Endoscopic treatment of bile duct stones with benign choledochojejunal anastomotic stenosis.

[BACKGROUND AND AIMS]: Endoscopic interventions for bile duct stones (BDS) with benign choledochojejunal anastomotic stenosis (bCJS) are challenging. Therefore, we investigated endoscopic interventions for BDS with bCJS. [METHODS]: Seventeen patients with BDS with bCJS were retrospectively analyzed. Patient characteristics, technical success, adverse events (AEs), and recurrence were evaluated. [RESULTS]: In 17 patients, the median diameters of the bile duct and BDS were both 8 mm. The median number of BDS was 3. The technical success rate was 94% (16/17). Ten patients underwent balloon dilation at the choledochojejunal anastomotic site (CAS), the median diameter of balloon dilation was 10.5 mm, and waist disappearance was achieved in 2. Six patients had fully covered self-expandable metal stents (FCSEMS) with a diameter of 10 mm placed at the CAS. BDS were removed after balloon dilation or FCSEMS removal, and 6 out of 16 patients were treated with a combination of lithotripsy and 5 with peroral direct cholangioscopy (PDCS). Regarding AEs, perforation at the CAS by balloon dilation occurred in 1 patient. The median follow-up was 3701 days. Nine out of 16 patients (56%) had recurrence. The patients treated with combination of PDCS at BDS removal (p=0.022) and waist disappearance at the CAS by balloon dilation (p=0.035) had significantly fewer recurrences. [CONCLUSIONS]: Endoscopic interventions for BDS with bCJS are useful and relatively safe; however, long-term follow-ups showed frequent recurrences. Recurrence was common in patients not treated with the combination of PDCS at BDS removal and those without waist disappearance at the CAS by balloon dilation.

Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma.

BACKGROUNDS AND AIMS: Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC). APPROACH AND RESULTS: In HCC cell lines, LG2m was expressed in alpha-fetoprotein (AFP)-negative, CD90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001). CONCLUSIONS: LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.

Oral Corticosteroids Impair Mucin Production and Alter the Posttransplantation Microbiota in the Gut.

INTRODUCTION: Gut microbiota alterations cause inflammation in patients with ulcerative colitis (UC). Fecal microbiota transplantation (FMT) enables manipulating the microbiota's composition, but the mechanisms underlying colonization of the posttransplantation microbiota are poorly understood. METHODS: In this open-label, nonrandomized study, the FMT efficacy and changes in the gut microbiota were evaluated in 8 UC patients with mild-to-moderately active endoscopic colonic lesions. Compositional changes in the fecal and mucosal microbiotas between donors and recipients were examined via 16S rRNA-based sequencing. To investigate the effects of oral corticosteroids on microbiota colonization, FMT was performed in germ-free prednisolone (PSL)-administered mice to examine the factors determining colonization. RESULTS: Four UC patients achieved clinical remission (CR) after FMT, and 3 also achieved endoscopic remission. The fecal microbiotas of the CR patients changed similar to those of the donors after FMT. The mucin-coding gene, MUC2, was less expressed in the colons of the PSL-dependent patients than in the PSL-free patients. In the mice, PSL treatment decreased the fecal mucin production and altered the posttransplantation fecal microbiota composition. Adding either exogenous mucin or the mucin secretagogue, rebamipide, partially alleviated the PSL-induced dysbiosis of the gut microbiota. Administering rebamipide with FMT from healthy donors relieved inflammation in mice with Enterococcus faecium-induced colitis. CONCLUSION: Colonic mucin controlled the gut microbiota composition, and oral corticosteroid treatment modified the gut microbiota partly by reducing the colonic mucin.

Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma.

AIM: Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti-tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC. METHODS: We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level. RESULTS: Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar-plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti-tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression-free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56 days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively. CONCLUSIONS: Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC.

Characteristics of Immune Response to Tumor-Associated Antigens and Immune Cell Profile in Patients With Hepatocellular Carcinoma.

