Gastric Adenocarcinoma in Helicobacter pylori-Negative Autoimmune Gastritis: A Case Report and Literature Review.

Recent studies have suggested that gastric cancer does not occur in patients with Helicobacter pylori-negative autoimmune gastritis (AIG); however, this notion is controversial. We encountered a case of gastric cancer associated with AIG in which H. pylori infection was excluded. A woman in her 70s was referred to our hospital for endoscopic resection of an antral adenoma. An H. pylori antibodies test, stool antigens test, H. pylori culture, and histological analysis using Giemsa staining yielded negative results. AIG was suspected because the antrum was endoscopically normal but the body was severely atrophic, which are typical findings of AIG. Anti-parietal cell antibodies were 40-fold positive, the gastrin level was 2950 pg/ml, and the pepsinogen I level, pepsinogen II level, and pepsinogen I/II ratio were 6.3 ng/ml, 5.7 ng/ml, and 1.1, respectively. A pathological examination of the gastric body revealed severe oxyntic atrophy with hyperplasia of enterochromaffin-like cells, whereas the antrum showed no pyloric gland atrophy or inflammation. These findings indicated that the patient had H. pylori-negative AIG. Four years later, a depressed lesion in the lower body and a flat lesion at the angle were observed; the former was a poorly cohesive carcinoma, and the latter was a differentiated adenocarcinoma. Surgical resection revealed that the lesion in the lower body was a poorly cohesive carcinoma invading the submucosa with vascular involvement, whereas the lesion in the angle was an intramucosal differentiated adenocarcinoma. A review of previous studies of gastric cancer with H. pylori-negative AIG suggested that patients with histologically and serologically advanced gastritis are at high risk for carcinogenesis. Even in H. pylori-negative cases, severe gastric mucosal atrophy in AIG cases may indicate a carcinogenic risk; therefore, surveillance for gastric cancer is especially recommended for these cases. Large cohort studies on the association between H. pylori-negative AIG and gastric cancer are warranted.

Antiviral susceptibility of SARS-CoV-2 and influenza viruses from 3 co-infected pediatric patients.

In Japan, influenza activity was low throughout the COVID-19 pandemic until the 2022-23 season, when the first influenza outbreak occurred since the 2020-21 season. In our influenza surveillance during the COVID-19 pandemic, co-infection with SARS-CoV-2 and influenza virus had not been detected; however, in January 2024, we identified three pediatric outpatients co-infected with these viruses: one with SARS-CoV-2 Omicron EG.5 sublineage HK.3 and influenza A(H3N2) and two with SARS-CoV-2 Omicron BA.2.86 sublineage JN.1.5 and influenza A(H1N1)pdm09. We evaluated the susceptibility of SARS-CoV-2 against RNA-dependent RNA polymerase inhibitors (remdesivir and molnupiravir) and 3C-like protease inhibitors (nirmatrelvir and ensitrelvir), and that of influenza viruses against neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir) and the cap-dependent endonuclease inhibitor baloxavir. All viruses tested were susceptible to these antiviral drugs and did not possess amino acid substitutions associated with reduced antiviral susceptibility. The patients were treated with anti-influenza drugs and did not develop severe symptoms despite the co-infection. Since SARS-CoV-2 and influenza viruses continue to evolve, continuous monitoring of their circulation remains essential to assess public health measures and support clinical management.

Unique bile acid profiles in the bile ducts of patients with primary sclerosing cholangitis.

BACKGROUND: The relationship between primary sclerosing cholangitis (PSC) and biliary bile acids (BAs) remains unclear. Although a few studies have compared PSC biliary BAs with other diseases, they did not exclude the influence of cholestasis, which affects the composition of BAs. We compared biliary BAs and microbiota among patients with PSC, controls without cholestasis, and controls with cholestasis, based on the hypothesis that alterations in BAs underlie the pathophysiology of PSC. METHODS: Bile samples were obtained using endoscopic retrograde cholangiopancreatography from patients with PSC (n = 14), non-hepato-pancreato-biliary patients without cholestasis (n = 15), and patients with cholestasis (n = 13). RESULTS: The BA profiles showed that patients with PSC and cholestasis controls had significantly lower secondary BAs than non-cholestasis controls, as expected, whereas the ratio of cholic acid/chenodeoxycholic acid in patients with PSC was significantly lower despite cholestasis, and the ratio of (cholic acid + deoxycholic acid)/(chenodeoxycholic acid + lithocholic acid) in patients with PSC was significantly lower than that in the controls with or without cholestasis. The BA ratio in the bile of patients with PSC showed a similar trend in the serum. Moreover, there were correlations between the alteration of BAs and clinical data that differed from those of the cholestasis controls. Biliary microbiota did not differ among the groups. CONCLUSIONS: Patients with PSC showed characteristic biliary and serum BA compositions that were different from those in other groups. These findings suggest that the BA synthesis system in patients with PSC differs from that in controls and patients with other cholestatic diseases. Our approach to assessing BAs provides insights into the pathophysiology of PSC.

