Effect of lemborexant on pharmacokinetics of clozapine: A potential drug-drug interaction mediated by time-dependent inhibition of CYP3A4.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (Ctrough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 µM and 4.1 µM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events.

Increased Spleen Volume in Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab in Comparison to Lenvatinib: A Retrospective Analysis.

INTRODUCTION: We previously reported 2 cases of esophageal varices rupture during atezolizumab and bevacizumab (Atez/Bev) treatment, in which the spleen volume gradually increased. The aim of this retrospective study is to compare the chronological change in spleen volume of patients treated with Atez/Bev and lenvatinib (LEN). METHODS: Seventy-two patients (Atez/Bev group, n = 26; LEN group, n = 46) were included in this retrospective study. The splenic parenchyma area was measured based on CT imaging. We used mixed-effect regression models with random intercepts to test the difference in the rate of change in spleen volume between the Atez/Bev and LEN groups. RESULTS: The median age of the Atez/Bev and LEN groups was 74.0 (71.0-82.0) and 72.0 (67.5-76.0), respectively. About 80% patients were male. The mALBI grade was classified as 1, 2a, 2b, and 3 in 10 (38.5%), 6 (23.1%), 10 (38.5%), and zero (0.0%) patients, respectively, in the Atez/Bev group and 21 (45.7%), 9 (19.6%), 15 (32.6%), and 1 (2.2%) patient in the LEN group (p = 0.9). The median baseline neutrophil-to-lymphocyte ratio (NLR) was 2.61 (1.80-3.41) in the Atez/Bev group and 2.71 (1.76-3.67) in the LEN group (p = 1.0). The median baseline spleen volume was 185 (132-246) cm3 in the Atez/Bev group and 231 (150-355) cm3 in the LEN group. The spleen volume gradually increased during Atez/Bev treatment (2.41 cm3 per week), while it was mostly consistent during LEN treatment (0.32 cm3 per week). Among patients with mALBI grade 2b or 3, the spleen volume increased in the Atez/Bev group (2.99 cm3 per week) and slightly decreased in the LEN group (0.82 cm3 per week), without statistical significance (p = 0.07). Among patients with a baseline NLR of >2.68, the spleen volume increased at a rate of 2.57 cm3 per week in the Atez/Bev group and decreased at a rate of 1.18 cm3 per week in the LEN group. The difference in the slope of the two groups was statistically significant (p = 0.04). DISCUSSION/CONCLUSION: Atez/Bev treatment could result in an increased spleen volume. Caution is required when managing patients treated with Atez/Bev, especially those with a high NLR.

Efficacy and Safety of the Combination of Nano-Liposomal Irinotecan and 5-Fluorouracil/L-Leucovorin in Unresectable Advanced Pancreatic Cancer: A Real-World Study.

INTRODUCTION: This retrospective study investigated the efficacy and safety of nano-liposomal irinotecan (nal-IRI) plus 5-fluorouracil/L-leucovorin (5-FU/l-LV) treatment in the second-line or later setting for advanced pancreatic cancer under real-world conditions. METHODS: Between June 2020 and September 2021, a total of 44 patients with unresectable advanced pancreatic cancer treated with nal-IRI + 5-FU/l-LV in our affiliated hospitals were included. The prognosis, predictive factors (including systemic inflammation-based prognostic indicators), and adverse events were investigated. RESULTS: The median age was 68 (interquartile range 62-73) years old, and 22 patients (50.0%) were male. Concerning tumor factors, 9 patients (20.5%) had local advanced disease and 35 patients (79.5%) had metastases. Twenty-five of the 44 patients were receiving second-line treatment, and 19 were receiving third-line or later treatment. The median overall survival (OS) and progression-free survival were 9.0 (range, 0.7-15.4) months and 4.4 (range, 0.6-15.4) months, respectively. The overall response rate was 5.3%. The disease control rate was 44.7%. Patients with a neutrophil-to-lymphocyte ratio of ≥2.7 had a significant risk of a poor OS (HR = 0.275, p = 0.017). Adverse events were manageable, although gastrointestinal symptoms and neutropenia were observed. The most common grade ≥3 adverse event was neutropenia, which was reported in 20% of patients. CONCLUSIONS: Nal-IRI + 5-FU/l-LV therapy was considered to be a useful regimen as second-line or later treatment for unresectable advanced pancreatic cancer, even in clinical practice.

