Trends of Early Helicobacter pylori-Uninfected Gastric Cancer in an Aging Regional Area.

Background/Objectives: We aimed to determine the trends over time and current status of early Helicobacter pylori-uninfected gastric cancer (HpUIGC) treatment in a region with an aging population. Methods: This retrospective, multi-center observational study was conducted at seven major general hospitals in Kagoshima Prefecture. From January 2009 to July 2022, 2091 patients who received endoscopic resection (ER) for early gastric cancer (EGC) were retrospectively enrolled, of which 35 were identified as early HpUIGC cases. Results: The number of ERs for EGC demonstrated a significant increasing trend from 2010 to 2021 (p = 0.01 for trend). Furthermore, the 12-year period from 2010 to 2021 was divided into an early and late phase every 6 years. In the early phase, there were 5 cases (0.7%) of early HpUIGC, while in the late phase, there were 25 cases (2.1%), indicating a significant increase in the proportion of ERs for early HpUIGC cases in the late phase (p = 0.02). Conclusions: The proportion of ERs for early HpUIGC, which are more common in relatively young patients, may be increasing as a proportion of all ERs for GC, even in areas of Japan with an aging population.

Case Report: The leopard sign as a potential characteristic of chronic granulomatous disease-associated colitis, unrelated to colitis severity.

Background: Chronic granulomatous disease (CGD) is an inborn immune disorder in which the phagocytic system cannot eradicate pathogens, and autoinflammation occurs. Approximately half of the patients have associated gastrointestinal symptoms. Although most cases with CGD-associated colitis present nonspecific histology, colonoscopy in some cases shows brownish dots over a yellowish oedematous mucosa, which is termed a "leopard sign". However, the significance of these signs remains unclear. Methods: We collected data from patients with CGD whose colonoscopic findings showed the leopard sign. Results: Three patients with CGD and leopard signs were enrolled in this study. One patient underwent colonoscopy for frequent diarrhoea and weight gain failure, and another for anal fistula. The third patient was without gastrointestinal symptoms and underwent colonoscopy as a screening test before allogeneic haematopoietic cell transplantation (HCT). Endoscopic findings showed a mild leopard sign in the first case; however, non-contiguous and diffuse aphthae were observed throughout the colon. The other two cases were unremarkable except for the leopard sign. All the patients achieved remission with oral prednisolone or HCT. One patient underwent colonoscopy after HCT; results revealed improvements in endoscopy (including the leopard sign) and histological findings. However, another patient underwent colonoscopy after prednisolone treatment; this revealed no change in the leopard sign. Conclusion: The leopard sign in the colon may be a characteristic endoscopic finding of CGD, even in patients who do not develop severe gastrointestinal symptoms; however, it does not reflect the severity of CGD-associated colitis.

Glycoprotein non-metastatic melanoma protein B expression correlates with the prognosis of acute liver injury/failure.

Background: Glycoprotein non-metastatic melanoma protein B (GPNMB) is expressed in macrophages during recovery from acute liver injury (ALI) in carbon tetrachloride (CCl4)-induced liver injury model mice. In this retrospective study, we assessed whether GPNMB levels in the serum and injured liver correlate with liver injury severity and prognosis in patients with ALI or acute liver failure (ALF). Methods: The study involved 56 patients with ALI or ALF who visited the Kagoshima University Hospital. Serum GPNMB level was measured over time, and the localization, proportion, origin, and phenotype of GPNMB-expressing cells in the injured liver were assessed. Finally, the phenotypes of human monocyte-derived macrophages and peripheral blood mononuclear cells (PBMCs) of patients with ALI and ALF were analyzed. Results: Peak GPNMB levels were significantly higher in patients with ALF and hepatic encephalopathy (HE), as well as in those who underwent liver transplantation or died, than in others. The peak GPNMB level correlated with prothrombin activity, prothrombin time-international normalized ratio, Model for End-stage Liver Disease score, and serum hepatocyte growth factor level. GPNMB was expressed in CD68-positive macrophages, and its level increased with the severity of liver injury. The macrophages showed the same polarization as M2c macrophages induced with interleukin-10 from human monocytes. Moreover, PBMCs from patients with ALF exhibited an immunosuppressive phenotype. Conclusion: We found that GPNMB levels in the serum and injured liver, which increased in patients with ALF, especially in those with HE, correlated with the severity of liver injury and prognosis of ALI and ALF. Moreover, GPNMB-positive macrophages exhibited the M2c phenotype. Our results indicate that persistently high GPNMB levels may be a prognostic marker in patients with ALI and ALF.