The gut-liver axis in hepatobiliary diseases.

Recent advances in the analysis of intestinal bacteria have led to reports of variations in intestinal bacterial levels among hepatobiliary diseases. The mechanisms behind the changes in intestinal bacteria in various hepatobiliary diseases include the abnormal composition of intestinal bacteria, weakening of the intestinal barrier, and bacterial translocation outside the intestinal tract, along with their metabolites, but many aspects remain unresolved. Further research employing clinical studies and animal models is expected to clarify the direct relationship between intestinal bacteria and hepatobiliary diseases and to validate the utility of intestinal bacteria as a diagnostic biomarker and potential therapeutic target. This review summarizes the involvement of the microbiota in the pathogenesis of hepatobiliary diseases via the gut-liver axis.

IL-15-producing splenic B cells play pathogenic roles in the development of autoimmune hepatitis.

Background & Aims: B-cell depletion therapy with an anti-CD20 is an effective treatment strategy for patients with refractory autoimmune hepatitis (AIH). However, the mechanisms underlying B-cell action are unclear. Methods: Herein, we used the adeno-associated virus IL-12 model, in which hepatic IL-12 expression triggers liver injuries characteristic of AIH. We also analysed the clinical samples of patients with AIH. Results: B-cell depletion using anti-CD20 or splenectomy was found to improve liver functions and decrease the cytotoxic CD8+ T-cell (cytotoxic T lymphocyte [CTL]) count in the liver. This improvement was reversed by the adoptive transfer of splenic B cells derived from AAV IL-12-treated mice to splenectomised mice as it caused the hepatic CTL count to increase. RNA-sequencing analysis identified IL-15 as a key factor in pathogenic B cells, which promotes CTL expansion and subsequent migration to the liver via the CXCL9/CXCR3 axis. Indeed, IL-15 neutralisation ameliorated hepatitis by suppressing splenic and hepatic CTLs in vivo. The close distribution of B220+ B cells and CD8+ T cells in the spleen of AIH mice suggested mutual interactions. Mechanistically, IFNγ and CD40L/CD40 signalling were indispensable for the expression of IL-15 in B cells, and in vitro co-culture experiments revealed that splenic CD40L+CD8+ T cells promoted IL-15 production in B cells, which led to CTL expansion. In patients with AIH, high serum IL-15 concentration and IL-15+ B-cell counts, positively correlating with serum alanine aminotransferase levels, support translation and potential therapeutic targeting in human AIH. Conclusions: This investigation elucidated the roles of IL-15-producing splenic B cells that occur in concert with pathogenic CD8+ T cells during the development of AIH. Impact and Implications: IL-15-producing B cells were shown to exacerbate experimental AIH via cytotoxic T lymphocyte expansion. CD40L+CD8+ T cells promoted IL-15 expression in B cells, indicating the mutual interaction of both cells. High serum IL-15 concentrations, IL-15+ B-cell counts, and CD40L+IL-15Rα+CD8+ T-cell counts were confirmed in the blood of patients with AIH.

Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC.

Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis.

The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.

Severe graft-versus-host disease-like enterocolitis accompanied with cytomegalovirus-reactivation in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug adverse reaction with skin eruption and visceral organ involvement. The characteristic clinical features of DIHS/DRESS are reactivation of human herpesviruses (HHV) and the development of autoimmune diseases, but their pathogenesis and associations are not yet understood. Here, we report a 66-year-old man who presented with fever, generalized erythema, diffuse lymphadenopathy, and diarrhea after 3 weeks of treatment with zonisamide. Reactivation of HHV-6 and cytomegalovirus (CMV) was detected during the clinical course. The patient was diagnosed with DIHS/DRESS and treated with systemic prednisolone, i.v. immunoglobulin therapy, and ganciclovir. However, severe enterocolitis persisted for 6 months. A series of examinations revealed features of both CMV enterocolitis, as indicated by identification of a few CMV-positive cells on immunohistochemical analysis, and graft-versus-host disease (GVHD)-like enterocolitis indicated by orange-peel appearance on endoscopic examination and histopathological loss of goblet cells. Intractable enterocolitis continued and the patient finally died of pneumonia. An autoimmune predisposition in DIHS/DRESS patients in combination with CMV reactivation was considered to trigger the severe enterocolitis of this case that showed GVHD-like features of the gastrointestinal tract. GVHD-like organ damage is a pathological condition rarely observed in DIHS/DRESS but should be recognized as one of the most severe complications of the disease.

