Factors associated with increased risk of lurasidone-induced somnolence: Two case-control studies based on one bioequivalence trial in healthy volunteers.

Somnolence is a common adverse effect of antipsychotic drugs used to treat psychotic disorders. It causes problems in many areas of life, such as gainful employment, driving, childcare, and social interactions. Somnolence is a major problem for a relatively new antipsychotic drug, lurasidone, whose dose-effect relationship remains unclear. Based on data from a bioequivalence study of two 40 mg lurasidone hydrochloride tablets, we designed two case-control studies to explore the correlation between somnolence and exposure to lurasidone and determine the factors associated with lurasidone-induced somnolence. In the first case-control study, lurasidone was administered to healthy volunteers; 30 experienced somnolence (as pre-defined) but 29 did not. Moreover, plasma concentration at 1 h was significantly associated with somnolence (OR = 1.124; p = 0.001). In the second case-control study, 48 volunteers administered lurasidone were classified into somnolence and no-somnolence groups based on different time-related criteria. We observed a positive association between plasma concentration at 0.75 h and somnolence (OR = 1.024; p = 0.002). Receiver operating characteristic analysis revealed that a plasma lurasidone concentration >21.65 ng/mL 1 h after administration strongly predicted somnolence. Our findings in healthy volunteers need to be further validated in patients in clinical settings to determine the optimal dose and duration of lurasidone administration.

Glycyrrhizin for treatment of CRS caused by CAR T-cell therapy: A pharmacological perspective.

Chimeric antigen receptor T (CAR T)-cell therapy promises to revolutionize the management of hematologic malignancies and possibly other tumors. However, the main side effect of cytokine release syndrome (CRS) is a great challenge for its clinical application. Currently, treatment of CRS caused by CAR T-cell therapy is limited to tocilizumab (TCZ) and corticosteroids in clinical guidelines. However, the theoretical risks of these two agents may curb clinicians' enthusiasm for their application, and the optimal treatment is still debated. CAR T-cell therapy induced-CRS treatment is a current research focus. Glycyrrhizin, which has diverse pharmacological effects, good tolerance, and affordability, is an ideal therapeutic alternative for CRS. It can also overcome the shortcoming of TCZ and corticosteroids. In this brief article, we discuss the therapeutic potential of glycyrrhizin for treating CRS caused by CAR T-cell therapy from the perspective of its pharmacological action.

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia.

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. SIGNIFICANCE: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369.

A Bioequivalence Study of Avanafil in Healthy Chinese Male Subjects Under Fasting and Fed Conditions: Results of a Randomized, Open-Label, Single-Dose, 2-Sequence, 2-Period Crossover Study.

This bioequivalence study was conducted to determine the pharmacokinetics and safety profiles of an originator and a generic avanafil formulation in Chinese male subjects under fed and fasting conditions. Each eligible subject was initially randomly given avanafil (200 mg) in a test-reference or reference-test order, before being switched to another study drug sequence after 7 drug-free days. The bioequivalence of test and reference avanafil were determined if the 90%CIs of the geometric mean ratio (GMR) for the area under plasma concentration-time curve (AUC) from time 0 to infinity (AUC0-∞ ), AUC from time 0 to the last detectable concentration (AUC0-t ), and the maximum plasma concentration (Cmax ) fell within the range 80%-125%. Under fasting/fed conditions, the 90%CIs of GMR for AUC0-∞ , AUC0-t , and Cmax were 98.9% to 109.5%/96.0% to 101.2%, 99.6% to 110.3%/96.6% to 102.4%, and 99.3% to 116.8%/94.3% to 106.7%, respectively, which were all within the 80%-125% range. Adverse events (AEs) occurred in 20.8% of subjects under fasting conditions and 20.7% of subjects under fed conditions, with a severity of grade 1. No significant difference was found in the rate of occurrence of AEs and drug-related AEs in the test and reference-avanafil groups (all P > .05). We concluded that the test and reference avanafil were bioequivalent in healthy Chinese male subjects under fasting and fed conditions.

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials.

PURPOSE: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. PATIENTS AND METHODS: In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). RESULTS: A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. CONCLUSIONS: This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.

Oliguric acute kidney injury after microwave ablation of large liver tumors: incidence and preventive measures.