Host antitumor immune responses may be different between hepatocellular carcinoma (HCC) caused by metabolic disorders and HCC associated with hepatitis virus infection. In this study, we examined the immune response of tumor-associated antigen (TAA)-specific T cells and immune cell profile in patients with HCC separated by cause. Thirty-two patients with hepatitis B virus (HBV)-related HCC, 42 patients with hepatitis C virus-related HCC, and 18 patients with nonalcoholic steatohepatitis (NASH)-related HCC were analyzed. The frequencies of TAA-specific T cells, the expression levels of surface markers on each immune cell, and the expression of each TAA in HCC tissue were measured. The immune response to TAA and immune cell profile were markedly different among the three groups. The immune response to TAA in the NASH-related HCC group was weaker than the responses in the other two groups. In patients with NASH-related HCC, the frequencies of effector regulatory T cells (eTregs) and cluster of differentiation 8-positive (CD8+ ) T cells strongly expressing cytotoxic T-lymphocyte antigen (CTLA)-4 were high. The frequency of CD8+ T cells strongly expressing programmed cell death 1 was the highest in patients with HBV-related HCC. Among these immune cell profiles, the frequencies of C-X-C motif chemokine receptor 3+ eTregs and CTLA-4+ CD8+ T cells were inversely correlated with the strength of the TAA-specific T-cell immune response, and the restoration of TAA-specific T-cell responses by anti-CTLA-4 antibody was observed. Conclusion: The immune response to TAA were markedly different among the three groups, and a correlation with the immune cell profile was observed, suggesting that development of immunotherapy based on the etiology of HCC may lead to more effective treatment outcomes.

Characteristics of Impaired Dendritic Cell Function in Patients With Hepatitis B Virus Infection.

Dendritic cells (DCs) are antigen-presenting cells with a central role in host immune response. This study analyzed gene expression and DC function in hepatitis B virus (HBV) patients, functions impaired because of HBV, and identified the genes related to these functions. Peripheral blood mononuclear cells from 64 HBV patients and 19 healthy controls were analyzed. Peripheral blood DCs were stained with antibodies against human leukocyte antigen-DR/Lin-1/CD123/CD11c and separated into plasmacytoid DCs (pDCs) and myeloid DCs by fluorescence-activated cell sorting. Using an interferon-gamma enzyme-linked immunospot assay, we analyzed antigen-specific response in HBV-infected patients. Regarding DC function, we analyzed antigen-presenting capacity, cell migration capacity, phagocytic capacity, and cytokine production capacity. DC gene expression was analyzed by microarray to identify genes related to DC function. No difference was found in the number of DCs in peripheral blood between healthy participants and HBV patients. In cell-surface marker analysis, CD80, CD83, CD86, CD40, and C-C motif chemokine receptor 7 expression levels in pDCs were related to the HBV-specific T-cell response. DCs from HBV patients exhibited decreases in antigen-presenting capacity, migration capacity, and cytokine production capacity. In gene expression analysis, immune-related genes with greatly reduced expression levels in chronic hepatitis B patients were identified. Of these genes, interleukin (IL)-6 signal transducer (IL6ST) expression level positively correlated with DC surface marker expression level. Adjustment of IL6ST expression level in DCs and treatment with oncostatin M resulted in recovery of DC function. Conclusion: IL6ST expression was identified as one cause of decline in DC function in HBV patients. Adjustment of IL6 family cytokine signaling may be useful for recovering reduced DC function in HBV infection.

Overuse of antianaerobic drug is associated with poor postchemotherapy prognosis of patients with hepatocellular carcinoma.