[A Case of Hepatocellular Carcinoma Complicated by Liver Metastasis of Colon Cancer during the Course of Treatment].

A 72‒year‒old man with hepatocellular carcinoma(HCC)was treated with transarterial chemoembolization(TACE)and radiofrequency ablation(RFA). Six months after RFA, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid(Gd‒ EOB‒DTPA)‒enhanced magnetic resonance imaging(MRI)revealed multiple metastatic recurrences in the liver. TACE was performed for the recurrent HCC. However, the treatment response on the Gd‒EOB‒DTPA‒enhanced MRI showed that the lesions had advanced and that the liver metastatic nodules had ring‒shaped contrast effects. We suspected metastatic liver cancer based on the MRI findings and performed colonoscopy. Finally, we diagnosed the patient with multiple hepatic metastases of sigmoid colon cancer based on the results of the endoscopic colon biopsy and percutaneous liver tumor biopsy. In conclusion, we had a teachable case of the treatment of HCC.

Identification of a Novel Bone Marrow Cell-Derived Accelerator of Fibrotic Liver Regeneration Through Mobilization of Hepatic Progenitor Cells in Mice.

Granulocyte colony stimulating factor (G-CSF) has been reported to ameliorate impaired liver function in patients with advanced liver diseases through mobilization and proliferation of hepatic progenitor cells (HPCs). However, the underlying mechanisms remain unknown. We previously showed that G-CSF treatment increased the number of bone marrow (BM)-derived cells migrating to the fibrotic liver following repeated carbon tetrachloride (CCl4 ) injections into mice. In this study, we identified opioid growth factor receptor-like 1 (OGFRL1) as a novel BM cell-derived accelerator of fibrotic liver regeneration in response to G-CSF treatment. Endogenous Ogfrl1 was highly expressed in the hematopoietic organs such as the BM and spleen, whereas the liver contained a relatively small amount of Ogfrl1 mRNA. Among the peripheral blood cells, monocytes were the major sources of OGFRL1. Endogenous Ogfrl1 expression in both the peripheral blood monocytes and the liver was decreased following repeated CCl4 injections. An intrasplenic injection of cells overexpressing OGFRL1 into CCl4 -treated fibrotic mice increased the number of HPC and stimulated proliferation of hepatic parenchymal cells after partial resection of the fibrotic liver. Furthermore, overexpression of OGFRL1 in cultured HPC accelerated their differentiation as estimated by increased expression of liver-specific genes such as hepatocyte nuclear factor 4α, cytochrome P450, and fatty acid binding protein 1, although it did not affect the colony forming ability of HPC. These results indicate a critical role of OGFRL1 in the mobilization and differentiation of HPC in the fibrotic liver, and administration of OGFRL1-expressing cells may serve as a potential regenerative therapy for advanced liver fibrosis. Stem Cells 2019;37:89-101.

Association between Skeletal Muscle Depletion and Sorafenib Treatment in Male Patients with Hepatocellular Carcinoma: A Retrospective Cohort Study.

