Profiles associated with significant hepatic fibrosis consisting of alanine aminotransferase >30 U/L, exercise habits, and metabolic dysfunction-associated steatotic liver disease.

AIM: In patients with steatotic liver disease (SLD), significant hepatic fibrosis is a prognostic factor with various etiologies, including inflammation and metabolic dysfunction. This study aimed to investigate independent factors and profiles associated with significant hepatic fibrosis, including alanine aminotransferase (ALT) levels >30 U/L and metabolic dysfunction-associated SLD (MASLD), in health check-up examinees. METHODS: This single-center, retrospective, observational cohort study enrolled 1378 consecutive health checkup examinees from April 2018 to September 2022. Shear wave elastography (SWE) was performed during a routine ultrasound examination, and patients with liver stiffness ≥6.60 kPa were defined as having significant hepatic fibrosis. Patients were classified into nonsignificant hepatic fibrosis (n = 1220) or a significant hepatic fibrosis (n = 158) group according to this definition. RESULTS: In multivariate analysis, the independent factor for significant hepatic fibrosis was aging (≥65 years; OR 9.637, 95% CI 6.704-13.852, p < 0.0001). According to decision tree analysis, the initial classifier was aging (≥65 years). After aging, an ALT level >30 U/L was the second relevant factor for significant hepatic fibrosis, regardless of age. An undirected graphical model showed that an ALT level of >30 U/L was directly associated with significant hepatic fibrosis. In patients aged ≥65 years with an ALT level >30 U/L, significant hepatic fibrosis was observed in 52% of the patients. Meanwhile, in patients aged ≥65 years with an ALT level ≤30 U/L, MASLD was the third classifier, with significant hepatic fibrosis observed in 38% of patients. CONCLUSIONS: ALT levels >30 U/L and MASLD may be involved in the pathogenesis of significant hepatic fibrosis in patients aged ≥65 years.

Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study.

AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

Metabolic dysfunction-associated fatty liver disease directly related to liver fibrosis independent of insulin resistance, hyperlipidemia, and alcohol intake in morbidly obese patients.

AIM: Hepatic fibrosis is associated with various factors, including metabolic dysfunction-associated fatty liver disease (MAFLD), insulin resistance, and alcohol intake in patients with morbid obesity. We investigated factors directly associated with hepatic fibrosis in patients with morbid obesity using a graphical model. METHODS: We enrolled 134 consecutive patients with morbid obesity who underwent liver biopsy during sleeve gastrectomy (median age 43.5 years; MAFLD 78.4%; homeostasis model assessment of insulin resistance [HOMA-IR] 5.97; >20 g/day alcohol intake 14.2%). Patients were classified into none/mild (F0/1; n = 77) or significant/advanced fibrosis (F2/3; n = 57) groups, based on histology. Factors associated with F2/3 were analyzed using logistic regression analysis and a graphical model. RESULTS: F2/3 was observed in 42.5% of the enrolled patients. The prevalence of MAFLD and HOMA-IR values were significantly higher in the F2/3 group than in the F0/1 group; however, no significant difference in alcohol intake was observed between the two groups. On logistic regression analysis, MAFLD, but not HOMA-IR or alcohol intake, was the only independent factor associated with F2/3 (odds ratio 7.555; 95% confidence interval 2.235-25.544; p = 0.0011). The graphical model revealed that F2/3 directly interacted with MAFLD, diabetes mellitus, HOMA-IR, and low-density lipoprotein cholesterol. Among these factors, MAFLD showed the strongest interaction with F2/3. CONCLUSIONS: We determined that MAFLD was more directly associated with significant/advanced fibrosis than insulin resistance or hyperlipidemia, and alcohol intake was not directly associated with hepatic fibrosis. Metabolic dysfunction-associated fatty liver disease could be the most important factor for hepatic fibrosis in patients with morbid obesity.

Hepatic expression of sodium-glucose cotransporter 2 (SGLT2) in patients with chronic liver disease.

