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This report extends our previous study on experimental autoimmune hepatitis in C57BL/6 (B6) mice. Cellular immunity involved in the induction of liver injury in this model was studied by transfer of primed spleen cells from hepatitis donor mice to syngeneic normal recipient mice. The most prominent liver damage in recipient B6 mice was induced by transfer of nylon wool adherent spleen cells from hepatitis donor mice, and T cells in this fraction were the essential requirement for the liver damage in the recipient mice. Nylon wool adherent spleen cells from hepatitis donor mice after depletion of the suppressor T-cell function by low-dose (300 rad) irradiation induced more severe liver injury compared to the same cells without irradiation. When the recipient mice were depleted of lymphocytes by low or high dose (700 rad) whole body irradiation, transfer of primed spleen cells from hepatitis donor mice did not induce liver lesion in the lymphocyte-depleted mice. This low susceptibility of lymphocyte-depleted recipient mice to primed spleen cells of hepatitis mice was no longer demonstrated after reconstitution with normal spleen cells. In a cell-migration study using 51Cr-labelled spleen cells, it was shown that a considerable number of infiltrating cells in the liver of recipient mice were derived from recipient mice themselves. These results seem to indicate that cell-to-cell interaction between radiosensitive precursor cells of recipient mice and liver-antigen-primed T cells from hepatitis donor mice play an essential role in the induction of liver injury in the recipient mice. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the safety and efficacy of lenvatinib in real-world settings, including patients excluded from the REFLECT trial, a phase III trial that compared lenvatinib with sorafenib., Patients and Methods: This multicenter, nonrandomized, open-label prospective study was conducted at 10 medical facilities in Japan (jRCTs031190017). Eligible patients had advanced hepatocellular carcinoma (HCC) and were suitable for lenvatinib therapy. The study included patients with high tumor burden (with >50% intrahepatic tumor volume, main portal vein invasion, or bile duct invasion), Child-Pugh B status, and receiving lenvatinib as second-line therapy following atezolizumab plus bevacizumab., Results: From December 2019 to September 2021, 59 patients were analyzed (47 and 12 patients with Child-Pugh A and B, respectively). In patients with Child-Pugh A, the frequency of aspartate aminotransferase elevation was high (72.7%) in the high-burden group. No other significant ad verse events (AE) were observed even in second-line treatment. However, patients with Child-Pugh B had high incidence of grade ≥3 AE (100.0%) and high discontinuation rates caused by AE (33.3%) compared with patients with Child-Pugh A (80.9% and 17.0%, respectively). Median progression-free survival was 6.4 and 2.5 months and median overall survival was 19.7 and 4.1 months in Child-Pugh A and B, respectively. Lenvatinib plasma concentration was higher in patients with Child-Pugh B on days 8 and 15 and correlated with dose modifications and lower relative dose intensity., Conclusions: Lenvatinib is safe and effective for advanced HCC in patients with Child-Pugh A, even with high tumor burden. However, it carries a higher risk of AE and may not provide adequate efficacy for patients with Child-Pugh B status., (©2023 American Association for Cancer Research.)

Many molecular targeted agents, including biologics, have emerged for inflammatory bowel diseases (IBD), but their high prices have prevented their widespread use. This study aimed to reveal the changes in patient characteristics and the therapeutic strategies of IBD before and after the implementation of biologics in Japan, where the unique health insurance system allows patients with IBD and physicians to select drugs with minimum patient expenses. The analysis was performed using a prospective cohort, including IBD expert and nonexpert hospitals in Japan. In this study, patients were classified into two groups according to the year of diagnosis based on infliximab implementation as the prebiologic and biologic era groups. The characteristics of therapeutic strategies in both groups were evaluated using association analysis. This study analyzed 542 ulcerative colitis (UC) and 186 Crohn's disease (CD). The biologic era included 53.3% of patients with UC and 76.2% with CD, respectively. The age of UC (33.9 years vs. 38.8 years, P < 0.001) or CD diagnosis (24.3 years vs. 31.9 years, P < 0.001) was significantly higher in the biologic era group. The association analysis of patients with multiple drug usage histories revealed that patients in the prebiologic era group selected anti-tumor necrosis factor (TNF)-α agents, whereas those in the biologic era group preferred biologic agents with different mechanisms other than anti-TNF-α. In conclusion, this study demonstrated that both patient characteristics and treatment preferences in IBD have changed before and after biologic implementation., (© 2023. Springer Nature Limited.)

