Root Cause Analysis of Ambulatory Adverse Drug Events That Present to the Emergency Department.

J Patient Saf. 2016 Sep;12(3):119-24

Authors: Gertler SA, Coralic Z, López A, Stein JC, Sarkar U

Abstract
BACKGROUND: Adverse drug events (ADEs) among patients self-administering medications in home/community settings are a common cause of emergency department (ED) visits, but the causes of these ambulatory ADEs remain unclear. Root cause analysis, rarely applied in outpatient settings, may reveal the underlying factors that contribute to adverse events.
STUDY OBJECTIVES: To elicit patient and provider perspectives on ambulatory ADEs and apply root cause analysis methodology to identify cross-cutting themes among these events.
METHODS: Emergency department clinical pharmacists screened, identified, and enrolled a convenience sample of adult patients 18 years or older who presented to a single, urban, academic ED with symptoms or diagnoses consistent with suspected ADEs. Semistructured phone interviews were conducted with the patients and their providers. We conducted a qualitative analysis. We applied a prespecified version of the injury prevention framework (deductive coding), identifying themes relating to the agent (drug), host (patient), and environment (social and health systems). These themes were used to construct a root cause analysis for each ADE.
RESULTS: From 18 interviews overall, we identified the following themes within the injury prevention framework. Agent factors included high-risk drugs, narrow therapeutic indices, and uncommon severe effects. Host factors included patient capacity or understanding of how to use medications, awareness of side effects, mistrust of the medical system, patients with multiple comorbidities, difficult risk-benefit assessments, and high health-care users. Environmental factors included lack of social support, and health systems issues included access to care, encompassing medication availability, access to specialists, and a lack of continuity and communication among prescribing physicians. Root cause analysis revealed multiple underlying factors relating to agent, host, and environment for each event.
CONCLUSION: Patient and physician perspectives can inform a root cause analysis of ambulatory ADEs. Such methodology may be applied to understand the factors that contribute to ambulatory ADEs and serve as the formative work for future interventions improving home/community medication use.

PMID: 24583958 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/06/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A Randomized, Placebo-Controlled Trial Evaluating the Safety and Efficacy of Adding Omarigliptin to Antihyperglycemic Therapies in Japanese Patients with Type 2 Diabetes and Inadequate Glycemic Control.

Diabetes Ther. 2017 Jun 06;:

Authors: Gantz I, Okamoto T, Ito Y, Sato A, Okuyama K, O'Neill EA, Engel SS, Lai E, Omarigliptin Study 015 Group

Abstract
INTRODUCTION: Daily dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used with other orally administered antihyperglycemic agents (AHA), as combination therapy, to treat Japanese patients with type 2 diabetes. When combination therapy is indicated, use of a once-weekly (q.w.) orally administered DPP-4 inhibitor might be an appropriate therapeutic option for some patients.
METHODS: A 52-week trial was conducted to assess the safety and tolerability (primary objectives) and glycemic efficacy (secondary objectives) of the q.w. DPP-4 inhibitor omarigliptin as add-on therapy to five different classes of orally administered AHA [sulfonylurea (SU), glinide (GL), biguanide (BG), thiazolidinedione (TZD), or α-glucosidase inhibitor (AGI)] commonly used in Japan and having different mechanisms of drug action from DPP-4 inhibitors. The trial consisted of an initial 24-week double-blind, placebo-controlled period during which patients (stratified by background AHA) were randomized to omarigliptin 25 mg q.w. or placebo, followed by a 28-week open-label period during which patients on placebo were switched to omarigliptin.
RESULTS: After 24 weeks, the percentages of patients with adverse events (AEs), serious AEs, drug-related AEs, AEs of symptomatic hypoglycemia, or who discontinued from trial medication because of an AE were generally similar in the omarigliptin and placebo groups, in all background AHA strata and in the overall population. From a mean baseline HbA1c of approximately 8.0%, the placebo-adjusted least-squares mean changes from baseline ranged from -0.80% (AGI stratum) to -1.16% (TZD stratum); p < 0.001 for all background AHA strata. During the open-label period, no safety signals emerged with longer-term treatment. At week 52, the change from baseline in HbA1c in the omarigliptin/omarigliptin group was similar to that of the placebo/omarigliptin group.
CONCLUSIONS: Addition of once-weekly omarigliptin to AHA therapy with an SU, GL, BG, TZD, or AGI for up to 52 weeks was generally safe and well tolerated, and provided persistent efficacy.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01697592.
FUNDING: MSD K.K., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

PMID: 28589493 [PubMed - as supplied by publisher]

Pharmacovigilance Programme of India: Recent developments and future perspectives.

