Carnitine insufficiency is associated with fatigue during lenvatinib treatment in patients with hepatocellular carcinoma.

BACKGROUND: Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. METHODS: This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). RESULTS: Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). CONCLUSIONS: Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.

Plasma concentration and efficacy of tolvaptan in cirrhotic patients with refractory ascites.

To investigate the relationship between the exposure and efficacy of tolvaptan, we measured pharmacokinetics of total drug at 7 days after repeated doses of 3.75 mg/day tolvaptan in 16 patients with hepatic edema. Nine patients (56.3%) were responders, which were defined as those with body weight reduction of >1.5 kg/week. Serum albumin levels were significantly lower in responders than in non-responders (P = 0.031). However, the pharmacokinetics varied greatly among individuals and was not relevant to the clinical response.

Gadoxetic acid-enhanced magnetic resonance imaging to predict paritaprevir-induced hyperbilirubinemia during treatment of hepatitis C.

BACKGROUND: Paritaprevir inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, which transport bilirubin. Hyperbilirubinemia is an adverse event reported during hepatitis C treatment. Gadoxetic acid is also transported by OATP1B1/1B3. We evaluated whether the enhancement effect in gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the plasma concentration of paritaprevir and might anticipate the development of hyperbilirubinemia. METHODS: This prospective study evaluated 27 patients with hepatitis C who underwent gadoxetic acid-enhanced MR imaging prior to treatment with ombitasvir, paritaprevir, and ritonavir. The contrast enhancement index (CEI), a measure of liver enhancement during the hepatobiliary phase, was assessed. Plasma trough concentrations, and concentrations at 2, 4, and 6 h after dosing were determined 7 d after the start of treatment. RESULTS: Seven patients (26%) developed hyperbilirubinemia (≥ 1.6 mg/dl). Paritaprevir trough concentration (Ctrough) was significantly higher in patients with hyperbilirubinemia than in those without (p = 0.022). We found an inverse relationship between CEI and Ctrough (r = 0.612, p = 0.001), while there was not a significantly weak inverse relationship between AUC0-6 h and CEI (r = -0.338, p = 0.085). The partial correlation coefficient between CEI and Ctrough was -0.425 (p = 0.034), while excluding the effects of albumin and the FIB-4 index. Receiver operating characteristic (ROC) curve analysis showed that the CEI was relatively accurate in predicting hyperbilirubinemia, with area under the ROC of 0.882. Multivariate analysis showed that the CEI < 1.61 was the only independent predictor related to the development of hyperbilirubinemia, with an odds ratio of 9.08 (95% confidence interval 1.05-78.86, p = 0.046). CONCLUSIONS: Hepatic enhancement with gadoxetic acid was independently related to paritaprevir concentration and was an independent pretreatment factor in predicting hyperbilirubinemia. Gadoxetic acid-enhanced MR imaging can therefore be useful in determining the risk of paritaprevir-induced hyperbilirubinemia.

Consequences of Different Corticosteroids on Serum Potassium and Prostate-Specific Antigen in Patients Receiving Abiraterone for Castration-Resistant Prostate Cancer: A Retrospective Observational Study.

BACKGROUND: Abiraterone acetate is an androgen synthesis inhibitor approved for the treatment of castration-resistant prostate cancer (CRPC). Although co-administration of either prednisone or prednisolone at 10 mg/d has been recommended to reduce the risk of abiraterone-induced hyperaldosteronism (notably hypokalemia) and to give adjunctive pain relief effects, whether these glucocorticoids can be substituted by dexamethasone remains unknown. METHODS: We performed a retrospective review of medical records of patients who were given abiraterone for the treatment of CRPC with either prednisolone (ABI/PSL) 10 mg/d or dexamethasone (ABI/DEX) 0.5 or 1 mg/d between 2014 and 2017 in Juntendo University Nerima Hospital. Demographic and biochemical data including prostate-specific antigen (PSA) level were retrieved from the electronic medical records. RESULTS: Fifty-three eligible patients (27 in ABI/PSL group and 26 in ABI/DEX group) were extracted from the records. Both groups showed no significant changes in serum potassium level before and after starting treatment. In the ABI/PSL group, 12 patients (46%) showed elevations of PSA and 7 patients (27%) discontinued treatment within 3 months. In contrast, in the ABI/DEX group, only 6 patients (25%) showed elevations of PSA and 3 patients (13%, all were given dexamethasone 1 mg/d) discontinued treatment. CONCLUSIONS: Dexamethasone and prednisolone may be equally effective in preventing abiraterone-induced hypokalemia.