Sodium-glucose cotransporter 2 (SGLT2) occurs in the proximal renal tubule cells. We investigate the hepatic expression of SGLT2 and its related factors in patients with chronic liver disease. This is a retrospective human study. The liver tissues were biopsied from patients with chronic liver disease (n = 30). The expression levels of SGLT2 were evaluated by immunostaining. Furthermore, the undirected graphical model was used to identify factors associated with hepatic expression levels of SGLT2. The SGLT2 expression was observed in not only the kidney, but also the liver in immunostaining (SGLT2 intensity: kidney 165.8 ± 15.6, liver 114.4 ± 49.0 arbitrary units, P < 0.01) and immunoblotting. There was no significant difference in hepatic expression of SGLT2 in the stratified analysis according to age, sex, BMI, and the severity of the liver disease. In the undirected graphical model, SGLT2 directly interacted with various factors such as sex, fatty change, neutrophil-to-lymphocyte ratio, triglyceride, hemoglobin A1c, creatinine, and albumin (partial correlation coefficient 0.4-0.6 for sex and 0.2-0.4 for others). The expression of SGLT2 was observed in the hepatocytes of patients with chronic liver disease. The undirected graphical model demonstrated the complex interaction of hepatic expression levels of SGLT2 with gender, inflammation, renal function, and lipid/glucose/protein metabolisms.

[Two Cases of Metastatic Colorectal Cancer Treated with TAS-102 plus Bevacizumab].

Trifluridine/tipiracil (TAS-102) is an important chemotherapeutic agent recommended by the Japanese guidelines as third- or fourth-line treatment for colorectal cancer. Some studies have reported that administration of TAS-102 concomitant with bevacizumab prolongs progression-free and overall survival in colorectal cancer. We describe 2 patients treated with a chemotherapeutic regimen comprising TAS-102 concomitant with bevacizumab for recurrent colorectal cancer. No adverse events ≥Grade 3(except for hematotoxicity)were observed in these patients. The patient received several courses of chemotherapy with adjustments of the dose and dosing intervals to prevent neutropenia. Combination therapy using TAS-102 and bevacizumab is a feasible Late-line chemotherapeutic regimen for colorectal cancer.

[A Case of HER2 Positive Unresectable Gastric Cancer Leading to Conversion Therapy with Chemotherapy].

A 72‒year‒old man visited our hospital with a chief complaint of epigastralgia. Upper gastrointestinal endoscopy revealed type 3 advanced gastric cancer at the body of the stomach. Following an investigation, he was diagnosed with human epidermal growth factor receptor 2‒positive gastric cancer with invasion to the pancreas as well as the paraaortic lymph node, and multiple liver metastases were also observed. The cancer was judged to be cT4a, N2M1(H1 LYM: No. 16), cStage Ⅳ and thus was considered suitable for chemotherapy. We performed capecitabine plus cisplatin plus trastuzumab therapy. After 3 courses, the primary lesion and swollen lymph nodes decreased in size. After 20 chemotherapy courses, the primary lesion relapsed, so conversion surgery was performed. The patient underwent total gastrectomy, distal pancreatectomy, and partial resection of the liver. We planned to perform adjuvant chemotherapy, but the patient declined it because of anorexia. At 18 months after the operation, recurrence of the tumor was detected at the celiac artery. Chemotherapy was performed as follows: capecitabine plus trastuzumab 10 courses, ramucirumab plus paclitaxel, irinotecan, and nivolumab. However, the patient eventually died 71 months after the first visit.

[Two Cases of Advanced Gastric Cancer Diagnosed as Pathological Complete Response after Preoperative Chemotherapy with S-1 and Oxaliplatin].

We herein report 2 cases of gastric cancer treated by S-1 and oxaliplatin combination therapy before later undergoing gastrectomy. The pathological results of both cases demonstrated complete response. Case 1 had a giant tumor which was suspected to have invaded the pancreas. Case 2 was associated with extensive lymph node metastasis. Based on the findings of these 2 cases, preoperative chemotherapy with S-1 and oxaliplatin for advanced gastric cancer shows sufficient efficacy.