A successful case of an endoscopic submucosal dissection using a combination of the pocket-creation method and traction with a spring-and-loop with clip for early gastric cancer with severe ulcer scarring.

Video 1ESD for gastric cancer with severe scarring using PCM and S-O clip.

Usefulness of the aldehyde breath test for predicting metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharyngeal squamous cell carcinoma.

BACKGROUND: The rate of metachronous recurrence after endoscopic submucosal dissection for early-stage esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma is as high (10-15%). The acetaldehyde breath test may detect acetaldehyde dehydrogenase 2 gene polymorphisms. Therefore, we evaluated its usefulness in assessing metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. METHODS: A total of 76 patients underwent endoscopic submucosal dissection for esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma and were followed up for at least 3 years (non-recurrence group: 52 patients; recurrence group: 24 patients). The risk factors for carcinogenesis were compared between the recurrence and non-recurrence groups, and the acetaldehyde-to-ethanol ratio was assessed. The cutoff acetaldehyde-to-ethanol ratio that correlated with recurrence was established, and the cumulative recurrence rate was evaluated. RESULTS: The recurrence group had a higher acetaldehyde-to-ethanol ratio, daily alcohol consumption, and Lugol-voiding lesion grade than the non-recurrence group in the univariate analysis. The cutoff acetaldehyde-to-ethanol ratio for recurrence was 28.1 based on the receiver operating characteristic curve. The multivariate analysis revealed an acetaldehyde-to-ethanol ratio of > 28.1 and a Lugol-voiding lesion grade associated with carcinogenesis. Patients with an acetaldehyde-to-ethanol ratio of ≥ 28.1 had a significantly high recurrence rate using the Kaplan-Meier method. CONCLUSIONS: The acetaldehyde-to-ethanol ratio detected using the acetaldehyde breath test could be a novel biomarker of metachronous recurrence after endoscopic submucosal dissection in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. TRIAL REGISTRATION NUMBER: UMIN000040615.

Survey of Smokers Among Workers at One Facility: A Cross-sectional Study With Propensity Score Matching.

BACKGROUND/AIM: Smoking has been reported to be a risk factor for a variety of diseases. In Japan, the Brief Job Stress Questionnaire (BJSQ) has been administered by the Ministry of Health, Labour and Welfare since December 2015, but few reports have focused on its relationship with smoking. We investigated the current situation of smokers among staff of Kagoshima University who underwent a medical check-up. PATIENTS AND METHODS: Of 2,478 people who underwent a medical check-up in May and June 2021, we targeted 2,237 workers who reported whether they smoked. We examined results of the medical check-up and BJSQ and the background of smokers (n=139, 6.2%). We compared smokers and non-smokers (n=2,098) using propensity score matching (PSM) for sex, age, drinking habits, medication for dyslipidaemia, and overtime working hours at a 1:1 ratio. RESULTS: The results showed that white blood cell count (p=0.044), platelet count (p<0.001), glutamyl transferase (p=0.023), and triglyceride (p=0.027) were significantly higher among current smokers in comparison with current non-smokers. Smokers reported significantly more stress than non-smokers in terms of social support (p=0.027). CONCLUSION: As a result of PSM, several blood test items related to non-communicable diseases (lifestyle-related diseases) showed high values in current smokers, and these individuals reported significantly more stress than non-smokers. According to the emphasis on group analysis in the Total Health Promotion Plan revised in 2020, our findings can be helpful in enhancing smoking cessation programs in the workplace.

