Liver Function in Older Patients With Unresectable Hepatocellular Carcinoma After Administration of Lenvatinib.

BACKGROUND: The age of patients with advanced hepatocellular carcinoma (HCC) eligible for molecular-targeted drug treatment is increasing. We assessed liver function after lenvatinib administration according to age in patients with advanced HCC. PATIENTS AND METHODS: In this retrospective, multicenter, observational study, we reviewed the records of patients with HCC who received lenvatinib treatment (March 2018-March 2020). Liver function was measured using the Albumin-Bilirubin Index (ALBI). RESULTS: Of 119 patients, with a median age of 72.0 years, median overall survival was 15.3 months. Overall survival was significantly better in the group which maintained liver function (p=0.02). Older age (≥72 years) was associated with liver-function deterioration within 8 weeks (odds ratio=2.47, 95% confidence interval=1.06-5.75, p=0.035). The ALBI score was significantly higher in the older group at 4 and 8 weeks after lenvatinib administration. CONCLUSION: Lenvatinib administration was more likely to adversely affect liver function in older patients; dose adjustment should be considered in such patients.

Comprehensive Prospective Analysis of the Factors Contributing to Aspiration Pneumonia Following Endoscopic Submucosal Dissection in Patients with Early Gastric Neoplasms.

Endoscopic submucosal dissection (ESD) has become the first-line treatment for early gastric neoplasms; however, a subset of patients treated by this method develop aspiration pneumonia. We conducted a comprehensive prospective analysis of the factors contributing to post-ESD aspiration pneumonia in early gastric neoplasms in this study, with special focus on whether pre-treatment oral care can prevent aspiration pneumonia. Sixty-one patients who underwent ESD for gastric neoplasms were randomly assigned to the oral care or control groups. ESD was performed under deep sedation. Of 60 patients whose data were available for analysis, 5 (8.3%) experienced pneumonia confirmed either by chest radiography or computed tomography. Although no difference in the rate of pneumonia was found between the control and oral care groups, the post-oral care bacteria count was significantly higher in the saliva of patients who developed pneumonia compared to those without pneumonia. In addition, the presence of vascular brain diseases and the dose of meperidine were also significantly associated with the occurrence of pneumonia. These results suggest that the number of oral bacteria as well as pre-existing vascular brain diseases and high-dose narcotics can affect the incidence of post-ESD pneumonia.

Gastric mucormycosis complicated by a gastropleural fistula: A case report and review of the literature.

RATIONALE: Mucormycosis is a rare opportunistic fungal infection with poor prognosis. The incidence of mucormycosis has been increasing, and it is a threat to immunocompromised hosts. We present a case of gastric mucormycosis complicated by a gastropleural fistula during immunosuppressive treatment for adult-onset Still disease (AOSD). PATIENT CONCERNS: An 82-year-old woman diagnosed with AOSD who developed gastric ulcers during the administration of an immunosuppressive therapy with corticosteroids, cyclosporine, and tocilizumab complained of melena and epigastralgia. Esophagogastroduodenoscopy showed multiple ulcers covered with grayish or greenish exudates. DIAGNOSES: The patient diagnosed with mucormycosis based on culture and biopsy of the ulcers, which showed nonseptate hyphae branching at wide angles. Mucor indicus was identified using polymerase chain reaction. INTERVENTIONS AND OUTCOMES: Although liposomal amphotericin B was administered, gastric mucormycosis was found to be complicated by a gastropleural fistula. The patient died because of pneumonia due to cytomegalovirus infection, and autopsy revealed the presence of Mucorales around the fistula connecting the stomach and diaphragm. LESSONS: Gastric mucormycosis is refractory to treatment and fatal. Surgical resection, if possible, along with antifungal drugs can result in better outcomes.

Successful Treatment with Adalimumab for Intestinal Behcet's Disease during Pregnancy.

