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Background Accurate evaluation of liver fibrosis in patients with chronic liver damage is required to determine the appropriate treatment. Various approaches, including laboratory tests and transient elastography, have been used to evaluate liver fibrosis. Recently, transient elastography with acoustic radiation force impulse (ARFI) has been developed and applied with conventional ultrasonography. The aim of this study was to evaluate the clinical utility of transient elastography with ARFI and to compare the results with this method and those of the Fibroscan ® procedure. Methods One hundred and thirty-one patients with liver damage, who underwent liver biopsy at our department, were enrolled prospectively in this study. Elastography with ARFI (applied with ACUSON S2000 ® ), and Fibroscan ® was performed at the same time as liver biopsy. These measurements were compared with histological findings in liver biopsy specimens, and measurement accuracy was evaluated by receiver-operating characteristic analysis. Results Elastography values with both procedures were significantly correlated with the stages of liver fibrosis and there was little difference in the results obtained using the 2 procedures. The accuracy of differential diagnosis between no fibrosis at F0 and more than F1 stage was insufficient with ARFI, but this procedure was sufficient for diagnosing advanced fibrosis. The accuracy of ARFI was almost equivalent to that of the Fibroscan ® method. Moreover, both ARFI and Fibroscan ® values increased in proportion to the severity of hepatic inflammation when fibrosis stage is low, but not in proportion to the severity of steatosis. Conclusions Transient elastography with ARFI is simple, non-invasive and useful for diagnosing the stage of fibrosis in chronic liver disease. The utility of ARFI was almost equivalent to that of the Fibroscan ® method.

Background Biliary atresia commonly leads to liver fibrosis and cirrhotic complications, including esophageal varices. Objective To evaluate liver and spleen stiffness measurements using acoustic radiation force impulse (ARFI) imaging for diagnosing grade of liver fibrosis and predicting the presence of esophageal varices in patients treated for biliary atresia. Materials and methods ARFI imaging of the spleen and native liver was performed in 28 patients with biliary atresia. We studied the relation between ARFI imaging values and liver histology findings ( n =22), upper gastrointestinal endoscopy findings ( n =16) and several noninvasive test results. Diagnostic accuracy was assessed using receiver operating characteristic curve analyses. Results Liver stiffness measurements exhibited a significant difference among the different grades of liver fibrosis ( P =0.009), and showed higher values in patients with high-risk esophageal varices than in the other patients ( P =0.04). The areas under the receiver operating characteristic curves of liver stiffness measurements for liver fibrosis grades  ≥ F2, ≥F3 and = F4 were 0.83, 0.93 and 0.94, respectively. Patients with high-risk esophageal varices were preferentially diagnosed by the combined liver and spleen stiffness measurements (area under the curve, 0.92). Conclusion Liver and spleen stiffness measurements using ARFI imaging are potential noninvasive markers for liver fibrosis and esophageal varices in patients treated for biliary atresia.

Background Living donor liver transplantation in children often results in venous complications, leading to portal hypertension. Spleen stiffness measurements have been recently proposed as a new, noninvasive parameter for portal hypertension in cirrhotic patients. Objective To evaluate the diagnostic value of spleen stiffness measurements by acoustic radiation force impulse (ARFI) imaging in diagnosing venous complications after pediatric living donor liver transplantation. Materials and methods We prospectively enrolled 69 patients after pediatric living donor liver transplantation using a left-side liver allograft. Around the time of the protocol liver biopsy examination, spleen stiffness measurements by ARFI imaging were performed via the left intercostal space at the center of the spleen parenchyma and repeated five times. Imaging examinations around the time of the spleen stiffness measurements were retrospectively reviewed. Regarding venous complications, significant portal and hepatic venous stenosis was defined as >50% stenosis on multiphasic computed tomography. Results After post hoc exclusion, 62 patients were studied. Portal and hepatic venous stenosis was identified in three and two patients, respectively. The median spleen stiffness values were 2.70 and 4.00 m/s in patients without and with venous complications, respectively ( P  < 0.001). Spleen stiffness measurements showed good diagnostic power for venous complications, and the cutoff value was determined as 2.93 m/s, with 100% sensitivity and 78.9% specificity. Spleen stiffness measurements decreased with the relief of venous stenosis resulting from an interventional radiology procedure. Conclusion Spleen stiffness measurements by ARFI imaging might provide a useful quantitative index for venous complications after pediatric living donor liver transplantation.

Accurate evaluation of liver fibrosis in patients with chronic liver damage is required to determine the appropriate treatment. Various approaches, including laboratory tests and transient elastography, have been used to evaluate liver fibrosis. Recently, transient elastography with acoustic radiation force impulse (ARFI) has been developed and applied with conventional ultrasonography. The aim of this study was to evaluate the clinical utility of transient elastography with ARFI and to compare the results with this method and those of the Fibroscan^sup ®^ procedure. One hundred and thirty-one patients with liver damage, who underwent liver biopsy at our department, were enrolled prospectively in this study. Elastography with ARFI (applied with ACUSON S2000^sup ®^), and Fibroscan^sup ®^ was performed at the same time as liver biopsy. These measurements were compared with histological findings in liver biopsy specimens, and measurement accuracy was evaluated by receiver-operating characteristic analysis. Elastography values with both procedures were significantly correlated with the stages of liver fibrosis and there was little difference in the results obtained using the 2 procedures. The accuracy of differential diagnosis between no fibrosis at F0 and more than F1 stage was insufficient with ARFI, but this procedure was sufficient for diagnosing advanced fibrosis. The accuracy of ARFI was almost equivalent to that of the Fibroscan^sup ®^ method. Moreover, both ARFI and Fibroscan^sup ®^ values increased in proportion to the severity of hepatic inflammation when fibrosis stage is low, but not in proportion to the severity of steatosis. Transient elastography with ARFI is simple, non-invasive and useful for diagnosing the stage of fibrosis in chronic liver disease. The utility of ARFI was almost equivalent to that of the Fibroscan^sup ®^ method.[PUBLICATION ABSTRACT]