Indian J Pharmacol. 2016 Nov-Dec;48(6):624-628

Authors: Kalaiselvan V, Thota P, Singh GN

Abstract
Promoting safe use of medicines is a priority of Indian Pharmacopoeia Commission that functions as the National Coordination Center (NCC) for Pharmacovigilance Programme of India (PvPI). One hundred and seventy-nine adverse drug reactions (ADRs) monitoring centers currently report ADRs to NCC. Current India contribution to global safety database reaches 3% and the completeness score is 0.93 out of 1. NCC is taking several measures to enhance patient safety including capacity building for monitoring, surveillance, collaboration with national health programs and other organizations to increase ADR reporting and to ensure that PvPI is a vital knowledge database for Indian regulators. The Central Drugs Standard Control Organization has notified important safety label changes on drugs such as carbamazepine and piperacillin + tazobactam in the year 2015, other drugs are under monitoring for regulatory interventions.

PMID: 28066097 [PubMed - indexed for MEDLINE]

Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System.

Drug Saf. 2017 Jun 05;:

Authors: Cutroneo PM, Giardina C, Ientile V, Potenza S, Sottosanti L, Ferrajolo C, Trombetta CJ, Trifirò G

Abstract
INTRODUCTION: Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear.
OBJECTIVE: The aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS).
METHODS: We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA(®)) queries (SMQs).
RESULTS: Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders).
CONCLUSIONS: This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs.

PMID: 28585152 [PubMed - as supplied by publisher]

[Use of pharmacogenetic testing to prevent adverse drug reactions during statin therapy].

Ter Arkh. 2017;89(1):82-88

Authors: Rumyantsev NA, Kukes VG, Kazakov RE, Rumyantsev AA, Sychev DA

Abstract
The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors' experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.

PMID: 28252633 [PubMed - indexed for MEDLINE]

Stemming the Rising Tide of Drug Burden.

Consult Pharm. 2016 Nov 01;31(11):612

Authors: Edward Davidson H

PMID: 28107117 [PubMed - indexed for MEDLINE]

Preexposure Prophylaxis for HIV Prevention in a Large Integrated Health Care System: Adherence, Renal Safety, and Discontinuation.

J Acquir Immune Defic Syndr. 2016 Dec 15;73(5):540-546

Authors: Marcus JL, Hurley LB, Hare CB, Nguyen DP, Phengrasamy T, Silverberg MJ, Stoltey JE, Volk JE

Abstract
BACKGROUND: Placebo-controlled and open-label studies have demonstrated the safety and efficacy of daily oral preexposure prophylaxis (PrEP) in preventing HIV infection, but data are limited on real-world PrEP use.
METHODS: We conducted a cohort study from July 2012 through June 2015 of Kaiser Permanente Northern California members initiating PrEP. We assessed pharmacy refill adherence and discontinuation, decreases in estimated glomerular filtration rate (eGFR), and sexually transmitted infection (STI)/HIV incidence.
RESULTS: Overall, 972 individuals initiated PrEP, accumulating 850 person-years of PrEP use. Mean adherence was 92% overall. Black race/ethnicity [adjusted risk ratio (aRR) 3.0; 95% confidence interval: 1.7 to 5.1, P < 0.001], higher copayments (aRR 2.0; 1.2 to 3.3, P = 0.005), and smoking (aRR 1.6; 1.1 to 2.3, P = 0.025) were associated with <80% adherence. PrEP was discontinued by 219 (22.5%); female sex (aRR 2.6; 1.5 to 4.6, P < 0.001) and drug/alcohol abuse (aRR 1.8; 1.3 to 2.6, P = 0.002) were associated with discontinuation. Among 909 with follow-up creatinine testing, 141 (15.5%) had an eGFR <70 mL·min·1.73 m and 5 (0.6%) stopped PrEP because of low eGFR. Quarterly STI positivity was high and increased over time for rectal chlamydia (P < 0.001) and urethral gonorrhea (P = 0.012). No HIV seroconversions occurred during PrEP use; however, 2 occurred in individuals who discontinued PrEP after losing insurance coverage.
CONCLUSIONS: PrEP adherence was high in clinical practice, consistent with the lack of HIV seroconversions during PrEP use. Discontinuation because of renal toxicity was rare. STI screening every 6 months, as recommended by current guidelines, may be inadequate. Strategies are needed to increase PrEP access during gaps in insurance coverage.

