Prolonged SARS-CoV-2 infection during obinutuzumab and bendamustine treatment for follicular lymphoma: A case report.

Key Clinical Message: SARS-CoV-2 infection has been associated with a prolonged course and a poor prognosis in patients who receive anti-CD20 antibodies. However, there are no established treatments for such patients. Serial changes in the SARS-CoV-2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed. Abstract: We report a case of prolonged SARS-CoV-2 infection during obinutuzumab and bendamustine treatment for follicular lymphoma. Four years previously, the patient had been diagnosed with follicular lymphoma (Stage IIIA, Grade 2). She received several chemotherapy regimens, including rituximab and radiation therapy. Although these therapies achieved complete response temporally, they did not continue and recurred at 8 months before. Obinutuzumab and bendamustine therapy was selected, and she received five courses of obinutuzumab and bendamustine. She also received a SARS-CoV-2 mRNA vaccine two times. Although she did not have any symptoms, a routine check-up just before the 6th course of obinutuzumab and bendamustine revealed SARS-CoV-2 infection. Because she was immunosuppressed and was considered to be at high risk for the exacerbation of her disease, molnupiravir was immediately administered, and her SARS-CoV-2 antigen decreased. However, it was not completely cleared and flared-up at 6 weeks, with symptoms of COVID-19 appearing. Despite intensive treatment for SARS-CoV-2 infection, including remdesivir, baricitinib, tocilizumab and intravenous immunoglobulin, her SARS-CoV-2 antigen titer never became negative, and she finally died of respiratory failure caused by prolonged SARS-CoV-2 infection. Serial changes in the SARS-CoV-2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed.

A Newly Developed Method-Based Xanthine Oxidoreductase Activities in Various Human Liver Diseases.

Studies evaluating xanthine oxidoreductase (XOR) activities in comprehensive liver diseases are scarce, and different etiologies have previously been combined in groups for comparison. To accurately evaluate XOR activities in liver diseases, the plasma XOR activities in etiology-based comprehensive liver diseases were measured using a novel, sensitive, and accurate assay that is a combination of liquid chromatography and triple quadrupole mass spectrometry to detect [13C2, 15N2]uric acid using [13C2, 15N2]xanthine as a substrate. We also mainly evaluated the association between the plasma XOR activities and parameters of liver tests, purine metabolism-associated markers, oxidative stress markers, and an inflammation marker. In total, 329 patients and 32 controls were enrolled in our study. Plasma XOR activities were generally increased in liver diseases, especially in the active phase, such as in patients with hepatitis C virus RNA positivity, those with abnormal alanine transaminase (ALT) levels in autoimmune liver diseases, and uncured hepatocellular carcinoma patients. Plasma XOR activities were numerically highest in patients with acute hepatitis B. Plasma XOR activities were closely correlated with parameters of liver tests, especially serum ALT levels, regardless of etiology and plasma xanthine levels. Our results indicated that plasma XOR activity might reflect the active phase in various liver diseases.

[Liver injury in patients with moderate II COVID-19 who received dexamethasone monotherapy].

We examined 171 patients with novel coronavirus disease 2019 (COVID-19) with liver injury in the respiratory failure groups and the nonrespiratory failure groups and investigated 41 patients with moderate II COVID-19 with respiratory failure who received dexamethasone (Dex) monotherapy in the liver injury group and the nonliver injury group at the time before treatment. The respiratory failure group had 64% more liver damage than the nonrespiratory failure group, was older, had more men, and had significantly more complications from lifestyle-related diseases such as hypertension and diabetes. Obesity was more common in the liver injury group prior to Dex monotherapy, and the liver CT value was significantly lower than in the nonliver injury group. Liver injury worsened in 41% of patients after Dex monotherapy, but there was no significant difference in the frequency before Dex monotherapy between the liver injury group and the nonliver injury group, and the degree of liver injury was mild in all cases, improving in 38% of the liver injury group. Dex monotherapy was a safe treatment for moderate II COVID-19, which frequently resulted in liver injury.