Next-Generation Sequencing Analysis of Pancreatic Cancer Using Residual Liquid Cytology Specimens from Endoscopic Ultrasound-Guided Fine-Needle Biopsy: A Prospective Comparative Study with Tissue Specimens.

This study evaluated the feasibility and clinical utility of liquid-based cytology (LBC) specimens via endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) for next-generation sequencing (NGS) of pancreatic cancer (PC). We prospectively evaluated the performance of DNA extraction and NGS using EUS-FNB samples obtained from PC. Thirty-three consecutive patients with PC who underwent EUS-FNB at our hospital were enrolled. DNA samples were obtained from 96.8% of the patients. When stratified with a variant allele frequency (VAF) > 10% tumor burden, the NGS success rate was 76.7% (n = 23) in formalin-fixed paraffin-embedded (FFPE), 83.3% (n = 25) in LBC, and 76.7% (n = 23) in frozen samples. The overall NGS success rate was 86.7% (n = 26) using FFPE, LBC, or frozen samples. The detection rates for the main mutated genes were as follows: 86.7% for KRAS, 73.3% for TP53, 66.7% for CDKN2A, 36.7% for SMAD4, and 16.7% for ARID1A. LBC had the highest median value of VAF (23.5%) for KRAS and TP53. PC mutation analysis using NGS was successfully performed using LBC compared with FFPE and frozen samples. This approach provides an alternative and affordable source of molecular testing materials.

Hepatocyte growth factor ameliorates dextran sodium sulfate­induced colitis in a mouse model by altering the phenotype of intestinal macrophages.

Hepatocyte growth factor (HGF) serves key roles in cell motility, proliferation and immunoregulatory functions. However, the effect of HGF on macrophages is unclear. The present study aimed to elucidate the effect of HGF on the phenotypic alterations of intestinal lamina propria mononuclear cells (LPMCs). Colitis was induced in a mouse model using dextran sodium sulfate (DSS). Subsequently, LPMCs were isolated from the mice with chronic colitis and the expression levels of cytokine­encoding genes in the LPMCs were determined. CD11b­positive macrophages isolated from LPMCs were cultured with HGF, and alterations in the levels of M1 or M2 markers were evaluated by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and flow cytometry. In addition, the cytokine levels were assessed using RT­qPCR and ELISA. HGF shifted the phenotype of macrophages from M1 to M2­like, as determined by increased mRNA expression levels of arginase­1, CD206 and IL­10, and reduced mRNA expression levels of CD86 and IL­6 in mice with DSS­induced colitis. Moreover, HGF could ameliorate DSS­induced colitis owing to its immunosuppressive effect on immune cells. These findings indicated that HGF treatment may not only promote the regeneration of epithelial cells but also lead to tissue repair by phenotypic alteration of M1 macrophages to M2­like macrophages.

Focal Type 2 Autoimmune Pancreatitis Mimicking Pancreatic Cancer: Treatment with Neoadjuvant Chemotherapy and Surgery.

A 51-year-old man was referred to our hospital for the further examination of main pancreatic duct interruption. Imaging findings showed a 25-mm-diameter mass lesion located in the pancreatic head. Endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) was performed on the mass. Cytology suggested adenocarcinoma, but the histological diagnosis was not confirmed. We made a comprehensive diagnosis of resectable pancreatic cancer. The mass shrank after preoperative adjuvant chemotherapy, and the patient underwent surgery. The final pathological diagnosis was type 2 autoimmune pancreatitis (AIP). Two years after surgery, AIP had not recurred in the remaining pancreas.

Comparison of recurrent biliary obstruction with the use of metal and plastic stents in EUS-guided biliary drainage: A propensity score-matched analysis.