PURPOSE: Acute kidney injury (AKI), especially oliguric AKI, is a recognized complication following microwave ablation (MWA) of large liver tumors. This study evaluated the clinical features, mechanisms, risk factors and prevention strategies for oliguric AKI after MWA of large liver tumors. METHODS: From March 2011 to May 2015, 441 patients with liver tumors ≧5 cm received MWA in our hospital. The clinical features, prevention strategies, further mechanisms and possible risk factors for oliguric AKI after MWA were analyzed. RESULTS: One hundred four (23.6%) patients had AKI after MWA; 11 (10.6%) patients had oliguric AKI, and 93 (89.4%) patients had nonoliguric AKI. All patients with nonoliguric AKI recovered without any special treatments. The eleven patients with oliguric AKI received appropriate treatments and had completely normal renal function three months later. Using double needles for ablation was a risk factor for nonoliguric AKI, while high preoperative levels of red blood cells (RBC), hemoglobin (HGB) and albumin (Alb) were risk factors for oliguric AKI. The decrease levels of hemoglobin were significantly high in oliguric AKI patients (p < .05). Patients with oliguric AKI had abnormally high postoperative transaminase and renal function indicators. Compared to postoperative prevention, intraoperative prevention significantly lowered the occurrence of oliguric AKI (0% vs. 3.7%, p = .018) and shortened the hospital stay. CONCLUSIONS: Patients who underwent MWA for large liver tumors are prone to develop oliguric AKI. Implementation of intraoperative strategies during MWA can effectively prevent the occurrence of this severe complication.

Clinical outcome in elderly Chinese patients with primary hepatocellular carcinoma treated with percutaneous microwave coagulation therapy (PMCT): A Strobe-compliant observational study.

Percutaneous microwave ablation therapy (PMCT) has been recommended for elderly hepatocellular carcinoma (HCC) patients who cannot tolerate surgery due to their age or presence of comorbidities. Few studies have investigated efficacy and treatment outcomes for PMCT treatment in these patients, especially in China, where patients are more often diagnosed and treated early in life. This study evaluated the safety and efficacy of ultrasound-guided PMCT in treatment-naive elderly HCC patients, and analyzed risk factors associated with poor treatment outcomes.The 65 HCC patients in this retrospective study were divided into 2 groups: <65 years old or ≥65 years old. Patients received PMCT every month until tumor was unobservable and were then followed for 1 month after ablation. The primary clinical endpoint was the rate of complete tumor ablation, and secondary endpoints were progression-free survival and overall survival.Patients ≥65 years old had significantly poorer performance status than younger patients, but similar rates of complete ablation. Multiple tumors and hypertension were associated with a significantly higher risk of death, while higher postoperative alanine aminotransferase levels were associated with a significantly lower risk of death. Patients with tumor sizes >5 to ≤ 10 cm were at a significantly higher risk for disease progression than patients with tumor sizes >1 to ≤ 3 cm. Complete ablation significantly lowered the risk of disease progression.PMCT is safe and effective for patients ≥65 years of age, achieving total ablation in more than 90% of patients. Age and comorbidities did not affect clinical outcome.

Feasibility, safety, and efficacy of ultrasound-guided percutaneous microwave ablation for giant hepatic hemangioma.

BACKGROUND: Hepatic hemangioma is a common benign liver tumor. The majority of cases are asymptomatic and require no specific treatment. The aim of this study was to evaluate the feasibility, safety and efficacy of microwave ablation (MWA) for symptomatic or enlarging giant hepatic hemangioma (≥10 cm). METHODS: From December 2013 to June 2016, 12 patients with giant hepatic hemangioma (≥10 cm) underwent ultrasound-guided percutaneous MWA, and ablation-related complications were observed. All patients were followed up with magnetic resonance or enhanced CT imaging at one month postoperatively to evaluate efficacy. RESULTS: This study included a total of 13 giant hepatic hemangiomas (mean: 11.7 ± 1.6 cm) in 12 patients who initially underwent 16 sessions of MWA; three lesions were treated with two sessions of planned ablation. The average ablation time for a single hepatic hemangioma was 39.0 ± 14.4 minutes. Two patients had acute postoperative non-oliguric renal insufficiency without intra-abdominal hemorrhage, liver failure or other complications. Initially, complete ablation was achieved in ten lesions in nine patients (76.9%, 10/13). One patient underwent a second session of MWA at 5 months postoperatively due to fast growing residual tissue; complete necrosis was achieved after treatment. The remaining two cases did not receive any invasive treatment due to small residual volumes. The total complete ablation rate was 84.6% (11/13). CONCLUSION: Image-guided MWA is a safe, feasible, effective treatment for giant hepatic hemangioma; these findings may open a new avenue for treatment.

