Current prognostic factors of advanced gastric cancer patients treated with chemotherapy: real world data from a Japanese 12 institutions.

BACKGROUND: Understanding the prognostic factors of advanced gastric cancer before starting chemotherapy is important to determine personalized treatment strategies. However, the details of chemotherapy and the prognosis of advanced gastric cancer patients have changed with the time and environment. The aim of this study was to understand the current reality of chemotherapy and to estimate the prognostic factors of advanced gastric cancer patients before starting chemotherapy at multiple centers. This includes specialized cancer hospitals and community hospitals, with the latest data under the Japanese insurance system. METHODS: We evaluated the clinical parameters and treatment details of 1025 patients who received systemic chemotherapy for unresectable advanced gastric cancer from 2012 to 2018 at 12 institutions in Japan. Prognostic factors were analyzed using the Cox proportional hazards regression model. RESULTS: As of April 2021, 953 (93%) patients had died, while 72 (7%) patients survived. The median overall survival and progression-free survival of first-line chemotherapy was 11.8 months (95% confidence interval, 10.8-12.3 months) and 6.3 months (95% confidence interval, 5.9-6.9 months), respectively. Multivariate analysis revealed eight prognostic factors: age < 40 years, performance status ≥2, no gastrectomy, diffuse histological type, albumin <3.6, alkaline phosphatase ≥300, creatinine ≥1.0 and neutrophil-to-lymphocyte ratio > 3.0. Patients using trastuzumab showed better survival than patients without (16.1 months vs. 11.1 months; P = 0.0005). CONCLUSIONS: We identified eight prognostic factors for patients with advanced gastric cancer undergoing Japanese standard chemotherapy. Our results will help clinicians develop treatment strategies for every patient.

Multicenter Prospective Study on the Safety of Upper Gastrointestinal Endoscopic Procedures in Antithrombotic Drug Users.

BACKGROUND: The Japan Gastroenterological Endoscopy Society updated its guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment in July 2012. However, the safety of endoscopic procedures in antithrombotic drug users has not been fully investigated. AIMS: To evaluate the safety of upper gastrointestinal endoscopic procedures in antithrombotic drug users. METHODS: From September 2013 to September 2015, patients who were taking antithrombotic drugs and who underwent upper gastrointestinal endoscopic procedures were prospectively enrolled at five hospitals. Incidences of bleeding and thrombosis during endoscopic procedures were evaluated. RESULTS: A total of 270 patients [221 for endoscopic mucosal biopsy and 49 for endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) were enrolled. The bleeding rate was 0.9% for endoscopic mucosal biopsy and 22% for EMR/ESD, respectively. The bleeding rate after endoscopic mucosal biopsy was not significantly high, even if antithrombotic drugs were continued (0 vs. 1%, P > 0.99), while it was significantly higher among multiple antithrombotic drug users than single drug users (5.9 vs. 0%, P < 0.05). The bleeding rate after EMR/ESD was also higher among multiple antithrombotic drug users than single drug users, but was not significantly different (33 vs. 14%, P = 0.17). Moreover, there were no differences in bleeding rates according to the cessation or continuance of antithrombotic drugs (20 vs. 25%, P = 0.74). There were no thromboembolisms in all cases. CONCLUSIONS: Upper gastrointestinal endoscopic procedures performed under the new guidelines appear acceptable. However, endoscopic procedures among multiple antithrombotic drug users show a greater potential for bleeding.

Propofol sedation with a target-controlled infusion pump and bispectral index monitoring system in elderly patients during a complex upper endoscopy procedure.

BACKGROUND AND AIMS: Although the usefulness of propofol sedation during endoscopic submucosal dissection (ESD) for gastric neoplasms was reported previously, information is limited on its use in elderly patients. We investigated the safety and efficacy of propofol sedation with a target-controlled infusion (TCI) pump and bispectral index (BIS) monitoring system (TCI/BIS system) in elderly patients during gastric ESD. METHODS: Included were 413 consecutive gastric ESD procedures involving 455 lesions (379 patients) performed in patients under propofol sedation with a TCI/BIS system between October 2009 and September 2013. Patients were divided into 3 groups: group A, age <70 years (n = 162); group B, age ≥70 and <80 years (n = 171); and group C, age ≥80 years (n = 80). We compared the propofol dose and adverse events (eg, hypotension and hypoxemia) during ESD. RESULTS: Older groups required a lower target concentration of propofol (group A: median 2.1 µg/mL [interquartile range (IQR), 1.9-2.3]; group B: median 1.6 µg/mL [IQR, 1.3-1.8]; and group C: median 1.4 µg/mL [IQR, 1.2-1.6]; P < .0001). Hypotension tended to occur in the younger group, and hypoxemia occurred at a significantly higher rate in the older groups, although the number of cases was small. Low preoperative systolic blood pressure (≤125 mm Hg) was associated with hypotension (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.12-2.70; P = .013) and abnormal pulmonary function was associated with hypoxemia in groups B and C (OR, 4.54; 95% CI, 1.01-31.5; P = .048). CONCLUSIONS: Elderly patients required lower doses of propofol with the TCI/BIS system than younger patients. Attention to hypoxemia is necessary in elderly patients, particularly patients with abnormal pulmonary function.