The effect of skeletal muscle mass (SMM) on the outcomes of sorafenib treatment for hepatocellular carcinoma (HCC) has not been established. We measured the SMM in HCC patients treated with sorafenib, evaluated the patients' survival, and evaluated the association between skeletal muscle depletion and sorafenib treatment. Of the 97 HCC patients treated with sorafenib at our institution in the period from July 2009 to February 2015, our study included 69 patients (51 males, 18 females) who had received sorafenib for ≥ 8 weeks and whose follow-up data were available. SMM was calculated from computed tomography images at the mid-L3 level (cm2) and normalized to height (m2) to yield the L3 skeletal muscle index (L3-SMI, cm2/m2). The median L3-SMI value was higher in the males (43 cm2/m2) compared to the females (36 cm2/m2). In the males only, the multivariate Cox regression identified an L3-SMI <43 cm2/m2 as independently associated with higher mortality compared to an L3-SMI ≥43 cm2/m2 (hazard ratio 2.315, 95% confidence interval: 1.125-4.765, p=0.023). Skeletal muscle depletion is a factor predicting poor prognosis for male patients with advanced HCC treated with sorafenib.

A case of idiopathic portal hypertension associated with nodular regenerative hyperplasia-like nodule of the liver and mixed connective tissue disease.

A 51-year-old woman was diagnosed with mixed connective tissue disease (MCTD) in 2011. She underwent treatment with prednisolone. Her hepatobiliary enzyme level increased, and multiple nodules were found in both liver lobes in abdominal imaging studies. Ultrasonography revealed large and small hyperechoic lesions with indistinct or well-defined borders. No findings of classic hepatocellular carcinoma or liver cirrhosis were observed on contrast-enhanced computed tomography, but some nodules showed an enhanced effect of the central lesion that was characteristic of focal nodular hyperplasia (FNH) in an arterial phase. On gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging, slightly high-intensity nodules, 10-40mm in size, were observed on T1- and T2-weighted images. The nodules showed highest intensities in the hepatocyte phase and were enhanced with the uptake of Gd-EOB-DTPA as compared with the background liver. FNH was suspected based on the imaging findings, but we performed a liver tumor biopsy for differential diagnosis of the malignant lesion. Based on the immunohistopathological examination results, the final diagnosis was idiopathic portal hypertension associated with nodular regenerative hyperplasia (NRH)-like nodule of the liver. Benign nodular hepatocellular lesions are caused by abnormal hepatic circulation and were previously known as anomalous portal tract syndrome. Our case of atypical NRH with large nodules may be included in this disease entity. Here, we report a rare case of MCTD with NRH-like nodules and idiopathic portal hypertension with a review of literature.

[Drug-induced liver injury caused by a dietary supplement (Kin-toki Shoga(®)) made from ginger].

A 70-year-old woman who took a dietary supplement, Kin-toki Shoga(®) made from ginger for peripheral psychroesthesia and numbness, experienced an epigastric sense of incongruity and appetite loss and passed brown urine for 2 months. Although she had stopped taking the supplement, her symptoms had not improved. She was admitted to our hospital because of jaundice and liver dysfunction. After an investigation of causes, she was diagnosed with drug-induced liver injury caused by Kin-toki Shoga(®). Liver dysfunction gradually improved with conservative treatment. She was discharged on the 25th day of illness. Liver biopsy findings were compatible with drug-induced liver injury.

Drug-induced Steatohepatitis Caused by Long-term Use of Topical Steroids for Atopic Dermatitis: A Case Report.

Atopic dermatitis is common in children and often treated with topical corticosteroids (TCs). A boy in his late teens who had been using TCs for atopic dermatitis was diagnosed with liver damage during a health checkup. A medical examination revealed severe steatotic liver disease and elevated liver enzyme levels despite the absence of typical symptoms such as central obesity. After discontinuation of TCs, an improvement in liver enzyme levels was observed, leading to the diagnosis of drug-induced steatohepatitis. This case underscores the potential liver risks associated with prolonged TC use in children, highlighting the need for parental education.

Characteristics of extreme ultraviolet emission from mid-infrared laser-produced rare-earth Gd plasmas.

We characterize extreme ultraviolet (EUV) emission from mid-infrared (mid-IR) laser-produced plasmas (LPPs) of the rare-earth element Gd. The energy conversion efficiency (CE) and the spectral purity in the mid-IR LPPs at λL = 10.6 µm were higher than for solid-state LPPs at λL = 1.06 µm, because the plasma produced is optically thin due to the lower critical density, resulting in a CE of 0.7%. The peak wavelength remained fixed at 6.76 nm for all laser intensities studied. Plasma parameters at a mid-IR laser intensity of 1.3×10(11) W/cm(2) was also evaluated by use of the hydrodynamic simulation code to produce the EUV emission at 6.76 nm.