Overuse of antibiotic drugs alters the composition of gut microbiota and has detrimental effects on the host. In our study, we investigated association of gut flora and antibiotics in the prognosis of patients with liver cancer who have undergone chemotherapy by analyzing two independent clinical studies. We retrospectively subanalyzed a previously reported randomized controlled trial (RCT) on hepatic arterial infusion chemotherapy in patients with hepatocellular carcinoma (HCC) to investigate the association between use of antibiotics and prognosis. In the other study, we prospectively determined the abundance of specific bacterial genus in patients with HCC by sequencing 16S ribosomal RNA and assessed its association with survival. Subanalysis of the RCT data showed that, of 26 types of antibiotics used, administration of carbapenem before or during chemotherapy was associated with poor progression-free survival (PFS) and overall survival (OS) of patients with HCC (carbapenem + vs. -; median PFS, 78 days vs. 154 days, p = 0.0053; median OS, 177 days vs. 475 days, p = 0.0003). Multivariate analysis revealed that antianaerobic drug use is an independent predictor of poor prognosis. In the prospective study, the abundance of Blautia in fecal microbiota correlated positively with both PFS and OS of patients with HCC who underwent chemotherapy. Use of antibiotics targeting anaerobes is associated with a poor prognosis in patients with HCC who have undergone chemotherapy, whereas the intestinal anaerobic bacteria, Blautia is associated with a good prognosis. These findings might indicate the need for caution regarding overuse of broad-spectrum antibiotics targeting anaerobes in patients with HCC.

Development of novel diagnostic system for pancreatic cancer, including early stages, measuring mRNA of whole blood cells.

Pancreatic ductal adenocarcinoma (PDAC) is the most life-threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real-time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%-84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%-73.9%), 63.6% (40.7%-82.8%), and 47.8% (26.8%-69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%-100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC.

Danaparoid sodium-based anticoagulation therapy for portal vein thrombosis in cirrhosis patients.

BACKGROUND: Portal vein thrombosis (PVT) is a common complication of cirrhosis. However, in patients with PVT and cirrhosis, there is no clear evidence supporting effective treatment modalities. In this study, we examined the effectiveness and safety of anticoagulation therapy using danaparoid sodium for PVT in patients with cirrhosis. METHODS: This retrospective study assessed 52 cirrhotic patients with PVT treated with danaparoid sodium for 2 weeks between November 2008 and September 2018. The primary outcome measure was the post-treatment status of PVT assessed by reduction in thrombus volume and safety of the therapeutic intervention. PVT status was evaluated with contrast-enhanced computed tomography (CECT). All patients received 1250 units of danaparoid sodium twice daily by intravenous injection for 14 days. Patients on antithrombin III (AT-III) combination therapy were additionally administered 1500 units of AT-III on days 1-5 and days 8-12. Effectiveness was evaluated by CECT from between days 13 and 18. The secondary outcome measure was the prognosis of PVT. RESULTS: All patients showed reduction in PVT volume without complications. Return of plasma AT-III level to > 70% during the treatment period contributes to ≥75% reduction of PVT volume. The prognosis in PVT patients depends on hepatic reserve capacity. When limited to Child-Pugh B and C liver cirrhosis patients, a ≥ 75% reduction of PVT volume improved the prognosis. CONCLUSIONS: Danaparoid sodium-based anticoagulation therapy was effective and safe for PVT in patients with cirrhosis. Return of plasma AT-III level to the normal range during the treatment period contributes to reduction of PVT volume. A reduction of ≥75% in PVT volume may improve the prognosis of Child-Pugh B and C decompensated cirrhosis patients with PVT.

Serum C16:1n7/C16:0 ratio as a diagnostic marker for non-alcoholic steatohepatitis.