Background and Objectives: In transpapillary biliary drainage, metal stents (MSs) exhibit a lower incidence of a biliary obstruction than plastic stents (PSs). However, few studies have compared recurrent biliary obstruction (RBO) when MSs and PSs are used in EUS-guided hepaticogastrostomy (EUS-HGS) and choledochoduodenostomy (EUS-CDS). We retrospectively evaluated the RBO for both stents in each procedure. Patients and Methods: : Between November 2012 and December 2020, 85 and 53 patients who underwent EUS-HGS and EUS-CDS for unresectable malignant biliary obstruction, respectively, were enrolled. Factors associated with RBO were assessed. Clinical outcomes were compared between the MS and PS groups using propensity score matching. Results: : The clinical success rate and procedure-related adverse events were similar in the MS and PS groups. Multivariate analysis identified the use of PS as a factor associated with RBO (EUS-HGS, P = 0.03; EUS-CDS, P = 0.02). After matching, the median time to RBO in EUS-HGS (MS: 313; PS: 125 days; P = 0.01) in the MS group was longer than that in the PS group. The cumulative incidence of RBO at 1, 3, and 6 months in the MS group was significantly lower than that in the PS group for EUS-HGS (MS: 4.0%, 8.2%, and 8.2%; PS: 12.4%, 24.9%, and 39.5%, respectively, P = 0.01). Conclusions: : MS exhibited a lower rate of RBO than PS for EUS-HGS and EUS-CDS.

Effects of Sprayable, Highly Adhesive Hydrophobized Gelatin Microparticles on Endoscopic Submucosal Dissection: A Swine Model.

INTRODUCTION: Sprayable wound dressings containing hydrophobized microparticles (hMPs) are characterized by strong adhesiveness. We examined the effect of hMPs derived from Alaska pollock gelatin on endoscopic submucosal dissection (ESD) ulcers. METHODS: (1) In an in vivo model of miniature swine gastric ESD, gastric ulcers were created by ESD and then sprayed with hMPs or untreated followed by microscopic examination. (2) In an ex vivo ESD model of resected stomach, a pinhole-shaped perforation was created on the ESD ulcer of resected stomach; hMPs were then sprayed on the perforation; and air leakage and intragastric pressure were measured. (3) In an in vivo duodenal ESD model of miniature swine, duodenal artificial ESD ulcers with pinhole-shaped perforation were examined; ulcers were classified into hMPs-sprayed and nonsprayed groups, and inflammation in the intrinsic muscle layer and serosa were compared between the groups. RESULTS: (1) Histological observation of submucosal tissues showed a decreased number of invading inflammatory cells in hMP-sprayed tissues compared with the control in miniature swine gastric ESD (p < 0.05). In addition, the rates of anti-alpha smooth muscle actin and type I collagen positivity were significantly lower in the hMPs group than in the control group (p < 0.05). (2) Intragastric pressure could not be measured in the nonsprayed group, whereas no air leakage was observed in the sprayed group when pressurized up to 26 mm Hg in the resected stomach model. (3) The sprayed group showed suppressed inflammation of the intrinsic muscular layer and serosa in both cases compared with the nonsprayed group in miniature swine duodenal ESD (p < 0.05). CONCLUSIONS: Sprayable, tissue-adhesive hMPs are a promising medical material for intraoperative and postoperative treatment of ESD-induced wound via anti-inflammation and strong adhesiveness.

Clinical Effect of Lenvatinib Re-Administration after Transcatheter Arterial Chemoembolization in Patients with Intermediate Stage Hepatocellular Carcinoma.

