An increasing trend of gastric cancer deaths and inadequate preventive measures in elderly adults.

BACKGROUND: Japan became the world's first country to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system in February 2013. Thereafter, H. pylori eradication dramatically increased and gastric cancer deaths began to decrease in Japan. However, the details of gastric cancer deaths and its prevention in the very elderly have not been fully elucidated. METHODS: We analyzed the temporal trend of gastric cancer deaths referencing data from Ministry of Health, Labour and Welfare reports and "Cancer Statistics in Japan-2021" and assessed the numbers of H. pylori test and gastric cancer screening using a national database and a report of cancer screening in Shimane Prefecture, respectively. RESULTS: Although gastric cancer deaths in total population have clearly decreased since 2013, those in people aged 80 years and older are still increasing. People aged 80 years and older represent 9% of the total population and accounted for half of all gastric cancer deaths in 2020. The numbers of H. pylori eradication and gastric cancer screening in people aged 80 years and older were 25% and 25% of those in other generations, respectively. CONCLUSION: In spite of a dramatic increase in H. pylori eradication and a clear decrease in gastric cancer deaths in Japan, gastric cancer deaths in people aged 80 years and older are increasing. This might be due to fewer H. pylori eradication in the elderly than in other generations, indicating the difficulty of gastric cancer prevention in the very elderly.

Helicobacter pylori genomes reveal Paleolithic human migration to the east end of Asia.

A virulence bacterium, Helicobacter pylori, evolved parallel to its host human, therefore, can work as a marker for tracing the human migration. We found H. pylori strains indigenous in the southernmost islands of Japanese Archipelago, Okinawa, and defined them as hspOkinawa and hpRyukyu. Genome data of the strains revealed that hspOkinawa diverged from other East Asian strains about 20,000 years ago, and that hpRyukyu diverged about 45,000 years ago. The closest strains of hpRyukyu were found from Afghanistan, Punjab, and Nepal, which suggest this strain originated in the central Asia and traveled across the Eurasian continent during Paleolithic era. The divergence date of hpRyukyu corresponds with human fossil records in Okinawa. Although it is controversial from human DNA analyses whether descendants of the Paleolithic migrants remain in the modern Japanese population, this study reveals that the bacterium of Paleolithic origin remains in the stomachs of current Japanese.

Alterations in the oral microbiome of individuals with a healthy oral environment following COVID-19 vaccination.

BACKGROUND: Several reports suggest that the microbiome of the digestive system affects vaccine efficacy and that the severity of coronavirus disease (COVID-19) is associated with decreased diversity of the oral and/or intestinal microbiome. The present study examined the effects of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine on the oral microbiome. METHODS: Forty healthy Japanese oral healthcare personnel were recruited, and unstimulated saliva was collected before vaccination, after the 1st vaccination, and after the 2nd vaccination. Genomic DNA was extracted from saliva samples, and PCR amplicons of the 16S rRNA gene were analyzed using next-generation sequencing. Microbial diversity and composition were analyzed using Quantitative Insights into Microbial Ecology 2. In addition, alterations in microbial function were assessed using PICRUSt2. RESULTS: SARS-CoV-2 mRNA vaccination significantly increased oral bacterial diversity and significantly decreased the proportion of the genus Bacteroides. CONCLUSIONS: The SARS-CoV-2 mRNA vaccine alters the oral microbiome; accordingly, vaccination might have beneficial effects on oral health.

Economic and health impacts of Helicobacter pylori eradication strategy for the treatment of peptic ulcer disease: A cost-effectiveness analysis.

BACKGROUND: Most peptic ulcer cases are associated with Helicobacter pylori (H. pylori) infection or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). H. pylori eradication therapy is recommended for the treatment of H. pylori-positive peptic ulcers. We aimed to assess and validate the cumulative economic and health effects of H. pylori eradication strategy for the treatment of peptic ulcers compared with PPI therapy strategy. MATERIALS AND METHODS: We developed a cohort state-transition model for H. pylori eradication strategy and PPI therapy strategy over a lifetime horizon from a healthcare payer perspective. We targeted two hypothetical cohorts of H. pylori-positive patients with gastric and duodenal ulcers aged 20, 30, 40, 50, 60, 70, and 80. The main outcomes were costs, quality-adjusted life-years (QALYs), life expectancy life-years (LYs), incremental cost-effectiveness ratios, ulcer recurrence cases, and ulcer-associated deaths. One-way and probabilistic sensitivity analyses were conducted to assess the impact of uncertainty. RESULTS: In the base-case analysis, H. pylori eradication strategy was less costly with greater benefits than PPI therapy strategy in all age groups. Cost-effectiveness was not sensitive to any variables in all age groups. Sensitivity analyses showed strong robustness of the results. From 2000 to 2020, H. pylori eradication strategy saved US$14.07 billion over a lifetime, increased 8.65 million QALYs and 1.23 million LYs over a lifetime, and prevented 551,298 ulcer recurrence cases and 59,465 ulcer-associated deaths, compared with PPI therapy strategy. CONCLUSIONS: H. pylori eradication strategy not only has contributed significantly to preventing ulcer recurrence and reducing ulcer-associated deaths but also has resulted in great cost savings. All over the world, H. pylori eradication strategy is likely to have yielded a comparable magnitude of economic and health benefits, depending on the epidemiology of H. pylori-related peptic ulcers and the healthcare environment in each country.

Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer.

In 2020, the worldwide incidence and mortality of colorectal cancer (CRC) were third and second, respectively. As the 5-y survival rate is low when CRC is diagnosed at an advanced stage, a reliable method to predict CRC susceptibility is important for preventing the onset and development and improving the prognosis of CRC. Therefore, we focused on the normal colonic mucosa to investigate changes in gene expression that may induce subsequent genetic alterations that induce malignant transformation. Comprehensive gene expression profiling in the normal mucosa adjacent to colon cancer (CC) compared with tissue from non-colon cancer patients was performed. PCR arrays and qRT-PCR revealed that the expression of 5 genes involved in the immune response, including MYD88, was increased in the normal mucosa of CC patients. The expression levels of MYD88 were strikingly increased in precancerous normal mucosa specimens, which harbored no somatic mutations, as shown by immunohistochemistry. Microarray analysis identified 2 novel RNA-controlling molecules, EXOSC3 and CNOT4, that were significantly upregulated in the normal mucosa of CC patients and were clearly visualized in the nuclei. Forced expression of EXOSC3 and CNOT4 in human colonic epithelial cells increased the expression of IFNGR1, MYD88, NFκBIA, and STAT3 and activated ERK1/2 and JNK in 293T cells. Taken together, these results suggested that, in the inflamed mucosa, EXOSC3- and CNOT4-mediated RNA stabilization, including that of MYD88, may trigger the development of cancer and can serve as a potential predictive marker and innovative treatment to control cancer development.

Nine Cases of SARS-CoV-2-PCR-positive Samples Showed No Increase of Antibodies Against SARS-CoV-2.

BACKGROUND/AIM: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been affecting Hokkaido, Japan since late February 2020 until present. The aim of this study was to report the relationship between anti-SARS-CoV-2 antibody-positive and SARS-CoV-2 PCR-positive cases by analyzing anti-SARS-CoV-2 antibodies (IgG and total-Ig). PATIENTS AND METHODS: Serum samples were collected from care workers and nurses in two nursing homes and two hospitals which underwent virus outbreak. All people were confirmed to be SARS-CoV-2-positive by RT-qPCR and their sera was analyzed for anti-SARS-CoV-2 antibodies (IgG and total-Ig). RESULTS: Although 34 out of 43 samples (79.1%) showed enough amount of anti-SARS-CoV-2 antibodies, 9 RT-qPCR -positive samples (20.9%) showed absence of anti-SARS-CoV-2 antibodies in their sera. CONCLUSION: The results that 20.9% of RT-qPCR-positive samples with SARS-CoV-2 showed absence of anti-SARS-CoV-2 antibodies provides a possibility that the innate immune reaction could eliminate the virus without activating adaptive immune reaction.

Economic and health impacts of introducing Helicobacter pylori eradication strategy into national gastric cancer policy in Japan: A cost-effectiveness analysis.

BACKGROUND: Helicobacter pylori (H. pylori) eradication reduces gastric cancer risk. Since 2013, a population-wide H. pylori eradication strategy for patients with chronic gastritis has begun to prevent gastric cancer in Japan. The aim of this study was to evaluate the economic and health effects of H. pylori eradication strategy in national gastric cancer prevention program. MATERIALS AND METHODS: We developed a cohort state-transition model for H. pylori eradication and no eradication over a lifetime horizon from a healthcare payer perspective, and performed one-way and probabilistic sensitivity analyses. We targeted a hypothetical cohort of H. pylori-positive patients aged 20, 30, 40, 50, 60, 70, and 80. The main outcomes were costs, quality-adjusted life-years (QALYs), life expectancy life-years (LYs), incremental cost-effectiveness ratios, gastric cancer cases, and deaths from gastric cancer. RESULTS: H. pylori eradication was more effective and cost-saving for all age groups than no eradication. Sensitivity analyses showed strong robustness of the results. From 2013-2019 for 8.50 million patients, H. pylori eradication saved US$3.75 billion, increased 11.11 million QALYs and 0.45 million LYs, and prevented 284,188 cases and 65,060 deaths. For 35.59 million patients without eradication, H. pylori eradication has the potential to save US$14.82 billion, increase 43.10 million QALYs and 1.66 million LYs, and prevent 1,084,532 cases and 250,256 deaths. CONCLUSIONS: National policy using population-wide H. pylori eradication to prevent gastric cancer has significant cost savings and health impacts for young-, middle-, and old-aged individuals in Japan. The findings strongly support the promotion of H. pylori eradication strategy for all age groups in high-incidence countries.