PMID: 27851714 [PubMed - indexed for MEDLINE]

Searching for Positive Side Effects of Common Drugs.

Trends Pharmacol Sci. 2017 02;38(2):111

Authors: Cvek B

PMID: 27823801 [PubMed - indexed for MEDLINE]

Incidence of Exposure of Patients in the United States to Multiple Drugs for Which Pharmacogenomic Guidelines Are Available.

PLoS One. 2016;11(10):e0164972

Authors: Samwald M, Xu H, Blagec K, Empey PE, Malone DC, Ahmed SM, Ryan P, Hofer S, Boyce RD

Abstract
Pre-emptive pharmacogenomic (PGx) testing of a panel of genes may be easier to implement and more cost-effective than reactive pharmacogenomic testing if a sufficient number of medications are covered by a single test and future medication exposure can be anticipated. We analysed the incidence of exposure of individual patients in the United States to multiple drugs for which pharmacogenomic guidelines are available (PGx drugs) within a selected four-year period (2009-2012) in order to identify and quantify the incidence of pharmacotherapy in a nation-wide patient population that could be impacted by pre-emptive PGx testing based on currently available clinical guidelines. In total, 73 024 095 patient records from private insurance, Medicare Supplemental and Medicaid were included. Patients enrolled in Medicare Supplemental age > = 65 or Medicaid age 40-64 had the highest incidence of PGx drug use, with approximately half of the patients receiving at least one PGx drug during the 4 year period and one fourth to one third of patients receiving two or more PGx drugs. These data suggest that exposure to multiple PGx drugs is common and that it may be beneficial to implement wide-scale pre-emptive genomic testing. Future work should therefore concentrate on investigating the cost-effectiveness of multiplexed pre-emptive testing strategies.

PMID: 27764192 [PubMed - indexed for MEDLINE]

Reporting of Adverse Events in Published and Unpublished Studies of Health Care Interventions: A Systematic Review.

PLoS Med. 2016 Sep;13(9):e1002127

Authors: Golder S, Loke YK, Wright K, Norman G

Abstract
BACKGROUND: We performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events.
METHODS AND FINDINGS: Studies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status. The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies. A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases. The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published.
CONCLUSIONS: There is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events.

PMID: 27649528 [PubMed - indexed for MEDLINE]

Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes.

J Am Coll Cardiol. 2016 Apr 05;67(13):1639-50

Authors: Schwartz PJ, Woosley RL

Abstract
Drug-induced long QT syndrome (diLQTS) and congenital LQTS (cLQTS) share many features, and both syndromes can result in life-threatening torsades de pointes (TdP). Our understanding of their mechanistic and genetic similarities has led to their improved clinical management. However, our inability to prevent diLQTS has resulted in removal of many medicines from the market and from development. Genetic and clinical risk factors for diLQTS and TdP are well known and raise the possibility of TdP prevention. Clinical decision support systems (CDSS) can scan the patient's electronic health records for clinical risk factors predictive of diLQTS and warn when a drug that can cause TdP is prescribed. CDSS have reduced prescriptions of QT-prolonging drugs, but these relatively small changes lack the power to reduce TdP. The growing genetic evidence linking diLQTS to cLQTS suggests that prevention of TdP in the future may require inclusion of both genetic and clinical predictors into CDSS.

PMID: 27150690 [PubMed - indexed for MEDLINE]

Hydroxyurea in Pediatric Patients With Sickle Cell Disease: What Nurses Need to Know.

