A Phase I/II Study of Valemetostat (DS-3201b), an EZH1/2 Inhibitor, in Combination with Irinotecan in Patients with Recurrent Small-Cell Lung Cancer.

Purpose: Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted.

Patients And Methods: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC.

A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor.

Purpose: To evaluate DS-6157a, an antibody-drug conjugate targeting G protein-coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST).

Patients And Methods: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg.

Development of an individualized procedure to induce reward-related impulsivity and evaluating its impact on drinking control.

High impulsivity predisposes young adults to engage in hazardous alcohol use. Experimental research has shown that reward-related impulsivity is causally-related to heavier drinking. Correlational studies suggest that positive alcohol outcome expectancies mediate this effect, but causation has yet to be established.

Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug-drug interaction study in patients with ALK + advanced tumors.

Purpose: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively.

Methods: This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors.

Phase 1/2 study of ceritinib in Chinese patients with advanced anaplastic lymphoma kinase-rearranged non-small cell lung cancer previously treated with crizotinib: Results from ASCEND-6.

Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC) treated with crizotinib inevitably relapse, with brain as common site of progression.

Patients And Methods: ASCEND-6, a phase 1/2, single-arm study, included adult Chinese patients with stage IIIB or IV ALK+ NSCLC pretreated with crizotinib as the last therapy (irrespective of prior chemotherapies [≤2]). Primary endpoints were pharmacokinetics (PK), safety, and tolerability.

Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non-Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study.

Introduction: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients.

Methods: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal.

Application of time-dependent modeling for the exposure-efficacy analysis of ceritinib in untreated ALK-rearranged advanced NSCLC patients.

Purpose: Ceritinib 750 mg/day was approved for the treatment of patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) based on ASCEND-4 study. The objective of this article is to introduce the use of time-dependent modeling approach in the updated exposure-efficacy analysis of ceritinib for the first-line indication.

Methods: Exposure-efficacy analyses, including data from 156 patients, were first conducted using time-independent logistic regression model for response of complete or partial response and Cox regression model for progression-free survival (PFS).

Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study.

Introduction: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.

Methods: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.

ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC).

Introduction: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure.

Methods: ASCEND-8 is a multicenter, randomized, open-label, phase 1 study.

Changes in dural sac caliber with standing MRI improve correlation with symptoms of lumbar spinal stenosis.

Purpose: Weight bearing does alter the dimension of lumbar spinal canal, but no study has analyzed its clinical correlation. This study aims to evaluate whether the changes in dural sac cross-sectional area (DSCA) and sagittal anteroposterior (AP) diameter on standing magnetic resonance imaging (MRI) correlate better with clinical symptoms of lumbar spinal stenosis.

Methods: Seventy consecutive patients with neurogenic claudication were prospectively recruited to undergo a 0.

Assessment of drug-drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK-positive non-small cell lung cancer.

Purpose: The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.

Methods: A healthy subject drug-drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed.

Population Pharmacokinetics of Ceritinib in Adult Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase.

Ceritinib is a second-generation selective and potent oral anaplastic lymphoma kinase (ALK) inhibitor approved for ALK-positive advanced non-small cell lung cancer previously treated with crizotinib. Population pharmacokinetic (PK) analysis was performed to describe the PK of ceritinib and was used to evaluate the covariate effects on systemic exposure at its label dose (750 mg orally once daily). Ceritinib concentration-time data from 4 clinical studies were described by a 1-compartment model with delayed first-order absorption and time-dependent elimination.

Predation by Red Foxes (Vulpes vulpes) at an Outdoor Piggery.

Outdoor pig operations are an alternative to intensive systems of raising pigs; however for the majority of outdoor pork producers, issues of biosecurity and predation control require significant management and (or) capital investment. Identifying and quantifying predation risk in outdoor pork operations has rarely been done, but such data would be informative for these producers as part of their financial and logistical planning. We quantified potential impact of fox predation on piglets bred on an outdoor pork operation in south-western Australia.

Improvement of learning domains of nursing students with the use of authentic assessment pedagogy in clinical practice.