Adolescents with chronic hepatitis C might be good candidates for direct-acting antiviral therapy.

Three Japanese adolescents with chronic hepatitis C were treated by direct-acting antivirals (DAAs). No adverse events or laboratory abnormalities were observed during and after DAA therapy, and a sustained virological response was achieved in all cases. The emotional functioning of the patients and their mothers were improved after DAA therapy.

Successful treatment of Japanese hemophilia patient co-infected with HIV and HCV genotype 4a by glecaprevir/pibrentasvir therapy.

Although direct-acting antiviral (DAA)-based anti-hepatitis C virus (HCV) therapies are very effective for patients with genotypes 1 and 2, evidence of the efficacy of DAA-based therapy for the special population of patients with genotypes 3-6 is insufficient due to the relatively small number of these subjects in Japan. Human immunodeficiency virus (HIV)/HCV-co-infected patients are recommended to be treated as HCV-mono-infected patients by the latest version of the Japan Society of Hepatology guidelines. However, evidence of efficacy in patients with HIV/HCV genotype 3-6 co-infection is insufficient. Currently, HCV genotypes 3-6 can be treated with two DAA-based therapies, including glecaprevir (GLE)/pibrentasvir (PIB) therapy in Japan. We experienced a relatively rare case of a Japanese hemophilia patient co-infected with HIV/HCV genotype 4a. We evaluated resistance-associated substitutions (RASs) against GLE and PIB before GLE/PIB therapy and found that he had no RASs. He was treated with 12 weeks of GLE/PIB therapy and achieved a sustained virologic response at post-treatment weeks 24. Although the treatment was well tolerated, the patient developed hyper-low-density lipoproteinemia that was probably associated with HCV elimination during the therapy. Additional studies are needed to confirm the efficacy and safety of GLE/PIB therapy for this special population in Japan.

The first reported case of Noonan syndrome complicated with hepatocellular carcinoma.

Noonan syndrome is a genetic multisystem disorder and is associated with mutation of genes encoding the proteins in the RAS-MAPK pathway. We reported the first case of Noonan syndrome complicated with hepatocellular carcinoma.

Correlative microscopy and block-face imaging (CoMBI) method for both paraffin-embedded and frozen specimens.

Correlative microscopy and block-face imaging (CoMBI), a method that we previously developed, is characterized by the ability to correlate between serial block-face images as 3-dimensional (3D) datasets and sections as 2-dimensional (2D) microscopic images. CoMBI has been performed for the morphological analyses of various biological specimens, and its use is expanding. However, the conventional CoMBI system utilizes a cryostat, which limits its compatibility to only frozen blocks and the resolution of the block-face image. We developed a new CoMBI system that can be applied to not only frozen blocks but also paraffin blocks, and it has an improved magnification for block-face imaging. The new system, called CoMBI-S, comprises sliding-type sectioning devices and imaging devices, and it conducts block slicing and block-face imaging automatically. Sections can also be collected and processed for microscopy as required. We also developed sample preparation methods for improving the qualities of the block-face images and 3D rendered volumes. We successfully obtained correlative 3D datasets and 2D microscopic images of zebrafish, mice, and fruit flies, which were paraffin-embedded or frozen. In addition, the 3D datasets at the highest magnification could depict a single neuron and bile canaliculus.

The feasibility of a fully synthetic and self-assembled peptide solution as submucosal injection material: a preliminary animal study.