A 36-year-old Japanese woman with intestinal Behcet's disease was admitted to our hospital due to a recurrent ileocecal ulcer. Because infliximab (IFX) showed secondary failure, IFX was switched to adalimumab (ADA). After the third injection of ADA, she was unexpectedly 4-weeks pregnant. ADA was continued until 20 gestational weeks. Remission of the disease activity was maintained during pregnancy, and the birth was uneventful. The ileocecal ulcer disappeared after her delivery. ADA was detected in the umbilical blood after 119 days from the last infusion. The placental transition and timing of neonatal vaccination should be considered in cases of pregnancy with TNF antibody therapy.

Advantages of fecal lactoferrin measurement during granulocyte and monocyte adsorptive apheresis therapy in ulcerative colitis.

BACKGROUND: Fecal lactoferrin has been introduced as a useful tool for the diagnosis and monitoring of inflammatory bowel disease (IBD). The aim of this study was to assess if fecal lactoferrin can be employed to predict or estimate the effect of granulocyte and monocyte adsorptive apheresis (GMA) in ulcerative colitis (UC). METHODS: This was a prospective study involving 21 patients with UC. Patients with moderately-to-severely active UC who were scheduled to undergo GMA were recruited. Changes in fecal lactoferrin concentration were compared between the GMA-responder and -nonresponder groups. RESULTS: In the GMA-responder group, fecal lactoferrin significantly increased 1 week after the introduction of GMA and then significantly decreased after GMA sessions. Fecal lactoferrin concentrations were significantly higher in the GMA-responder group than in the GMA-nonresponder group at 1 and 2 weeks after the introduction of GMA. Multivariate logistic regression analysis revealed that fecal lactoferrin concentration 1 week after the introduction of GMA was the most contributing factor for the effectiveness of GMA in patients with UC. CONCLUSIONS: In the GMA-responder group, fecal lactoferrin concentration significantly increased 1 week after the introduction of GMA. Fecal lactoferrin may be beneficial for predicting clinical response of GMA in patients with UC at an early stage of GMA treatment.

Efficacy of long-term 4.0 g/day mesalazine (Pentasa) for maintenance therapy in ulcerative colitis.

BACKGROUND: High-dose (4.0 g/day) mesalazine is typically used for induction therapy, but its efficacy as maintenance therapy remains to be determined. We conducted a multicenter retrospective study to investigate the efficacy of continuous treatment with 4.0 g/day of mesalazine. MATERIAL/METHODS: Japanese ulcerative colitis (UC) patients receiving acute induction therapy with 4.0 g/day mesalazine were enrolled and followed. Those who clinically improved or who achieved clinical remission were categorized into 2 sub-groups according to the median duration of treatment with 4.0 g/day of mesalazine. The clinical relapse frequency and the time to relapse were analyzed. RESULTS: We enrolled 180 patients with active UC, and then 115 patients who clinically improved or who achieved clinical remission after treatment with 4.0 g/day mesalazine were categorized into 2 sub-groups according to the median of treatment duration: a short-term treatment group (≤105 days, n=58) and a long-term treatment group (>105 days, n=57). Overall, 45 (39.1%) patients relapsed: 28 (48.3%) in the short-term treatment group and 17 (29.8%) in the long-term treatment group. This difference was statistically significant (p<0.05). The relapse-free rate in the long-term treatment group was significantly higher than that in the short-term treatment group (p<0.05). The mean time to relapse in the long-term treatment group was significantly longer than that in the short-term treatment group (425.6±243.8 days vs. 277.4±224.5 days; p<0.05). CONCLUSIONS: Long-term continuous treatment with high-dose mesalazine (4.0 g/day) may be more effective than short-term treatment for maintenance of remission in UC patients.

Possible diagnostic role of antibodies to Crohn's disease peptide (ACP): results of a multicenter study in a Japanese cohort.