[Case of Peritoneal Dissemination from Gastrointestinal Stromal Tumor of Jejunum Treated with Repeated Non-Curative Surgery].

A 71-year-old male presented with abdominal distension and fever to our hospital. Abdominal CT revealed a huge tumor in abdomen, and non-curative surgery was performed. Peritoneal dissemination was widespread and the tumor invaded the bladder and sigmoid-colon mesenterium. Two months after the initial surgery, CT showed liver metastasis, and oral administration of imatinib mesylate was started. The peritoneal dissemination and liver metastasis showed a decrease, and this was well controlled for 45 months without severe side effects. Abdominal CT revealed peritoneal dissemination in the ileocecum after 43 months since the administration of imatinib. Therefore, sunitinib treatment was initiated. After 3 months of sunitinib administration, the tumor perforated. Emergency operation was performed to resect the ileocecum, and sunitinib was continued for 1 year. In GIST with liver metastasis and peritoneal dissemination, repeated surgical resection combined with chemotherapy is important to improve the patient's survival.

[Long-Term Survival of Gastric Cancer with Multiple Liver and Lymph Node Metastases-A Case Report].

Currently, chemotherapy against unresectable advanced gastric cancer is progressing with the development new drugs and due to results of several clinical trials. Here, we reported a case of long-term survival of gastric cancer with multiple liver and lymph node metastases. A 68-year-old man was diagnosed with gastric cancer and Virchow lymph node, para-aortic lymph node, and multiple liver metastases at another hospital. He was referred to our hospital from Yamashita Naika Syokakika. We administrated 4 courses of S-1 plus CDDP. The main tumor and all metastatic lesions were significantly reduced. Subsequently, total gastrectomy, partial liver resection, and left neck and para-aortic lymph node resection(conversion surgery)were performed. The cancer cell was remnant at the main tumor and para-gastric lymph node. No cancer cells were detected in another lesion(R0 resection). Postoperatively, only S-1 was administered. However, 28 months after undergoing gastrectomy, liver metastasis occurred. Therefore, S-1 plus oxaliplatin, paclitaxel plus ramucirumab, and CPT-11 plus CDDP were administered. Liver metastases again increased and decreased, respectively. However, 46 months after gastrectomy, liver metastasis recurred and nivolumab was administered. Subsequently, liver metastases disappeared. At 55 months after gastrectomy, rectal resection was performed against rectal cancer and partial liver resection against liver metastases. Cancer cells were not detected in the resected specimens.

[A Super-Elderly Patient with Recurrent Colon Cancer with Metastasis Effectively Treated with Capecitabine plus Bevacizumab Chemotherapy-A Case Report].

The safety and feasibility of chemotherapy for elderly patients is unclear. We report a super-elderly patient with liver metastases from colorectal cancer successfully treated with capecitabine plus bevacizumab chemotherapy. An 87-year-old woman underwent a colectomy for transverse colon. At 4 months postoperatively, she underwent hepatectomy for liver metastases. At 9 months after the first surgery, a new liver metastases(S4)was found. At this time, she rejected another hepatectomy. Therefore, we selected capecitabine plus bevacizumab chemotherapy, considering her age. After 18 courses of administration, the liver metastasis did not progress, and no new metastatic lesions were found on CT examination. Although as adverse events Grade 2 hand-foot syndrome developed, no other adverse event occurred. The patient's PS score was maintained at 0. We suggest capecitabine plus bevacizumab chemotherapy is an effective regimen for super-elderly patients with colorectal cancer.

[A Case of Unresectable Pancreas Cancer with 32 Months Survival after Chemotherapy].

