BACKGROUND AND AIMS:Various viral mutations have been reported to influence disease pathogenesis in infectious diseases. However, these mutations may remain undetected due to patient population changes. Although many causes have been proposed, the exact reasons remain unclear. This study analyzed viral mutations linked to hepatocellular carcinoma (HCC) in patients with hepatitis B by comparing factors between condition-matched patient groups of different human leukocyte antigen (HLA) genotypes. METHODS:HLA genotypes of 2281 healthy individuals, 370 patients with hepatitis B virus (HBV)-derived HCC, and 408 patients with chronic hepatitis B were analyzed to identify HLA genotypes associated with HCC development. Patients with HCC were grouped by HLA-DPB1 genotype to identify HBV genomic variants linked to HCC. RESULTS:The HLA-DPB1*02:01, 04:01, and 04:02 alleles suppressed chronic hepatitis B (CHB) and HCC development (P = 4.53 × 10-9, 3.20 × 10-3, and 3.03 × 10-4, respectively). Conversely, HLA-DPB1*05:01 and 09:01 alleles were significantly associated with CHB and HCC development (P = 1.01 × 10-7, 6.51 × 10-8, respectively). Among HLA-DPB1*02:01 patients, the S166L amino acid (AA) mutation in the PreS/S region of the HBV genome was significantly identified. HLA-DPB1*05:01 homozygous patients significantly had K130M/V131I AA mutations in the X region of the HBV genome, whereas HLA-DPB1*05:01-09:01 heterozygous patients significantly had the H94Y AA mutation in the X region. Stratification by HLA genotype changed the mutation position and strengthened the odds ratios for developing HCC due to viral mutations. CONCLUSIONS:Our analysis revealed that viral mutations associated with HCC vary by HLA genotype. These findings suggest a host-pathogen genetic interaction. HLA genotype stratification may aid in advancing personalized genomic medicine, which has been challenging to apply to chronic diseases.

Galactose-deficient (agalactosyl) IgG is significantly increased in the serum of patients with rheumatoid arthritis, and autoantibodies against it are used in clinical tests. Subsequent studies also show increased agalactosyl IgG in many chronic inflammatory diseases. In this study, we generated antibody 42B1 recognizing agalactosyl IgG and developed a new method to evaluate chronic inflammatory diseases with it. Using an ELISA with antibody 42B1, we measured serum levels of agalactosyl IgG in 32 patients with inflammatory bowel disease (IBD), 60 patients with chronic liver disease, 60 patients with chronic pancreatitis, and 32 subjects undergoing health checkups who did not have IBD. Serum agalactosyl IgG levels were increased in all patients with chronic inflammations and partially correlated with clinical parameters. Among the subjects undergoing health checkups, some subjects showed a 15 % elevation of serum agalactosyl IgG levels, suggesting possible latent chronic inflammation. Future studies will examine the 42B1 antibody ELISA in various autoimmune diseases. Altogether, the 42B1 antibody for determination of serum agalactosyl IgG levels is a novel diagnostic tool for chronic inflammation.

Non-acquired immunodeficiency syndrome-defining malignancies (NADMs) are the crucial cause of mortality in people living with haemophilia and human immunodeficiency virus (PLWHH). We aimed to analyse the types and characters of NADMs in PLWHH after approval of direct-acting antivirals (DAA), considering that most PLWHH are infected with hepatitis C virus (HCV). We conducted a nationwide questionnaire mail survey across 395 HIV core facilities in Japan between May 2022 and February 2023. Eight-year data from 64 respondent hospitals ( n = 328 PLWHH; 2015-2022) were collected; 35 NADM cases were identified and analysed. Standardised cancer incidence ratios (SCIRs) were calculated. The median age of PLWHH with NADMs was 51 years (interquartile range: 47-62 years); the SCIR was 2.08 (95% confidence interval [CI]: 1.48-2.90) for all malignancies (including carcinoma in situ ). Liver cancer accounted for most NADMs (43% [15/35]). The SCIRs of liver cancer (23.09 [95% CI: 13.92- 38.30]) and papillary thyroid cancer (9.38 [2.35-37.50]) significantly increased after adjusting for general Japanese male sex and age. Among PLWHH with liver cancers, 73% (11/15) achieved HCV-sustained virological response. Notably, for patients aged <= 50 years, 47% (7/15) were affected by liver cancers, and 27% (4/15) succumbed to NADMs. This study presents the largest survey of NADMs in PLWHH after DAA approval. Our findings emphasised the elevated risk of malignancies in PLWHH, underscoring the need for early cancer screening and preventive measures, particularly against liver cancers, even in younger PLWHH.