BACKGROUND: Various noninvasive tests have been studied to screen for patients with Crohn's disease (CD), and were found to have limited accuracy and sensitivity, particularly in Asian populations. The aim of our study was to explore the possible diagnostic utility of antibodies to the CD peptide (ACP) in patients with CD. METHODS: In a multicenter study using enzyme-linked immunosorbent assay, serum ACP levels were determined in 196 patients with CD, 210 with ulcerative colitis, 98 with other intestinal diseases, 132 with other inflammatory diseases, and 183 healthy controls. and then examined for correlation to clinical variables. The diagnostic utility of ACP was evaluated by receiver operating characteristics analysis and compared with anti-Saccharomyces cerevisiae antibodies (ASCA). RESULTS: ACP levels were significantly elevated in the CD patients, but not in the other groups that included UC, other intestinal diseases, other inflammatory diseases and the healthy controls. Among these other groups, ACP levels were not significantly different. In the CD patients, ACP had a higher sensitivity and specificity (63.3 and 91.0 %, respectively) than ASCA (47.4 and 90.4 %). ACP levels were negatively associated with disease duration, but not with CDAI, disease location, or medical treatment. CONCLUSIONS: ACP, a newly proposed serologic marker, was significantly associated with CD and was highly diagnostic. Further investigation is needed across multiple populations of patients and ethnic groups, and more importantly, in prospective studies.

Frequency of elevated biomarkers in patients with cryptogenic hepatocellular carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) continues to increase in Japan, but the clinical characteristics of Japanese patients with HCC have not been well described. The aim of this study was to determine the frequencies and utilities of elevated a-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) levels as biomarkers in cryptogenic HCC. MATERIAL/METHODS: A total of 2638 patients with HCC diagnosed between 1999 and 2010 in the Nagasaki Association Study of Liver (NASLD) were recruited for this study. The cause of HCC was categorized into 4 groups; HCC-B, HCC-C, HCC-BC, and HCC-nonBC. The significance of factors was examined for HCC-nonBC using logistic regression analysis in all patients. RESULTS: Multivariate analysis identified age, sex, BMI, alcohol consumption, platelet count, AST, ALT, AFP, DCP, and TNM stage as independent and significant risk factors for HCC-nonBC. According to TNM stage, the median AFP levels in HCC-nonBC with TNM stages I, II, and III were significantly lower than in either HCC-B or HCC-C. In TNM stage IV, the median AFP level in HCC-nonBC was significantly lower than in either HCC-B or HCC-BC. The median DCP levels in HCC-nonBC with TNM stages I and II were significantly higher than those in either HCC-B or HCC-C. In TNM stage III, the median DCP level in HCC-nonBC was significantly higher than that in HCC-C. CONCLUSIONS: DCP was more sensitive than AFP for the diagnosis of early stage cryptogenic HCC. DCP should be used as the main serum test for cryptogenic HCC detection.

Baseline serum cholesterol is associated with a response to pegylated interferon alfa-2b and ribavirin therapy for chronic hepatitis C genotype 2.

Background. HCV infection is associated with lipid disorders because this virus utilizes the host lipid metabolism to sustain its life cycle. Several studies have indicated that higher concentrations of serum cholesterol and LDL before treatment are important predictors of higher rates of sustained virological response (SVR). However, most of these studies involved patients infected with HCV genotype 1. Thus, we performed a multi-institutional clinical study to evaluate the impact of lipid profiles on SVR rates in patients with HCV genotype 2. Methods. A total of 100 chronic hepatitis C patients with HCV genotype 2 who received peg-IFN alfa-2b and ribavirin therapy were consecutively enrolled. The significance of age, sex, BMI, AST level, ALT level, WBC, hemoglobin, platelet count, gamma-glutamyltransferase, total cholesterol level (TC), LDL level, HCV RNA, and histological evaluation was examined for SVR using logistic regression analysis. Results. The 100 patients infected with HCV genotype 2 were divided into 2 groups, an SVR group and a non-SVR group. Characteristics of each group were subsequently compared. There was no significant difference in the level of HCV RNA, BMI, platelet, TG, or stage of fibrosis between the groups. However, there were significant differences in the levels of TC and LDL-C. In multivariate logistic regression analysis using baseline characteristics, high TC level was an independent and significant risk factor (relative risk 18.59, P = 0.015) for SVR. Conclusion. Baseline serum total cholesterol levels should be considered when assessing the likelihood of sustained treatment response following the course of peg-IFN and ribavirin therapy in patients with chronic HCV genotype 2 infection.