Actual Status of Involvement of Helicobacter pylori Infection That Developed Gastric Cancer from Group A of ABC (D) Stratification - Study of Early Gastric Cancer Cases That Underwent Endoscopic Submucosal Dissection.

BACKGROUND/AIMS: Patients who are Helicobacter pylori antibody negative and have normal pepsinogen (PG) levels (group A of ABC (D) stratification) are considered unlikely to develop gastric cancer. This study aimed to clarify the involvement (uninfection, present infection or previous infection) of H. pylori in group A patients with early gastric cancer who underwent endoscopic submucosal dissection (ESD) by examining their background gastric mucosa endoscopically and histologically. METHODS: This study included 166 patients with gastric cancer who were treated by ESD. Patients were classified according to PG levels and H. pylori antibody titers. Three biopsies (greater curvature of the antrum, lesser curvature of the middle corpus and greater curvature of the middle corpus) from group A were histologically analyzed and compared with those of groups B, C, D and after eradication). RESULTS: In group A (34 patients), 32 patients had endoscopic atrophy (group A'). Histological neutrophil activity, chronic inflammation and atrophy scores were lower in group A' than in other groups. Group A' scores were similar to those of the after eradication group. CONCLUSION: Most of the group A patients with early gastric cancer were not uninfected with H. pylori, but had previous infections, thus carrying carcinogenic risk.

[A Study to Determine the Optimum Antigens for the Serodiagnosis of Helicobacter Pylori Infection in Japanese Patients and the Association with IgG Subclass and Gastric Cancer].

Atrophic gastritis is caused by Helicobacter pylori infection, and is involved in gastric cancer. In this study, we investigated the association with total IgG and IgG subclass antibodies using several strains isolated from Japanese in H. pylori positive and negative individuals, and gastric atrophy using measuring pepsinogen I and II levels. We found that total IgG antibody measurement using typical Japanese genotype as an antigen was available for diagnosis of H. pylori infection, whereas IgG1 and IgG2 antibodies were not for diagnosis. Furthermore, the IgG1/G2 ratio was elevated in a patient with gastric cancer. The accuracy of serodiagnosis of H. pylori infection may increase when the optimal antigens are used, and measurement IgG subclass may provide additional prediction of gastric cancer.

Endoscopic and clinical features of gastric emphysema.

Gastric emphysema is characterized by the presence of intramural gas in the stomach without bacterial infection. Due to its rarity, most reports on gastric emphysema have been limited to single-case studies, and this condition's clinical and endoscopic features have not been thoroughly investigated. In this study, we analyzed 45 patients with gastric emphysema from 10 institutions and examined their characteristics, endoscopic features, and outcomes. The mean age at diagnosis of gastric emphysema in our study population (35 males and 10 females) was 68.6 years (range, 14-95 years). The top five underlying conditions associated with gastric emphysema were the placement of a nasogastric tube (26.7%), diabetes mellitus (20.0%), post-percutaneous endoscopic gastrostomy (17.8%), malignant neoplasms (17.8%), and renal failure (15.6%). Among the 45 patients, 42 were managed conservatively with fasting and administration of proton pump inhibitors. Unfortunately, seven patients died within 30 days of diagnosis, and 35 patients experienced favorable recoveries. The resolution of gastric emphysema was confirmed in 30 patients through computed tomography (CT) scans, with a mean duration of 17.1 ± 34.9 days (mean ± standard deviation [SD], range: 1-180 days) from the time of diagnosis to the disappearance of the gastric intramural gas. There were no instances of recurrence. Endoscopic evaluation was possible in 18 patients and revealed that gastric emphysema presented with features such as redness, erosion, coarse mucosa, and ulcers, with fewer mucosal injuries on the anterior wall (72.2%), a clear demarcation between areas of mucosal injury and intact mucosa (61.1%), and predominantly longitudinal mucosal injuries on the stomach folds (50.0%). This study is the first English-language report to analyze endoscopic findings in patients with gastric emphysema.

