[A case of gastric cancer showing a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse events].

The Japanese guidelines for the treatment of gastric cancer recommend nivolumab as third-line chemotherapy for metastatic gastric cancer. We report a case of gastric cancer exhibiting a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse event (irAE). A 64-year-old man with advanced HER2-positive gastric cancer and distant lymph node metastasis received nivolumab as fourth-line therapy. After two courses of nivolumab, the lymph nodes showed progression. However, the treatment was discontinued because of interstitial pneumonia as an irAE. Disease regression was sustained for approximately 11 months without the readministration of nivolumab.

Phase II Prospective Study of Trastuzumab in Combination with S-1 and Oxaliplatin (SOX100) Therapy for HER2-Positive Advanced Gastric Cancer.

PURPOSE: The standard first-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) is trastuzumab in combination with cisplatin and fluoropyrimidines. We evaluated the efficacy and safety of S-1 and oxaliplatin (100 mg/m2) (SOX100) combined with trastuzumab, a monoclonal antibody against HER2 for HER2-positive AGC. METHODS: In this single-arm, multicenter phase II study, patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, oxaliplatin (100 mg/m2) intravenously on day 1, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: A total of 25 patients from six centers were enrolled from December 2015 to March 2020. In the 25 patients evaluable for analysis, the 1-year survival rate was 70.8% [90% confidence interval (CI) = 55.5-86.1%], whereas the median OS, PFS, and ORR were 17.8 (95% CI 10.5-22.9) months, 7.6 (95% CI 5.0-10.9) months, and 75.0% (95% CI 53.3-90.2), respectively. Major grade 3/4 adverse events included anorexia (20%), anemia (16%), peripheral sensory neuropathy (16%), and diarrhea (15%). CONCLUSION: SOX100 combined with trastuzumab was effective with a favorable safety profile in patients with HER2-positive AGC.

Neuroendocrine carcinoma of the ampulla of Vater causing ectopic adrenocorticotropic hormone-dependent Cushing's syndrome.

Ectopic adrenocorticotropic hormone (ACTH) is rarely secreted by neuroendocrine tumors. Although neuroendocrine tumors may occur at any site in the gastrointestinal system, they very rarely occur in the ampulla of Vater and have a poor prognosis. The present study described the first Cushing's syndrome as a result of ectopic ACTH arising from the ampulla of Vater neuroendocrine carcinoma. A 69-year-old female was admitted with clinical features of Cushing's syndrome, confirmed biochemically by hypokalemia, and elevated levels of ACTH and cortisol. In further investigations, a tumor of the ampulla of Vater and liver metastases were detected. Pathological analysis of the biopsy confirmed a neuroendocrine carcinoma, which was immunohistochemically positive for chromogranin A, synaptophysin, cluster of differentiation 56 and ACTH. Therefore, the present study diagnosed a functional and metastatic neuroendocrine carcinoma of the ampulla of Vater with ectopic ACTH production causing Cushing's syndrome. The patient succumbed to mortality 4 months later, despite administration of combined chemotherapy with irinotecan and cisplatin.

A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer.

BACKGROUND: We evaluated the efficacy and safety of 5-weekly S-1 and cisplatin combined with trastuzumab, a monoclonal antibody against human epidermal growth factor receptor type 2 (HER2) for HER2-positive advanced gastric cancer (AGC). METHODS: This phase II study treatment consisted of S-1 (80-120 mg per day) orally on day 1-21, cisplatin (60 mg/m(2)) intravenously on day 8, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival, progression-free survival (PFS), response rate (RR), and safety. RESULTS: A total 22 patients from seven centers were enrolled. In the 20 patients evaluable for analysis, the 1-year survival rate was 70 % (95 % confidence interval (CI) 49.9-90.1 %), and median survival time, PFS, and RR were 15.3, 7.5 months and 41.2 %, respectively. Major grade 3/4 adverse events were neutropenia (30 %), anorexia (30 %), leukopenia (25 %), fatigue (20 %), and anemia (15 %). CONCLUSIONS: Five-weekly S-1 and cisplatin combined with trastuzumab showed effective with favorable safety profile in patients with HER2-positive AGC.

[A case of malignant tumor of the ascending part of duodenum with osteoclast-like giant cells].