The present study clarified the prognosis of intermediate-stage hepatocellular carcinoma (HCC) patients who received lenvatinib (LEN) followed by transcatheter arterial chemoembolization (TACE) on demand. We retrospectively evaluated 88 intermediate-stage HCC patients who received LEN. The median age was 74 (range: 47-92) years old, 67 patients were male, and 82 were classified as Child-Pugh A. LEN was administered until disease progression or discontinuation due to adverse events (AEs). The mean duration of LEN treatment was 7.0 months. The response and disease control rates were 51.1% and 89.8%, respectively. The median progression-free survival and overall survival (OS) after the initiation of LEN were 6.8 months and 29.9 months, respectively. The OS in patients for whom LEN was re-administered after TACE (TACE-LEN) was better than that in patients who received other therapies (e.g., only TACE, TACE-other therapy, or only other therapy) even with propensity score matching (p = 0.008). A Cox proportional hazard analysis showed that TACE-LEN was most strongly associated with the OS (hazard ratio: 0.083, 95% confidence interval: 0.019-0.362, p = 0.001). LEN was administered for approximately 11.1 months after TACE. In intermediate-stage HCC patients who can tolerate LEN without discontinuation due to AEs, TACE-LEN may prolong the prognosis.

Role of apoptosis inhibitor of macrophages in patients with IgG4­related disease/autoimmune pancreatitis and the clinical characteristics associated with this condition.

Type 1 autoimmune pancreatitis (AIP) is a pancreatic manifestation of IgG4-related disease (IgG4-RD) and is a unique chronic inflammatory disease characterized by fibrosis. IgG4-RD is caused by an autoimmune mechanism that mimics malignant tumors and inflammatory disorders. Apoptosis inhibitor of macrophages (AIM) can function as a biomarker of autoimmune or inflammatory diseases with tissue fibrosis, including in inflammatory bowel disease and chronic liver disease. Therefore, the aim of the present study was to clarify the role of serum AIM levels and the clinical characteristics of patients with IgG4-RD and AIP. For this purpose, serum AIM concentrations were assessed using ELISA and the association between AIM and the laboratory and clinical data from patients with IgG4-RD/AIP, patients with pancreatic cancer (PC) and healthy controls (HCs), was determined. The results demonstrated that the serum AIM concentrations were not associated with the laboratory data. However, the serum AIM levels were significantly elevated in patients with AIP compared with the HCs and patients with PC. Furthermore, the serum AIM levels significantly decreased following steroid therapy in patients with AIP who were in remission. Overall, the present study demonstrates that serum AIM levels may be a potentially useful biomarker for the differential diagnosis of AIP and for evaluating the therapeutic reactivity of affected patients.

Adrenomedullin for biologic-resistant Crohn's disease: A randomized, double-blind, placebo-controlled phase 2a clinical trial.

BACKGROUND AND AIM: Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). METHODS: This was a multicenter, double-blind, placebo-controlled phase 2a trial that evaluated 24 patients with biologic-resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. RESULTS: No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin-treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin-treated groups at 24 weeks (P = 0.043) in the mixed-effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. CONCLUSION: In this trial, we observed a long-lasting (24 weeks) decrease in CDAI in the adrenomedullin-treated groups. Adrenomedullin might be beneficial for biologic-resistant CD, but further research is needed.

[Stenotic ischemic enteritis secondary to intraperitoneal band infiltration: a case report].

A 55-year-old man presented with vomiting and upper abdominal pain. Two months later, computed tomography revealed jejunal wall thickening and contrast enhancement. Double-balloon endoscopy revealed severe jejunal stenosis and mucosal prolapse. The patient was diagnosed with stenotic ischemic small bowel inflammation and underwent partial small bowel resection. Clinicians should consider intraperitoneal band formation in the differential diagnosis of patients without a history of abdominal surgery or trauma. Surgical resection should be considered to prevent strangulation ileus.

A case of autoimmune hepatitis with thymoma and myasthenia gravis.