BACKGROUND AND AIM: An injection solution is required to create a submucosal cushion (SMC) for safe endoscopic resection procedures. The aim of this preliminary animal study was to clarify the safety and efficacy of a novel fully synthetic and self-assembled peptide (FSSP) solution as a submucosal injection material (SMIM). METHOD: To compare the submucosal-lifting properties, 0.3% FSSP, Eleview®, sodium hyaluronate acid solution (SHA) and normal saline (NS) were randomly injected using an injection needle into the submucosa of exposed stomach and colon in five living dogs in a blind fashion. The mean height, and volume of SMCs were measured using a digital caliper immediately and 10, 20, 30, and 40 min after injecting each solution. All resected specimens were examined histopathologically. RESULTS: In both the colon and stomach, ANOVA for repeated measures showed the significant interaction between time and solution for the time-dependent change in the height. In the colon, FSSP created significantly higher SMC than NS 20 min after injection (p = .0015) and Eleview® and NS 40 min after injection (p = .0009 and p = .0002). Furthermore, FSSP and SHA tended to maintain height and volume when compared to the other two solutions. In the stomach, FSSP and SHA tended to maintain height and volume when compared to the other two solutions. There were no significant differences between the histopathological finding and the injecting solutions used. CONCLUSION: FSSP seems to be useful as a SMIM for endoscopic resection especially in the colon. Further studies are needed prior to clinical use of FSSP.

Impact of the Prognostic Nutritional Index on the Survival of Japanese Patients with Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Retrospective Study.

Objective The purpose of this multicenter retrospective study was to investigate the impact of the prognostic nutritional index (PNI) on the survival of Japanese patients with hepatocellular carcinoma (HCC) treated with sorafenib. Methods A total of 178 HCC patients from May 2009 to December 2015 at our affiliated hospitals was included in this study. The PNI was calculated as follows: 10×serum albumin (g/dL) +0.005×total lymphocyte count (per mm3). The patients were divided into two groups according to the cut-off value of the PNI and as calculated by a receiver operating characteristic curve analysis. Results The optimum cut-off value of the PNI was set at 46.8. We defined the 33 patients with a PNI≥46.8 as the PNI-high group and the 145 patients with a PNI<46.8 as the PNI-low group. The response rate was 20.0% in the PNI-high group and 8.1% in the PNI-low group, without any statistically significance (p=0.09). The duration of sorafenib therapy and the overall survival in the PNI-high group were significantly better than those in the PNI-low group. The PNI-high group was thus found to be a predictive factor associated with the duration of sorafenib therapy [hazard ratio (HR) 0.58; 95% confidence interval (CI) 0.39-0.87, p=0.008] and overall survival (HR 0.62; 95% CI 0.39-0.99, p=0.046) in a multivariate analysis. Conclusion The PNI is a simple and useful marker for predicting the survival of patients with HCC treated with sorafenib.

Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis.

BACKGROUND: Nuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated. METHODS: Wild-type, Car-null, Pxr-null, and Car/Pxr-null mice were treated with a CAR/PXR agonist or vehicle and administered 2.5% DSS in the drinking water. The typical clinical symptoms, histological scoring, proinflammatory cytokine, and apoptosis were analyzed. RESULTS: Mice treated with the PXR agonist pregnenolone-16α-carbonitrile (PCN) were protected from DSS-induced colitis, as in a previous study. Mice treated with the CAR agonist, 4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were also protected from DSS-induced colitis. Interestingly, the protective effects of PCN in the Car-null mice and those of TCPOBOP in the Pxr-null mice both decreased. PCN or TCPOBOP pretreatment significantly decreased the macrophage and monocyte infiltration in DSS-induced colitis. PXR and CAR agonists reduced the mRNA expression of several proinflammatory cytokines in a PXR- and CAR-dependent manner, respectively. CAR inhibited apoptosis by inducing Gadd45b. PXR inhibited TNF-α and IL-1b and CAR induced Gadd45b in in vitro cell analyses. CONCLUSIONS: We showed that CAR and PXR cooperatively ameliorate DSS-induced colitis. PXR and CAR protected against DSS-induced colitis by inhibiting proinflammatory cytokines and apoptosis, respectively.

Long-term Results of Bariatric Surgery for Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis Treatment in Morbidly Obese Japanese Patients.