We report a case of unresectable pancreas cancer. A 70-year-old woman presented with worsening diabetes and serum CA19-9 elevation. A tumor with portal vein and supra-mesenteric vein invasion was observed by computed tomography. She was diagnosed with unresectable pancreas head cancer that was locally advanced. Chemotherapy was administered with gemcitabine and nab-paclitaxel for 19 courses, followed by gemcitabine alone for 4 courses. After the addition of 6 courses of chemotherapy, a 60%dose of chemotherapy was administered for 13 courses due to severe neutropenia. The patient died 32 months after the first visit. The 60% dose of gemcitabine and nab-paclitaxel also inhibited tumor growth. These findings suggest the effective and safe long-term use of gemcitabine and nab-paclitaxel.

[Resection of Paraaortic Lymph Node Recurrence Wherein Complete Response to Bevacizumab Was Observed after Surgery for Sigmoid Colon Cancer].

We report a case of resection of a paraaortic lymph node recurrence, wherein complete response to bevacizumab was observed. Our patient was a 50-year-old woman who had a paraaortic lymph node recurrence during adjuvant chemotherapy with FOLFOX 6 months after surgery for sigmoid colon cancer. She was treated with chemotherapy consisting of FOLFOX plus bevacizumab/FOLFIRI plus bevacizumab, which suppressed progression of the periaortic lymph node recurrence. She underwent surgery for the paraaortic lymph node recurrence, and the pathologic result was complete response. We report that bevacizumab was effective for her paraaortic lymph node recurrence.

Resistance exercise in combination with aerobic exercise reduces the incidence of serious events in patients with liver cirrhosis: a meta-analysis of randomized controlled trials.

BACKGROUND: Exercise, particularly resistance exercise, is beneficial for sarcopenia in patients with liver cirrhosis. However, the effects of exercise on events remain unclear. We aimed to examine the effects of exercise on serious events in patients with liver cirrhosis using a meta-analysis of randomized controlled trials (RCTs). METHODS: A literature search was conducted in 2022. Eleven RCTs were selected for the meta-analysis (exercise group, n = 232; control group, n = 193). Serious events were defined as death or serious complications according to the original articles. A meta-analysis was performed using a random-effects model. The primary outcome was the incidence of serious events. RESULTS: In the 11 RCTs, the incidence of serious events was 5.6% (13/232) and 12.3% (24/193) in the exercise and control groups, respectively. However, a meta-analysis demonstrated no significant difference in the incidence of serious events between the two groups (risk difference [RD] - 0.03, 95% confidence intervals (CI) - 0.07 to 0.02). In a stratification analysis based on a combination of aerobic and resistance exercise, five RCTs (n = 185) were enrolled. The incidence of serious events was 6.25% (7/112) and 24.7% (18/73) in the combination exercise and control groups, respectively. A meta-analysis demonstrated a significant reduction in the incidence of serious events in the combination exercise group compared with the control group (RD - 0.12; 95% CI - 0.21 to - 0.03). CONCLUSIONS: Resistance exercise in combination with aerobic exercise reduces serious events in patients with liver cirrhosis. A combination of aerobic and resistance exercise may be beneficial to improve the prognosis of patients with liver cirrhosis.

The Inter-Organ Crosstalk Reveals an Inevitable Link between MAFLD and Extrahepatic Diseases.

Fatty liver is known to be associated with extra-hepatic diseases including atherosclerotic cardiovascular disease and extra-hepatic cancers, which affect the prognosis and quality of life of the patients. The inter-organ crosstalk is mediated by metabolic abnormalities such as insulin resistance and visceral adiposity. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a new definition for fatty liver. MAFLD is characterized by the inclusion criteria of metabolic abnormality. Therefore, MAFLD is expected to identify patients at high risk of extra-hepatic complications. In this review, we focus on the relationships between MAFLD and multi-organ diseases. We also describe the pathogenic mechanisms of the inter-organ crosstalk.

A low-intensity 10-min resistance exercise program that ameliorated hepatic fibrosis indices and altered G-CSF/IP-10/PDGF-BB in a patient with nonalcoholic fatty liver disease: A case report.

