The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome: the results of the ReFOCUS study

<p><b>Background</b>: Volanesorsen, an investigational inhibitor of apoC-III synthesis, significantly reduced triglyceride levels in clinical trials in patients with familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by marked chylomicronemia leading to a spectrum of symptoms, including recurrent abdominal pain and episodes of potentially fatal acute pancreatitis (AP).</p> <p><b>Objective</b>: To determine the effect of volanesorsen on burden of disease on patients with FCS</p> <p><b>Methods</b>: ReFOCUS was a retrospective global web-based survey open to patients with FCS who received volanesorsen for ≥3 months in an open-label extension study. The survey included questions about patients’ experiences before and after volanesorsen treatment.</p> <p><b>Results</b>: Twenty-two respondents had received volanesorsen for a median of 222 days. Volanesorsen significantly reduced the number of symptoms per patient across physical, emotional, and cognitive domains. Significant reductions from baseline were reported for steatorrhea, pancreatic pain, and constant worry about an attack of pain/AP. Respondents reported that volanesorsen improved overall management of symptoms and reduced interference of FCS with work/school responsibilities. Reductions in the negative impact of FCS on personal, social, and professional life were also reported.</p> <p><b>Conclusions</b>: Treatment with volanesorsen has the potential to reduce disease burden in patients with FCS through modulation of multiple symptom domains.</p

The deubiquitinating enzyme USP17 is associated with non-small cell lung cancer (NSCLC) recurrence and metastasis

USP17 is a cell cycle regulated deubiquitinating enzyme that is highly expressed in tumor-derived cell lines and has an established role in cell proliferation and chemotaxis. This is the first study to examine the clinical significance of USP17 expression in non-small cell lung cancer (NSCLC). USP17 was overexpressed in both squamous and adenocarcinoma NSCLC tissue. Patients with USP17 positive tumors had significantly reduced recurrence-free survival than patients with USP17 negative tumors. Moreover, USP17 was more highly expressed in patients with recurrence of disease at distant sites, suggesting that USP17 levels may correlate with NSCLC distant metastases. Overall, these findings establish USP17 as a potentially valuable novel biomarker for metastatic lung cancer

Relationship between osmolarity and creatinine.

<p>Triplicate levels of osmolarity and creatinine were measured in urine from 119 hematuric patients. There was a modest relationship between osmolarity and creatinine (R Square = 0.519).</p

Creatinine, Osmolarity and Protein distributions.

<p>Triplicate levels of the standards were measured in 120 hematuric patients and then averaged. (A) Osmolarity was normally distributed; (B) creatinine and (C) protein had skewed distributions.</p

Comparison between measured protein levels and protein dipstick analyses.

<p>Total protein levels (mg/ml) in urine were determined by Bradford assay A_{595 nm} (Hitachi U2800 spectrophotometer) using Bovine Serum Albumin as standard. Dipstick analyses were undertaken using Aution Sticks 10EA. Analyses were interpreted using PocketChem (Arkray factory, Inc. Japan). Protein levels were plotted against dipstick results with the Y –axis reference line indicating the usual lower limit of sensitivity for urine dipstick testing (0.25 mg/ml).</p

Comparison of protein levels across final diagnostic categories.

<p>Urinary protein levels measured in 120 patients with hematuria were related to final diagnostic categories in (ANOVA; p = 0.022). Subsequently, we carried out a one way ANOVA with post-hoc Dunnett T3 analyses using log₁₀ transformed protein data. Higher protein levels were measured in urine from patients diagnosed with bladder cancer in comparison to those with no diagnosis (p = 0.073). There were no significant differences between the protein levels measured in patients with confounding pathologies and levels measured in the urines from bladder cancer patients (p = 0.621) or between patients with no diagnosis and patients with confounding pathologies (p = 0.316).</p

SDS PAGE on urine samples.

<p>SDS PAGE was carried out on urine from each patient. A dense band was frequently observed at approximately 64–66 kDa. This band represents albumin. Eight representative samples demonstrate the diverse relationship between this albumin band on the SDS PAGE and corresponding IL-8 levels measured in urine from the same patient sample. Corresponding IL-8 levels are illustrated in the 95% confidence limit error bar chart directly below each lane. The density of the albumin band was not always indicative of the IL-8 levels. Four patients had non-muscle invasive bladder cancer (NMI), one patient had muscle invasive bladder cancer (MI), two patients had no diagnosis (ND), and one patient had benign prostate enlargement.</p

Regression analyses to determine the relationship between differences in standards and biomarkers over time.

<p>Scatter plots, based on data from 72 hematuric patients, plotting the differences between biomarker levels on recruitment and follow-up against the differences between protein levels on recruitment and follow-up for (A) IL-6, (B) IL-8 and (C) VEGF. The regression line and 95% confidence interval show significant associations (p<0.0001 for all biomarkers). Differences in biomarker levels across time were associated with differences in protein levels.</p

Paired t-test comparing standard levels measured on recruitment and at follow-up.

<p>Urine samples were obtained on two visits; one on recruitment and a second at follow-up (median = 11 (1 to 20 months)) from 72 patients who had presented with hematuria. The mean difference between log10 protein levels decreased over time (p = 0.097).</p

AUROC for IL-6, IL-8 and VEGF.

<p>The lowest area under receiver operating characteristic (AUROC) were determined after protein normalization as represented by the solid black curve which was always closest to the diagonal reference line i.e., IL-6 = 0.634 (0.523 to 0.745); IL-8 = 0.677 (0.570 to 0.784); and VEGF = 0.609 (0.501 to 0.716). The AUROCs for uncorrected biomarker levels (thick grey curve), and those standardized using osmolarity (dashed black curve) or creatinine (dashed grey curve) were very similar for individual biomarkers : (A) IL-6 = 0.693 (0.592 to 0.794), 0.683 (0.582 to 0.784) and 0.678 (0.578 to 0.779), respectively; (B) IL-8 = 0.706 (0.608 to 0.804), 0.701 (0.603 to 0.799) and 0.694 (0.592 to 0.795), respectively; and (C) VEGF = 0.705 (0.610 to 0.799), 0.687 (0.591 to 0.783) and 0.680 (0.583 to 0.777), respectively. Figures in brackets are 95% Confidence Intervals.</p