BACKGROUND: Patients with morbid obesity are complicated with metabolic diseases and have a high incidence of non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH). METHODS: We report on a follow-up study of a cohort included 102 obese patients (55 males and 47 females, mean age 42.9 ± 10.6 years) undergoing bariatric surgery for the management of morbid obesity. Abdominal computed tomography was performed before and 1 year after surgery. Anthropometric and biochemical measurements were performed at 1, 3, and 5 years after surgery. RESULTS: The mean body mass index (BMI) of the NAFLD patients improved from 42.5 ± 8.3 kg/m2 to 28.5 ± 6.9, and 29.1 ± 5.7, 29.7 ± 5.5 kg/m2 at 1, 3, and 5 years, respectively. The liver fat accumulation and visceral fat areas were significantly improved at 1 year after surgery. The decrease in the BMI, waist-hip ratio, body fat percentage, and basal metabolic rate remained decreased for at least 5 years after surgery. Blood test findings including AST, ALT, γ-GTP, uric acid, albumin, CRP, HDL cholesterol, LDL cholesterol, triglycerides, and homeostasis model assessment insulin resistance (HOMA-IR) were also still improved at least 5 years after surgery. CONCLUSION: Bariatric surgery is useful for ensuring the long-term treatment of NAFLD/NASH in morbidly obese Japanese patients. Bariatric surgery is a therapeutic option for patients resistant to conventional treatment.

ß-Hydroxy-ß-methyl Butyrate/L-Arginine/L-Glutamine Supplementation for Preventing Hand-Foot Skin Reaction in Sorafenib for Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: Sorafenib is standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a notorious side-effect of this therapy. This study evaluated prophylactic benefits of an oral nutritional supplement (ONS) on sorafenib-associated HFSR in advanced HCC. PATIENTS AND METHODS: This was a prospective, single-center, open-label trial arm using combined ONS and sorafenib in patients with unresectable HCC from August 2014 to February 2018. Control patients received sorafenib without ONS from 2011 to 2014. From September 2014, prophylactic ONS containing ß-hydroxy-ß-methylbutyrate (HMB), L-arginine, and L-glutamine was given. Sorafenib dosage was 400 mg/day for both groups. RESULTS: Each group comprised 22 men and three women. Age, sex, Child-Pugh score, and clinical stage excluding IV-B did not significantly differ between the groups. HFSR occurred after 2 weeks: 15/25 patients in the control group (60%; HFSR grade 1: 6, grade 2: 7, grade 3: 2) vs. 8/25 in the ONS group (32%; HFSR grade 1: 4, grade 2: 4, grade 3: 0; p=0.047, Pearson's Chi-square test). CONCLUSION: Prophylactic HMB, L-arginine and L-glutamine supplementation effectively prevented sorafenib-associated HFSR in patients with advanced HCC.

Non-invasive prediction of non-alcoholic steatohepatitis in Japanese patients with morbid obesity by artificial intelligence using rule extraction technology.

AIM: To construct a non-invasive prediction algorithm for predicting non-alcoholic steatohepatitis (NASH), we investigated Japanese morbidly obese patients using artificial intelligence with rule extraction technology. METHODS: Consecutive patients who required bariatric surgery underwent a liver biopsy during the operation. Standard clinical, anthropometric, biochemical measurements were used as parameters to predict NASH and were analyzed using rule extraction technology. One hundred and two patients, including 79 NASH and 23 non-NASH patients were analyzed in order to create the prediction model, another cohort with 77 patients including 65 NASH and 12 non-NASH patients were analyzed to validate the algorithm. RESULTS: Alanine aminotransferase, C-reactive protein, homeostasis model assessment insulin resistance, albumin were extracted as predictors of NASH using a recursive-rule extraction algorithm. When we adopted the extracted rules for the validation cohort using a highly accurate rule extraction algorithm, the predictive accuracy was 79.2%. The positive predictive value, negative predictive value, sensitivity and specificity were 88.9%, 35.7%, 86.2% and 41.7%, respectively. CONCLUSION: We successfully generated a useful model for predicting NASH in Japanese morbidly obese patients based on their biochemical profile using a rule extraction algorithm.