P. gingivalis Lipopolysaccharide Stimulates the Upregulated Expression of the Pancreatic Cancer-Related Genes Regenerating Islet-Derived 3 A/G in Mouse Pancreas.

Although epidemiological studies have shown a relationship between periodontal disease and pancreatic cancer, the molecular mechanisms involved remain unclear. In this study, the effects of systemic administration of Porphyromonas gingivalis lipopolysaccharide (PG-LPS) on gene expression were comprehensively explored in mouse pancreas that did not demonstrate any signs of inflammation. PG-LPS was prepared in physiological saline and intraperitoneally administered to male mice at a concentration of 5 mg/kg every 3 days for 1 month. After extracting total RNA from the excised mice pancreas, a comprehensive DNA microarray analysis of gene expression was performed. Tissue specimens were also subjected to hematoxylin-eosin staining and immunohistochemistry using anti-regenerating islet-derived 3A and G (Reg3A/G) antibody. ImageJ software was used to quantify the area of Reg3A/G positive cells in pancreatic islets by binarizing image date followed by area extraction. The results were compared using Mann-Whitney U test. Data are presented as mean ± standard deviation (SD) with p < 0.05 considered as significant. Reg3G, a gene related to pancreatic cancer, was one of the 10 genes with the highest levels of expression in the pancreas stimulated with PG-LPS. The comprehensive analysis revealed a 73-fold increase in Reg3G expression level in the PG-LPS group when compared with the control group; in addition, the expression level of Reg3A was increased by 11-fold in the PG-LPS group. Image analysis showed that the ratio of Reg3A/G positive cells was higher in the PG-LPS group than the control. Immunostaining showed the presence of Reg3A/G-positive cells in the alpha-cell equivalent areas around the islets of Langerhans in the PG-LPS group. These results support the notion that periodontal disease may be a risk factor for pancreatic cancer.

Gastric cancer deaths by age group in Japan: Outlook on preventive measures for elderly adults.

In February 2013, Japan became the first country in the world to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system. Now that eradication therapy is covered by NHI, its usage has increased dramatically, and gastric cancer deaths have begun to decrease. We undertook a detailed epidemiological analysis to investigate effects of expanded NHI coverage for H. pylori eradication therapy on gastric cancer deaths in specific age groups. Numbers of gastric cancer deaths were determined by referencing data from Ministry of Health, Labour and Welfare reports and "Cancer Statistics in Japan - 2018" published by the Foundation for Promotion of Cancer Research. Gastric cancer deaths across all age groups have been clearly decreasing since 2013, but deaths of people aged 80 years and older are still increasing. The number of gastric cancer deaths in people aged in their 80s was 2 times higher than in people aged in their 70s and 4 times higher than in people aged in their 60s. The number of people in their 80s who had an endoscopy was less than half that of people in their 60s and 70s. The eradication therapy has increased dramatically, and gastric cancer deaths are clearly decreasing in Japan. However, this decrease in deaths has not extended to elderly adults aged in their 80s, which suggests that measures to prevent gastric cancer in people aged 80 years and older will be critical to achieving the mission of eliminating gastric cancer in Japan.

Changes of Dyspeptic Symptom after Successful Eradication in Helicobacter pylori-Associated Dyspepsia.

