Lessons LearnedDespite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.Background.Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.Methods.Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3–60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Results.A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.Conclusion.Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.
Workers exposed to DMF with higher urine AMCC levels were more likely to develop liver diseases. In addition, SBA and HA have the potential to act as early indicators of toxic hepatic fibrosis activities for occupational health surveillance.
Background
Systemic inflammatory response is closely related to the development and prognosis of liver failure. This study aimed to establish a new model combing the inflammatory markers including neutrophil/lymphocyte ratio (NLR) and red blood cell distribution width (RDW) with several hematological testing indicators to assess the prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).
Methods
A derivation cohort with 421 patients and a validation cohort with 156 patients were recruited from three hospitals. Retrospectively collecting their clinical data and laboratory testing indicators. Medcalc-15.10 software was employed for data analyses.
Results
Multivariate analysis indicated that RDW, NLR, INR, TBIL and Cr were risk factors for 90-day mortality in patients with HBV-ACLF. The risk assessment model is COXRNTIC = 0.053 × RDW + 0.027 × NLR + 0.003 × TBIL+ 0.317 × INR + 0.003 × Cr (RNTIC) with a cut-off value of 3.08 (sensitivity: 77.89%, specificity: 86.04%). The area under the receiver operating characteristics curve (AUC) of the RNTIC was 0.873 [95% CI(0.837–0.903)], better than the predictive value of MELD score [0.732, 95% CI(0.687–0.774)], MELD-Na [0.714, 95% CI(0.668–0.757)], CTP[0.703, 95% CI(0.657–0.747)]. In the validation cohort, RNTIC also performed a better prediction value than MELD score, MELD-Na and CTP with the AUC of [0.845, 95% CI(0.778–0.898)], [0.768, 95% CI (0.694–0.832)], [0.759, 95% CI(0.684–0.824)] and [0.718, 95% CI(0.641–0.787)] respectively.
Conclusions
The inflammatory markers RDW and NLR could be used as independent predictors of 90-day mortality in patients with HBV-ACLF. Compared with MELD score, MELD-Na and CTP, RNTIC had a more powerful predictive value for prognosis of patients with HBV-ACLF.
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