Adenosquamous Carcinoma of the Choledochus.

The patient was an 86-year-old man who was admitted with obstructive jaundice. Computed tomography revealed a tumor in the hilar choledochus with peripheral hepatic duct dilatation. Endoscopic cholangiography (ERC) demonstrated the defect in the choledochus. Brushing cytology during ERC showed Orange-G-philic keratinized atypical cells, which led to a diagnosis of squamous cell carcinoma. Chemotherapy with tegafur-gimeracil-oteracil potassium was ineffective and was discontinued due to adverse effects. The patient died 5 months after the diagnosis and autopsy revealed tubular adenocarcinoma of the hilar bile duct with squamous cell carcinoma component. Progression of the disease might influence the distribution of adenosquamous carcinoma. The clinicopathological sequence of adenosquamous carcinoma of the choledochus was documented.

Elevated serum uric acid level was a notable adverse event during combination therapy with sofosbuvir and ribavirin.

AIM: Combination therapy with sofosbuvir and ribavirin (SOF/RBV) has been recently available for chronic hepatitis C patients with genotype 2 (CHG2) in Japan. The domestic phase III clinical trial showed a high antiviral effect with a relatively safe adverse event (AE) profile. Our aim was to report an important AE detected during treatment. METHODS: A prospective multi-institutional study of 12-week combination therapy with SOF/RBV for CHG2 was carried out to evaluate efficacy and safety. RESULTS: The eligible subjects included 142 patients. Out of 50 assessable patients, 16% of the patients were diagnosed with hyperuricemia. The proportions of subjects with grade 1, grade 3, and grade 4 hyperuricemia were 12, 2, and 2%, respectively. Serum uric acid (UA) levels at week 1 of the therapy (W1) were numerically the highest during therapy in patients with hyperuricemia, and the ratio of W1/baseline serum UA levels was significantly higher than that of post-treatment week 4 or 8/baseline serum UA levels in assessable patients. Serum UA levels at W1 were significantly correlated with body mass index. The difference between serum UA levels at W1 and baseline serum UA levels was significantly correlated with the difference between serum creatinine levels at W1 and baseline serum creatinine levels. CONCLUSIONS: Elevated serum UA level was a notable AE associated with SOF/RBV therapy for CHG2. However, because of the small number of subjects, the exact frequency of AEs should be re-evaluated with larger cohorts. We need to remember that elevated serum UA level might develop during the therapy, especially at W1.

Indirect activation of pregnane X receptor in the induction of hepatic CYP3A11 by high-dose rifampicin in mice.

Rifampicin (RIF), a typical ligand of human pregnane X receptor (PXR), powerfully induces the expression of cytochrome P450 3A4 (CYP3A4) in humans. Although it is thought that RIF is not a ligand of rodent PXR, treatment with high-dose RIF (e.g. more than 20 mg/kg) increases the expression of CYP3A in the mouse liver. In this study, we investigated whether the induction of CYP3A by high-dose RIF in the mouse liver is mediated via indirect activation of mouse PXR (mPXR). The results showed that high-dose RIF increased the expression of CYP3A11 and other PXR-target genes in the liver of wild-type mice but not PXR-knockout mice. However, the results of reporter gene and ligand-dependent assembly assays showed that RIF does not activate mPXR in a ligand-dependent manner. In addition, high-dose RIF stimulated nuclear accumulation of mPXR in the mouse liver, and geldanamycin and okadaic acid attenuated the induction of Cyp3a11 and other PXR-target genes in primary hepatocytes, suggesting that high-dose RIF triggers nuclear translocation of mPXR. In conclusion, the present study suggests that high-dose RIF stimulates nuclear translocation of mPXR in the liver of mice by indirect activation, resulting in the transactivation of Cyp3a11 and other PXR-target genes.