Development of Ligand-based Big Data Deep Neural Network Models for Virtual Screening of Large Compound Libraries.

High-performance ligand-based virtual screening (VS) models have been developed using various computational methods, including the deep neural network (DNN) method. There are high expectations for exploration of the advanced capabilities of DNN to improve VS performance, and this capability has been optimally achieved using large data training datasets. However, their ability to screen large compound libraries has not been evaluated. There is a need for developing and evaluating ligand-based large data DNN VS models for large compound libraries. In this study, we developed ligand-based large data DNN VS models for inhibitors of six anticancer targets using 0.5 M training compounds. The developed VS models were evaluated by 10-fold cross-validation, achieving 77.9-97.8 % sensitivity, 99.9-100 % specificity, 0.82-0.98 Matthews correlation coefficient and 0.98-0.99 area under the curve, outperforming random forest models. Moreover, DNN VS models developed by pre-2015 inhibitors identified 50 % of post-2015 inhibitors with a 0.01-0.09 % false positive rate in screening 89 M PubChem compounds, also outperforming previous models. Experimental assays of the selected virtual hits of the EGFR inhibitor model led to reasonable novel structures of EGFR inhibitors. Our results confirmed the usefulness of the large data DNN model as a ligand-based VS tool to screen large compound libraries.

Knockdown of the differentially expressed gene TNFRSF12A inhibits hepatocellular carcinoma cell proliferation and migration in vitro.

Human hepatocellular carcinoma (HCC) has been reported to be highly insensitive to conventional chemotherapy. In the current study, the Agilent Whole Human Genome Oligo Microarray (4x44 K) was used in order to identify the differentially expressed genes between HCC and adjacent tissues, and the top 22 differentially expressed genes were confirmed through reverse transcription­quantitative polymerase chain reaction. Among the identified differences in gene expression, expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) was markedly higher in HCC tissue than in adjacent tissue. Previous studies have suggested that TNFRSF12A may serve a role in tumor growth and metastasis, thus in the current study, TNFRSF12A was knocked down in the SMMC7721 cell line through siRNA. This demonstrated that cells exhibited reduced reproductive and metastatic capacity ex vivo. Thus, the results of the current study suggest that TNFRSF12A may be a candidate therapeutic target for cancer including HCC, and additional genes that exhibited significantly different expression from normal adjacent tissues require further study.

Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma: clinical outcomes and prognostic factors.

OBJECTIVE: The aim of this study was to evaluate the clinical outcomes of ultrasound-guided percutaneous microwave ablation (US-guided PMWA) for the treatment of hepatocellular carcinoma (HCC) with the analysis of prognostic factors. MATERIALS AND METHODS: The treatment and survival parameters of 433 patients with HCC (≤10 cm), who met the inclusion criteria and had received US-guided PMWA in Renji Hospital from July 2010 to November 2014, were retrospectively analyzed. Imaging examination (contrast-enhanced CT or MR) and tumor markers (AFP and CA199) 1 month after MWA were used to evaluate the efficacy of US-guided PMWA. SPSS software was used to perform all statistical analyses. RESULTS: The initial complete ablation (CA) rate was 94.9 % (411/433). Twenty-two patients with incomplete ablation received repeat PMWA, and the total CA rate was up to 98.6 % (427/433). Multiple tumor number, tumor >5 cm in diameter, and higher serum AFP level (>20 ng/ml) were significant unfavorable prognosticators of progression-free survival (PFS). The cumulative 1-, 2-, and 3-year overall survival (OS) rates were 83.5, 66.1, and 58.7 %, respectively (median: 43 months). Tumor >5 cm in diameter and serum AFP >400 ng/ml were significant unfavorable prognosticators of OS. CONCLUSIONS: PMWA is well tolerated in HCC patients and capable of offering high CA rate. Tumor number, tumor size, and AFP level were significant prognosticators of patients' PFS, whereas tumor size and AFP level were significant prognosticators of OS.