Extraskeletal neoplasms with osteoclast-like giant cells are very rare. These tumors are most frequently reported in the breast and pancreas, and but rarely in other sites. We report a case of duodenal malignant tumor with osteoclast-like giant cells. The patient was a 76-year-old man who presented with vomiting. Computed tomography, magnetic resonance imaging, and gastrointestinal endoscopy revealed a giant tumor in the ascending part of duodenum. Biopsy specimens showed an undifferentiated malignant tumor with benign multinucleated giant cells. Immunohistochemical staining indicated that the tumor cells were reactive with vimentin, but not with epithelial markers or the other mesenchymal markers, and the multinucleated giant cells were reactive with CD68. Thus, we diagnosed a malignant tumor of the ascending part of duodenum with osteoclast-like giant cells. To the best of our knowledge, this is the first case of duodenal malignant tumor with osteoclast-like giant cells in Japan.

Lentinan with S-1 and paclitaxel for gastric cancer chemotherapy improve patient quality of life.

BACKGROUND/AIMS: Lentinan (LNT), a purified beta-glucan, is a biological and immunological modifier and has been used as an anticancer drug in combination with 5-fluorouracil for gastric cancer in Japan. In this prospective randomized study, we evaluated the effects of LNT combination with regard to quality of life (QOL) and LNT binding ratio in monocytes. METHODOLOGY: Twenty patients were evaluated for 12 weeks. One cycle was 3 weeks and S-1 (day1-14) and Paclitaxel (days1 and 8) were administered. LNT was used once a week (days 1, 8 and 15) and it was used for all 12 weeks in the LNT 12-wk group and only for the last 6 weeks in the LNT 6-wk group. QOL was evaluated weekly by QOL-ACD, and binding of LNT to monocytes was measured by flow cytometry. RESULTS: There were individual variations in the binding ratio of LNT to monocytes from 0.16% to 11.95%. Toxicity with chemotherapy was not improved in the LNT 12-wk group, however, the total QOL score was significantly elevated in the LNT 12-wk group (p = 0.018) but not in the LNT 6-wk group. CONCLUSION: LNT combination from the beginning of the chemotherapy may be an important factor for the improvement of patient QOL.

Role of prostaglandins in maintaining gastric mucus-cell permeability against acid exposure.

Regulation of gastric epithelial permeability is important in the protection of the gastric mucosa from secreted acid. However, the mechanism(s) for this regulation in gastric mucus cells remains unknown. In this study, we evaluated gastric epithelial-cell permeability in response to acid exposure by monitoring trans-epithelial electrical resistance (TEER) and paracellular permeability with carbon 14-labeled mannitol. We also examined the role of prostaglandins on gastric epithelial permeability. Rat gastric epithelial cells (RGM-1) were plated on 8-microm-pore tissue-culture inserts. Cells were exposed to solutions of differing pH (3-7.4), with and without the nonsteroidal antiinflammatory drug (NSAID) indomethacin (10(-7) mol/L), for 60 to 120 minutes. Transepithelial permeability was measured on the basis of TEER and the diffusion rate of [(14)C]mannitol. Prostaglandin E(2) (PGE(2)) was administered in some experiments with NSAIDs. After acid exposure (pH 3.0-5.0), TEER rapidly and significantly increased, peaking in 5 minutes. Diffusion of [(14)C]mannitol was blocked during the period when TEER increased. Pretreatment with the cyclooxygenase (COX) inhibitor indomethacin blocked the rapid acid-induced increase in TEER. A specific COX-2 inhibitor had no effect on this rapid increase in TEER. The blockade by indomethacin was eliminated by the addition of PGE(2). These findings suggest that when gastric-surface mucus cells are exposed to acid, gastric epithelial permeability decreases rapidly to inhibit acid back-diffusion. Prostaglandins play an important role in this protective response to acid exposure. COX inhibitors such as indomethacin may inhibit the regulation of epithelial permeability by reducing the concentration of PGE(2).

Contribution of capsaicin-sensitive afferent nerves to rapid recovery from ethanol-induced gastric epithelial damage in rats.

BACKGROUND AND AIM: It is well known that capsaicin-sensitive nerve signaling acts as a protective factor against various ulcerogens. However, the contribution of topical capsaicin-sensitive nerves within the stomach to rapid restitution has not been fully investigated. The present study was therefore conducted focusing on recovery from gastric mucosal damage induced by ethanol in vivo. METHODS: Male Sprague-Dawley rats were fasted and anesthetized. 51Cr-EDTA was administered intravenously and gastric mucosal integrity was continuously monitored by measuring the blood to lumen 51Cr-EDTA clearance. Capsaicin or vehicle was irrigated before, together with or after the perfusion of 20% ethanol, followed by perfusion with saline. In another experiment, ruthenium red, a capsaicin-sensitive cation antagonist, was given before the ethanol-capsaicin perfusion. Furthermore, this study was verified using lafutidine, a histamine H2-receptor antagonist, which has a gastric mucosal protective action through the capsaicin-sensitive afferent nerves. RESULTS: When capsaicin was administered before ethanol treatment, mucosal damage was significantly reduced and recovery was significantly rapid compared to the control. When capsaicin (160 micro M) and ethanol were administered simultaneously, the mucosal damage was exacerbated but recovery was nevertheless more rapid than the control group. With a lower dose of capsaicin (80 micro M), mucosal damage was not exacerbated and recovery was enhanced. When capsaicin or lafutidine was administered after the induction of ethanol injury no change was detected regarding the damage. However, recovery was significantly accelerated. Ruthenium red reversed the action of post-treatment with capsaicin on restitution. CONCLUSIONS: These results indicate that luminal administration of capsaicin exerts protection against and accelerates restitution from gastric damage in the very early phase after ethanol injury. This action is probably due to activation of topical capsaicin-sensitive afferent nerves in the rat.