[A case of hepatic portal venous gas caused by transient type ischemic enteritis].

We report a case of hepatic portal venous gas (HPVG) caused by transient type ischemic enteritis. The patient was a 65-year-old woman, previously given a diagnosis of hypertension and diabetes mellitus. She was admitted to our hospital because of vomiting and epigastric pain. Abdominal computed tomography showed dilatation of the stomach and small intestine, with hepatic portal and superior mesenteric venous gas. Upper gastrointestinal endoscopy showed diffuse edematous and erosive change, and an extensive ulcer in the duodenum. There was no muscular defence, and physical and laboratory examinations did not indicate necrotic bowel. We diagnosed as HPVG caused by ischemic enteritis, and she responded to conservative treatment. We discuss a rare case of HPVG caused by transient type ischemic enteritis with references.

Evaluation of new prognostic staging systems (SLiDe score) for hepatocellular carcinoma patients who underwent hepatectomy.

BACKGROUND/AIMS: A new prognostic staging system, the SLiDe (S, stage; Li, liver damage; De, des-gamma-carboxy prothrombin) score was recently proposed. We examined 207 HCC patients following hepatic resection to determine the usefulness of this staging system for HCC patients after surgery. METHODOLOGY: Disease-free and overall survival rates were calculated according to the Kaplan-Meier method, and differences between groups were tested for significance using the log-rank test. RESULTS: Regarding disease-free survival, there were no significant differences in survival between SLiDe score 0 vs 1, between score 2 vs 3, and between score 4 vs 5. There were significant differences between 0-1 vs 2-3 (p < 0.01) and between 2-3 vs 4-5 (p < 0.01). Regarding overall survival, there were no significant differences in survival between score 0 vs 1, between score 2 vs 3, and between score 4 vs 5. There were significant differences between 0-1 vs 2-3 (p < 0.05) and between 2-3 vs 4-5 (p < 0.01). CONCLUSIONS: The SLiDe score, a staging system that combines tumor factors, a tumor marker and hepatic function, might be a better predictor of prognosis in HCC patients who have undergone hepatic resection.

Intraosseous fat necrosis associated with alcoholic pancreatitis.

A 50-year-old man with a 30-year history of alcohol abuse was admitted because of abdominal pain. Based on an elevated serum amylase level and abdominal computed tomography findings, a diagnosis of alcoholic pancreatitis was made. The pancreatitis improved after 1 month of conservative therapy, but the patient complained of a tender right ankle that showed no abnormal findings on X-ray examination. Two months later, the patient was readmitted for recurrent pancreatitis and a swollen, warm, tender right ankle. Imaging studies, including plain radiographs, magnetic resonance imaging, and a bone scintigram showed the typical findings of intraosseous fat necrosis of the right tibia. We report a rare case of intraosseous fat necrosis associated with alcoholic pancreatitis.

[A case of groove pancreatitis observed from initial stage].

We report a case of groove pancreatitis. A 60-year-old man was admitted to our hospital because of nausea and vomitting. CT showed a mass lesion in the groove between the pancreas head, duodenum and common bile duct. He was given a diagnosis of the groove pancreatitis, and underwent endoscopic balloon dilation. Groove pancreatitis is rare, and we discuss this case with references.

