Research Spotlight

Posted July 15th 2018

A psychometric evaluation of the Concise Health Risk Tracking Self-Report (CHRT-SR)- a measure of suicidality-in patients with stimulant use disorder.

Katherine E. Sanchez Ph.D.

Katherine E. Sanchez Ph.D.

Sanchez, K., M. O. Killian, T. L. Mayes, T. L. Greer, J. M. Trombello, R. Lindblad, B. D. Grannemann, T. J. Carmody, A. J. Rush, R. Walker and M. H. Trivedi (2018). “A psychometric evaluation of the Concise Health Risk Tracking Self-Report (CHRT-SR)- a measure of suicidality-in patients with stimulant use disorder.” J Psychiatr Res 102: 65-71.

Full text of this article.

Stimulant use disorders are both common and associated with suicidal ideation and attempts. The psychometric properties of the 12-item Concise Health Risk Tracking Scale Self-Report (CHRT-SR), a measure that was created to assess suicidal thinking and several factors associated with a propensity to act, has been established in persons with mood disorders. This is a secondary analysis to assess the CHRT-SR in 302 stimulant abusing patients that had participated in a clinical trial. A confirmatory factor analysis (CFA) was conducted to assess the factor validity of the 12-item CHRT-SR model with a second-order Propensity factor. The CHRT-SR total score and 2 factor scores (Propensity and Suicidal Thoughts) demonstrated acceptable internal consistency and test-retest reliabilities. These two subscales and the total score were modestly but significantly associated with measures of depression and life satisfaction, demonstrating construct validity. Two additional items assessing Impulsivity were also analyzed, and demonstrated acceptable internal consistency, test-retest reliability, and construct validity. The CHRT-SR appears to be a reliable and valid tool to assess suicidality in persons with stimulant use disorder.


Posted July 15th 2018

Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer.

Carlos Becerra M.D.

Carlos Becerra M.D.

Rodon, J., A. Perez-Fidalgo, I. E. Krop, H. Burris, A. Guerrero-Zotano, C. D. Britten, C. Becerra, J. Schellens, D. A. Richards, M. Schuler, M. Abu-Khalaf, F. M. Johnson, M. Ranson, J. Edenfield, A. P. Silva, W. Hackl, C. Quadt, D. Demanse, V. Duval and J. Baselga (2018). “Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer.” Cancer Chemother Pharmacol Jun 7. [Epub ahead of print].

Full text of this article.

PURPOSE: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2. METHODS: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed. RESULTS: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%). CONCLUSIONS: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.


Posted July 15th 2018

Risk of heart failure in diabetic patients receiving sulfonylureas: reply.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2018). “Risk of heart failure in diabetic patients receiving sulfonylureas: reply.” Eur J Heart Fail 2018 Jun 11. [Epub ahead of print].

Full text of this article.

Editors: I sincerely appreciate the comments of Vaccaro et al. regarding their experience in the TOSCA.IT trial. It seems clear that the TOSCA.IT investigators took specific steps to enroll a population of patients with type 2 diabetes, who were at low risk of developing heart failure during follow‐up. As a result, very few heart failure events were recorded in the trial, and consequently, the trial did not have adequate statistical power to determine if the risks of heart failure were truly similar in patients taking sulfonylureas and pioglitazone. In order to validly conclude that the two classes of drugs were associated with similar risks of heart failure, the TOSCA.IT trial would have had to record 10 times as many heart failure events. Given the low risk of the population that was studied, achievement of this target number of events would have required the enrolment of substantially more patients and a far longer period of follow‐up. Since this was not practical, the results of TOSCA.IT cannot provide reliable information concerning comparative risks of heart failure related to the use of sulfonylureas and pioglitazone. Even if additional data were to show that the increased risks of heart failure with sulfonylureas and pioglitazone were similar, it is important to worry about whether any increase in risk is acceptable, especially since certain antidiabetic medications (i.e. metformin and sodium–glucose co‐transporter 2 inhibitors) appear to reduce the risk of heart failure.1 Preventing heart failure and other macrovascular complications of diabetes is a critical goal of treatment. For most middle‐aged to elderly patients with type 2 diabetes, the heightened risk of macrovascular events is much greater and occurs much earlier than the risk of microvascular events. Furthermore, since risk reduction of macrovascular events is not clearly related to glycemic control, the appropriate choice of an antidiabetic medication must be determined not only by its effects to lower glycated hemoglobin but by its independent actions to reduce the risk of cardiovascular death, myocardial infarction and heart failure. (Full text of this letter; no abstract available.)


Posted July 15th 2018

Questioning the obvious: does dyspnoea really matter in heart failure?

Milton Packer M.D.

Milton Packer M.D.E

Packer, M. (2018). “Questioning the obvious: does dyspnoea really matter in heart failure?” Eur Heart J Jun 22. [Epub ahead of print].

Full text of this article.

Dyspnoea is the cardinal manifestation of heart failure and remains its most perplexing feature. Those afflicted with chronic heart failure typically report both symptoms of dyspnoea and exercise intolerance, but does dyspnoea actually limit activities of daily living? It is maddeningly difficult to know if patients with heart failure stop exercising because they are short of breath or because they are limited for some other reason and incidentally report dyspnoea as an accompanying symptom. Although it may seem obvious that dyspnoea impairs quality of life in heart failure, it is time to question the obvious. Our thinking about dyspnoea in heart failure has long been heavily influenced by observations in patients with acute heart failure, particularly those who present with acute pulmonary oedema. This syndrome is characterized by abrupt and marked increases in cardiac filling and pulmonary venous pressures, which are accompanied by overwhelming dyspnoea at rest. Classically, patients exhibited pink frothy sputum upon coughing, the result of the transudation of fluid from the pulmonary capillaries into the alveoli. The presentation was so dramatic that it seemed reasonable to surmise that oxygen transport was impaired, and that the resulting hypoxaemia was responsible for the sensation of dyspnoea. However, most patients with acute heart failure following myocardial injury are not hypoxaemic, even though they are generally dyspnoeic. (Excerpt from the text of this editorial, p. 1; no abstract available.)


Posted July 15th 2018

Is the Popularity of Dipeptidyl-Peptidase-4 Inhibitors Justified? Insights From Mechanistic Studies and Clinical Trials.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2018). “Is the Popularity of Dipeptidyl-Peptidase-4 Inhibitors Justified? Insights From Mechanistic Studies and Clinical Trials.” Am J Med 131(7): e287- e289.

Full text of this article.

Because of their ease of use and patient acceptability, dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly prescribed to lower blood glucose in type 2 diabetes, typically, together with metformin. DPP-4 inhibitors do not require parenteral administration, and unlike other incretin-based agents, they have few gastrointestinal adverse effects. When compared with older antidiabetic drugs, DPP-4 inhibitors do not cause weight gain and are unlikely to trigger episodes of hypoglycemia.1 In contrast to sodium-glucose transporter 2 (SGLT2) inhibitors, they do not lead to genitourinary infections. Collectively, these features contribute to the popularity of DPP-4 inhibitors in the management of diabetes. Yet, aside from the symptomatic benefits of controlling blood glucose, antidiabetic drugs should prevent macrovascular and microvascular events. So we should ask: is the prominent place of DPP-4 inhibitors supported by a favorable effect of these drugs on the course of type 2 diabetes? (Excerpt from text of this commentary, p. e287; no abstract available.)