Spleen-derived lipocalin-2 in the portal vein regulates Kupffer cells activation and attenuates the development of liver fibrosis in mice.

The liver has an immune tolerance against gut-derived products from the portal vein (PV). A disruption of the gut-liver axis leads to liver injury and fibrosis. The spleen is connected to the PV and regulates immune functions. However, possible splenic effects on liver fibrosis development are unclear. Lipocalin-2 (Lcn2) is an antimicrobial protein that regulates macrophage activation. To clarify the role of the spleen in liver fibrosis development, we induced liver fibrosis in mice after splenectomy, and investigated liver fibrosis development. Liver fibrosis resulted in significantly increased splenic Lcn2 levels, but all other measured cytokine levels were unchanged. Splenectomized mice showed enhanced liver fibrosis and inflammation accompanied by significantly decreased Lcn2 levels in PV. Lipopolysaccharide-stimulated primary Kupffer cells, resident liver macrophages, which were treated with recombinant Lcn2 (rLcn2) produced less tumor necrosis factor-α and Ccl2 and the activation of hepatic stellate cells, the effector cells for collagen production in the liver, was suppressed by co-culture with rLcn2-treated Kupffer cells. In addition, the involvement of gut-derived products in splenectomized mice was evaluated by gut sterilization. Interestingly, gut sterilization blocked the effect of splenectomy on liver fibrosis development. In conclusion, spleen deficiency accelerated liver fibrosis development and decreased PV Lcn2 levels. The mechanism of splenic protection against liver fibrosis development may involve the splenic Lcn2, triggered by gut-derived products that enter the liver through the PV, regulates Kupffer cells activated by the gut-liver axis. Thus, the splenic Lcn2 may have an important role in regulating the immune tolerance of the liver in liver fibrosis development.

Gadoxetic Acid-Enhanced MR Imaging Predicts Simeprevir-Induced Hyperbilirubinemia During Hepatitis C Virus Treatment: A Pilot Study.

Simeprevir is a substrate for organic anion-transporting polypeptides (OATPs) that transport bilirubin. Hyperbilirubinemia is an adverse event reported during treatment of chronic hepatitis C patients with simeprevir plus pegylated interferon and ribavirin. Because gadoxetic acid is also a substrate of OATPs, pretreatment gadoxetic acid-enhanced magnetic resonance imaging (MRI) may predict hyperbilirubinemia during treatment. This prospective study therefore evaluated 11 consecutive patients with chronic hepatitis C who underwent gadoxetic acid-enhanced MRI prior to treatment with simeprevir plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin for an additional 12 weeks. Their contrast enhancement index (CEI), an index of liver parenchymal enhancement during the hepatobiliary phase, was assessed before treatment. Plasma trough concentrations (Ctrough ) of simeprevir were determined 7 days after its administration, and serum bilirubin concentrations were measured throughout the course of treatment. Six patients (55%) developed hyperbilirubinemia (≥1.6 mg/dL) during treatment. Ctrough was significantly higher in patients with than without hyperbilirubinemia (P = .009), with a strong inverse relationship between CEI and Ctrough (r = -0.911, P < .001). CEI was significantly lower in patients with than without hyperbilirubinemia (P = .009), but there were no significant differences between the 2 groups in pretreatment serum albumin concentrations and FIB-4 index, an index of liver fibrosis. Hepatic enhancement with gadoxetic acid was related to Ctrough of simeprevir. Gadoxetic acid-enhanced magnetic resonance imaging may predict the development of hyperbilirubinemia during treatment of hepatitis C patients with simeprevir plus pegylated interferon and ribavirin.

Use of finger-piece method for indocyanine green clearance test.

AIM: The indocyanine green (ICG) finger-piece method (FPM), which allows measurement of the ICG concentration by mounting a light sensor onto a finger, is used to assess liver function. We compared the ICG FPM with the conventional ICG blood sampling method (BSM) in patients with liver disorders. METHODS: Ninety consecutive patients simultaneously underwent the ICG BSM and ICG FPM. After ICG administration, blood samples were collected at 5, 10, and 15 min for the ICG BSM. The ICG concentration was measured through the finger piece by an ICG clearance meter. RESULTS: Seventy-one patients (78.9%) had Child-Pugh class A liver disease, and 19 (21.1%) had class B or C. The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values (r = 0.886, P < 0.001). Bland-Altman analysis showed good agreement between the two methods (mean difference, 0.012 ± 0.018). The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values both in patients with Child-Pugh class A liver disease (r = 0.821, P < 0.001) and class B or C liver disease (r = 0.859, P < 0.001). CONCLUSION: The ICG FPM may be an alternative to the ICG BSM for liver function assessment.