BACKGROUND AND AIMS: Accurate diagnosis of non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver disease (NAFLD) is clinically important. Therefore, there is a need for easier ways of diagnosing NASH. In this study, we investigated the serum fatty acid composition and evaluated the possibility of using the serum fatty acid composition as a diagnostic marker of NASH. METHODS: The subjects were 78 NAFLD patients (non-alcoholic fatty liver [NAFL]: 30, NASH: 48) and 24 healthy individuals. Fatty acids extracted from the liver tissue and serum were identified and quantified by gas chromatography. In addition, we evaluated the relationship between serum and liver tissue fatty acid composition, patient background, and liver histology. The diagnostic performance of NASH was evaluated by calculating the area under the receiver operating characteristic (AUROC). RESULTS: The results of the fatty acid analysis showed the C16:1n7/C16:0 ratio to have the strongest correlation between serum and liver tissue (r = 0.865, P < 0.0001). The serum C16:1n7/C16:0 ratio in the NASH group was higher compared with that in the NAFL group (P = 0.0007). Evaluation of the association of the serum C16:1n7/C16:0 ratio with liver histology revealed significant correlation with lobular inflammation score, ballooning score, and fibrosis score. The AUROC for predicting NASH in all NAFLD patients was 0.7097. The AUROC was nearly equivalent even when the study subjects were restricted to patients with a fibrosis score ≤ 2 only (AUROC 0.6917). CONCLUSION: Measuring the serum C16:1n7/C16:0 ratio may be an effective non-invasive method for diagnosing NASH, particularly in its early stages.

Association Between High-Avidity T-Cell Receptors, Induced by α-Fetoprotein-Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Levels of α-fetoprotein (AFP) are measured for surveillance and diagnosis of hepatocellular carcinoma (HCC). We performed a phase 1 trial to evaluate the safety and efficacy of AFP-derived peptides as an anti-tumor vaccine for patients with advanced HCC, and characterized induction of AFP-specific T-cell receptors (TCRs). METHODS: We performed a prospective study of 15 patients with HCC seen at Kanazawa University Hospital in Japan from March 2010 through March 2012. Each patient was given a subcutaneous injection of 3 mg AFP-derived peptides (AFP357 and AFP403) in an emulsion with incomplete Freund's adjuvant every other week for at least 6 weeks. Patients were evaluated every 8 weeks by radiologic imaging; adverse events and toxicities were categorized and graded using the common terminology criteria for adverse events. Criteria for discontinuation included unacceptable toxicities and disease progression defined as progressive disease using the Response Evaluation Criteria In Solid Tumors criteria. Patients' immune responses were monitored using an interferon-gamma enzyme-linked immunospot assay. Peptide-specific TCRs were assessed using a rapid TCR cloning and evaluation system. The observation period was 730 days. A complete response was defined as the disappearance of all tumors; stable disease was defined as tumors whose total diameter remained between >70% and <120% of the baseline measurement, without new lesions. RESULTS: We did not observe any serious adverse reactions to the peptides, which were well tolerated. Of the 15 patients who received at least 3 injections, 5 (33%) had an immune response to the peptides. One of the 15 patients had a complete response and disease stabilized in 8 patients. In 4 of the 15 patients, we detected AFP357-specific CD8 T cells; we cloned 14 different TCRs with different avidities for the peptide. A TCR with the highest avidity was observed in the patient who achieved a complete response for more than 2 years. CONCLUSIONS: In a phase 1 trial, administration of AFP-derived peptides to 15 patients with HCC did not cause adverse events and produced T cells with receptors that reacted to the peptides; 1 patient had a complete response and tumor growth slowed in 8 patients. T cells from the patient with a complete response expressed a highly functional TCR induced by the peptide vaccines. UMIN-CTR no: UMIN000003514.

Immune response to human telomerase reverse transcriptase-derived helper T cell epitopes in hepatocellular carcinoma patients.