AIM:Patients with chronic hepatitis B (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitis B virus (HBV) RNA, hepatitis B core-related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitis C. METHODS:We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1 year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15. RESULTS:Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86 ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB-4 index, alpha-fetoprotein and gamma-glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0 ng/mL, gamma-glutamyl transpeptidase ≥22 U/L, FIB-4 index ≥1.93, and GDF-15 ≥1.17 ng/mL groups. In patients with no or more than three of these five risk factors, the 10-year HCC cumulative incidence rates were 0% and 41.0%, respectively. CONCLUSIONS:High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs.

Video 1Three cases of underwater EMR for small gastric neoplasms in the reconstructed gastric conduit after esophagectomy.

<p>Supplementary Figures S1-S5</p>

60歳女性．肝細胞癌多発肺転移に対してアテゾリズマブ・ベバシズマブ併用療法を開始した14日後から四肢末梢の感覚障害と四肢の筋力低下が出現した．脳脊髄液検査では蛋白および細胞数の上昇を認め，血清中のGalNAc-GD1a IgG抗体とGal-C IgG抗体が陽性であった．神経伝導速度検査で脱髄型末梢神経障害を認め，アテゾリズマブ関連の薬物性ギラン・バレー症候群と診断した．大量免疫グロブリン療法にて筋力低下は軽快した．今回，肝細胞癌に対して使用した免疫チェックポイント阻害薬として免疫関連副作用でギラン・バレー症候群を呈し，早期治療介入により症状改善を得た症例を経験したため報告する．

Objectives Real-world evidence on the safety and effectiveness of direct-acting antivirals in patients infected with chronic hepatitis C virus (HCV) genotypes (GTs) 3, 4, 5, or 6 in Japan is limited. This prospective observational study assesses the real-world safety profile and treatment effectiveness among patients prescribed sofosbuvir with ribavirin (SOF+RBV) for HCV GT3-6 infection in Japan. Methods Adults receiving 24-week SOF+RBV treatment for HCV GT3-6 infection were prospectively enrolled and observed through 24 weeks post-treatment for treatment-emergent adverse events (AEs) considered related to SOF and/or RBV by treating physicians and for a sustained virologic response at 12 and 24 weeks post-treatment (SVR12, SVR24). Incidence rates of related AEs and serious AEs (SAEs) were calculated. Proportions of patients experiencing related AEs/SAEs and those achieving SVR12 and SVR24 were assessed overall and by baseline characteristics, including treatment experience and cirrhosis status. Results Among the 50 patients included in the safety analysis, 92% had GT3 infection. The incidence rates of related AEs and SAEs were low overall (1.52 and 0.25 per 100 person-weeks, respectively), with 6.0% and 14.0% patients experiencing AEs related to SOF or RBV, respectively. There were no marked differences in the occurrence of related AEs/SAEs by patient baseline characteristics. SVR12 and SVR24 were achieved in 83.7% (41/49) and 82.2% (37/45) of patients, respectively. Lower effectiveness was observed among treatment-experienced patients and patients with cirrhosis at baseline. Conclusion This study demonstrated that SOF+RBV treatment for HCV GT3-6 infection was safe, effective, and an important treatment option for this difficult-to-treat patient population in Japan.