Lurasidone for the Treatment of Schizophrenia: Design, Development, and Place in Therapy.

This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.

Three cases of immune-related hypopituitarism after atezolizumab-bevacizumab treatment for hepatocellular carcinoma.

We herein report three cases of immune-related hypopituitarism after atezolizumab-bevacizumab treatment for hepatocellular carcinoma (HCC). Case 1 was a man in his 60s with hepatitis C-related liver cirrhosis. He had been diagnosed with HCC and undergone surgical resection. However, HCC recurred 17 months after surgery. After 13 cycles of atezolizumab-bevacizumab therapy, general fatigue, appetite loss, and muscle weakness appeared. The plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were decreased. He was diagnosed with central adrenal insufficiency associated with hypopituitarism. Glucocorticoid therapy rapidly improved his symptoms. Case 2 was a man in his 70s with HCC associated with non-alcoholic steatohepatitis (NASH). After eight cycles of atezolizumab-bevacizumab therapy, general fatigue, appetite loss, and muscle weakness appeared. Hyponatremia and eosinophilia were observed. He was also diagnosed with hypopituitarism, and glucocorticoid therapy rapidly improved his symptoms. Case 3 was a man in his 60s with HCC associated with alcoholic liver cirrhosis. After 10 cycles of atezolizumab-bevacizumab therapy, hypopituitarism developed. In these cases, the presence of hyponatremia and/or eosinophilia was useful for making a diagnosis. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody is reported to be likely to induce hypophysitis two to three months after its administration. In contrast, anti-programmed cell death 1 (PD-1) antibody is likely to induce hypopituitarism six to seven months after its administration. These three patients treated with anti-programmed death ligand 1 (PD-L1) antibody developed hypopituitarism six to nine months later, close to the condition with anti-PD-1 antibody administration. Although immune-related hypopituitarism after atezolizumab-bevacizumab treatment is rare, we should be alert for hypopituitarism developing during atezolizumab-bevacizumab treatment.

An autopsy case of alpha-fetoprotein-producing large duodenal adenocarcinoma.

We report an autopsy case of a large duodenal adenocarcinoma that produced alpha-fetoprotein (AFP). The patient was a man in his 70s with diabetes mellitus. He presented with epigastralgia and was referred to our hospital. Upper gastrointestinal endoscopy and abdominal computed tomography revealed a large tumor of 11 cm in diameter in the descending limb of the duodenum. A tumor biopsy showed poorly differentiated adenocarcinoma. Although his carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were within the normal range, his AFP levels were significantly elevated (42,078.4 ng/mL). Due to vascular invasion, curative resection was not feasible, and chemotherapy was chosen as the treatment option. After gastrojejunostomy was performed to enable oral intake, one cycle of modified leucovorin/5-fluorouracil/oxaliplatin (mFOLFOX6) therapy was administered. However, it proved ineffective, and the patient's anorexia gradually worsened. Ultimately, he succumbed to the progression of cancer cachexia. Autopsy findings revealed a 14-cm-long duodenal carcinoma primarily located in the duodenal bulb, with direct invasion into the stomach, pancreas, and liver. A pathological examination confirmed a diagnosis of poorly differentiated adenocarcinoma with AFP production. Duodenal cancer is rare, and AFP-producing duodenal cancer is even rarer, with only 21 reported cases, including our own. We present this autopsy case of AFP-producing duodenal adenocarcinoma and review the cases reported in the relevant literature.

Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study.