BACKGROUND AND AIMS: Human telomerase reverse transcriptase is a catalytic enzyme involved in telomere elongation. It is expressed in many tumours, including hepatocellular carcinoma. The purpose of the present study was to identify major histocompatibility complex class II-restricted helper T cell epitopes derived from human telomerase reverse transcriptase in patients with hepatocellular carcinoma. METHODS: TEPITOPE software was used to predict helper T cell epitopes based on the entire amino acid sequence of human telomerase reverse transcriptase, and peptides were synthesized based on the predicted sequence. Interferon (IFN)-γ enzyme linked immunospot assay was performed to examine the T cell response to each of the synthesized peptides in peripheral blood mononuclear cells. Furthermore, the peptides were labelled with fluorescein isothiocyanate to test their binding affinity for major histocompatibility complex class II molecules. Lastly, the association between patient characteristics and the level of immune response to these epitopes was examined. RESULTS: Positive T cell response (>10% enzyme linked immunospot positivity) was detected against 4 of 10 peptides. Among all peptides, positive T cell response to the hTERT68 peptide was detected most frequently. While hTERT68 was HLA-DRB1*0405-restricted, it also bound to other MCH class II molecules. Positive helper T cell response was detected most frequently in hepatocellular carcinoma patients with a low serum alpha-foetoprotein level. Several treatments for hepatocellular carcinoma enhanced the immune response against the peptides. CONCLUSION: Our findings indicate that helper T cell epitopes identified in the present study may be useful to investigate immune responses and for immunotherapy in hepatocellular carcinoma patients.

Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma.

Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (<3.0 cm), absence of major portal vein invasion, absence of distant metastasis, Union Internationale Contre Le Cancer tumor lymph node metastasis stage (I or II), neutrophil lymphocytic ratio (<2.1) and the frequency of MDSCs (<30.5 %) as factors that prolonged overall survival time after HAIC. Even in the group adjusted with progressive levels of tumors, patients with a low frequency of MDSCs had a significantly longer overall survival time. In conclusion, the frequency of MDSCs before the treatment is a prognostic factor in HAIC against HCC.

Blood neutrophil to lymphocyte ratio as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy.

AIM: Inflammation plays a critical role in cancer. The aim of the present study was to investigate the impact of neutrophil to lymphocyte ratio (NLR) on patients with advanced hepatocellular carcinoma (HCC) treated with hepatic arterial infusion chemotherapy (HAIC). METHODS: We retrospectively evaluated 266 patients with advanced HCC treated with HAIC between March 2003 and December 2012. NLR was calculated from the differential leukocyte count by dividing the absolute neutrophil count by the absolute lymphocyte count. RESULTS: The cut-off level of NLR was set as the median value of 2.87 among all patients in this study. The objective response rate in the patients with low NLR was 37.6%, which was significantly better than that of the patients with high NLR (21.1%; P < 0.01). Multivariate analysis revealed that low NLR remained associated with the response to HAIC (P = 0.024). Median progression-free survival and median overall survival in patients with high NLR were 3.2 and 8.0 months, respectively, which were significantly shorter than that of the patients with low NLR (5.6 and 20.7 months; P < 0.01 and P < 0.01, respectively). High NLR was an independent unfavorable prognostic factor in multivariate analysis. The patient outcome was stratified more clearly by NLR calculated after HAIC added to calculations before HAIC. Serum platelet-derived growth factor-BB level was positively correlated with NLR. CONCLUSION: Results suggest that NLR is a useful predictor in patients with advanced HCC treated with HAIC. These findings may be useful in determining treatment strategies or in designing clinical chemotherapy trials in future.

In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation.

Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy.

Mouse IgA modulates human gut microbiota with inflammatory bowel disease patients.

BACKGROUND: The imbalance of commensal bacteria is called dysbiosis in intestinal microflora. Secreted IgA in the intestinal lumen plays an important role in the regulation of microbiota. Although dysbiosis of gut bacteria is reported in IBD patients, it remains unclear what makes dysbiosis of their microflora. The intervention method for remedy of dysbiosis in IBD patients is not well established. In this study, we focused on the quality of human endogenous IgA and investigated whether mouse monoclonal IgA which binds to selectively colitogenic bacteria can modulate human gut microbiota with IBD patients. METHODS: IgA-bound and -unbound bacteria were sorted by MACS and cell sorter. Sorted bacteria were analyzed by 16S rRNA sequencing to investigate what kinds of bacteria endogenous IgA or mouse IgA recognized in human gut microbiota. To evaluate the effect of mouse IgA, gnotobiotic mice with IBD patient microbiota were orally administrated with mouse IgA and analyzed gut microbiota. RESULTS: We show that human endogenous IgA has abnormal binding activity to gut bacteria in IBD patients. Mouse IgA can bind to human microbiota and bind to selectively colitogenic bacteria. The rW27, especially, has a growth inhibitory activity to human colitogenic bacteria. Furthermore, oral administration of mouse IgA reduced an inflammation biomarker, fecal lipocalin 2, in mice colonized with IBD patient-derived microbiota, and improved dysbiosis of IBD patient sample. CONCLUSION: Oral treatment of mouse IgA can treat gut dysbiosis in IBD patients by modulating gut microbiota.