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.

Two Cases of Intravascular Lymphoma Diagnosed by Gastrointestinal Endoscopic Biopsy.

Two cases of intravascular lymphoma (IVL) were diagnosed by endoscopic biopsy. Both patients were admitted to our hospital with a fever of an unknown origin. An elevated serum level of soluble interleukin-2 receptor antibody suggested IVL. An upper gastrointestinal endoscopy was performed. A biopsy of both the reddened and normal gastroduodenal mucosa (Case 1) and a biopsy of a gastric antral ulcer, multiple polyploid lesions resembling submucosal tumors in the duodenum, and the patient's normal mucosa (Case 2) revealed vascular infiltration by CD20-positive atypical lymphocytes, confirming the diagnosis of IVL. The performance of a gastrointestinal biopsy for suspected IVL is important, even if there are no visible endoscopic abnormalities.

Clinical features of spontaneous coronary artery dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an infrequent but increasingly recognized cause of acute coronary syndrome (ACS). Previous case reports demonstrated that this condition occurs in young females with a low atherosclerotic risk factor burden and may be associated with peripartum or postpartum status. The purpose of this study was to review patients with angiographically confirmed SCAD to provide additional insight into the diagnosis and treatment of this condition. METHODS AND RESULTS: We screened medical records of all patients with ACS from March 2001 to November 2012. From these patients, we selected patients with SCAD based on coronary angiographic review. Of a total of 1159 ACS patients, 10 patients (0.86%) were diagnosed with SCAD. The mean age of these patients was 46 years, and 9 were female. ST-elevation myocardial infarction (STEMI) was observed in 9 patients and 5 patients had no coronary risk factors. One patient was treated conservatively with medication alone and 3 patients underwent thrombectomy. Balloon angioplasty was performed in 2 patients, and a bare metal stent was placed in one of these patients later. In the remaining 4 patients, bare metal stents were implanted emergently. Follow-up coronary angiography showed appropriate repair of SCAD in all 10 patients. CONCLUSIONS: In our experience, the clinical features of SCAD appear to be similar to those reported previously. SCAD appears to be rare, but it should be considered in ACS patients, especially in younger females.

Modulation of maltose preference by selection from dextrin, maltose and glucose diets in zinc-deficient rats.

This study examined whether the chain length of glucose in the diet could affect the selection of foods by Zn-adequate and Zn-deficient rats. Dextrin, maltose and glucose were used as sources of carbohydrate in the diet and the selection patterns of the rats were analyzed for 28 d by a 3-choice selection. Diets provided as a set of three either Zn-adequate or Zn-deficient diets were rotated daily. The Zn-adequate control rats selected widely from the three diets throughout the 28 d. In contrast, rats fed a Zn-deficient diet selected exclusively and continuously the dextrin diet or dextrin and glucose diets from the three diets over the experimental periods. The average daily total food intakes of rats fed a Zn-deficient diet were very significantly decreased. The selections of dextrin, maltose and glucose diets in the 3-choice methods of the control rats were 5.7+/-1.6(b), 5.8+/-2.0(b) and 2.7+/-0.9(a) g/d, respectively (p<0.05), and those of the Zn-deficient rats were 6.4+/-2.5(c), 0.8+/-1.3(a) and 2.6+/-1.4(b) g/d, respectively (p<0.05). The ratios of the selected maltose-diet in the Zn-adequate control and the Zn-deficient rats were 40.8+/-13.8 and 9.0+/-15.6%, respectively (p<0.01) and those of the dextrin-diet were 40.3+/-11.4 and 63.0+/-22.3%, respectively (p<0.05). The decreased preference for the maltose-diet in the Zn-deficient rats may reflect the increased selection of the dextrin-diet.