A 44-year-old woman presented with cough, facial edema, and progressive fatigue. Computed tomography (CT) showed an anterior mediastinal mass, and laboratory findings showed liver injury. She was diagnosed with thymoma and scheduled for thymectomy after radiation and chemotherapy. However, she was referred to our department due to exacerbation of liver injury. Autoimmune hepatitis (AIH) was suspected based on the findings of elevated anti-nuclear antibody and immunoglobulin G levels. Histological findings of a liver biopsy confirmed the diagnosis of AIH. After oral steroid therapy initiation, she had diplopia and ptosis. Five days after steroid treatment, bulbar symptoms, such as nasal voice and dysarthria, appeared. A physical examination and electrophysiological tests confirmed myasthenia gravis (MG), and to prevent MG crisis, immunoadsorption plasmapheresis and tacrolimus were started by the neurologist. MG symptoms and liver damage gradually improved, she was then treated with chemotherapy and radiation for thymoma and underwent thymectomy, now showing no relapse of AIH or MG. We report the first case of MG developing immediately after the introduction of prednisolone for AIH complicated with thymoma.

Effects of immune checkpoint inhibitor therapy resumption in patients with malignant tumors after moderate-to-severe immune-related adverse events.

BACKGROUND AND AIMS: Immune checkpoint inhibitors (ICIs) are used to treat several cancers, but they sometimes induce immune-related adverse events (irAEs). Patients with irAEs often have improved antitumor responses, but discontinuation of ICIs after irAEs is considered necessary. Resuming the use of ICIs after irAEs is preferable, but few studies have investigated the safety of ICI resumption after irAEs. Therefore, we evaluated the factors associated with the recurrence of irAEs after ICI resumption to investigate the safety of this approach. METHODS: In this observational study, we enrolled patients treated with ICIs from September 2014 to March 2020 at our institution. Patient characteristics, ICIs, grades of irAEs, ICI discontinuation or resumption rates, and recurrence rates of irAEs after ICI therapy were analysed. RESULTS: Two-hundred eighty-seven patients were included in the present study, and 76 patients experienced grade 2 or higher irAEs. Forty-two patients underwent ICI resumption after recovering from irAEs, and 13 of them had a recurrence of irAEs. Among those 13 patients, six had a recurrence of the same irAE, and seven experienced other irAEs. Ten of the 13 patients had grade ≥2 irAEs, and none had fatal irAEs. In the grade 2 or higher irAE group, more patients had irAEs associated with multiple organs and of initial grade ≥2 than those in the grade 1 and no recurrent irAEs group. CONCLUSIONS: Patients with initial multisystemic irAEs and irAEs of grade ≥2 were more likely to experience relapse or develop new grade ≥2 irAEs after ICI resumption.

Clinical features of obscure gastrointestinal bleeding undergoing capsule endoscopy: A retrospective cohort study.

BACKGROUND: Capsule endoscopy has been widely used to investigate obscure gastrointestinal bleeding (OGIB) in the small intestine since its approval in 2001. However, the clinical features of OGIB remain unclear. AIM: We retrospectively examined the clinical features and risk factors of OGIB in patients who underwent capsule endoscopy in our hospital. METHODS: We included 420 of the 431 patients who underwent capsule endoscopy from June 2014 to May 2021, in whom the small intestine could be observed. We retrospectively compared the clinical features and treatment of OGIB cases, with or without active small bowel bleeding (n = 173), with other cases (n = 247). Patient sex, age, diabetes mellitus, and heart failure histories were matched for the analysis. RESULTS: The male/female ratio was 247/173 and the average age was 51.54 years. In multivariate analysis, the use of direct oral anticoagulants was significant (P = 0.016), and vascular lesions (P = 0.018) were observed in OGIB cases. When OGIB cases with and without active small bowel bleeding were compared, serum albumin level was lower in cases with active bleeding (P = 0.031). When treatment of OGIB cases were compared, those without vascular lesions could be treated conservatively (P = 0.0047). In the 1:1 propensity score matching analysis, serum creatinine level was elevated in cases of active bleeding (P = 0.029), and cases without vascular lesions were treated conservatively (P = 0.010). CONCLUSIONS: Use of direct oral anticoagulants is frequently associated with OGIB. OGIB patients without vascular lesions may be treated conservatively.