Gastroduodenitis Associated with Active Ulcerative Colitis Treated with Infliximab: Different Clinical Course in the Colon and Gastroduodenal Lesions.

A 29-year-old man with severe ulcerative colitis and gastroduodenitis was initially treated with oral mesalamine and high-dose intravenous steroid therapy; however, his epigastralgia and vomiting did not improve. After initiating infliximab, the patient experienced prompt improvement in symptoms and inflammation. Although steroids were effective for the colon, they proved ineffective for gastroduodenal lesions, highlighting the necessity for molecular-targeted agents, such as infliximab, in these cases. The timing for administering such agents should be carefully considered.

Photodynamic therapy with talaporfin sodium for endoscopically unresectable gastric cancer using a novel simultaneous light-emitting method.

We describe a case of gastric cancer treated by photodynamic therapy (PDT) with talaporfin sodium using a novel simultaneous light-emitting method. An 82-year-old man was diagnosed with gastric cancer near the cardia with suspected deep submucosal invasion. Surgical resection was deemed high-risk owing to an underlying pulmonary disease. After ruling out endoscopic procedures due to intense fibrosis resulting from the scarring, PDT with talaporfin sodium was chosen. PDT was successfully conducted using an endoscope with simultaneous light emission. The patient experienced a complete response to the treatment and showed no signs of recurrence during follow-up. This case highlights the potential of PDT with talaporfin sodium as a viable alternative for challenging cases, particularly in patients unsuitable for surgery and endoscopic resection. Furthermore, the novel simultaneous light-emitting method may improve the efficiency of the procedure. This case demonstrates the potential of PDT in gastric cancer treatment, especially for high-risk patients.

Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy.

Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.

Necessity of pharyngeal anesthesia during transoral gastrointestinal endoscopy: a randomized clinical trial.

BACKGROUND/AIMS: The necessity for pharyngeal anesthesia during upper gastrointestinal endoscopy is controversial. This study aimed to compare the observation ability with and without pharyngeal anesthesia under midazolam sedation. METHODS: This prospective, single-blinded, randomized study included 500 patients who underwent transoral upper gastrointestinal endoscopy under intravenous midazolam sedation. Patients were randomly allocated to pharyngeal anesthesia: PA+ or PA- groups (250 patients/group). The endoscopists obtained 10 images of the oropharynx and hypopharynx. The primary outcome was the non-inferiority of the PA- group in terms of the pharyngeal observation success rate. RESULTS: The pharyngeal observation success rates in the pharyngeal anesthesia with and without (PA+ and PA-) groups were 84.0% and 72.0%, respectively. The PA- group was inferior (p=0.707, non-inferiority) to the PA+ group in terms of observable parts (8.33 vs. 8.86, p=0.006), time (67.2 vs. 58.2 seconds, p=0.001), and pain (1.21±2.37 vs. 0.68±1.78, p=0.004, 0-10 point visual analog scale). Suitable quality images of the posterior wall of the oropharynx, vocal fold, and pyriform sinus were inferior in the PA- group. Subgroup analysis showed a higher sedation level (Ramsay score ≥5) with almost no differences in the pharyngeal observation success rate between the groups. CONCLUSION: Non-pharyngeal anesthesia showed no non-inferiority in pharyngeal observation ability. Pharyngeal anesthesia may improve pharyngeal observation ability in the hypopharynx and reduce pain. However, deeper anesthesia may reduce this difference.