J Pediatr Oncol Nurs. 2016 Sep;33(5):339-44

Authors: Rees AL

Abstract
Sickle cell disease (SCD) is an inherited disorder in which sickled red blood cells occlude the small vessels of the body, reducing oxygen delivery to tissues and ultimately negatively affecting many of the body's major organs. Hydroxyurea has proven beneficial in the treatment of SCD and prevention of disease-related complications. The 2014 guidelines put forth by the National Heart, Lung, and Blood Institute recommend hydroxyurea treatment in infants 9 months and older, children, and adolescents with SCD-SS or SCD-Sβ(0) thalassemia regardless of clinical severity. This is a change from the 2002 guidelines in which hydroxyurea was recommended for adolescents and children with SCD-SS or SCD-Sβ(0) thalassemia with frequent episodes of pain, a history of acute chest syndrome, severe and symptomatic anemia or other severe vaso-occlusive events. Nurses play a critical role in working with patients and families to provide education, guidance, and support to improve compliance to mitigate the long-term effects of SCD.

PMID: 26611755 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/06/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation.

Am Heart J. 2017 Jun;188:42-52

Authors: Goldberg DJ, Zak V, Goldstein BH, Chen S, Hamstra MS, Radojewski EA, Maunsell E, Mital S, Menon SC, Schumacher KR, Payne RM, Stylianou M, Kaltman JR, deVries TM, Yeager JL, Paridon SM, Pediatric Heart Network Investigators

Abstract
BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes.
OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan.
METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five.
RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts.
CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.

PMID: 28577680 [PubMed - in process]

Large-Scale Prediction of Drug-Target Interaction: a Data-Centric Review.

AAPS J. 2017 Jun 02;:

Authors: Cheng T, Hao M, Takeda T, Bryant SH, Wang Y

Abstract
The prediction of drug-target interactions (DTIs) is of extraordinary significance to modern drug discovery in terms of suggesting new drug candidates and repositioning old drugs. Despite technological advances, large-scale experimental determination of DTIs is still expensive and laborious. Effective and low-cost computational alternatives remain in strong need. Meanwhile, open-access resources have been rapidly growing with massive amount of bioactivity data becoming available, creating unprecedented opportunities for the development of novel in silico models for large-scale DTI prediction. In this work, we review the state-of-the-art computational approaches for identifying DTIs from a data-centric perspective: what the underlying data are and how they are utilized in each study. We also summarize popular public data resources and online tools for DTI prediction. It is found that various types of data were employed including properties of chemical structures, drug therapeutic effects and side effects, drug-target binding, drug-drug interactions, bioactivity data of drug molecules across multiple biological targets, and drug-induced gene expressions. More often, the heterogeneous data were integrated to offer better performance. However, challenges remain such as handling data imbalance, incorporating negative samples and quantitative bioactivity data, as well as maintaining cross-links among different data sources, which are essential for large-scale and automated information integration.

PMID: 28577120 [PubMed - as supplied by publisher]

Phase II trial of dacomitinib, a pan-HER (human epidermal growth factor receptor) tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification.

Neuro Oncol. 2017 Jun 01;:

Authors: Sepúlveda-Sánchez JM, Vaz MÁ, Balañá C, Gil-Gil M, Reynés G, Gallego Ó, Martínez-García M, Vicente E, Quindós M, Luque R, Ramos A, Ruano Y, Pérez-Segura P, Benavides M, Sánchez-Gómez P, Hernández-Laín A

Abstract
Background.: We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor (EGFR) gene amplification with or without EGFRvIII deletion.
Methods.: Patients with first recurrence were enrolled in two cohorts: Cohort A) patients with EGFR gene amplification without EGFRvIII mutation; Cohort B) patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS) [RANO criteria] at 6 months (PFS6).
Results.: 30 patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% male, ECOG-PS 0/1/2 (10.2%/65.3%/24.5%). PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 months; Cohort B: 2.6 months). Four patients were progression-free at 6 months and three patients did so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 months; Cohort B: 6.7 months). The best overall response included one complete response and two partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs.
Conclusion.: Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients that could benefit from dacomitinib.