Early Gastric Cancer Arising From Hyperplastic Polyps After Argon Plasma Coagulation for Gastric Vascular Ectasia Satoshi Harada, MD, Yuko Sakakibara, MD, Hisashi Ishida, MD, PhD, Kiyoshi Mori, MD, PhD, and Eiji Mita, MD, PhD Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan Department of Pathology, National Hospital Organization Osaka National Hospital, Osaka, Japan

In recent years, with the rising incidence of patients having long-term Crohn's disease, there has been an increase in the number of reports of carcinogenesis from dysplasia with chronic inflammation as the primary pathogenic factor. We hereby report a case of multiple metastases that appeared 5 years after surgery, in a patient with rectal cancer who had Crohn's disease. A man in his 50s was diagnosed with Crohn's disease which affected his small and large intestines 21 years back. The patient was being treated with oral steroids, 5-aminosalicylic acid, and modified nutrition. Infliximab was added to the treatment after it was introduced 11 years ago. He also had a history of rectal cancer and had undergone surgery for the same 5 years back. He was diagnosed with stage II cancer, and had not received any adjuvant chemotherapy. However, 5 years after surgery, multiple metastases recurred, and chemotherapy with mFOLFOX6 was administered. Additionally, for treating his Crohn's disease, which was also active, infliximab was changed to vedolizumab;however, the patient died a year later. Colorectal cancer accompanied with Crohn's disease has a higher risk of developing metastasis and is associated with poorer prognosis as compared to the noncomplicated colorectal cancer. Regarding treatment modalities, while searching for multidisciplinary treatment methods centered on surgical treatment in collaboration with medical oncologists and radiologists, the safety of treatment for Crohn's disease in patients with cancer must be borne in mind. The rising prevalence of cases of colorectal cancer with Crohn's disease is expected to lead to the formulation of specialized diagnostic and treatment strategies for these patients.

Yamamoto, Shunsuke MD, PhD, FJGES; Matsushima, Kensuke MD; Sakakibara, Yuko MD; Sakamori, Ryotaro MD, PhD; Mita, Eiji MD, PhD Author Information

When removing large flat colonic polyps (LFCPs) en bloc endoscopic submucosal dissection (ESD) may be suitable; however, it requires significant expertise and a long procedural time. The use of a conventional monopolar snare for endoscopic mucosal resection (EMR) of large lesions increases the risk of deep mural injury [1]. Bipolar snares are safer than monopolar snares because the current passes only through the tissue between the two electrodes, so causing minimal damage to the muscle layer [2]. The Dragonare dedicated bipolar soft snare (Zeon Medical Inc., Japan) has a unique mechanism where one electrode is at the tip of the snare and the other at the sheath, which allows uniform cauterization of the tissue. The soft nature of the snare allows stabilization of its tip at the distal margin of the lesion while opening the snare, thereby enabling en bloc resection of LFCPs. This requires a slower cutting technique compared with monopolar devices. Herein, we report two cases in which EMR was performed using the bipolar soft snare (26mm) for LFCPs (▶Video 1). The first patient was a 78-year-old man who had a 25-mm nongranular laterally spreading tumor (LST) found in his descending colon (▶Fig. 1). Although submucosal invasion was suspected, the patient wanted to undergo endoscopic treatment. Underwater bipolar EMR (BEMR) was performed and the lesion was completely removed, without the occurrence of any adverse events (▶Fig. 2). Pathological examination confirmed the lesion was a submucosal invasive adenocarcinoma (▶Fig. 3); however, the patient chose not to undergo an additional surgical resection. The second patient was an 86-year-old man who had a 30-mm granular-type LST found in his ascending colon (▶Fig. 4 a). Injection-based BEMR was performed, and the lesion was completely removed, without the occurrence of any adverse events (▶Fig. 4 b). Pathological examination revealed a focally high grade tubulovillous adenoma. BEMR with dedicated snares could be a new alternative when treating LFCPs. ESD can be replaced with BEMR for eligible polyps.

<p>Supplementary materials and supplementary figure legends 1-5.</p>

The incidence of colorectal and small bowel cancers associated with CD development is often accompanied by chronic active inflammation at the site. Although the duodenum can be accessed easily during endoscopy, it is challenging to diagnose malignant transformation prior to the surgery. Early diagnosis of CD-associated cancers is necessary.

