Research Spotlight

Posted April 15th 2016

A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.

Carlos Becerra M.D.

Carlos Becerra, M.D.

Coveler, A. L., A. H. Ko, D. V. Catenacci, D. Von Hoff, C. Becerra, N. C. Whiting, J. Yang and B. Wolpin (2016). “A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.” Invest New Drugs Mar 18. [Epub ahead of print]

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Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.


Posted April 15th 2016

Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from Fabry mice.

Raphael Schiffmann M.D.

Raphael Schiffmann, M.D.

Meng, X. L., T. S. Day, N. McNeill, P. Ashcraft, T. Frischmuth, S. H. Cheng, Z. P. Liu, J. S. Shen and R. Schiffmann (2016). “Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from Fabry mice.” J Inherit Metab Dis. Mar 10. [Epub ahead of print]

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Fabry disease is caused by deficient activity of alpha-galactosidase A and subsequent intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Vascular endothelial cells may play important roles in disease pathogenesis, and are one of the main target cell types in therapeutic interventions. In this study, we generated immortalized aortic endothelial cell lines from a mouse model of Fabry disease. These cells retained endothelial cell-specific markers and functions. Gb3 expression level in one of these clones (referred to as FMEC2) was highly susceptible to culture media, and appeared to be regulated by glucosylceramide synthase. Results also showed that Gb3 could be upregulated by hydrocortisone. FMEC2 express the mannose 6-phosphate receptor and sortilin but not the mannose receptor. Uptake studies suggested that sortilin plays a role in the binding and internalization of mammalian cell-produced alpha-galactosidase A. Moss-aGal (a plant-made enzyme) was endocytosed by FMEC2 via a receptor other than the aforementioned receptors. In conclusion, this study suggests that glucosylceramide synthase and hydrocortisone may play important roles in modulating Gb3 levels in Fabry mouse aortic endothelial cells, and that endocytosis of recombinant alpha-galactosidase A involves a combination of multiple receptors depending on the properties of the enzyme.


Posted April 15th 2016

Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Alan M. Menter M.D.

Alan M. Menter, M.D.

Menter, A., K. A. Papp, M. Gooderham, D. M. Pariser, M. Augustin, F. A. Kerdel, S. Fakharzadeh, K. Goyal, S. Calabro, W. Langholff, S. Chavers, D. Naessens, J. Sermon and G. G. Krueger (2016). “Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).” J Eur Acad Dermatol Venereol. Mar 30. [Epub ahead of print]

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BACKGROUND: Drug survival is a marker for treatment sustainability in chronic diseases such as psoriasis. OBJECTIVE: The aim of these analyses was to assess survival of biologic treatments in the PSOriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is a large, prospective, international, disease-based registry of patients with psoriasis receiving (or eligible for) systemic therapy in a real-world setting. Drug survival is defined as the time from initiation to discontinuation (stop/switch) of biologic therapy on registry. The number of patients who discontinued each treatment and the duration of therapy were recorded. Using Kaplan-Meier survival curves and Cox-regression analyses [hazard ratios (HR) and 95% confidence intervals (CIs)], time to discontinuation was compared across cohorts undergoing first-, second- or third-line treatment with ustekinumab, infliximab, adalimumab or etanercept. RESULTS: As of the 2013 data cut, 12 095 patients with psoriasis were enrolled in PSOLAR. Of the 4000 patients initiating any new biologic therapy, approximately 3500 started a first-line, second-line or third-line biologic therapy during the registry. Lack of effectiveness was the most common reason for discontinuation across biologic therapies. Based on the multivariate analysis, significantly shorter times to discontinuation were observed for infliximab [HR (95%CI) = 2.73 (1.48-5.04), P = 0.0014]; adalimumab [4.16 (2.80-6.20), P < 0.0001]; and etanercept [4.91 (3.28-7.35) P < 0.0001] compared with ustekinumab [reference treatment]) for first-line biologic use; results were similar for treatment effects for second/third-line therapies. Although limited in power, analyses in patients with concurrent psoriatic arthritis confirmed by a rheumatologist reflect observations in the overall psoriasis population. CONCLUSION: Drug survival was superior for ustekinumab compared with infliximab, adalimumab and etanercept in patients with psoriasis.


Posted April 15th 2016

Influence of Chronic Renal Failure on Cardiac Structure.