PMID: 28575464 [PubMed - as supplied by publisher]

A safety assessment of biological therapies targeting the IL-23/IL-17 axis in inflammatory bowel diseases.

Expert Opin Drug Saf. 2017 Jun 02;:

Authors: Verstockt B, Deleenheer B, Van Assche G, Vermeire S, Ferrante M

Abstract
Introduction Many different compounds targeting the interleukin 23/17 axis have been developed and successfully studied in several autoimmune diseases, including inflammatory bowel diseases. Nevertheless, interfering with key immunological pathways raises potential safety concerns. This review focuses on the safety profile of these novel biological therapies. Areas covered A literature search until March 2017 was performed to collect safety data on different compounds targeting this pathway, with emphasis on ustekinumab and secukinumab. Firstly, the authors discuss briefly how genetics can inform about potential safety issues. Secondly, they extensively describe safety issues (common adverse events, infections, malignancies…), immunogenicity, exposure to ustekinumab in specific populations and provide advice for vaccination. Finally, they address safety profiles of secukinumab and other biological targeting the IL-23/17 axis in IBD. Expert opinion Current evidence suggests that ustekinumab therapy overweigh the potential drug-related risks. Additional safety data beyond randomized-controlled trials, derived from statistically powered, large prospective studies with long-term follow-up are urgently needed to assess the real-life ustekinumab-related risks and to establish the correct position of these novel class of biologicals in IBD treatment. Combining immunomodulators with ustekinumab seems to be safe, though prospective data specifically addressing this topic are currently missing. Similarly, the combination of different biological therapies still has to be studied.

PMID: 28573876 [PubMed - as supplied by publisher]

A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma.

Cancer. 2017 Feb 15;123(4):576-582

Authors: Pal SK, Drabkin HA, Reeves JA, Hainsworth JD, Hazel SE, Paggiarino DA, Wojciak J, Woodnutt G, Bhatt RS

Abstract
BACKGROUND: Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy.
METHODS: Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc.
RESULTS: A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations.
CONCLUSIONS: The encouraging OS and favorable safety profile observed with sonepcizumab should prompt further investigation of the agent in combination with VEGF-directed agents or checkpoint inhibitors. Cancer 2017;123:576-582. © 2016 American Cancer Society.

PMID: 27727447 [PubMed - indexed for MEDLINE]

Supportive care utilization and treatment toxicity in children with Down syndrome and acute lymphoid leukaemia at free-standing paediatric hospitals in the United States.

Br J Haematol. 2016 Aug;174(4):591-9

Authors: Salazar EG, Li Y, Fisher BT, Rheingold SR, Fitzgerald J, Seif AE, Huang YS, Bagatell R, Aplenc R

Abstract
Although inferior outcomes of children with Down syndrome (DS) and acute lymphoid leukaemia (ALL) are established, national supportive care patterns for these patients are unknown. A validated retrospective cohort of paediatric patients diagnosed with ALL from 1999 to 2011 was assembled from the US Pediatric Health Information System (PHIS) database to examine organ toxicity, sepsis, and resource utilization in children with and without DS. Among 10699 ALL patients, 298 had DS-ALL (2·8%). In a multivariate model, DS was associated with increased risk of cardiovascular (odds ratio [OR] 2·0, 95% confidence interval [CI] 1·6-2·7), respiratory (OR 2·1, 95% CI: 1·6-2·9), neurologic (OR 3·4, 95% CI 1·9-6·2), and hepatic (OR 1·4, 95% CI 1·0-1·9) dysfunction and sepsis (OR 1·8, 95% CI: 1·4-2·4). Children with DS-ALL used significantly more respiratory support, insulin, and anti-infectives, including broad-spectrum Gram-positive agents, quinolones, and azoles. They used significantly fewer analgesics and antiemetics compared to non-DS-ALL children. Ultimately, this study confirms the increased risk of infectious and end-organ toxicity in children with DS-ALL and quantifies important differences in resource utilization between children with DS and non-DS ALL. These findings highlight the importance of investigating the impact of these care variations and developing specific supportive care guidelines for this population.

PMID: 27161549 [PubMed - indexed for MEDLINE]