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.

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.

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.

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.

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.

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.