Surgical treatment and adjuvant chemotherapy in hepatocellular carcinoma patients with advanced vascular involvement.

BACKGROUND/AIMS: In advanced hepatocellular carcinoma (HCC) with vascular involvement of major vessels, patients have a poor prognosis after surgical treatment. METHODOLOGY: Patient outcomes after surgical resection and the usefulness of adjuvant chemotherapy were examined in 12 patients with major hepatic vessel involvement who underwent hepatectomy with combined resection of major blood vessels. RESULTS: The main portal vein was resected in 8 patients, the inferior vena cava in 3, hilar bile duct in 2 and hepatic artery in 1. Eleven patients underwent hemihepatectomy and 1 underwent segment 4 and 5 resection. The portal branch was repaired by venoplasty. The vena cava wall was repaired by suture closure. The hepatic artery was replaced by end-to-end anastomosis. The bile duct was repaired by Roux-en-Y hepaticojejunostomy. Although 2 patients had biliary leakage, there were no postoperative complications in 10 patients. The tumor recurrence rate was 83% in the early period and cancer death within 1 year was observed in 6 (50%), while 3 with tumor recurrence survived for more than 2 years and 2 survived without recurrence. In 233 HCC patients who underwent hepatectomy, 10 patients including 2 present cases received adjuvant chemotherapy at the time of tumor recurrence and 2 had complete responses. While in 11 patients receiving chemotherapy without resection, the response rate using Gemcitabine (66%) was higher than that using low dose Cisplatin plus 5-Fluorouracil (22%). CONCLUSIONS: Complete surgical resection combined with main vascular resection could be safely performed in most advanced stage HCC patients and adjuvant chemotherapy in the early period after resection would be necessary, which may achieve longer survival in some patients even in the advanced stage.

Clinical implications of antimitochondrial antibodies in type 1 autoimmune hepatitis: a longitudinal study.

BACKGROUND/AIMS: Autoimmune hepatitis (AIH) is a chronic liver disease characterized by the presence of antinuclear antibodies. However, antimitochondrial antibodies (AMA) and bile duct changes, which are the characteristics of primary biliary cirrhosis (PBC), can be detected in AIH patients. METHODOLOGY: Twenty patients with definite AIH were prospectively followed-up, and the serial changes in AMA profiles were determined. We also examined the correlations between these antibodies and histopathological findings in the liver. RESULTS: Of the 20 patients, 7 (35%) had bile duct injury, and 2 of these 7 patients also showed chronic nonsuppurative destructive cholangitis or ductopenia of interlobular bile ducts histopathologically. Serologically, 7 patients (35%) were positive for AMA at least once by immunoblotting during the follow-up periods. There were no significant differences in biochemical hepatobiliary indices, the presence of bile duct lesions, or the changes in biochemical profiles between AMA-positive and AMA-negative AIH patients during the follow-up periods. CONCLUSIONS: We confirmed that AMA and certain histopathological findings that are characteristics of PBC can be seen in some AIH patients. However, there was no significant correlation between AMA positivity and the histopathological findings in the liver, or biochemical hepatobiliary indices. Thus, the clinical implications of AMA in AIH patients remain unclear.

[A case of double common bile duct with gastric ulcer].

A 51-year-old man visited the Sasebo General Hospital because of a niche and a ductal lesion with reflux of barium in the lesser curvature of the gastric body in the upper gastrointestinal series of an annual medical checkup. Endoscopic examination showed an ulcer and a depressed lesion draining yellowish serous liquid in the stomach. Abdominal CT scan and MRCP revealed the ductal structure reached from the lesser curvature of the gastric body to the left lobe of the liver besides the ordinary pancreatobiliary system. ERCP showed normal common bile duct, gall bladder, and right intrahepatic bile duct, while the fistulography using cannula through the gastric depressed lesion revealed an accessory bile duct communicating to the left intrahepatic bile duct. The both biliary systems were completely separated, resulting in the diagnosis of double common bile duct of type IIIa.