Background/Aim: There is an increasing use of immunotherapy for non-small cell lung cancer (NSCLC) patients. The present study analysed the effect of antibiotic use on the outcome of NSCLC patients undergoing treatment with anti-programmed cell death-1 (anti-PD-1) immunotherapy. Patients and Methods: This was a retrospective study of 69 NSCLC patients. Eighteen out of 69 patients received antibiotics within 21 days before or within 21 days after start of anti-PD-1 therapy. Results: Patients treated with anti-PD-1 antibodies receiving antibiotics had greatly decreased objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) compared to those who did not use antibiotics. Multivariate analysis showed that antibiotic treatment of patients on anti-PD-1 antibody therapy was an independent negative predictive factor of PFS; however, it was not a significant independent predictive factor of OS. Conclusion: Use of antibiotics within 21 days before and after anti-PD-1 treatment initiation in patients with NSCLC strongly reduced OS and PFS, suggesting the two treatments should not be combined.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Immune checkpoint inhibitors (ICIs) targeting PD-1 improve outcomes in advanced non-small cell lung cancer (NSCLC), but responses are heterogeneous and tissue biomarkers are imperfect. Circulating immunoglobulins integrate B- and T-cell function and may reflect systemic immune competence. We investigated whether plasma immunoglobulin levels during ICI therapy are associated with clinical outcomes in stage IV NSCLC. In this single-center retrospective study, 55 patients received anti-PD-1-based regimens: anti-PD-1 monotherapy ( n  = 31), chemotherapy plus anti-PD-1 ( n  = 18), or ipilimumab plus nivolumab ( n  = 6). Plasma IgG, IgA, and IgM were measured at baseline and after 1–4 cycles, and associations with objective response, progression-free survival (PFS), and overall survival (OS) were evaluated. In the chemotherapy plus anti-PD-1 group, IgG decreased significantly on treatment ( p  = 0.0030), whereas no significant changes in any isotype were observed with anti-PD-1 monotherapy. In the monotherapy cohort, post-treatment IgG was higher in responders than in non-responders ( p  = 0.0262) and was associated with longer PFS ( p  = 0.0218) and OS ( p  = 0.0166). In multivariable Cox models in the monotherapy cohort, higher post-treatment IgG remained independently associated with longer PFS (adjusted HR 0.28, 95% CI 0.11–0.75; p  = 0.011) and OS (adjusted HR 0.29, 95% CI 0.09–0.87; p  = 0.028). Sensitivity analyses incorporating PD-L1 status and 6-week landmark analyses showed similar trends. In exploratory pooled analyses, no significant association between post-treatment IgG and PFS or OS was observed across all 55 patients. IgA and IgM were not significantly associated with outcomes. Higher early on-treatment plasma IgG may serve as a non-invasive biomarker of favorable outcome, particularly in the anti-PD-1 monotherapy setting, warranting prospective validation and mechanistic studies.

Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown. We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs). The genera and were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of (P = 0.022) and (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of (P = 0.001) and (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of (P = 0.013) and the unclassified (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, and (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, (P = 0.021) and (P= 0.033) were statistically significantly more common in those without irAEs. Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.

Cancer immune therapy by immune checkpoint inhibitors (ICIs) is a promising therapeutic strategy for various cancer types. Among ICIs, anti-programmed cell death protein-1 (PD1) and anti-programmed death-ligand 1 (PD-L1) antibodies have shown a remarkable clinical benefit. The present study aimed to address the functional and clinical significance of serum levels of soluble PD-L1 (sPD-L1) in patients. A total of 21 patients, 11 with NSCLC, nine with gastric cancer and one with bladder cancer, who underwent anti-PD-1 therapy were evaluated for sPD-L1 concentration by ELISA analyses at diagnosis and after treatment. Pretreatment levels of sPD-L1 in patients who received ICIs were not remarkably correlated with the overall survival of these patients (r=0.3394, p=0.1323). Reduction of plasma sPD-L1 level was significantly correlated with tumor regression in patients administered four cycles of treatment (p<0.05). sPD-L1 might be derived and secreted from tumors and might be useful to identify primary responders to ICIs at a relatively early treatment timepoint.

Inosine, a bacterial metabolite and agonist of the adenosine A2A receptor, modulates antitumor immunity. However, its precise effects on immune checkpoint inhibitors remain unclear. This study aimed to evaluate the impact of inosine on the efficacy of anti-programmed cell death protein 1 (PD-1) therapy and explore strategies to counteract any potential inhibitory effects. In in vitro co-culture systems, inosine selectively suppressed cancer cell growth without impairing T-cell viability. In a murine subcutaneous tumor model, inosine treatment reduced tumor growth and was associated with elevated interferon-gamma levels in the tumor microenvironment, along with increased infiltration by tumor-infiltrating lymphocytes and enhanced splenic CD4⁺ and CD8⁺ T-cell frequencies. However, the combination of inosine with anti-PD-1 therapy attenuated the antitumor effect and increased cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in splenic T cells compared to levels after anti-PD-1 monotherapy. To overcome this inhibitory effect, we tested whether adding an anti-CTLA-4 antibody could restore antitumor immunity. Notably, the combination of inosine with both anti-PD-1 and anti-CTLA-4 antibodies significantly enhanced antitumor efficacy. These findings suggest that inosine may synergize with dual ICI therapy and represent a promising adjunct to improve immunotherapeutic outcomes.