Background: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics., Methods: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGK R ) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed., Results: A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGK R , 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGK R . No significant difference was observed in the baseline characteristics between HPD and non-HPD., Conclusion: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated., (© 2023. The Author(s).)

Purpose: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies., Methods: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events., Results: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3)., Conclusion: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial., (© 2023. The Author(s).)

Serum autoantibodies respond not only to tumor-associated antigens of hepatocellular carcinoma (HCC) but also to those of liver cirrhosis (LC) and chronic hepatitis (CH). The present prospective multi-institutional study evaluated the diagnostic properties of six autoantibodies in distinguishing HCC from LC and CH. A total of 416 participants were enrolled: 149 With HCC, 76 with LC, 103 with CH and 88 healthy controls. Titers of serum autoantibodies to Sui1, RalA, p62, p53, c-myc and NY-ESO-1 were determined using enzyme-linked immunosorbent assays. All six antibodies were positive for HCC: s-Sui1-Abs (44%), s-RalA-Abs (23%), s-p62-Abs (21%), s-p53-Abs (13%), s-c-myc-Abs (11%) and s-NY-ESO-1-Abs (6%). The positivity rates of all six antibodies combined were 5% for healthy controls, 52% for CH, 58% for LC and 66% for HCC. The positivity rates of s-Sui1-Abs, s-RalA-Abs and s-p53-Abs were higher for HCC compared with those of LC and CH. However, the positivity rates of s-p62-Abs, s-c-myc-Abs and s-NY-ESO-1-Abs for HCC were not higher compared with those for LC and CH. Overall, autoantibodies were useful in differentiating patients with HCC from healthy individuals. However, they were not specific to HCC and were also present in the sera of individuals with CH and LC. These autoantibodies may be induced during the development of HCC. Clinical trial registration number: UMIN000014530 (date of registration 2011/07/11)., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Okada et al.)

Background: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy., Methods: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions., Results: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively., Conclusion: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib., Competing Interests: Sadahisa Ogasawara received grant support from Eisai, Bayer, and Eli Lilly, advisory fees from Eisai, Bayer, MSD, AstraZeneca, and Eli Lilly, and honoraria from Eisai, Bayer, MSD, AstraZeneca, and Eli Lilly. Yoshihiko Ooka received honoraria from Eisai. Naoya Kato received grant support from Eisai, Bayer, Takeda, and Eli Lilly, advisory fees from Eisai, Bayer, and Eli Lilly, and honoraria from Eisai, Bayer, and Eli Lilly. The other authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial., Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan., Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7-6.9 for first line, 4.8 months; 95% CI 3.8-5.9 for second or later line, p = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin - bilirubin scores., Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients., Competing Interests: S.O. and N.K.: received grant support, advisory fee and honoraria from Eisai. Y.O. received honoraria from Eisai. The other authors who took part in this study indicated that they did not have anything to declare regarding funding or conflict of interest with respect to this study., (Copyright © 2020 by S. Karger AG, Basel.)