Acid-induced mesenteric hyperemia in rats: role of CGRP, substance P, prostaglandin, adenosine, and histamine.

Intraduodenal acidification produces a mesenteric hyperemia that is mediated in part by mucosal capsaicin-sensitive afferent nerves and the bradykinin B2 receptor in anesthetized rats. We hypothesized that novel mechanisms mediated by substance P, adenosine, and histamine1 receptors are involved. Confirmation of a role for calcitonin gene-related peptide (CGRP) but not endogenous prostaglandin was also sought. In study 1, vehicle or antagonists (CGRP(8-37), CP 96345) was administered intravenously. Capsaicin or acid was administered intraduodenally, followed by intravenous CGRP or substance P. In study 2, pretreatments included indomethacin, 8-phenyltheophylline, pyrilamine, or the respective vehicles. Acid was then administered intraduodenally. In both studies, superior mesenteric artery blood flow was monitored. In study 1, the antagonists significantly attenuated capsaicin- and acid-induced mesenteric hyperemia. In study 2, the pretreatments did not alter acid-induced hyperemia. The data confirmed the role of CGRP and indicated for the first time an involvement for substance P in acid-induced mesenteric hyperemia.

Increased intake of n-3 polyunsaturated fatty acids elevates the level of apoptosis in the normal sigmoid colon of patients polypectomized for adenomas/tumors.

To clarify preventive effects of n-3 polyunsaturated fatty acids (PUFAs) against colorectal carcinogenesis, we performed a dietary intervention in patients polypectomized for colorectal adenomas/tumors. For the former the following dietary advice was given: (1) decrease intake of fat from 30 to 20% of the total; (2) decrease consumption of n-6PUFAs containing foods, and increase intake of n-3 PUFAs for 2 years. For the comparison group only decreased intake of fat (30-20%) was recommended. Samples of normal sigmoid colon mucosa, obtained by colonoscopic check once a year during the intervention period, were used to investigate COX-2, cell proliferation (Ki67 expression), p53, Bcl-2 and Bax by immunostaining and determine the apoptosis index (AI) by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labeling (TUNEL) in 21 and 20 patients in experimental and comparison groups, respectively, who completed the 2 years of the intervention. After 24 months, the AI and positive cells of Bax and the ratio of Bax/Bcl-2 in normal sigmoid colon mucosa for the experimental group was significantly increased, whereas this change was not found in comparison group. These observations demonstrated for the first time that increased intake of n-3 PUFAs promotes apoptosis of normal colon mucosa in human which is related to effect on Bax or the balance of Bax and Bcl-2.

Ruthenium red-sensitive cation channels, but not calcitonin gene-related peptide or substance P-mediated mechanisms, protect duodenal villi against acid-induced damage.

Intestinal mucosal capsaicin-sensitive afferent nerves mediate, in part, the protective mesenteric hyperemia after intraduodenal acidification. Mechanisms associated the sensory neuropeptides, e.g. calcitonin gene-related peptide (CGRP), substance P, and ruthenium red-sensitive cation channels contribute to acid-induced mesenteric hyperemia, but whether they play a role in protection against acid-induced duodenal villous damage is not known. We tested the hypothesis that in doses that attenuate acid-induced hyperemia, inhibitors of these mechanisms will exacerbate acid-induced duodenal villous damage. Intravenous vehicle, specific receptor antagonists of CGRP (CGRP(8-37)), substance P (CP 96345), intraduodenal ruthenium red or vehicle was administered, followed by intraduodenal perfusion with 0.1 N HCl. Duodenal tissue was processed for hematoxylin and eosin staining. Villous damage was scored by blinded observers. Deep villous injury was significantly increased after treatment with ruthenium red, but not with CGRP(8-37) or CP 96345. These findings support the hypothesis that ruthenium red-sensitive cation channels, but not neuropeptides associated with intestinal mucosal afferent nerves, are involved in the acid-sensing mechanism which mediates the protection against acid-induced duodenal villous damage.