Long noncoding RNA ZNFX1-AS1 suppresses growth of hepatocellular carcinoma cells by regulating the methylation of miR-9.

Many long noncoding RNAs have been reported to play pivotal roles in cancer biology. Among them, the long noncoding RNA ZNFX1-AS1 has been confirmed to function in breast cancer progression, but the role of ZNFX1-AS1 in hepatocellular carcinoma (HCC) growth and the related molecular mechanisms still remains unknown. In the present study, we first identified the expression of ZNFX1-AS1 in HCC patients' specimens and HCC cell lines through quantitative reverse transcription polymerase chain reaction. Next, the effects of ZNFX1-AS1 on HCC cell growth and apoptosis were analyzed. MTT assay was used to measure the cell numbers, and fluorescence-activated cell sorting analysis was performed to evaluate cell apoptosis. Finally, the relationship between ZNFX1-AS1 and miR-9 in HCC was studied. Our results suggest that ZNFX1-AS1 was markedly downregulated in HCC samples and cell lines. Overexpression of ZNFX1-AS1 inhibited the cell proliferation and colony formation in HCC cell lines and also induced HCC cell apoptosis. Additionally, miR-9 was lowly expressed in HCC tissues and positively correlated with ZNFX1-AS1 expression. Meanwhile, significant upregulation of miR-9 and downregulation of the methylation of miR-9 promoter CpG island were observed when ZNFX1-AS1 was overexpressed. In summary, our results indicate that ZNFX1-AS1 plays a vital role in HCC progression via regulating the methylation of miR-9 and may be a potential tumor suppressor.

Hepatocellular carcinoma: thyroid hormone promotes tumorigenicity through inducing cancer stem-like cell self-renewal.

Cancer stem-like cells (CSCs) play a key role in maintaining the aggressiveness of hepatocellular carcinoma (HCC), but the cell-biological regulation of CSCs is unclear. In the study, we report that thyroid hormone (TH) promotes cell self-renewal in HCC cells. TH also increases the percentage of CD90 + HCC cells and promotes drug resistance of HCC cells. By analyzing primary human HCC samples, we found that TRα transcript level is significantly elevated in primary liver cancer and portal vein metastatic tumor, compared to that of adjacent normal liver tissue. Knocking down TRα not only inhibits HCC self-renewal in vitro but also suppresses HCC tumor growth in vivo. Interestingly, treatment of TH leads to activation of NF-κB, which is required for the function of TH on inducing HCC cell self-renewal. We also found TRα and p65 cooperatively drive the expression of BMI1 by co-binding to the promoter region of BMI1 gene. In summary, our study uncovers a novel function of TH signaling in regulating the CSCs of HCC, and these findings might be useful for developing novel therapies by targeting TH function in HCC cells.

Evaluation of the safety and efficacy of percutaneous radiofrequency ablation for treating multiple breast fibroadenoma.

BACKGROUND: This study was conducted to evaluate the safety and efficacy of ultrasound (US)-guided percutaneous radiofrequency ablation (RFA) for multiple breast fibroadenoma as an alternative to surgical resection. PATIENTS AND METHODS: Sixty-five patients with multiple breast fibroadenoma accepted general anesthesia and US-guided percutaneous RFA in our hospital from September 2014 to January 2016. Contrast-enhanced US (CEUS) was used immediately after operation to determine whether the tumor was ablated completely. The complete ablation rate (CAR) and the change of focal volume were evaluated by CEUS at the 1st month and the 3rd month after operation. RESULTS: All the patients were diagnosed by needle biopsy. Among all the patients, 256 nodules were found. Forty-six nodules (17.96%) were located <5 mm from epidermis; 26 nodules (10.15%) were located below areola. Complete ablation was achieved for 251 nodules (98.04%) after the 1st month of operation. The volume reduce rate was 39.06% and 75.99% at the 1st and the 3rd month after operation, respectively, of which 45 nodules were completely absorbed (17.58%). There was a statistically significant difference of the volume reduction rate (VRR) after operation (P < 0.01) compared with preoperative breast nodules volume. There were no complications such as skin burn, hemorrhage, and hematoma, nipple discharge in the process during and after RFA. CONCLUSION: Given advantages of high CAR, mild injury, rapid recovery, and cosmetic outcome desired by the patients, RFA has the potential to become the preferred method in the treatment of breast fibroadenoma.