Features of patients who developed hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C Virus.

BACKGROUND: The features of hepatitis C virus patients with a sustained virologic response (SVR) who developed hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) therapy are unclear. METHODS: The study population included 1494 DAA-SVR patients without a history of HCC. The cumulative carcinogenesis rate after the end of treatment (EOT) and factors related to HCC were analyzed. RESULTS: Sixty (4.0%) patients developed HCC during a median observation period of 47.6 months. At four years, the cumulative carcinogenesis rate was 4.7%. A Cox proportional hazards analysis showed that age ≥73 years (hazard ratio [HR]: 2.148), male sex (HR: 3.060), hyaluronic acid (HA) ≥75 ng/mL (HR: 3.996), alpha-fetoprotein at EOT (EOT-AFP) ≥5.3 ng/mL (HR: 4.773), and albumin at EOT (EOT-Alb) <3.9 g/dL (HR: 2.305) were associated with HCC development. Especially, EOT-AFP ≥5.3 ng/mL was associated with HCC development after 3 years from EOT (HR: 6.237). Among patients who developed HCC, AFP did not increase in patients with EOT-AFP <5.3 ng/mL at the onset of HCC. Of these 5 factors, EOT-AFP ≥5.3 ng/mL was scored as 2 points; the others were scored as 1 point. The 4-year cumulative carcinogenesis rate for patients with total scores of 0-2, 3-4, and 5-6 points were 0.6%, 11.9%, and 27.1%, respectively (p<0.001). CONCLUSIONS: EOT-AFP ≥5.3 ng/mL is useful for predicting HCC development after an SVR. However, AFP does not increase in patients with EOT-AFP <5.3 ng/mL at the onset of HCC. The combination of EOT-AFP, age, sex, HA, and EOT-Alb is important for predicting carcinogenesis.

Serine palmitoyltransferase long chain subunit 3 is associated with hepatocellular carcinoma in patients with NAFLD.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is continuously increasing, with the proportion of patients with liver carcinogenesis due to non-alcoholic steatohepatitis (NASH) rising accordingly. Although it is important to identify individuals with hepatic carcinogenesis among patients with NAFLD, useful biomarkers have not yet been established. Previously, in a mouse model of diabetes mellitus without genetic modifications, we reported that a high-fat diet increases serine palmitoyltransferase long chain subunit 3 (SPTLC3) expression in liver tissue, accompanied by high frequency of liver carcinogenesis. Serine palmitoyltransferase (SPT) catalyzes the metabolism of fatty acids, particularly sphingolipid synthesis, and SPTLC3 has been identified as its catalytic subunit, but its role in liver disease is unclear. In the present study, the importance of SPTLC3 in NAFLD development was investigated. SPTLC3 mRNA expression was observed in a liver cancer cell line and in liver tissues from patients with NAFLD and liver cancer. In total, 99 patients with NAFLD (66 without hepatocellular carcinoma (HCC) and 33 with HCC were recruited, having been diagnosed by liver biopsy or imaging, along with 6 healthy volunteers (HVs). Serum was collected from patients and HVs, and SPTLC3 level was assessed by ELISA. SPTLC3 expression was higher in non-cancerous compared with that in cancerous liver tissues. Serum SPTLC3 levels were negatively correlated with platelet count and positively correlated with hyaluronic acid levels, suggesting an association with liver fibrosis. Moreover, SPTLC3 levels were significantly higher in the HCC group than in the HV and NAFLD groups. Multivariate analysis of HCC-related factors identified platelets, alanine transferase, albumin and SPTLC3 as independent factors associated with HCC. Furthermore, in patients with other chronic liver diseases (hepatitis B and C, and alcoholic liver disease), no significant differences in serum SPTLC3 levels were observed between patients with or without HCC. Thus, SPTLC3 expression increases specifically with the progression of NAFLD. Overall, the present results indicate that SPTLC3 may be involved in the development of liver carcinogenesis during NAFLD.