BACKGROUND: Helicobacter pylori (H. pylori) gastritis could cause dyspepsia, and eradication is recommended as the first-line treatment. Patients who continuously have their symptoms under control > 6 months after eradication are defined as having H. pylori-associated dyspepsia (HPD), whereas patients who do not benefit from successful eradication are defined as having functional dyspepsia. OBJECTIVES: We assessed changes in dyspeptic symptoms after successful eradication of H. pylori by using a questionnaire. METHODS: We studied H. pylori-infected dyspeptic participants with abdominal symptom scores > 4 points on the Global Overall Symptom (GOS) scoring items and received eradication therapy. We evaluated their symptoms using the GOS questionnaire before their eradications, at 1-month and at 1-year check-ups after eradication therapy. RESULTS: Thirty dyspeptic participants (mean age 59.6 ± 15.3 years) answered every questionnaire. Fourteen participants (46.7%) had HPD, whereas 16 participants (53.3%) were non-HPD patients. The questionnaire at 1 month showed sensitivity of 64.3% (9/14) and specificity of 56.3% (9/16) for HPD. Approximately 60% of H. pylori-infected dyspepsia participants were identified as having HPD or non-HPD within 1 month after their eradications. CONCLUSIONS: Approximately 60% of HPD participants improved at 1 month after eradication. The questionnaire at 1 month helped diagnose HPD in advance and guided next treatment choice.

Randomized controlled trial: PPI-based triple therapy containing metronidazole versus clarithromycin as first-line treatment for Helicobacter pylori in adolescents and young adults in Japan.

BACKGROUND/AIMS: Treating Helicobacter pylori infection in young people is effective for preventing gastric cancer. This study compares the efficacy of triple therapies in adolescents and young adults in Japan. METHODS: This multicenter, randomized trial was conducted between February 2012 and March 2015. Infected participants were stratified into adolescents (13-19 years) and young adults (20-39 years). They were randomly assigned to a clarithromycin based (PAC) or metronidazole based (PAM) triple therapy for 1 week. RESULTS: Overall, 137 and 169 participants received the PAC and PAM treatments, respectively. In adolescents, the H. pylori eradication rates were 60.5% and 63.4% for PAC, and 98.3% and 100% for PAM in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively. In young adults, the eradication rates were 67.0% and 66.7% for PAC, and 95.5% and 96.3% for PAM in ITT and PP analyses, respectively. The eradication rate of PAM was significantly higher than that of PAC in both strata. No severe adverse events were observed. CONCLUSION: In Japan, PAM may be selected as a first-line treatment for young people with H. pylori if antibiotic susceptibility tests cannot be performed.

Preliminary study of automatic gastric cancer risk classification from photofluorography.

AIM: To perform automatic gastric cancer risk classification using photofluorography for realizing effective mass screening as a preliminary study. METHODS: We used data for 2100 subjects including X-ray images, pepsinogen I and II levels, PGI/PGII ratio, Helicobacter pylori (H. pylori) antibody, H. pylori eradication history and interview sheets. We performed two-stage classification with our system. In the first stage, H. pylori infection status classification was performed, and H. pylori-infected subjects were automatically detected. In the second stage, we performed atrophic level classification to validate the effectiveness of our system. RESULTS: Sensitivity, specificity and Youden index (YI) of H. pylori infection status classification were 0.884, 0.895 and 0.779, respectively, in the first stage. In the second stage, sensitivity, specificity and YI of atrophic level classification for H. pylori-infected subjects were 0.777, 0.824 and 0.601, respectively. CONCLUSION: Although further improvements of the system are needed, experimental results indicated the effectiveness of machine learning techniques for estimation of gastric cancer risk.

Effect on Helicobacter pylori eradication therapy against gastric cancer in Japan.

BACKGROUND: In Japan, there have been approximately 50 000 deaths from gastric cancer annually for over 40 years with little variation. It has been reported that most gastric cancers in Japan are caused by Helicobacter pylori infection. H. pylori eradication therapy was approved for patients with chronic gastritis by the Japanese national health insurance scheme in February 2013 for patients with an endoscopic diagnosis of chronic gastritis is positive for H. pylori. We examined the effect on gastric cancer death rate 4 years after expansion of health insurance coverage. AIM: We conducted an epidemiological study and analyzed trends in prescription for H. pylori eradication therapy. We used the electronic medical claims database from Hokkaido, Japan to evaluate the impact of expansion of national health insurance coverage for H. pylori eradication therapy on deaths from gastric cancer. METHODS: Data on deaths from gastric cancer were obtained from the Japanese Ministry of Health, Labour and Welfare and the Cancer Statistics in Japan (2015). Analysis of electronic claims records was performed using the National Database, mainly focusing on Hokkaido. Prescriptions for H. pylori eradication therapy and the number of patients treated for gastric cancer were also extracted from the Hokkaido database. RESULTS: Approximately 1.5 million prescriptions for H. pylori eradication therapy were written annually. Gastric cancer deaths fell each year: 48 427 in 2013, 47 903 in 2014, 46 659 in 2015, and 45 509 in 2016, showing a significant decrease after expansion of insurance coverage for H. pylori eradication therapy (P<.0001). CONCLUSIONS: Prescriptions for H. pylori eradication therapy increased markedly after approval of the gastritis indication by the national health insurance scheme and was associated with a significant decrease in gastric cancer deaths.

Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02).

OBJECTIVE: Rikkunshito, an herbal medicine, is widely prescribed in Japan for the treatment of anorexia and functional dyspepsia, and has been reported to recover reductions in food intake caused by cisplatin. We investigated whether rikkunshito could improve chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients treated with cisplatin. METHODS: Patients with uterine cervical or corpus cancer who were to receive cisplatin (50 mg/m² day 1) and paclitaxel (135 mg/m² day 0) as first-line chemotherapy were randomly assigned to the rikkunshito group receiving oral administration on days 0-13 with standard antiemetics, or the control group receiving antiemetics only. The primary endpoint was the rate of complete control (CC: no emesis, no rescue medication, and no significant nausea) in the overall phase (0-120 hours). Two-tailed p<0.20 was considered significant in the planned analysis. RESULTS: The CC rate in the overall phase was significantly higher in the rikkunshito group than in the control group (57.9% vs. 35.3%, p=0.175), as were the secondary endpoints: the CC rate in the delayed phase (24-120 hours), and the complete response (CR) rates (no emesis and no rescue medication) in the overall and delayed phases (63.2% vs. 35.3%, p=0.095; 84.2% vs. 52.9%, p=0.042; 84.2% vs. 52.9%, p=0.042, respectively), and time to treatment failure (p=0.059). Appetite assessed by visual analogue scale (VAS) appeared to be superior in the rikkunshito group from day 2 through day 6. CONCLUSION: Rikkunshito provided additive effect for the prevention of CINV and anorexia.

Decreased RNA-binding motif 5 expression is associated with tumor progression in gastric cancer.

RNA-binding motif 5 is a putative tumor suppressor gene that modulates cell cycle arrest and apoptosis. We recently demonstrated that RNA-binding motif 5 inhibits cell growth through the p53 pathway. This study evaluated the clinical significance of RNA-binding motif 5 expression in gastric cancer and the effects of altered RNA-binding motif 5 expression on cancer biology in gastric cancer cells. RNA-binding motif 5 protein expression was evaluated by immunohistochemistry using the surgical specimens of 106 patients with gastric cancer. We analyzed the relationships of RNA-binding motif 5 expression with clinicopathological parameters and patient prognosis. We further explored the effects of RNA-binding motif 5 downregulation with short hairpin RNA on cell growth and p53 signaling in MKN45 gastric cancer cells. Immunohistochemistry revealed that RNA-binding motif 5 expression was decreased in 29 of 106 (27.4%) gastric cancer specimens. Decreased RNA-binding motif 5 expression was correlated with histological differentiation, depth of tumor infiltration, nodal metastasis, tumor-node-metastasis stage, and prognosis. RNA-binding motif 5 silencing enhanced gastric cancer cell proliferation and decreased p53 transcriptional activity in reporter gene assays. Conversely, restoration of RNA-binding motif 5 expression suppressed cell growth and recovered p53 transactivation in RNA-binding motif 5-silenced cells. Furthermore, RNA-binding motif 5 silencing reduced the messenger RNA and protein expression of the p53 target gene p21. Our results suggest that RNA-binding motif 5 downregulation is involved in gastric cancer progression and that RNA-binding motif 5 behaves as a tumor suppressor gene in gastric cancer.

Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) for esophageal cancer often causes postoperative stricture when more than three fourths of the circumference of the esophagus is dissected. Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium (CM) obtained from mesenchymal stem cells reportedly inhibits inflammation. In this study we evaluated whether CM could prevent esophageal stricture after ESD. METHODS: We resected a semi-circumference of pig esophagus by ESD. We prepared CM gel by mixing with 5% carboxymethyl cellulose and endoscopically applied it onto the wound bed immediately after ESD and on days 8 and 15 (weekly CM group) or administered it orally from days 1 to 4 (daily CM group). We also injected triamcinolone acetonide into the remaining submucosa immediately after ESD (steroid group). We killed the pigs on day 8 or day 22 to measure the stricture rate and to perform histologic analysis. RESULTS: Stricture rate in weekly and daily CM groups and steroid groups were significantly lower than in the control group on day 22. Moreover, CM significantly attenuated the number of activated myofibroblasts and fiber thickness on day 22. CM also significantly decreased the infiltration of neutrophils and macrophages compared with the control group on day 8. CONCLUSIONS: CM gel prevents esophageal stricture formation by suppressing myofibroblast activation and fibrosis after the infiltration of neutrophils and macrophages. Oral administration of CM gel is a promising treatment for the prevention of post-ESD stricture.