Th17 cells in the liver: balancing autoimmunity and pathogen defense.

In addition to carcinogenesis, T helper 17 (Th17) cells (a subtype of CD4 + T lymphocytes) are involved in the acute, chronic, and cirrhotic phases of liver diseases; however, their role in the development and progression of liver diseases remains unclear. It is difficult to elucidate the role of Th17 cells in liver diseases due to their dichotomous nature, i.e., plasticity in terms of pathogenic or host protective function depending on environmental and time phase factors. Moreover, insufficient depletion of Th17 cells by inhibiting the cytokines and transcription factors involved in their production causes difficulties in analyzing their specific role in vitro and in vivo murine models, partially due to complex interaction. This review summarizes the recent progress in understanding the plasticity and function of hepatic Th17 cells and type 3 cytokines.

Clinical usefulness of a rapid molecular assay, ID NOW™ influenza A & B 2, in adults.

INTRODUCTION: ID NOW™ Influenza A & B 2 (ID NOW 2) is a rapid molecular assay that combines two characteristics, namely the rapidness of rapid antigen detection test (RADT) and the high sensitivity of molecular assay. METHODS: The clinical performance of ID NOW 2 compared with real-time RT-PCR was evaluated in adults. RESULTS: The sensitivity of ID NOW 2 over multiple seasons from 2016/2017 to 2019/2020 was 97.3% (95% CI: 90.7-99.7) for Type A, 100% (95% CI: 81.9-100) for Type B, and 97.8% (95% CI: 92.2-99.7) for influenza (Type A + Type B), and it was significantly higher than the sensitivity of RADT, which was 80.0% (95% CI: 69.2-88.4) for Type A, 73.3% (95% CI: 44.9-92.2) for Type B, and 78.9% (95% CI: 69.0-86.8) for influenza. The sensitivity of RADT tended to be lower in patients in the particularly early period, within 12 h from disease onset; however, the sensitivity of ID NOW 2 remained high, increasing the difference between the sensitivity of RADT and ID NOW 2. The viral loads were low within 12 h from onset, and it was considered this affected the sensitivity of RADT due to its low analytical sensitivity. The specificity of ID NOW 2 was 98% or greater in all groups. CONCLUSIONS: Since ID NOW 2 has a high sensitivity and specificity in adults, it is anticipated to be used in clinical practice, particularly in patients who require early and accurate diagnosis.

Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment.

Human-to-human transmission of PA I38 mutant influenza A(H3N2) viruses with reduced baloxavir susceptibility has been reported in Japan. In December 2019, we detected a PA E23K mutant A(H1N1)pdm09 virus from a child without baloxavir treatment. The PA E23K mutant virus exhibited reduced baloxavir susceptibility but remained susceptible to neuraminidase inhibitors. Epidemiological data suggest possible transmission of this PA E23K mutant virus among humans, although its growth capability relative to that of the wild-type virus was reduced. Therefore, baloxavir susceptibility monitoring of influenza viruses is essential.

Clinical evaluation of ID NOW influenza A & B 2, a rapid influenza virus detection kit using isothermal nucleic acid amplification technology - A comparison with currently available tests.

In this study, we evaluated the performance of ID NOW Influenza A & B 2 (ID NOW 2), a rapid molecular point-of-care test for influenza within 13 min, in comparison with currently available tests. A total of 254 nasopharyngeal swabs (NPS) and 271 nasopharyngeal aspirates (NPA) collected from 373 children and 152 adults with influenza-like illness were tested using ID NOW 2, viral culture, rapid antigen detection test, and loop-mediated isothermal amplification test to evaluate the sensitivity and specificity compared with real-time reverse transcription polymerase chain reaction as the reference method. The sensitivities of ID NOW 2 for influenza A were 95.9% and 95.7% in NPS and NPA, respectively, and for influenza B were 100% and 98.7% in NPS and NPA, respectively. The specificity was 100% for both influenza A and influenza B in NPS and NPA. Sensitivity of each test method reflected the difference of analytical sensitivity among the tests, and ID NOW 2 was not affected by time after illness onset and patient age. In conclusion, ID NOW 2 demonstrated a high sensitivity and specificity that is useful for diagnosis of influenza in the clinical setting and infection control.

[The Relationship between Gut Microbiome, Immune System, and Cancer].

Various microbes having been living in our intestine and forming the gut microbiome. When dysbiosis which is typically characterized by reduced microbial diversity occurs, many types of diseases are triggered in our bodies. Recently, relationship between gut microbiome and our immune function are discovered gradually. From this view point, the gut microbiome may have an influence on cancer medicine such as development, therapy(immune checkpoint blockade or chemotherapy), and therapeutic toxicity. In real clinical practice, this influence is reported in some cases such as colorectal cancer and other malignancies. In the near future, the approach from gut microbiome may be a clue to improve the existent cancer diagnosis and therapy. In addition, the modulation of gut microbiome in itself, for example fecal microbiota transplant(FMT), probiotics, and limited usage of antibiotics, is expected to be hints for cancer medicine, though this is not yet established and further studies are needed.

Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019.

In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses' whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.

Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019.

In January 2019, two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir, were detected from epidemiologically unrelated hospitalised children in Japan. The viruses exhibited reduced susceptibility to baloxavir but were susceptible to neuraminidase inhibitors. Only one of the two children had been treated with baloxavir. An epidemiological analysis suggests possible transmission of the PA I38T mutant A(H3N2) virus among humans.

Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018.

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.

Clinical Evaluation of the Immunochromatographic System Using Silver Amplification for the Rapid Detection of Mycoplasma pneumoniae.

Mycoplasma pneumoniae infection is conventionally diagnosed using serum antibody testing, microbial culture, and genetic testing. Recently, immunochromatography-based rapid mycoplasma antigen test kits have been developed and commercialised for rapid diagnosis of M. pneumoniae infection. However, as these kits do not provide sufficient sensitivity and specificity, a rapid test kit with improved accuracy is desired. The present prospective study evaluated a rapid M. pneumoniae diagnostic system utilizing a newly developed silver amplification immunochromatography (SAI) system. We performed dilution sensitivity test and the prospective clinical study evaluating the SAI system. The subjects of the clinical study included both children and adults. All patients suspected to have mycoplasma pneumonia (169 patients) were sequentially enrolled. Twelve patients did not agree to participate and 157 patients were enrolled in the study. The results demonstrate excellent performance of this system with 90.4% sensitivity and 100.0% specificity compared with real-time polymerase chain reaction. When compared with loop-mediated isothermal amplification (LAMP) methods, the results also demonstrate a high performance of this system with 93.0% sensitivity and 100.0% specificity. The SAI system uses a dedicated device for automatic analysis and reading, making it highly objective, and requires less human power, supporting its usefulness in clinical settings.

Comparison between virus shedding and fever duration after treating children with pandemic A H1N1/09 and children with A H3N2 with a neuraminidase inhibitor.

BACKGROUND: Shedding of the pandemic virus during an influenza pandemic is thought to persist longer than shedding of influenza viruses during annual influenza seasons, because people have much less immunity against a pandemic influenza. A correlation is thought to exist between the length of virus shedding and the clinical severity of influenza illness. METHODS: We compared the virus isolation rates of children with pandemic A H1N1/09 influenza infection and children with A H3N2 influenza infection after the patients had been treated with one of three neuraminidase inhibitors (NAI) such as peramivir, laninamivir and oseltamivir. The clinical effectiveness of each NAI was assessed on the basis of the duration of the febrile period after the start of treatment. RESULTS: Influenza viruses were isolated from 15 of the 34 patients in the A H3N2 group (mean age 6.2 years) and from 4 of the 25 patients in the A H1N1/09 (mean age 5.6 years) virus group (44.1% versus 16.0%; P<0.05). However, the differences between the duration of fever in the patients in the A H3N2 group and A H1N1/09 group after treatment with the NAIs were not significant. CONCLUSIONS: The virus isolation rates after treatment with each of the NAIs were significantly lower in the A H1N1/09 group, suggesting that the pandemic A H1N1/09 virus was more sensitive to the NAIs than the seasonal A H3N2 virus was. Clinically, there were no significant differences in the effectiveness of the NAIs between the H1N1/09 infected group and H3N2 infected group.

Clinical evaluation of highly sensitive silver amplification immunochromatography systems for rapid diagnosis of influenza.

In this study, the clinical usefulness of silver amplification immunochromatography (SAI) influenza virus detection kits, which employed a photographic development technology to increase the sensitivity of the conventional immunochromatographic assay was evaluated. Influenza A and B virus strains of nasopharyngeal aspirates obtained from influenza patients were tested at different dilutions on the SAI system and conventional immunochromatographic assay kit (ESPLINE Influenza A & B-N), and detection limits were calculated for comparison. The detection ability of the SAI system was 8 times higher for Influenza A viruses and 32-64 times higher for Influenza B viruses. Then 1118 respiratory specimens were obtained from patients who presented with influenza-like symptoms between 2009 and 2012. The sensitivities of the SAI system were 91.2% for type A and 94.4% for type B viruses and higher than those of the conventional kit. The SAI system also showed excellent specificities, 95.8% for type A and 98.0% for type B viruses, and was able to detect influenza viruses even within 6h after the disease onset with 90% sensitivity. In conclusion, the SAI system is useful for diagnosis of influenza from early stages of the illness.