Influence of proton pump inhibitors and histamine H2 receptor antagonists on serum phosphorus level control by calcium carbonate in patients undergoing hemodialysis: a retrospective medical chart review.

BACKGROUND: Hyperphosphatemia is one of the common complications in patients undergoing hemodialysis. Although calcium carbonate (CaC) is often used to control serum inorganic phosphorus level in dialysis patients, co-administration of gastric acid reducers (ARs) may interfere with the phosphate binding effect of CaC. We performed a retrospective medical chart review to study whether ARs attenuate the hypophosphatemic effect of CaC in patients undergoing hemodialysis. METHODS: One hundred and eight chronic hemodialysis patients receiving either CaC alone or CaC concomitant with one of the ARs (proton pump inhibitors and histamine H2-receptor antagonists) were retrieved from the medical charts in Juntendo University Nerima Hospital. The patients were subdivided according to the interval between hemodialysis sessions (interdialysis interval of 48 or 72 h). A multivariate analysis was performed to identify clinical covariates associated with the variability of serum inorganic phosphorus levels. The study protocol was approved by the Institutional Review Board before the study was begun. RESULTS: Among patients on hemodialysis with a 72-h interdialysis interval, the magnitude of increase in serum inorganic phosphorus concentration in patients receiving CaC and AR was significantly greater than in those receiving CaC alone. While a similar trend was observed among patients with a 48-h interdialysis interval, the difference did not reach a significant level. A multivariate regression analysis revealed that concomitant administration of ARs with CaC and a longer interdialysis interval (72 h) were significantly and independently associated with the magnitude of increase in serum phosphorus concentration between dialysis sessions. No significant differences in albumin-corrected serum calcium concentrations and incidence of pathological fractures were observed between patients receiving CaC alone and those receiving CaC with ARs. CONCLUSIONS: Concomitant use of ARs with CaC may attenuate the hypophosphatemic effect of CaC in patients undergoing chronic hemodialysis. When hemodialysis patients require prescription of ARs for the prevention of upper gastrointestinal mucosal diseases (such as peptic ulcer), it may be prudent to choose a phosphate binder other than CaC.

Procedure Time for Gastric Endoscopic Submucosal Dissection according to Location, considering Both Mucosal Circumferential Incision and Submucosal Dissection.

Background. Previous assessments of technical difficulty and procedure time for endoscopic submucosal dissection (ESD) of gastric neoplasms did not take into account several critical determinants of these parameters. However, two key phases of ESD determine the total procedure time: the mucosal circumference incision speed (CIS) and submucosal dissection speed (SDS). Methods. We included 302 cases of en bloc and R0 resection of gastric neoplasms performed by 10 operators who had completed the training program at our hospital. Twelve locations were classified based on multiple criteria, such as condition of surrounding mucosa, lesion vascularity, presence of submucosal fat, ulcers, scars, fibrosis, and scope and device maneuverability. Lesions in different locations were classified into three groups based on the length of the procedure: fast, moderate, or late. Results. A significant difference was found in CIS and SDS for each location (p < 0.01), which demonstrates the validity of this classification system. In several locations, CIS and SDS were not consistent with each other. Conclusion. CIS and SDS did not correspond to each other even for lesions in the same location. Consideration of ESD procedure time for gastric neoplasms requires a more elaborate classification system than that previously reported.

Radiofrequency ablation combined with chemolipiodolization in a porcine liver: Comparison of the pharmacokinetic analysis with cisplatin powder and miriplatin.

AIM: To compare the pharmacokinetics of radiofrequency (RF) ablation with chemolipiodolization using cisplatin (CDDP) powder and miriplatin (MPT) in a porcine liver. METHODS: Twelve pigs were divided equally into four groups. After each CDDP powder-lipiodol suspension (n = 6; groups A and B) or MPT-lipiodol suspension (n = 6; groups C and D) was injected into the lateral left artery, one RF ablation was performed at the lateral left lobe of each pig. Six pigs (groups A and C) were killed on the same day as treatment, whereas the other pigs (groups B and D) were killed 7 days after the treatment. The platinum concentrations in venous blood were assayed at 15, 60 and 120 min, and 7 days after treatment. The platinum concentrations in the ablated area and the surrounding liver were also examined. RESULTS: Plasma platinum concentrations of the CDDP group peaked at 15 min, and then gradually diminished over time (µg units), while plasma platinum levels in the MPT group gradually increased over time (ng units). Liver tissue platinum concentrations of the CDDP group were significantly lower in non-ablative areas than in ablated areas at days 0 and 7, while liver concentrations of the MPT group were significantly higher in non-ablative areas than in ablated areas at day 7. CONCLUSION: MPT may be a suitable chemotherapeutic agent to stagnate platinum in the surrounding liver.