STUDY OBJECTIVES: We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months. METHODS: Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents. RESULTS: The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, P < .001; 2 mo: -3.20 ± 5.64, P < .001; 3 mo: -3.38 ± 5.61, P < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, P = 0.27), 2 months (0.082 ± 4.62, P = .89), or 3 months (-0.64 ± 4.80, P = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, P = .004), 2 months (-1.05 ± 2.97, P = .029), and 3 months (-1.24 ± 3.06, P = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, P < .001). CONCLUSIONS: Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced. CITATION: Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. J Clin Sleep Med. 2023;19(10):1753-1758.

Successful Treatment of Metastatic Gallbladder Carcinoma with a High Tumor Mutational Burden Using Pembrolizumab.

A woman in her 70s presented with gallbladder carcinoma with liver metastases and peritoneal dissemination. After standard chemotherapy failed, a liver biopsy was performed. A FoundationOne CDx analysis showed that the tumor mutational burden (TMB) was high (34 mutations/megabase). Treatment with pembrolizumab, which is an immune checkpoint inhibitor (ICI), resulted in a partial response, and there were no significant immune-related adverse events. According to recently published reports, the frequency of TMB-high biliary tract cancer (BTC) is 3.4-4%, which makes it extremely rare. In conclusion, ICIs may be effective in patients with TMB-high BTC.

Evaluation of Tensile Residual Stress in Welded Steel Plates Using Acoustically Stimulated Electromagnetic Response.

Residual stress is one factor involved in the degradation and damage of industrial products. It is important to understand the magnitude and distribution of residual stress to maintain the integrity of a product. Magnetic measurements are a potential nondestructive method for evaluating residual stress in steel because the hysteresis properties are sensitive to stress. In recent years, spatial mapping of local magnetic hysteresis loop has been performed by using the acoustically stimulated electromagnetic (ASEM) method, which obtains the conversion coefficients from local hysteresis parameters to tensile stress. In this study, we demonstrate the evaluation and spatial imaging of tensile residual stress through local hysteresis parameters using welded steel specimens. We confirm that local coercivity can be used for evaluating residual tensile stress in the high-stress region. In addition, the spatial distribution of residual stress is well visualized by imaging the ASEM response signals due to remanent magnetization.

A case of conversion hepatectomy for huge hepatocellular carcinoma with adrenal metastasis and vascular invasion after atezolizumab-bevacizumab treatment.

We herein report a case of huge hepatocellular carcinoma (HCC) with adrenal metastasis and vascular invasion successfully treated by conversion hepatectomy after atezolizumab-bevacizumab treatment. A 77-year-old male patient with chest pain was admitted. He had a history of HCC treatment; however, the patient stopped receiving follow-up treatment based on his own decision. This time, he visited the emergency department of our hospital for the first time in 5 years. The tumor at the right lobe had grown into a lump with adrenal metastases and was 15 cm in diameter. It had invaded the inferior vena cava. Atezolizumab-bevacizumab treatment was selected for HCC treatment. Before starting treatment, his liver function was preserved (Child-Pugh A5). His alpha fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) levels were 759.0 ng/mL and 5,681 mAU/mL, respectively. Atezolizumab-bevacizumab treatment resulted in a marked decrease in tumor marker levels and tumor staining. After nine courses of atezolizumab-bevacizumab treatment, it became difficult to continue the administration of bevacizumab because of proteinuria. Because the tumor had decreased in size and the tumor markers were in the normal range, we decided to perform conversion hepatectomy. The tumor was completely removed by combined resection of the diaphragm, and pathological analyses showed a complete response to atezolizumab-bevacizumab treatment. No viable tumor cells remained on histological analyses. The patient is doing well without any signs of recurrence at 3 months after conversion surgery.

Two cases of rapid progression of esophageal varices after atezolizumab-bevacizumab treatment for hepatocellular carcinoma.