Rectal neuroendocrine tumor (RNET) lymphovascular invasion (LVI) is regarded as an important predictor of nodal metastasis after endoscopic resection (ER). However, little is known about the frequency of immunohistochemical detection of LVI in RNETs. This study was performed to establish the actual detection of LVI rate in RNETs ≤10 mm and to evaluate associated clinical outcomes. We retrospectively reviewed the records for 98 consecutive patients treated by ER with a total of 102 RNETs ≤10 mm. Tissue sections were labeled with hematoxylin-eosin (HE) stain, the D2-40 monoclonal antibody to evaluate lymphatic invasion, and Elastica van Gieson (EVG) stain to detect venous invasion. LVI detection rate by HE versus immunohistochemical analysis was compared. Follow-up findings and clinical outcomes were also evaluated for 91 patients who were followed for ≥12 months. Lymphatic and venous invasion were detected using HE staining alone in 6.9% and 3.9% of patients, respectively, whereas they were detected using D2-40 and EVG staining in 20.6% and 47.1% of the patients, respectively. Thus, the LVI detection frequency using D2-40 and EVG staining (56.9%) was significantly higher than with HE (8.8%). Two out of seven patients who required additional surgery had regional lymph node metastases. However, among the 84 patients who were followed up without surgery, no distant metastases or recurrences were detected. Compared with HE staining, immunohistochemical analysis significantly increased the frequency of LVI detection in RNETs ≤10 mm. However, the clinical impact of LVIs detected using immunohistochemical analysis remains unclear. Clarification of the actual role of LVI using immunohistochemical analysis requires a patient long-term follow-up and outcomes., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Intermediate-stage hepatocellular carcinoma (HCC), defined according to the Barcelona Clinic Liver Cancer (BCLC) staging system, is a heterogeneous condition with variable clinical benefits from transarterial chemoembolization (TACE). This study aimed to develop a simple validated prognostic score based on the predictive factors for survival in patients with intermediate-stage HCC treated with TACE., Methods: Three-hundred and fifty patients with intermediate-stage HCC undergoing initial TACE at Chiba University Hospital (training cohort; n = 187) and two affiliated hospitals (validation cohort; n = 163) were included. Following variables were entered into univariate and multivariate Cox regression models to develop a points-based clinical scoring system: gender, age, etiology, pretreatment, Child-Pugh score, aspartate aminotransferase, creatinine, C-reactive protein, alfa-fetoprotein, size of the largest lesion, and number and location of lesions., Results: The number of lesions and the Child-Pugh score were identified as independent prognostic factors in the training cohort. The development of a 0-7-point prognostic score, named the Chiba HCC in intermediate-stage prognostic (CHIP) score, was based on the sum of three subscale scores (Child-Pugh score = 0, 1, 2, or 3, respectively, number of lesions = 0, 2, or 3, respectively, HCV-RNA positivity = 0 or 1, respectively). The generated scores were then differentiated into five groups (0-2 points, 3 points, 4 points, 5 points, and 6-7 points) by the median survival time (65.2, 29.2, 24.3, 13.1, and 8.4 months, respectively; p < 0.0001). These results were confirmed in the external validation cohort (p < 0.0001)., Conclusions: The CHIP score is easy-to-use and may assist in finding an appropriate treatment strategy for intermediate-stage HCC.

Catheter ablation is a widely used treatment for atrial fibrillation. Gastric hypomotility due to periesophageal vagal plexus injury is a consequence of the extracardiac penetration of ablative energy. Some affected patients develop severe gastric dilatation requiring hospitalization. However, most previous reports have stated the cause of the subject's condition to be "unknown" or described the symptoms using obscure terms, such as "paralytic" or "gastroparesis." For example, one report stated that a few sites of severe gastric dilatation were secondary to "pyloric spasms;" however, no illustrations were provided in the paper. "Superior mesenteric artery syndrome" is a suspected cause of such dilatation.

Aim: To evaluate the therapeutic efficacy of transcatheter arterial chemoembolization (TACE) using miriplatin emulsion in unresectable hepatocellular carcinoma (HCC)., Patients and Methods: The efficacy of TACE was evaluated by dynamic computed tomography or magnetic resonance imaging three months after TACE, according to the Response Evaluation Criteria in Cancer Study Group of Japan (RECICL). Adverse events were assessed using Common Terminology Criteria, version 4.0., Results: Eighteen patients with 48 lesions received TACE with miriplatin-lipiodol (LPD) suspension (miriplatin suspension) and 53 patients with 114 HCC tumors received TACE with miriplatin-LPD water-soluble contrast agent emulsion (miriplatin emulsion). TACE with miriplatin emulsion enabled for administration of a higher dose of miriplatin compared to TACE with miriplatin suspension (p=0.016), although there were no significant differences in the frequency of adverse events between the two groups. The treatment effect per tumor was significantly higher in the emulsion group than in the suspension group (p=0.001). The time-to-progression per tumor was significantly shorter in the suspension group than in the emulsion group (p=0.001)., Conclusion: TACE with miriplatin emulsion is more effective than that with miriplatin suspension.