Polymorphisms in the organic anion transporting polypeptide genes influence liver parenchymal enhancement in gadoxetic acid-enhanced MRI.

AIM: This study aimed to investigate whether genetic polymorphisms of the organic anion transporting polypeptides influence hepatic enhancement in gadoxetic acid-enhanced MRI. PATIENTS & METHODS: We analyzed the genotypes of SLCO1B1 388A>G, SLCO1B1 521T>C, SLCO1B3 334T>G and NR1H4 -1G>T and calculated the mean quantitative liver-spleen contrast ratio, as an index of liver parenchymal enhancement, in 226 patients with liver disease. RESULTS: Multiple linear regression analysis using the mean quantitative liver-spleen contrast ratio as the dependent variable revealed that not only Child-Pugh score, but also SLCO1B1*1b haplotype (ß = 0.12; p = 0.04), were significant predictors of liver parenchymal enhancement. In addition, SLCO1B3 334T>G (ß = -0.18; p = 0.03) was a significant predictor when the data were analyzed in a subgroup of 117 patients, excluding the carriers of NR1H4 -1G>T, who reportedly exhibit reduced transcriptional activity of SLCO1B3. CONCLUSION: These genetic variants, as well as hepatic function, may contribute to individual differences in hepatic enhancement with gadoxetic acid.

Liver function test by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging with consideration of intrahepatic regional differences.

BACKGROUND/AIMS: To accurately quantify liver function using gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced MR imaging. METHODOLOGY: A total of 105 patients with suspicion of a hepatic tumor (Child­Pugh scores: 5 in 56, 6 in 26, 7 in 20, and 8 in 3) who underwent Gd-EOB-DTPA-enhanced MR imaging and an indocyanine green retention rate at 15 min (ICG-R15) evaluation were retrospectively analyzed. The hepatobiliary images were taken at 20 min after Gd-EOB-DTPA injection. The quantitative liver­spleen contrast ratio (Q-LSC) was measured by calculating the signal intensity of the spleen and 12 intrahepatic points consisting of each central zone (near the porta hepatis) and peripheral zone (near the subcapsular zone) in the two main liver lobes. RESULTS: Each averaged Q-LSC of six points in the central zone or right lobe was significantly higher than that in the peripheral zone or left lobe regardless of hepatic function. The mean Q-LSC of the 12 points was significantly correlated with the ICG-R15 and significantly decreased with elevation of the Child­Pugh score. CONCLUSIONS: The hepatic enhancement by Gd-EOB-DTPA is influenced by zonal and lobar differences. This method with consideration of regional differences is valid for estimation of liver function by Gd-EOB-DTPA-enhanced MR imaging.

Youngest case of an early gastric cancer after successful eradication therapy.

A 28-year-old woman visited our clinic with a chief complaint of epigastralgia. She had received successful Helicobacter pylori (H. pylori) eradication therapy 5 years before. We repeated esophagogastroduodenoscopy, and a discolored depressed area with reddish spots and converging folds, 20 mm in size, was detected. No atrophic change including intestinal metaplasia or nodular gastritis was seen endoscopically. Two endoscopic biopsies revealed undifferentiated adenocarcinoma. No H. pylori was found, and the (13)C-urea breath test was also negative. Abdominal computed tomography demonstrated no nodal involvement, distant metastasis or fluid collection. She underwent a laparoscopy-assisted distal gastrectomy. Histologically, the resected specimen revealed an early undifferentiated gastric cancer that had invaded deeply into the submucosal layer. Nodal involvement was histologically confirmed. No atrophic change or H. pylori infection was evident histologically. This is the youngest patient ever reported to have developed a node-positive early gastric cancer after eradication of H. pylori.

Mallory-Weiss tear during gastric endoscopic submucosal dissection.