Endoscopic submucosal dissection of esophageal cancer using the Mucosectom2 device: a feasibility study.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is being increasingly used for superficial esophageal cancers. However, esophageal ESD is technically difficult, time consuming, and less safe compared with endoscopic mucosal resection (EMR). To perform ESD safely and more efficiently, various types of knives have been developed. This study compared the efficacy of our newly developed device, Mucosectom2, with that of conventional devices for esophageal ESD. PATIENTS AND METHODS: Between May 2007 and February 2011, ESD was performed for 172 esophageal lesions. Of these, 120 lesions were treated by conventional devices only, whereas 52 lesions were treated by conventional devices and the Mucosectom2. Procedure time, en bloc and R0 resection rates, and adverse events were retrospectively compared between the conventional and Mucosectom2 groups. RESULTS: The median procedure time was 48.0 minutes in the conventional group and 21.5 minutes in the Mucosectom2 group; the procedure time was significantly shorter in the Mucosectom2 group than in the conventional group (P < 0.0001). The en bloc and R0 resection rates were lower in the conventional group than those in the Mucosectom2 group, although these differences were not significant. The rate of exposure of the muscle layer in the Mucosectom2 group was significantly lower than in the conventional group (P = 0.04). The rates of perforation and postoperative bleeding were not significantly different between the two groups. CONCLUSIONS: This feasibility study suggests that, compared with conventional ESD devices, the Mucosectom2 may decrease the time required for esophageal ESD. Although our groups appeared comparable, they were studied at different times. Endoscopic expertise and endoscope quality may have differed during these periods, thereby affecting the results of our study. A prospective trial is therefore required to confirm our results.

The genetic diversity of Helicobacter pylori virulence genes is not associated with gastric atrophy progression.

Atrophy of the gastric mucosa is a precursor of intestinal-type gastric cancer, and Helicobacter pylori infection causes atrophic gastritis. The aim of this study was to determine whether the genetic diversity of H. pylori virulence genes is associated with the development and progression of gastric atrophy in humans. We isolated and cultured H. pylori strains from patients with gastric ulcer and duodenal ulcer accompanied by atrophic gastritis in background mucosa. H. pylori strains were stored at －80℃ prior to the experiments being carried out. We analyzed iceA, babA, vacA, cagA, and cagE genes by PCR. The cagA gene was analyzed through sequencing of the C-terminal region containing the EPIYA motif, which is related to tyrosine phosphorylation. Severe atrophy was observed in patients with gastric ulcer. The major phenotype of the vacA gene was s1c/m1 (93%). The cagA gene was detected in all strains. The cagE gene was not detected in 2 and 5 strains from the mild cases and severe cases, respectively. The major cagA EPIYA motif, which is amino acids repeat in the C terminus, was the A-B-D type (44 of 58 strains). The virulence genes were not statistically associated with the severity of atrophy in the background gastric mucosa in humans. Not only identification of bacterial virulence factors but also studies of the host response will be necessary to investigate the progression of gastric atrophy and subsequent cancer development in humans.

[New Helicobacters other than H. pylori].

Since discovery of Helicobacter pylori, more than 30 species non-H. pylori Helicobacter spp. (NHPH) have been reported. Those NHPH were now classified into gastric Helicobacter spp. and enterohepatic Helicobacter spp.(EHS). Gastric NHPH show tight spiral and long shape in the gastric mucosa, and we can distinguish from H. pylori by light microscope. Some gastric NHPH may be zoonosis and cause gastritis in human. H. hepaticus and H. cinaedi belongs in EHS were detected in human diseases. H. hepaticus may be associated with hepatobiliary diseases in humans. Surprisingly, it was reported that H. cinaedi infection was associated with atrial arrhythmias and atherosclerosis. Many NHPH will be recognized as human pathogen in the future.

Erratum: Prospective multicenter study of the efficacy and safety of cold forceps polypectomy for ≤ 6-mm non-ampullary duodenal low-grade adenomas.

[This corrects the article DOI: 10.1055/a-1793-9439.].

Prospective multicenter study of the efficacy and safety of cold forceps polypectomy for ≤ 6-mm non-ampullary duodenal low-grade adenomas.