Clinicopathological study of nonalcoholic fatty liver disease in Japan: the risk factors for fibrosis.

BACKGROUND/AIMS: We evaluated patients with nonalcoholic fatty liver disease (NAFLD) and compared the clinical and pathological features to identify the risk factors for NAFLD with severe fibrosis. METHODS: One hundred and eighty-two patients with biopsy-confirmed NAFLD from various medical centres were recruited into this study. RESULTS: The variables that were significantly associated with severe steatosis were male gender (mild:severe=36%:53%, P=0.02), younger age (mild:severe=57%:82%, P>0.001) and absence of type 2 diabetes (mild:severe=43%:71%, P>0.001). There was no significant difference in the degree of inflammation among the clinical groups. The variables that were significantly associated with severe fibrosis were female gender (mild:severe=54%:84%, P=0.002), older age (> or = 60 years old) (mild:severe=29%:53%, P=0.020), type 2 diabetes (mild:severe=42%:71%, P=0.020) and hypertension (mild:severe=24%:53%, P=0.002). Although there were more obese patients in the group with severe fibrosis, the association was not statistically significant (mild:severe=67%:78%, P=0.229). The prevalence of high serum triglyceride levels was similar between the two groups. The N (Nippon) score (total number of risk factor) could significantly predict severe fibrosis in NAFLD patients (1.48 +/- 1.14 vs. 2.66 +/- 0.94, P<0.001). CONCLUSIONS: The N score can be used to predict severe fibrosis in cases of NAFLD.

Sarcoidosis accompanied by systemic lupus erythematosus and autoimmune hepatitis.

A 52-year-old woman was admitted to our hospital for further examination of blurred vision, abnormal lung shadows and an elevated level of angiotensin-converting enzyme. Sarcoidosis was suspected, however, careful history taking revealed the existence of photosensitivity and polyarthralgia. Laboratory tests showed lymphocytopenia, liver dysfunction, hypergammaglobulinemia, and positive anti-nuclear, anti-double stranded DNA and anti-smooth muscle antibodies. Liver biopsy examination showed chronic active hepatitis. She was diagnosed with the triplex of sarcoidosis, systemic lupus erythematosus and autoimmune hepatitis. Marked improvement was noted after corticosteroid therapy.

Intracellular balance of oxidative stress and cytoprotective molecules in damaged interlobular bile ducts in autoimmune hepatitis and primary biliary cirrhosis: In situ detection of 8-hydroxydeoxyguanosine and glutathione-S-transferase-pi.

AIM: Bile duct injury has been thought to be absent in autoimmune hepatitis (AIH), but recent studies have indicated that AIH patients do have bile duct injury. In this study, the intracellular balance of oxidative stress and cytoprotection in biliary epithelial cells was investigated to clarify the pathogenesis of bile duct injury in AIH. METHODS: The intracellular status of oxidative DNA damage caused by oxidative stress and glutathione, an endogenous cytoprotective molecule, were examined in patients with AIH, primary biliary cirrhosis (PBC), and normal controls by immunostaining of 8-hydroxydeoxyguanosine (8-OHdG) and glutathione-S-transferase-pi. RESULTS: Immunohistochemically, 8-OHdG expression was detected as abundantly in the damaged bile ducts of AIH patients as in PBC patients. Moreover, in AIH, 8-OHdG expression was detected in damaged bile ducts more than in undamaged bile ducts. Glutathione-S-transferase-pi expression was relatively preserved in the damaged bile ducts of AIH patients compared to PBC patients, reflecting preservation of intracellular glutathione. CONCLUSIONS: In AIH, oxidative stress and DNA damage may be involved in the pathogenesis of bile duct injury in a manner similar to that found in PBC. However, relatively preserved intracellular glutathione may play a key role in preventing progressive bile duct loss following bile duct injury in AIH.