We developed a low-intensity 10-min resistance exercise program for nonalcoholic fatty liver disease (NAFLD). We report a case of NAFLD with elevated hepatic fibrosis indices, which were improved by a 60-week daily exercise program. A 71-year-old female patient with NAFLD whose hepatic fibrosis stage corresponded to F2 was referred to our hospital. She performed the exercise once a day with no changes in other lifestyle habits and medications. The homeostasis model assessment-insulin resistance value and NAFLD-liver fat score, the Hepamet fibrosis score, and the enhanced liver fibrosis score decreased. The FIB-4 index and serum levels of Mac-2 binding protein glycosylation isomer decreased to the reference values. We investigated the changes in chemokines/cytokines. The serum granulocyte-colony stimulating factor level was increased, and serum interferon-gamma-induced protein-10 and platelet-derived growth factor-BB levels were decreased. Our program may be beneficial for improving hepatic fibrosis in patients with NAFLD.

MAFLD associated with COPD via systemic inflammation independent of aging and smoking in men.

BACKGROUND AND AIM: Metabolic dysfunction and associated systemic inflammation are risk factors for chronic obstructive pulmonary disease (COPD) and COPD is highly prevalent in men. We investigated the impact of metabolic-associated fatty liver disease (MAFLD) and MAFLD-related systemic inflammation on COPD in men. METHODS: We enrolled 2,041 men with fatty liver. Patients were classified into the COPD (n = 420/2041) and non-COPD (n = 1621/2041) groups. COPD and its high-risk group were diagnosed using the Japanese Respiratory Society Disease statement. Systemic inflammation was evaluated using the C-reactive protein (CRP)/albumin ratio. Independent factors for COPD were investigated by multivariate analysis and decision-tree analysis. RESULTS: The prevalence of MAFLD was significantly higher in the COPD group than in the non-COPD group. In multivariable analysis, in addition to heavy smoking and aging, MAFLD was identified as an independent factor for COPD (OR 1.46, 95% CI 1.020-2.101, P = 0.0385). Decision-tree analysis showed that MAFLD, rather than heavy smoking, was the most influential classifier for COPD in non-elderly men (14% in MAFLD vs 6% in non-MAFLD groups). MAFLD was also the second most influential factor in elderly men who were not heavy smokers. In both groups, the CRP/albumin ratio was the first classifier for COPD (16% in the high CRP/albumin ratio group vs 3% in the low CRP/albumin ratio group of non-elderly men). CONCLUSIONS: MAFLD is an independent predictor of COPD in men. MAFLD had a significant impact on COPD through systemic inflammation in men of all ages who were not heavy smokers. MAFLD may be useful to broadly identify COPD in men.

Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome.

PURPOSE: To investigate walking ability in Japanese patients with Rett syndrome (RTT). METHODS: Walking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database. RESULTS: Univariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X. CONCLUSIONS: Meaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.

Effects of UV Irradiation on Penicillium Strains Isolated from a Bread Plant and the Application to Bakery Products.

We tested treatement with UV irradiation for controlling the growth of bread mold. First, we analyzed the sterilizing effect of a dose of approximately 25 mJ/cm2 radiation on nine Penicillium and two Talaromyces strains that were isolated from a bread-manufacturing plant. The P. chermesinum and P. paneum strains were sterilized completely at that dose, while it was only partially effective against P. corylophilum. P. chrysogenum and P. decumbens were sterilized at a dose of approximately 120 mJ/cm2, while T. amestolkiae was sterilized at approximately 150 mJ/cm2. Sterilization of T. cecidicola and P. hispanicum required more than 200 mJ/cm2 of radiation. These results suggest that UV resistance varies depending on the species and the strains. We also carried out UV irradiation of bread at 70 mJ/cm2: a dose at which the taste of bread is not affected; we observed that mold growth was delayed visibly compared to the non-irradiated bread. These results suggest that UV irradiation at 70 mJ/cm2 is effective at delaying mold growth, though it does not cause complete sterilization. This method should prove useful for extending the shelf-life of bread.