Background and study aims Because the endoscopic treatment for non-ampullary duodenal adenoma (NADA) has a non-negligible risk of adverse events (AEs), a safe and easy treatment for NADA is desirable. This was a multicenter prospective trial evaluating the efficacy and safety of cold forceps polypectomy (CFP) for diminutive NADAs. Patients and methods This study was prospectively conducted at six general hospitals and one university hospital. The inclusion criteria were histologic and endoscopic diagnosis of low-grade NADA measuring ≤ 6 mm. A second endoscopy was scheduled for 1 month after CFP. After confirmation of the success of CFP, 6-month and 12-month surveillance endoscopies were scheduled. The primary endpoint was the endoscopic and histologic disease disappearance rates at the 12-month endoscopy. Results Thirty-nine lesions from 38 patients were prospectively included. Median tumor size at enrollment was 5 mm (range 3-6 mm). There were four cases of remnant lesions at the second endoscopy, and the lesion disappearance rate of single CFP was 89.7 % (35 /39; 95 % confidence interval (CI), 76.9 %-97.9 %). In three cases, complete removal of the lesion was achieved with a single re-CFP, but one case required four repeat CFPs. The lesion disappearance rate at 12-month endoscopy was 97.4 % (38 /39; 95 %CI, 86.8 %-99.5 %). During the follow-up period, no AEs related to CFP were observed. Conclusions CFP for NADA ≤ 6 mm was safe and effective in this study. This common endoscopic method to remove lesions may be an option for treatment of diminutive NADAs.

Usefulness and problems of endoscopic ultrasonography in prediction of the depth of tumor invasion in early gastric cancer.

The objectives of this study were to evaluate the accuracy of endoscopic ultrasonography (EUS) in local and regional staging of early gastric cancer, to analyze the factors influencing the accuracy of EUS, and to reveal the usefulness and problems of EUS in pre-treatment staging of gastric cancer. We examined 105 lesions in 104 patients with histologically confirmed gastric cancer and retrospectively evaluated them with EUS. The diagnostic accuracy, sensitivity, and specificity of EUS were determined by comparing the pre-treatment EUS with the postoperative histopathological findings. The overall diagnostic accuracy of EUS for the depth of cancer invasion was 86%. The overall sensitivity and specificity were 60% and 96%, respectively. The accuracy significantly declined in lesions located in the upper-third of the stomach (70%). Type 0-I lesions tended to be over-staged (12&), and the upper-third lesions tended to be under-staged (23%). The accuracy significantly declined in differentiated adenocarcinoma with massive submucosal invasion (56.5%). EUS is useful for evaluating the depth of gastric cancer invasion which determines the feasibility of endoscopic treatment. However, it is noteworthy that the diagnostic accuracy of the invasion depth diminished for lesions in the upper third of the stomach.

Immune reactions against elongation factor 2 kinase: specific pathogenesis of gastric ulcer from Helicobacter pylori infection.

Helicobacter pylori (H. pylori) infection is a definite causative factor for gastric ulcers (GUs). In the present study we detected a specific antigen of gastric epithelial cells (HGC-27) using cell ELISA, which was recognized by the sera of GU patients (n = 20) but not in patients with chronic gastritis (CG; n = 20) or in healthy volunteers (HC; n = 10). This antigen was over-expressed by a stressful (heat-stressed) environment, and was identified as elongation factor 2 kinase (EF-2K) by western blotting. The GU patients' lymphocytes stimulated by H. pylori specifically disrupted heat-stressed HGC-27 cells in a cytotoxic assay. In flow cytometry, the effector cells (lymphocytes) from GU patients were significantly differentiated to T helper type 1 lymphocyte (Th1) and cytotoxic T lymphocyte (CTL) as opposed to those from CG patients. The target cells (HGC-27) expressed EF-2K and MHC-class I together with costimulatory molecules from heat stress. This antigen specific immune mechanism could have a prominent role in the pathogenesis of GU.

DEC205 mediates local and systemic immune responses to Helicobacter pylori infection in humans.

Helicobacter pylori infections cause gastritis and affect systemic immune responses; however, no direct association between immune cells and stomach bacteria has yet been reported. The present study investigated DEC205-mediated phagocytosis of H. pylori and the role of DEC205-positive macrophages in the human gastric mucosa. DEC205 mediated phagocytosis of H. pylori was detected immunocytochemically in PMA-stimulated macrophages differentiated from NOMO1 cells. Expression of DEC205 mRNA in peripheral blood mononuclear cells (PBMCs) from H. pylori-infected patients was analyzed following stimulation with H. pylori cell lysate. We found that anti-DEC205 antibodies inhibited phagocytosis of H. pylori. The number of cells double-positive for DEC205 and CD14 in human gastric mucosa was higher in H. pylori-infected patients. DEC205-positive macrophages invaded the extracellular space between epithelial cells within gastric pits. In addition, DEC205 mRNA expression was upregulated in human PBMCs stimulated with H. pylori lysate. These findings suggest DEC205-expressing macrophages are important for recognition of H. pylori in human gastric mucosa, which affects systemic immunity.