We report two cases of rapid progression of esophageal varices after atezolizumab-bevacizumab treatment for hepatocellular carcinoma (HCC). Case 1: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral. He was diagnosed with HCC 8 years previously. He had undergone surgical resection 4 times, radio-frequency ablation (RFA) several times, and transcatheter arterial chemoembolization (TACE). However, HCC progressed and could not be controlled by locoregional treatment. Systemic chemotherapy was, therefore, selected. Atezolizumab-bevacizumab was administered after lenvatinib and sorafenib failure. Before starting treatment, his liver function was preserved (Child-Pugh score 5 and class A). His alpha fetoprotein and des-gamma-carboxyprothrombin levels were 3.6 ng/mL and 443 mAU/mL, respectively. Esophagogastroduodenoscopy showed no remarkable esophageal varices before atezolizumab-bevacizumab treatment. Nine months after the initiation of atezolizumab-bevacizumab, the patient was admitted for hematemesis from esophageal varices. The disease control of HCC was classified as stable disease (SD) for the liver and lung metastases, and partial response for the lymph node metastases. Neither AST nor ALT was markedly elevated in the clinical course. Endoscopic variceal ligation (EVL) for the spurting point of large esophageal varices with red wale signs was able to successfully achieve hemostasis. Atezolizumab-bevacizumab was stopped and additional EVL eradicated the esophageal varices. However, the post-banding ulcer was prolonged in comparison to usual cases. Case 2: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral therapy. He was diagnosed with HCC 6 years previously. He had received RFA 2 times and TACE 7 times. Atezolizumab-bevacizumab was administered after lenvatinib failure. The disease control of HCC was classified as SD; however, the esophageal varices ruptured after 15 courses of atezolizumab-bevacizumab. Neither AST nor ALT were markedly elevated in the clinical course. The esophageal varices of these patients did not require treatment before atezolizumab-bevacizumab; however, they rapidly worsened and ruptured during atezolizumab-bevacizumab treatment. Although rare, similar cases with rapid progression of portal hypertension after atezolizumab-bevacizumab have been reported. We should pay attention to the worsening of esophageal varices during atezolizumab-bevacizumab treatment and poor wound healing after EVL.

Efficacy of Zinc Acetate Treatment for Patients with Decompensated Liver Cirrhosis Complicated by Hypozincemia.

The aim of this study was to evaluate the efficacy of zinc acetate treatment for patients with decompensated liver cirrhosis complicated by hypozincemia. We retrospectively analyzed 49 patients with decompensated liver cirrhosis complicated by hypozincemia who received zinc acetate treatment from August 2017 to March 2020. The relationships between serum zinc levels and several parameters including the prognosis, sarcopenia, and immunity were evaluated. Serum zinc levels measured at 3 months post-treatment and the incidence of adverse events were also determined. The median age was 69.0 years (IQR:59.5-78.8) and the male to female ratio was 29:20. Twenty-seven patients had a Child-Pugh classification of B and 22 had a Child-Pugh classification of C; the median Child-Pugh score was 9.0 (IQR, 8.0-11.0). The median serum zinc levels measured at 3 months post-treatment (74.7 (IQR, 50.0-101.0) µg/dL) were significantly elevated in comparison to the pre-treatment levels (43.0 (IQR, 34.0-51.0) µg/dL, P < 0.0001). The overall survival of patients with pre-treatment serum zinc levels of ≥60 µg/dL was significantly better than that of those with pre-treatment serum zinc levels of <60 µg/dL (P = 0.013). The survival of patients with zinc levels of ≥70 µg/dL at 3 months post-treatment was significantly better than those with levels of <70 µg/dL (P = 0.013). The serum albumin level, Child-Pugh score, albumin-bilirubin (ALBI) score and model for end-stage liver disease (MELD) score were identified as factors predicting a good response at 3 months post-treatment. There were no significant relations between the pretreatment serum zinc levels and skeletal muscle mass, lymphocyte count, and neutrophil lymphocyte ratio. There were no obvious problematic adverse events in patients who received zinc acetate treatment. The patients with higher basal zinc levels and good responders to zinc acetate treatment had a better prognosis. Zinc acetate was useful and safe for patients with decompensated liver cirrhosis complicated by hypozincemia.