With evolving healthcare demands, nursing educators need to constantly review their teaching methodologies in order to enhance learners' knowledge and competency of skills in the clinical settings. Learning is an active process in which meaning is accomplished on the basis of experience and that authentic assessment pedagogy will enable nursing students to play an active part in their learning. The study was conducted with an aim to examine nursing students' learning domains through the introduction of the authentic assessment pedagogy during their clinical practice.

Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects.

Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), which has shown acceptable safety and substantial antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) patients. Two food-effect studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg and a study with a light snack at 750 mg. Compared with the fasted state, AUC0-∞ (90%CI) of ceritinib was increased by 58% (34%, 86%) after the intake of a low-fat meal, by 73% (46%, 105%) after the intake of a high-fat meal, and by 54% (19%, 99%) after the intake of a light snack.

Diagnostic capability of low- versus high-field magnetic resonance imaging for lumbar degenerative disease.

Study Design: Cohort study.

Objective: To investigate the diagnostic capability of low-field magnetic resonance imaging (MRI) compared with high-field MRI for degenerative disease of the lumbar spine.

Summary Of Background Data: Low-field MRI has several advantages over high-field magnetic resonance systems (easier installation, lower purchase, and maintenance cost).

Liquid chromatography tandem mass spectrometry method for the quantitative analysis of ceritinib in human plasma and its application to pharmacokinetic studies.

Ceritinib is a highly selective inhibitor of an important cancer target, anaplastic lymphoma kinase (ALK). Because it is an investigational compound, there is a need to develop a robust and reliable analytical method for its quantitative determination in human plasma. Here, we report the validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the rapid quantification of ceritinib in human plasma.

Ceritinib in ALK-rearranged non-small-cell lung cancer.

Background: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.

Methods: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK.

Modeling hepatic osteodystrophy in Abcb4 deficient mice.

Hepatic osteodystrophy (HOD) denotes the alterations in bone morphology and metabolism frequently observed in patients with chronic liver diseases, in particular in case of cholestatic conditions. The molecular mechanisms underlying HOD are only partially understood. In the present study, we characterized the bone phenotypes of the ATP-binding cassette transporter B4 knockout mouse (Abcb4(-/-)), a well-established mouse model of chronic cholestatic liver disease, with the aim of identifying and characterizing a mouse model for HOD.

Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes.

Fibroblast growth factor 21 (FGF21) is a promising drug candidate for the treatment of type 2 diabetes. However, the use of wild type native FGF21 is challenging due to several limitations. Among these are its short half-life, its susceptibility to in vivo proteolytic degradation and its propensity to in vitro aggregation.

Mechanistic modeling of antigen sink effect for mavrilimumab following intravenous administration in patients with rheumatoid arthritis.

Mavrilimumab is a fully human monoclonal antibody that binds to granulocyte-macrophage colony stimulating factor receptor α (GM-CSFRα) with high affinity and specificity and has potential application in various inflammatory diseases. The objective of this investigation was to develop a mechanistic population model to characterize the pharmacokinetics of mavrilimumab, the GM-CSFRα-mediated clearance, and receptor occupancy following single intravenous dosing to patients with rheumatoid arthritis. The internalization rate of mavrilimumab-GM-CSFRα complex was fixed to a value determined from quantitative confocal fluorescent imaging.

Pharmacokinetic and pharmacodynamic modeling of a monoclonal antibody antagonist of glucagon receptor in male ob/ob mice.

Elevated basal concentrations of glucagon and reduced postprandial glucagon suppression are partly responsible for the increased hepatic glucose production seen in type 2 diabetic patients. Recently, it was demonstrated that an antagonistic human monoclonal antibody (mAb) blocking glucagon receptor (GCGR) has profound glucose-lowering effects in various animal models. To further understand the effects on glucose homeostasis mediated by such an antibody, a pharmacokinetic-pharmacodynamic (PK-PD) study was conducted in a diabetic ob/ob mouse model.

Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models--association with liver and adipose tissue effects.

Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions.

Intraosseous glomus tumor treated by toe-to-finger transfer: case report.

We report a case of intraosseous glomus tumor that developed in the right ring finger distal phalanx of a 19-year-old man. Clinical and radiographic findings were atypical. The tumor was excised en bloc because of the extensive involvement.