[Radiological examination for elderly patients with peptic ulcer].

In this review, radiological examination for elderly patients was discussed. In recent years, technology for endoscopy was remarkably developed and endoscopical diagnosis of peptic ulcer became much easier and safer than before. Thus, indication of a biphasic radiologic examination is decreasing especially for the elderly patients. There are many problems for radiological examination in the elderly. Most of problems are based on aging, i.e. difficulties in swallowing, moving, defecation, understanding instruction, etc. Clinical characteristics of peptic ulcer in aging people should be considered. The knowledge of complaining, complications, ulcer location, and etiology including H. pylori infection might be also important. These issues should be well understood before performing radiological examination in the elderly.

Immune responses in mice to intranasal and intracutaneous administration of a DNA vaccine encoding Helicobacter pylori-catalase.

We previously reported that the intracutaneous injection of DNA vaccines encoding Helicobacter pylori heat shock proteins elicited specific immune responses, and led to reduced infection in mice. In this study, we constructed DNA vaccine encoding H. pylori-catalase (pcDNA3.1-kat) and investigated the immune responses to intranasal and intracutaneous administration of pcDNA3.1-kat. C57/BL6 mice were immunized intracutaneously with 10 microg of pcDNA3.1-kat or intranasally with 50 microg of pcDNA3.1-kat. Catalase-specific IgG antibody was detected in the sera of intranasal and intracutaneous immunized mice. Both intranasal and intracutaneous immunized mice were significantly protected from colonization by H. pylori and had significantly reduced degrees of gastritis. These results demonstrate that DNA vaccine encoding H. pylori-catalase can induce an immune response against H. pylori, and that intranasal immunization works as well as intracutaneous immunization.

Role of bradykinin in acid-induced mesenteric hyperemia and duodenal villous damage.

Intestinal mucosal capsaicin-sensitive afferent nerves mediate, in part, the mesenteric hyperemia after intraduodenal acidification. The hyperemia plays a role in protecting the duodenal mucosa against acid damage. We tested the hypothesis that bradykinin contributes to this protective hyperemia. A specific antagonist of bradykinin will attenuate the hyperemia and exacerbate duodenal villous damage induced by acid. Study 1: Intravenous vehicle, or the specific bradykinin B2 receptor antagonist (HOE 140) was administered to anesthetized rats. This was followed by intraduodenal bolus administration of 160 microM capsaicin or 0.1 N HCl, and then intravenous bradykinin. Study 2: Intravenous administration of vehicle or HOE 140 was followed by duodenal perfusion with 0.1 N HCl. Superior mesenteric artery blood flow (pulsed Doppler flowmetry) (Study 1) and duodenal villous damage (histology) (Study 2) were recorded. HOE 140 significantly reduced the hyperemia induced by bradykinin and intraduodenal capsaicin or acid. Deep villous injury was significantly increased after treatment with HOE 140. These findings support the hypothesis that acid-induced and afferent nerve-mediated mesenteric hyperemia is modulated by a mechanism that involves bradykinin B2 receptor. Antagonism of bradykinin B2 receptor also increased acid-induced deep duodenal villous damage. Thus, maintenance of bradykinin-mediated mesenteric hyperemia, is a previous unrecognized mechanism associated with protection of the rat duodenal mucosa against acid-induced damage.

Rationale and study design of dietary intervention in patients polypectomized for tumors of the colorectum.

We have implemented a randomized controlled dietary intervention in patients polypectomized for tumors of the colorectum to elucidate potential beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) on the development of colorectal tumors. Those individuals in the experimental group were advised not only to decrease their consumption of fats/oils as a whole and foods supplying n-6 PUFAs but also to increase intake of foods and supplements containing n-3 PUFAs, while those in the comparison group were cautioned to reduce intake of fats/oils as a whole. Patients' compliance/adherence was monitored with a semi-quantitative food frequency questionnaire and by assessment of fatty acid concentrations in plasma, membranes of red blood cells and sigmoid colon samples. As for endpoints to assess tumor suppressive effects of n-3 PUFAs, the number/multiplicity, sizes and incidence rates of colorectal tumors were compared between the experimental and comparison groups after 12 and 24 months of the dietary intervention. On the specified assumption, the number of pairs needed for achieving statistical significance was calculated to be approximately 60-80. A randomized controlled trial is under way to secure enough patients, sustain compliance/adherence and minimize dropouts.