novel and useful technique for colonoscopy in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by exacerbations and remissions. The degree of inflammation as assessed by conventional colonoscopy is a reliable parameter of disease activity. However, even when conventional colonoscopy suggests remission and normal mucosal findings, microscopic abnormalities may persist, and relapse may occur later. Patients with long-standing, extensive ulcerative colitis have an increased risk of developing colorectal cancer. Ulcerative colitis-associated colorectal cancer is characterized by an early age at onset, poorly differentiated tumor cells, mucinous carcinoma, and multiple lesions. Early detection of dysplasia and colitic cancer is thus a prerequisite for survival. A relatively new method, magnifying chromoscopy, is thought to be useful for the early detection and diagnosis of dysplasia and colitic cancer, as well as the prediction of relapse.

Clinical utility of a new endoscopic scoring system for Crohn's disease

AIM:To evaluate the clinical value of the newly modified Simple Endoscopic Score for Crohn's disease(m SES-CD).METHODS:Seventy-six Crohn's disease(CD) patients who underwent transanal double balloon endoscopy(DBE) in our hospital between 2003 and 2012 were retrospectively reviewed. DBE is defined as small intestinal endoscopy using two attached balloons. We included patients with stenosis which hampered passage of the scope and those who underwent DBE with observation for at least 80 cm from the ileocecal valve. Our new m SES-CD assesses the endoscopic activity of two consecutive small intestinal segments located 0-40 cm and 40-80 cm from the ileocecal valve by DBE,in addition to the activity of four colorectal segments. To compare the usefulness of m SES-CD with SES-CD,we similarly divided the patients into two groups according to total m SES-CD score(low disease activity group,< 4; high disease activity group,≥ 4). The clinical value of m SES-CD in predicting clinical outcome in patients with CD was evaluated using the occurrence of surgery after DBE as an endpoint.RESULTS:Median age of the 76 CD patients was 36 years(range,16-71). Thirty-nine patients had stenosis which hampered passage of the DBE to 80 cm on the proximal side from the ileocecal valve. Median evaluable length of small intestine by DBE was 80 cm(range,3-200). A total of 74 patients had one or more small intestinal lesions detected by DBE,of which 62(83.8%) were within 80 cm of the ileocecal valve on the proximal side. Only two patients(2.7%) with proximal-side lesions more than 80 cm from the ileocecal valve did not have lesions within 80 cm. Patients with high m SES-CD scores showed significantly shorter surgeryfree survival than those with low scores(P < 0.05). In contrast,surgery-free survival did not significantly differ between the low and high SES-CD groups(P > 0.05). Multivariate analysis by a Cox proportional hazards model identified m SES-CD as an independent factor for surgery-free survival.CONCLUSION:m SES-CD is useful in evaluating the risk of surgery-free survival in patients with CD.

Value of colonoscopy for prediction of prognosis in patients with ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by exacerbations and remissions. Some UC patients remain refractory to conventional medical treatment while, in others, the effectiveness of drugs is limited by side-effects. Recently, cyclosporine and leukocyte removal therapy have been used for refractory UC patients. To predict the efficacy of these therapies is important for appropriate selection of treatment options and for preparation for colectomy. Endoscopy is the cornerstone for diagnosis and evaluation of UC. Endoscopic parameters in patients with severe or refractory UC may predict a clinical response to therapies, such as cyclosporine or leukocyte removal therapy. As for the patients with quiescent UC, relapse of UC is difficult to predict by routine colonoscopy. Even when routine colonoscopy suggests remission and a normal mucosal appearance, microscopic abnormalities may persist and relapse may occur later. To more accurately identify disease activity and to predict exacerbations in UC patients with clinically inactive disease is important for deciding whether medical treatment should be maintained. Magnifying colonoscopy is useful for the evaluation of disease activity and for predicting relapse in patients with UC.

Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival

BACKGROUND Despite the popularity of immune checkpoint inhibitors(ICIs)in the treatment of advanced cancer,patients often develop gastrointestinal(GI)and non-GI immune-related adverse events(irAEs).The clinical characteristics and survival outcomes of GI-irAEs have not been fully elucidated in previous reports.This necessitates the evaluation of the impact of GI-irAEs on patients receiving ICI treatment.AIM To evaluate the clinical characteristics of GI-irAEs and their impact on survival in patients treated with ICIs.METHODS In this single-center,retrospective,observational study,we reviewed the records of 661 patients who received ICIs for various cancers at Nagoya University Hospital from September 2014 to August 2020.We analyzed the clinical characteristics of patients who received ICI treatment.We also evaluated the correlation between GI-irAE development and prognosis in non-small cell lung cancer(LC)and malignant melanoma(MM).Kaplan-Meier analysis was used to compare the median overall survival(OS).Multivariate Cox proportional hazards models were used to identify prognostic factors.A P value<0.05 was considered statistically significant.RESULTS GI-irAEs occurred in 34 of 605 patients(5.6%)treated with an anti-programmed cell death-1/programmed death-ligand 1(anti-PD-1/PD-L1)antibody alone and in nine of 56 patients(16.1%)treated with an anti-cytotoxic T-lymphocyte antigen 4(CTLA-4)antibody alone or a combination of anti-PD-1 and anti-CTLA-4 antibodies.The cumulative incidence and median daily diarrhea frequency were significantly higher in patients receiving anti-CTLA-4 antibodies(P<0.05).In 130 patients with MM,OS was significantly prolonged in the group that continued ICI treatment despite the development of GI-irAEs compared to the group that did not experience GI-irAEs(P=0.035).In contrast,in 209 patients with non-small cell LC,there was no significant difference in OS between the groups.The multivariate analyses showed that a performance status of 2-3(hazard ratio:2.406;95%confidence interval:1.125–5.147;P=0.024)was an independent predictive factor for OS in patients with MM.CONCLUSION Patients receiving anti-CTLA-4 antibodies develop GI-irAEs more frequently and with higher severity than those receiving anti-PD-1/PD-L1 antibodies.Continuing ICI treatment in patients with MM with GI-irAEs have better OS.

Ostrich Antibody and Its Application to Skin Diseases, a Review and Case Report

Antibodies are immunoglobulins produced by B cells when antigens such as allergens or pathogens invade an animal’s body. The antibodies remove and inactivate antigens. Antibodies are distributed in internal body and mucosal membrane to protect living animals, but they are excellent proteins that can exert their functions, “antigen-antibody reactions,” even when removed from the body. For that reason, antibodies are being put to practical use in diagnostic kits for conditions such as pregnancy and influenza infection, and as anticancer drugs targeting specific tumor markers. The result has been an increasing use of antibodies for research, diagnosis, and therapeutic purposes. Unfortunately, antibodies from experimental mammals such as mice, rats, and rabbits, are not suited to industrial use because of their high production cost. Moreover, handling of these antibodies is difficult due to their vulnerability to heat, acids and alkalis. Accordingly, there is no adaptability to mass production. Recently, we developed a convenient method for the low-cost, mass-production of antibodies using egg-laying hen ostriches. The ostrich egg is an excellent source of antibodies for industrial purposes. The present report shows that the ostrich antibodies have therapeutic effects in ailments such as atopic dermatitis, acne, pyoderma, and pollen allergies. We have successfully produced and purified ostrich immunoglobulin yolk (IgY) against pollen allergens (Cryj1, Cryj2, Chao1, Chao2) and found that allergic reactions were alleviated in skin patch tests of allergic patients by using the ostrich IgY. In addition, we produced ostrich IgY against the homogenates of Staphylococcus aureus and Propionibacterium acnes, and applied to dermal lesions of atopic dermatitis and acne patients, and then observed the therapeutic effects on the dermatitis of volunteer subjects. Antibody against S. aureus also had the therapeutic effect on canine pyoderma caused by MRSA. A particular advantage in using ostrich antibodies is the fact that they inactivate and neutralize a specific antigen, without damaging the indigenous microflora of the dermal surface. In this review article and case repot, we wish to suggest that ostrich antibodies can contribute to the treatment of cutaneous disorders as an alternative to treatment with steroids or antibiotics.

Experimental Therapeutic Trial of an Antibody against the Cell Adhesion Molecule Gicerin for Lymphomas Using a Murine Cell Line

Chemotherapy, occasionally combined with radiotherapy, is a major method for treating lymphoma but frequently produces side-effects in patients. Thus, novel therapeutics should be developed as an alternative the chemotherapy in lymphoma patients. Although the cell adhesion molecule gicerins are almost entirely absent in most mature tissues, except for muscle and endothelial cells, various neoplastic cells strongly express gicerin in their cell membranes. This suggests the potential function of gicerin in the progression of tumors, including tumor growth, invasion and metastasis to distant organs from primary sites. In the present study, we assessed therapeutic effects of anti-gicerin antibodies on the murine lymphoma cell line YAC1. Gicerin was found to be expressed in the cell membrane of YAC1 cells and promoted the cell adhesion activity of the YAC1 cells on HUVECs, an endothelial cell line. In addition, YAC1 cells were implanted sub-cutaneously in mice in order to examine the therapeutic effects of anti-gicerin antibodies on lymphoma progression in vivo. The anti-gicerin antibodies suppressed and reduced the lymphoma tumor growth in the mice, whereas the growth of tumor mass was not inhibited by pre-immune IgG administrations. YAC1 cells were also implanted intravenously in mice in order to examine the effects of anti-gicerin antibodies on the pulmonary metastasis of lymphoma cells. The metastasis of the YAC1 cells to the lungs was inhibited by the injection of anti-gicerin antibodies. These findings indicate that anti-gicerin antibodies inhibit the progression of prednisolone-resistant lymphoma, making this a promising novel therapeutic method for treating refractory lymphoma cases.