Integrated Predictors by Propensity Scoring With Tumor Markers and Plasma Levels of microRNA-21-5p, IL-17, and IL-10 Complement Early Detection of Hepatocellular Carcinoma in Patients With Liver Cirrhosis.

Objectives: The clinical usefulness of tumor markers alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP) in the early detection of hepatocellular carcinoma (HCC) in patients with liver cirrhosis (LC), including those with marker decline after antiviral therapy, is limited. MicroRNAs (miRNAs) are expected to complement detection; however, their details remain unknown. Our prospective pilot study aimed to improve the surveillance of HCC high-risk LC patients by propensity scoring with tumor markers and additional predictors. Methods: Tumor markers and plasma levels of cytokines and miRNAs were observationally measured and statistically evaluated with propensity scoring in 85 eligible patients: 43 with current HCC (cHCC) including 8 with early-HCC, 22 with previous HCC cured (pHCC), and 20 with intact LC (iLC). Results: The analysis of the area under the receiver operating characteristic curve (AUC) showed that the best single predictor was AFP (0.794 for cHCC-discrimination and 0.771 for pHCC-discrimination). AFP-DCP integrated with miR-21-5p for cHCC-discrimination was 0.896; with IL-10 for pHCC-discrimination was 0.872, these were significantly better than those of AFP alone, independently (P < .01). The best single predictor for iLC-discrimination was IL-17 level (0.756). IL-17 integrated with AFP-DCP was 0.882, which was significantly better than that of IL-17 alone (P < .01). The positive likelihood ratio (pLR) for cHCC-discrimination by integration of AFP-DCP and miR-21-5p was 32.2. Preliminary validation analysis of early-HCCs compared to conventional AFP and DCP showed the combinations of AFP-DCP and 3 integrated predictors, miR-21-5p for cHCC-discrimination, IL-10 for pHCC-discrimination, and IL-17 for iLC-discrimination, sensitivity, specificity, and pLR, improved from 37.5% to 62.5%, 55.8% to 83.1%, and 0.85 to 3.70, respectively. Conclusion: The predictors of AFP-DCP combined with iR-21-5p, IL-10, and IL-17 by propensity scoring achieved higher discrimination of cHCCs, pHCCs, and iLCs, may be beneficial for the surveillance of early-HCCs, improving prediction of early-HCCs over conventional methods. However, further validation is required.

A case report involving suppressed nuclear receptor transcription factors 4a1 and Stevens-Johnson syndrome induced by a single dose of pembrolizumab and successfully treated with early steroid administration, resulting in complete remission of stage III lung cancer.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors is associated with immune-related adverse events (irAEs). A positive correlation between treatment efficacy and irAEs has been reported. Clinical indicators are required for appropriate interventions, such as steroid administration, to prevent fatal outcomes. Nuclear receptor transcription factor 4a (Nr4a), which is involved in T-cell anergy, exhaustion, and regulatory T cells, were observed not only in thymocytes but in peripheral blood mononuclear cells. We describe a case of Stevens-Johnson syndrome (SJS) that was induced by a single dose of pembrolizumab and successfully treated with steroids, leading to complete remission of lung cancer during the monitoring of immune response indices, including Nr4a1 mRNA. CASE PRESENTATION: A 68-year-old male with squamous cell lung cancer (cT2aN3M0, stage IIIb) received a single dose of pembrolizumab (200 mg). On Day 21 of treatment, SJS appeared, and the patient was treated with prednisolone 60 mg/day, which was gradually tapered off. After the disappearance of the SJS symptoms, complete remission of cancer was achieved and was maintained for more than 1 year. Acute increases in the plasma IFN-γ and IL-17 concentrations and a decrease in IL-10 concentrations were observed at the onset of SJS. Simple regression analysis showed that these changes in IL-17, IFN-γ and IL-10 were significantly influenced by the decreased expression of Nr4a1 mRNA. The pembrolizumab levels and prednisolone doses significantly influenced the suppression of Nr4a1 mRNA levels. Although Nr4a1 mRNA levels in the current case fluctuated during the observation period, they were significantly lower than those in a nonresponding progressive-disease case, as well as a pembrolizumab-responding case with non-SJS but similar background. The suppression of Nr4a1 in current case, might result in upregulation of cytotoxic T cells and a reduction in functional regulatory T cells, promoting favorable antitumor immunity. CONCLUSION: The immune responses involving Nr4a1 suppression might relate to complete remission of lung cancer in this case, despite causing SJS, which may be attributed to synergistic effects from pembrolizumab treatment and intervention with steroids. The current case indicates the preliminarily clinical benefit of evaluating Nr4a expression-related indices as the possible clinical covariates and may serve as a milestone for appropriate future chemotherapy interventions.

Concentration of Sulfate and Glucuronide Conjugates of Ritodrine in Twin Pregnancy.

Ritodrine, a drug for the treatment of threatened premature labor, is a highly selective beta-2 agonist with the major metabolites of sulfate and glucuronide conjugates. This study investigated the continuous evaluation of the concentration of ritodrine conjugates in relation to the clinical course in twin pregnancy. The subjects were 9 twin-pregnancy mothers who delivered after receiving ritodrine treatment between April 2012 and December 2013. Serum ritodrine sulfate and glucuronide conjugates were deconjugated using their specific enzymes. Ritodrine concentration was measured by liquid chromatography-tandem mass spectrometry. The continuous infusion rate of ritodrine was 2.66±0.67 (0.8-3.54) µg/min/kg, and the average concentration of unchanged ritodrine was 118.8±33.2 (63.8-194.0) ng/mL. During the study period between week 32 and week 36 of gestation, the average ratio of unchanged ritodrine concentration and sulfate ritodrine conjugate concentration for weeks 32, 33, 34, 35, and 36 were 1.7, 1.9, 1.5, 1.7, and 1.7 not significant (N.S.), respectively. The average ratio of unchanged ritodrine concentration and glucuronide ritodrine conjugate concentration were 1.8, 2.2, 1.9, 1.8, and 2.1 (N.S.), respectively. No statistical difference was identified in the ratios of unchanged ritodrine concentration and sulfate or glucuronide ritodrine conjugate concentrations. Large individual differences were shown in the concentration of sulfate and glucuronide during the gestational period. No change in the ratio of the formation of ritodrine metabolites was identified as the gestational age progressed.

Stereoselective analysis of ritodrine diastereomers in human serum using HPLC.

A sensitive and selective method has been developed for the determination of ritodrine diastereomers in human serum using high-performance liquid chromatography with a chiral stationary phase column and a fluorescence detector. No interfering peaks from endogenous substances were observed. The method showed good reproducibility and accuracy, and the standard curve was linear up to 100 ng/mL with a correlation coefficient of 0.999. Limit of detection (signal-to-noise = 3) and quantitation (signal-to-noise = 10) were found to be 2 and 5 ng/mL, respectively. This method is suitable for chiral pharmacological and pharmacokinetic studies as well as the therapeutic drug monitoring of ritodrine diastereomers for which no information currently exists.