Liver function can be improved in patients with chronic hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) treatment. However, to our knowledge, the impact of liver function improvement after SVR on prognosis has not been investigated. A total of 716 patients with chronic HCV infection and compensated advanced liver fibrosis who began receiving DAA treatment between September 2014 and August 2018 in 25 Japanese hospitals and achieved SVR were enrolled. The median age was 73 years, and 336 (47

40歳男性．心窩部痛で受診．腹部単純CTで門脈内血栓が疑われ，肝ダイナミックCTを撮像すると，肝内門脈から門脈本幹，上腸間膜静脈にかけて血栓像を認めた．乾燥濃縮人アンチトロンビンIII製剤を投与し，血栓は縮小した．その後ワルファリンカリウム投与により，血栓は増大なく経過している．血栓の原因精査として，血液検査，画像検査上は肝硬変を示唆する所見を認めず，肝生検病理所見上は，線維化は軽度で特発性門脈圧亢進症を示唆する所見も認めなかった．血栓性素因の検索を行い，血中プロテインC活性の低下を認めた．後日PROC遺伝子変異の解析を行ったところ，stop gain variant（p.Trp2*）をヘテロ接合体で認め，先天性プロテインC欠乏症と診断した．非肝硬変・非腫瘍性の門脈血栓症を認めた場合は，肝疾患の検索とともに血栓性素因を検索することが重要である．

Intrahepatic hepatocellular carcinoma (HCC) has a high recurrence rate after radiofrequency ablation (RFA). However, to date, no standalone predictive factors for intrahepatic distant recurrence after curative ablation have been reported. The aim of this study was to investigate predictive factors for intrahepatic distant recurrence after curative treatment with RFA for HCCs. This multicenter study consisted of 17 institutions that registered 821 patients. The risk factors for intrahepatic distant recurrence after complete ablation by RFA for primary HCC ≤ 2 cm in diameter were identified in a retrospectively collected training set (n = 636) and then validated in a prospectively collected validation set (n = 185). The cumulative intrahepatic distant and local recurrence rates (i.e., entire recurrence rate) in the training set were 23.6

Extracellular vesicles (EVs) contain proteins, mRNAs, and microRNAs, and their cargos have emerged as novel diagnostic markers in various diseases. We aimed to discover novel and noninvasive biomarkers of liver fibrosis by proteomic analysis using serum EVs in patients with chronic hepatitis C. We performed shotgun proteomics using serum EVs isolated from 54 patients with histologically assessed liver fibrosis. Shotgun proteomics identified a total of 974 proteins, and 445 proteins were detected in more than half of the patients. Among them, a total of 9 proteins were identified as proteins that tended to increase or decrease with liver fibrosis with a significance of p<0.005 and that were different between F1-2 patients and F3-4 patients with a significance of p<0.01. Among the 9 proteins, targeted proteomics using serum EVs isolated from the sera of another 80 patients with histologically assessed liver fibrosis verified that serum amyloid P component (SAP) and pro-platelet basic protein (PPBP) levels in EVs significantly decreased with the progression of liver fibrosis and were significantly lower in F3-4 patients than in F1-2 patients. The diagnostic accuracies of SAP and PPBP in EVs for the liver fibrosis stage were comparable to those of type IV collagen 7S, hyaluronic acid, and the fibrosis-4 index (FIB-4 index). Moreover, serum SAP and PPBP levels correlated with the levels in EVs, and the ability of serum SAP and PPBP to diagnose liver fibrosis stage was also comparable to the abilities of type IV collagen 7S, hyaluronic acid, and the FIB-4 index. In conclusion, proteomic analysis of serum EVs identified SAP and PPBP as candidate biomarkers for predicting liver fibrosis in patients with chronic hepatitis C. In addition, SAP and PPBP levels in serum are strongly correlated with those in EVs and could represent markers of liver fibrosis.

Transileocolic obliteration (TIO) is a useful treatment for gastric, duodenal, or rectal varices. However, TIO for esophageal varices has not yet been reported. We herein report successful TIO performed for refractory esophageal varices with a large paraesophageal vein, with no subsequent recurrence of varices.