Peter McCullough M.D.

Peter McCullough, M.D.

McCullough, P. A. and W. C. Roberts (2016). “Influence of Chronic Renal Failure on Cardiac Structure.” J Am Coll Cardiol 67(10): 1183-1185.

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It has been long recognized that patients with end-stage renal disease (ESRD) have an approximate 10-fold increase in mortality compared to age-matched individuals in the general population. Approximately one-half of this mortality is attributable to cardiovascular disease in the large domains of coronary artery disease, valvular abnormalities, arrhythmias, and cardiomyopathy. Our understanding of “structural heart disease” among those with ESRD has come from autopsy studies describing abnormalities including increased cardiac and left ventricular (LV) mass, mitral and aortic calcium, and marked calcific deposits in atherosclerotic plaques in the coronary arteries, aorta, and peripheral arteries. Morphological studies have also demonstrated high rates of pericardial disease (thickening and calcium) as well as myocardial hemosiderosis in ESRD. Physiological derangements over the course of many years, including pressure overload, volume overload, and derangements in myocyte function, also play a central role in the development of morphological abnormalities seen in ESRD. Cardiac ultrasonography has added to our understanding that these morphological changes have physiological consequences including impairment in LV systolic and diastolic function, chamber dilation and wall thickening, abnormal flow acceleration, and in some cases valvular stenosis. Coronary angiographic analysis has found in general that epicardial coronary arterial disease is more diffuse with more extensive calcium than those with normal renal function. The rate of coronary calcific deposition is more rapid than in the general population and is not reversible or able to be attenuated with any form of therapy we are presently aware of. (Excerpt from text, p. 1183; no abstract.)


Posted April 15th 2016

Accuracy of Two Clinical Tests for Ischiofemoral Impingement in Patients With Posterior Hip Pain and Endoscopically Confirmed Diagnosis.

Juan Gomez-Hoyos M.D.

Juan Gomez-Hoyos, M.D.

Gomez-Hoyos, J., R. L. Martin, R. Schroder, I. J. Palmer and H. D. Martin (2016). “Accuracy of Two Clinical Tests for Ischiofemoral Impingement in Patients With Posterior Hip Pain and Endoscopically Confirmed Diagnosis.” Arthroscopy. Mar 25. [Epub ahead of print]

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PURPOSE: To establish the accuracy of the long-stride walking (LSW) and ischiofemoral impingement (IFI) tests for diagnosing IFI in patients whose primary symptom is posterior hip pain. METHODS: Confirmed IFI cases and cases in which IFI had been ruled out were identified considering imaging, injections, and endoscopic assessment, combined with pain relief and negative IFI-specific tests after treatment. Demographic data, duration of symptoms, pain location, ischiofemoral space, quadratus femoris space, quadratus femoris edema, surgical findings, and visual analog scale score for pain before and after treatment were computed for all patients included in this study. Sensitivity, specificity, predictive values, likelihood ratios, and diagnostic odds ratios were computed individually for the LSW test and IFI test. RESULTS: Cases from 1,166 consecutive hip operations and charts from 564 consecutive outpatients were retrospectively reviewed to identify patients who underwent injection and/or endoscopic surgery because of posterior hip pain. Thirty individuals (21 women and 9 men) with a mean age of 49.8 years (range, 20 to 76 years; SD, 13.0 years) were included for analysis. Of the 30 patients, 17 (56.6%) were confirmed as positive for IFI and 13 (43.4%) were confirmed as negative for IFI. The IFI test had a sensitivity of 0.82, specificity of 0.85, positive predictive value of 0.88, negative predictive value of 0.79, positive likelihood ratio of 5.35, negative likelihood ratio of 0.21, and diagnostic odds ratio of 25.6. The LSW test had a sensitivity of 0.94, specificity of 0.85, positive predictive value of 0.89, negative predictive value of 0.92, positive likelihood ratio of 6.12, negative likelihood ratio of 0.07, and diagnostic odds ratio of 88.8. CONCLUSIONS: In patients with complaints of posterior hip pain and negative evaluation findings for lumbosacral spine involvement or static/dynamic mechanical axis malalignment, the IFI and LSW tests are highly accurate to help identify those with or without IFI. LEVEL OF EVIDENCE: Level III, diagnostic study.