An Open-label,Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor,in Diffuse Large B-cell Lymphoma

Background

Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. Entospletinib monotherapy was evaluated in a multicenter, phase II study of subjects with relapsed or refractory B-cell malignancy.

Gray matter density reduction associated with adjuvant chemotherapy in older women with breast cancer

Purpose

The purpose of this study was to evaluate longitudinal changes in brain gray matter density (GMD) before and after adjuvant chemotherapy in older women with breast cancer.

Methods

We recruited 16 women aged ≥?60 years with stage I–III breast cancers receiving adjuvant chemotherapy (CT) and 15 age- and sex-matched healthy controls (HC). The CT group underwent brain MRI and the NIH Toolbox for Cognition testing prior to adjuvant chemotherapy (time point 1, TP1) and within 1 month after chemotherapy (time point 2, TP2). The HC group underwent the same assessments at matched intervals. GMD was evaluated with the voxel-based morphometry.

Results

The mean age was 67 years in the CT group and 68.5 years in the HC group. There was significant GMD reduction within the chemotherapy group from TP1 to TP2. Compared to the HC group, the CT group displayed statistically significantly greater GMD reductions from TP1 to TP2 in the brain regions involving the left anterior cingulate gyrus, right insula, and left middle temporal gyrus (p_{FWE(family-wise error)-corrected}?<?0.05). The baseline GMD in left insula was positively correlated with the baseline list-sorting working memory score in the HC group (p_{FWE-corrected}?<?0.05). No correlation was observed for the changes in GMD with the changes in cognitive testing scores from TP1 to TP2 (p_{FWE-corrected}?<?0.05).

Conclusions

Our findings indicate that GMD reductions were associated with adjuvant chemotherapy in older women with breast cancer. Future studies are needed to understand the clinical significance of the neuroimaging findings. This study is registered on ClinicalTrials.gov (NCT01992432).

     

The role of MRI in the early evaluation of lung microwave ablation

Purpose: To retrospectively investigate the role of a contrast enhanced MRI (ceMRI) performed 24?h after a microwave ablation (MWA) of the lung, in predicting local tumour progression (LTP) and detecting complications compared to an unenhanced CT.

Material and methods: Forty-nine patients who underwent MWA of 77 lung metastases between 2008 and 2015 were included. All patients received an unenhanced chest CT and a ceMRI (including T2 and ceT1) 24?h after MWA. The conspicuities of the peripheral rim and the ablated tumour were scored using 1–3 scales and compared between examinations. The safety margin was measured directly (both scores ≥2) and indirectly using a subtraction method. The ability of each imaging modality to predict LTP based on safety margin width was analysed using receiver operating characteristic curves. The MRI ability to detect a pneumothorax was compared to CT.

Results: The peripheral rim was best visualised on T2 followed by T1 and CT. The tumour was best visualised on CT, followed by T1 and T2. Direct safety margin measurement was possible on CT, ceT1 and T2 in 68.8%, 64.9% and 27.3% of cases, respectively. Direct CT (AUC?=?0.77) and ceT1 (AUC?=?0.76) measurements had better diagnostic performance than indirect CT (AUC?=?0.72), ceT1 (AUC?=?0.70) and T2 (AUC?=?0.69) measurements. The MRI sensitivity and specificity for pneumothorax were 60.8% and 87.0%, respectively. Only one pneumothorax >1?cm was missed.

Conclusions: A ceMRI performed 24?h after MWA of lung tumours has a similar ability to predict LTP and detect important complications as a CT has.     

Persistent atrial fibrillation vs paroxysmal atrial fibrillation: differences in management

Introduction: Atrial fibrillation (AF) is the most common human arrhythmia. AF is a progressive disease, initially being nonsustained and induced by trigger activity, and progressing towards persistent AF through alteration of the atrial myocardial substrate. Treatment of AF aims to decrease the risk of stroke and improve the quality of life, by preventing recurrences (rhythm control) or controlling the heart rate during AF (rate control). In the last 20 years, catheter-based and, less frequently, surgical and hybrid ablation techniques have proven more successful compared with drug therapy in achieving rhythm control in patients with AF. However, the efficiency of ablation techniques varies greatly, being highest in paroxysmal and lowest in long-term persistent AF.

Areas covered: In this review, we discuss the fundamental differences between paroxysmal and persistent AF and the potential impact of those differences on patient management, emphasizing the available therapeutic strategies to achieve rhythm control.

Expert commentary: Treatment to prevent AF recurrences is suboptimal, particularly in patients with persistent AF. Emerging technologies, such as documentation of atrial fibrosis using magnetic resonance imaging and documentation of electrical substrate using advanced electrocardiographic imaging techniques are likely to provide valuable insights about patient-specific tailoring of treatments.     

Small molecules as therapy for uveitis: a selected perspective of new and developing agents

Introduction: Intraocular inflammation (uveitis) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes corticosteroids, disease-modifying anti-rheumatic drugs and more recently biologics as immune modulatory agents. The purpose of this article is to identify the role of new treatment approaches focusing on small molecules as therapeutic option in uveitis.

Areas covered: A MEDLINE database search was conducted through February 2017 using the terms ‘uveitis’ and ‘small molecule’. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Both, results from experimental as well as clinical research in this field were included. Since this field is rapidly evolving, a selection of promising agents had to be made.

Expert opinion: Small molecules may interfere at different steps of the inflammatory cascade and appear as an interesting option in the treatment algorithm of uveitis. Because of their highly targeted molecular effects and their favorable bioavailability with the potential of topical application small molecules hold great promise. Nevertheless, a careful evaluation of these agents has to be made, since current experience is almost exclusively based on experimental uveitis models and few registered trials.     

Studies on the pharmacokinetics of chlorambucl and prednimustine in patients using a new high-performance liquid chromatographic assay

Summary Following the oral administration of either chlorambucil/prednisolone or prednimustine to patients, the plasma levels of free chlorambucil and phenylacetic acid mustard, the -oxidation product of chlorambucil, were measured using a new high-performance liquid chromatographic (HPLC) assay. This assay permitted the simultaneous detection of the analyzed compounds with a lower limit of detection of 30 ng/ml. The pharmacokinetics of chlorambucil and phenylacetic acid mustard were found to be entirely different when prednimustine was administered as opposed to its components chlorambucil and prednisolone together. After the ingestion of the conjugate, the plasma concentration-time curves of chlorambucil and phenylacetic acid mustard showed a delayed pattern compared with those obtained after the administration of the components. The mean area under the concentration-time curves (AUCs) of prednimustine-derived chlorambucil and phenylacetic acid mustard were 25% and 40%, respectively, of the areas obtained after a stoichiometrically equivalent dose of chlorambucil. Free plasma prednimustine could not be detected at any time. This different pharmacokinetic behavior might offer an explanation for the superior therapeutic effects of prednimustine demonstrated by clinical studies.Supported by the Ministry of Science and Research, Land Nordrhein-Westfalen