Breast Cancer Metastasis to the Stomach That Was Diagnosed after Endoscopic Submucosal Dissection.

A 52-year-old woman presented with stage IIB primary breast cancer (cT2N1M0), which was treated using neoadjuvant chemotherapy (epirubicin, cyclophosphamide, and paclitaxel). However, the tumor persisted in patchy areas; therefore, we performed modified radical mastectomy and axillary lymph node dissection. Routine endoscopy at 8 months revealed a depressed lesion on the gastric angle's greater curvature, and histology revealed signet ring cell proliferation. We performed endoscopic submucosal dissection for gastric cancer, although immunohistochemistry revealed that the tumor was positive for estrogen receptor, mammaglobin, and gross cystic disease fluid protein-15 (E-cadherin-negative). Therefore, we revised the diagnosis to gastric metastasis from the breast cancer.

Does Helicobacter pylori Exacerbate Gastric Mucosal Injury in Users of Nonsteroidal Anti-Inflammatory Drugs? A Multicenter, Retrospective, Case-Control Study.

BACKGROUND/AIMS: The interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori remains controversial. We retrospectively investigated whether H. pylori infection exacerbates severe gastric mucosal injury among chronic NSAID users. METHODS: From January 2010 to December 2013, a total of 245 long-term NSAID (including low-dose aspirin) users who had undergone an esophagogastroduodenoscopy and had been evaluated for H. pylori infection were enrolled at Okayama University Hospital and Tsuyama Chuo Hospital. The degree of gastric mucosal injury was assessed according to the modified Lanza score (MLS). Severe gastric mucosal injury was defined as an MLS ≥4. Univariate and multivariate logistic regression analyses were performed. RESULTS: In the univariate analysis, age ≥75 years (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3 to 4.2), H. pylori-positivity (OR, 2.0; 95% CI, 1.2 to 3.5), and the concomitant use of proton pump inhibitors (PPIs) (OR, 0.48; 95% CI, 0.26 to 0.86) were significantly associated with severe gastric mucosal injury. The multivariate analysis was adjusted by age and sex and demonstrated that H. pylori-positivity (OR, 1.8; 95% CI, 1.0 to 3.3) and the concomitant use of PPIs (OR, 0.53; 95% CI, 0.28 to 0.99) significantly contributed to severe gastric mucosal injury. CONCLUSIONS: H. pylori infection exacerbates severe gastric mucosal injury among chronic NSAID users.

Morphological Changes in a Pyogenic Granuloma of the Esophagus Observed over Three Years.

A 78-year-old Japanese man underwent routine esophagogastroduodenoscopy, during which a reddish, flat elevated lesion was observed in the middle third of the esophagus. A bright red area of protrusion appeared in the center of the elevated lesion three months later, and the protruded nodule grew to be a blood blister six months after the initial endoscopy examination. The morphology of the lesion changed from a protruded nodule to a mass with two humps that subsequently returned to a single hump during the three-year observation period. A histological diagnosis of pyogenic granuloma was made based on a biopsy performed at six months. This report illustrates a rare case of an esophageal pyogenic granuloma presenting with a unique endoscopic appearance and morphologic changes. Endoscopic ultrasonography images are also presented.

Ectopic pancreas in the stomach successfully resected by endoscopic submucosal dissection.

A 32-year-old Japanese man presented with a gastric submucosal tumor. Esophagogastroduodenoscopy showed a sessile submucosal tumor measuring approximately 10 mm in diameter on the greater curvature of the gastric antrum. Endoscopic ultrasonography examination revealed a solid tumor with a diameter of 11.8 mm, which was located in the deep mucosal and submucosal layers. The internal echogenicity was homogenous and hypoechoic. Biopsy examinations were performed twice but were not diagnostic since only the intact mucosal layer was obtained. The patient was subsequently diagnosed with ectopic pancreas in the stomach by endoscopic submucosal dissection (ESD). This case underscores the usefulness of the ESD technique for the pathological diagnosis of gastric submucosal tumors.

Recurrence after radiotherapy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma with trisomy 18.

A 36-year-old Japanese woman presented with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the stomach. The gastric lesions only partially improved after eradication therapy for Helicobacter pylori. A fluorescence in situ hybridization analysis revealed no fusion genes of API2-MALT1, although trisomy of chromosome 18 was identified. Radiation therapy was initiated to treat the gastric lymphoma lesions, resulting in complete remission. However, MALT lymphoma recurred in the stomach 16 months later. This case indicates that intensive follow-up is required for MALT lymphoma associated with chromosomal aberrations in order to detect early relapse.