Purpose: Sorafenib provides a survival benefit for patients with advanced hepatocellular carcinoma (HCC). However, there has been little experience with it in Japan. This study evaluated the safety and tolerance of sorafenib in Japanese patients with HCC., Methods: Clinical data for patients given sorafenib for advanced HCC were captured from eight institutions. All patients were classified as Child-Pugh A and the treatment was started at 400 mg twice daily. We recorded adverse events, treatment duration, and survival retrospectively. Adverse events were graded using Common Terminology Criteria, version 3.0; tumor response was assessed according to Response Evaluation Criteria in Solid Tumor, version 1.1., Results: Of the 54 patients treated, their median age was 69 years (range 48-82), 91% were males, 52% had HCV infection, and 22% had HBV infection. The most common drug-related adverse events were hand-foot skin reactions (HFSR) (72%), aspartate transaminase elevation (55%), alanine aminotransferase elevation (52%), rash (50%), fatigue (41%), and diarrhea (32%). Liver failure occurred in 19%. The median time to treatment failure was 2 months. Dose reduction was required in 83% of the patients, and this occurred within 2 weeks in 44%. The median overall survival was 6.9 months., Conclusions: These data suggest that sorafenib is generally tolerated in Japanese patients with HCC. Nevertheless, the majority needed a dose reduction. Adverse events including HFSR, rash, and liver failure occurred more frequently in our patients than those reported elsewhere. Careful attention must be paid to these adverse events during sorafenib administration.

Immunopathogenicity of trypsin-solubilized or non-solubilized renal tubular basement membrane (TBM) of the Lewis (LEW) rat was investigated. Autoimmune tubulointerstitial nephritis (TIN) was induced in BALB/c mice by immunization with trypsin-solubilized LEW rat TBM, while immunization with non-solubilized TBM did not produce the disease. Based on this preliminary experiment we studied the characterization of immunogenic and nephritogenic TBM antigen of the LEW rat. TIN was characterized by severe mononuclear cell infiltrates with multi-nucleated giant cells in the interstitium, tubular destruction and intensive IgG and C3 deposits along the TBM. Anti-TBM antisera and eluate from the nephritic mouse kidneys reacted with the TBM of normal LEW rat kidney by immunofluorescence. LEW rat TBM was also detected immunofluorescently by using antisera from BALB/c mice immunized with autologous trypsin-solubilized TBM. A competitive inhibition test revealed a higher titer of anti-TBM antibody in the eluate than in the adsorption-treated antisera per microgram IgG. Immunoblotting showed one reactive band with a molecular weight of 45,000 daltons, and the blotting patterns in tryptic TBM of the Brown Norway (BN) and LEW rats appeared similar. Amino acid analysis of nephritogenic LEW rat tryptic TBM showed that it contained no hydroxyproline and hydroxylysine, suggesting that this TBM preparation was not collagenous. These findings suggest that tryptic digestion contributes to the release of nephritogenic antigen from the LEW rat TBM and that this antigen system might participate in the immune system involved in the anti-TBM associated TIN that is well known to be induced by non-digested TBM of TBM antigen positive animals.

Purified murine tubular basement membrane (TBM) antigen (molecular weight, 32,000) induced interstitial lesions in Brown Norway (BN) rats. TBM antigen prepared from mice of 3 inbred strains--BALB/c, C3H/He, and C57BL/6--and outbred ddY mice possessed both antigenicity and nephritogenecity. Using these TBM antigens, the roles of humoral and cellular immunity in the development of interstitial nephritis (IN) and the genetic control of the induction of IN in inbred mice were investigated. BALB/c mice were highly susceptible to IN and showed a high antibody response and a high lymphocyte proliferative response to syngeneic and allogeneic TBM antigen, whereas C57BL/6 mice did not. C3H/He mice, in which minimal interstitial lesions developed, showed a high antibody response but a low proliferative response of T cells to TBM antigen. TBM antigen sensitized T cells induced interstitial lesions, but anti-TBM antisera did not do so. Thus, the development of IN seemed to be related closely to cellular immunity. Further studies with their hybrids, backcrosses, congenic mice, and recombinant mice suggested that the induction of IN and the immune response to TBM antigen are controlled by 1 or a few dominant genes, whose loci are within, or closely linked to, the H-2 complex.