A 78-year-old woman was referred to our department for treatment of an early gastric cancer. Esophagogastroduodenoscopy (EGD) demonstrated a flat elevated lesion and a polypoid lesion on the greater curvature of the antrum. Histological analysis of, endoscopic biopsy samples taken from these lesions revealed an adenocarcinoma and a hyperplastic polyp, respectively. ESD was conducted for removal of the lesions. Carbon dioxide (CO(2)) instead of room air was used for insufflation, and the patient was adequately sedated without struggling or vomiting during the treatment. No significant bleeding from the lesion was observed during ESD, but fresh blood was identified endoscopically. Surprisingly, a Mallory-Weiss tear with active bleeding was detected on the lesser curvature of the gastric corpus. A total of eight hemoclips were applied for hemostasis. Both lesions were completely removed en bloc, and no bleeding or perforation developed after ESD. Histologically, the first lesion was a papillary carcinoma limited to the mucosal layer and without lymphovascular invasion or involvement of the surgical margins, while the second lesion was a benign hyperplastic polyp.

Use of selective serotonin reuptake inhibitors and upper gastrointestinal disease.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants in the world. Recent studies, however, have raised the concern that SSRIs increase the risk of gastrointestinal dysfunction. Therefore, we conducted a case-control study on gastrointestinal symptoms and endoscopic findings in patients who were taking SSRIs in Japan. METHODS: Forty-one patients who were taking SSRIs (SSRI-treated group) and 82 age- and sex-matched patients who were not taking antidepressants (control group) were selected from the population of patients who underwent endoscopic examination from January 1, 2005 to March 31, 2010 in our institution, and their subjective symptoms and endoscopic findings were analyzed. Patients who were taking proton pump inhibitors (PPIs) and/or histamine H(2)-receptor antagonists (H2RAs) were excluded from this study. RESULTS: The chief complaints at the endoscopic examination were classified into the following 4 categories: reflux symptoms, dysmotility symptoms, ulcer-like symptoms, and no upper abdominal symptoms. No significant difference was found in the complaint rate of each category between the SSRI-treated and the control groups. No significant differences were found between the groups in endoscopic findings, the LANZA score and the rate of chief complaints in patient classes stratified by the endoscopic finding. CONCLUSION: It was not evident that SSRIs induced mucosal damage of the upper gastrointestinal tract. And, it is considered that SSRIs do not increase the risk of upper gastrointestinal symptoms in patients treated with SSRIs for 1 month or longer. The present study suggests that SSRI medication does not have a bad influence on gastrointestinal symptoms and gastrointestinal organic diseases.

Endoscopic retrieval of a gastric trichobezoar.

A 9-year-old girl presented with a chief complaint of abdominal pain. Esophagogastroduodenal endoscopy (EGD) identified a long and large gastric trichobezoar extending into the duodenum. We attempted endoscopic retrieval after informed consent was obtained from the patient's mother. Initially, a gasper with 5-prolongs, commonly used for retrieval of endoscopically excised polyps, failed to remove the whole trichobezoar. When a net was used instead, it proved impossible to remove the trichobezoar completely. Therefore, we withdrew the scope from the mouth, leaving the net grasping the tricobezoar firmly in the stomach. Subsequently, we were able to retrieve about 70% of the trichobezoar manually by grasping the snare part of the net directly. A second pass found no deep laceration or perforation endoscopically. The remaining trichobezoar was completely retrieved with the net. The procedure was completed within 15 min. The retrieved specimens were 34 cm in length and 100 g in weight. The patient was discharged uneventfully 5 d thereafter. She was advised to visit a psychiatrist to avoid suffering from a relapse. Follow-up EGD showed no trichobezoar, and the patient's frontal hair grew back.

A novel endoscopic ablation of gastric antral vascular ectasia.

An 80-year-old woman was admitted to our hospital because of tarry stool with iron deficiency anemia. Her past history included autoimmune hepatitis. Esophagogastroduodenal endoscopy was performed to investigate the bleeding source and revealed multiple linear gastric vascular malformations in the antrum and cardia, compatible with Gastric antral vascular ectasia (GAVE). Endoscopic ablation was carried out with the tip of the hot biopsy forceps without opening at soft coagulation mode of 80W. The patient tolerated the procedure well and there were no complications associated with endoscopic therapies. After two sessions of endoscopic ablation her anemia improved to around 10 g/dL, an increase of 3.6 g/dL. Various endoscopic treatments have been described to manage GAVE. The most popular is argon plasma coagulation (APC), although APC is associated with over-distension induced by the argon plasma gas. To avoid over-distension and to reduce the abdominal discomfort/pain of this patient, we have used hot biopsy forceps instead of APC. Our case suggests that this procedure is effective, easy and convenient, as no special equipment or skill is necessary.