Phase I and pharmacokinetic study of veliparib,a PARP inhibitor,and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.     

Management of acute food protein-induced enterocolitis syndrome emergencies at home and in a medical facility

ObjectiveAcute food protein-induced enterocolitis syndrome (FPIES) is characterized by delayed repetitive vomiting after ingestion of a trigger food, and severe reactions may lead to dehydration, hypotension, and shock. We provide recommendations on management of FPIES emergencies in a medical facility and at home.Data SourcesThis review summarizes the literature on clinical context, pathophysiology, presentation, and treatment of FPIES emergencies.Study SelectionsWe referred to the 2017 International Consensus Guidelines for the Diagnosis and Management of FPIES and performed a literature search identifying relevant recent primary articles and review articles on clinical management.ResultsManagement of FPIES emergencies in a medical facility is based on severity of symptoms and involves rehydration, ondansetron, and corticosteroids. A proactive approach for reactions occurring at home involves prescribing oral ondansetron and providing an individualized treatment plan based on the evolution of symptoms and severity of past reactions. A better understanding of the pathophysiology of FPIES and randomized trials on ondansedron and cocorticosteroid use could lead to more targeted treatments.ConclusionChildren with FPIES are at risk for severe symptoms constituting a medical emergency. Management of FPIES emergencies is largely supportive, with treatment tailored to the symptoms, severity of the patient’s condition, location of reaction, and reaction history.     

Stakeholder-Generated Implementation Strategies to Promote Evidence-Based ADHD Treatment in Community Mental Health

Community implementation of evidence-based practices (EBPs) for Attention Deficit/Hyperactivity Disorder (ADHD) is greatly lacking. A recent randomized community-based trial of an EBP for ADHD (Supporting Teens’ Autonomy Daily; STAND) demonstrated suboptimal implementation and effectiveness outcomes. In the present study, we conducted an Innovation Tournament (IT) with agency staff stakeholders (N?=?26) to identify barriers to successful implementation of STAND and implementation strategies for a revised service delivery model. We conducted member-checking of agency staff-generated ideas with parents (N?=?226) and subsequent querying of additional parent (N?=?226) and youth-generated (N?=?205) strategies to improve care. Go-Zone plots were utilized to identify strategies with the highest feasibility and importance. Practical barriers (i.e., transportation, scheduling difficulties) and parent/youth engagement were the most commonly cited obstacles to successful implementation of STAND in community contexts. Eighteen “winning” implementation strategies were identified that survived member checking. These were classified as train and educate stakeholders (n?=?5; e.g., train agency supervisors to deliver supervision, digitize treatment materials and trainings), engage consumers (n?=?9; e.g., begin treatment with rapport building sessions, increase psychoeducation), provide interactive assistance (n?=?2; e.g., add group supervision, increase roleplay in supervision), and use of evaluative/iterative strategies (n?=?2; e.g., perform fidelity checks, supervisor review of session recordings). Parents and youth desired longer duration of treatment and increased focus on maintenance. Strategies will be developed and tested as part of a pilot effectiveness trial designed to refine STAND’s service delivery model.

Trial Registration NCT02694939 www.clinicaltrials.gov

     

Gambling and Problem Gambling in Canada in 2018: Prevalence and Changes Since 2002

Objective:The purpose of this study was to provide an updated profile of gambling and problem gambling in Canada and to examine how the rates and pattern of participation compare to 2002.Method:An assessment of gambling and problem gambling was included in the 2018 Canadian Community Health Survey and administered to 24,982 individuals aged 15 and older. The present analyses selected for adults (18+).Results:A total of 66.2% of people reported engaging in some type of gambling in 2018, primarily lottery and/or raffle tickets, the only type in which the majority of Canadians participate. There are some significant interprovincial differences, with perhaps the most important one being the higher rate of electronic gambling machine (EGM) participation in Manitoba and Saskatchewan. The overall pattern of gambling in 2018 is very similar to 2002, although participation is generally much lower in 2018, particularly for EGMs and bingo. Only 0.6% of the population were identified as problem gamblers in 2018, with an additional 2.7% being at-risk gamblers. There is no significant interprovincial variation in problem gambling rates. The interprovincial pattern of problem gambling in 2018 is also very similar to what was found in 2002 with the main difference being a 45% decrease in the overall prevalence of problem gambling.Conclusions:Gambling and problem gambling have both decreased in Canada from 2002 to 2018 although the provincial patterns are quite similar between the 2 time periods. Several mechanisms have likely collectively contributed to these declines. Decreases have also been reported in several other Western countries in recent years and have occurred despite the expansion of legal gambling opportunities, suggesting a degree of inoculation or adaptation in large parts of the population.     

Aortic flow after valve sparing root replacement with or without neosinuses reconstruction

Objectives

This study applied advanced 4-dimensional flow magnetic resonance imaging processing to assess differences in aortic flow dynamics after valve sparing root replacement, with and without reconstruction of the Valsalva sinuses.

The association of psychiatric medication use with adherence in patients with HIV

Over two million new cases of HIV infection will occur annually, worldwide. Triple drug anti-retroviral therapy (ART) decreases the viral load in patients with HIV, helping to stop progression of HIV infection to AIDs. Our study assessed how pharmacologic treatment for mental health issues affects medication adherence and viral load in patients with HIV. We conducted a retrospective chart review of 163 patients with HIV who had at least 2 visits at the HIV-clinic at Ascension St. John Hospital. Data were collected on demographics, medications, CD4 counts and viral loads. Data were analyzed using Student’s t-test, the χ² test, the Mann–Whitney U test and logistic regression. “Poor Compliance” was defined as at least 2 consecutive visits with a CD4 count <200?µL and/or with viral load ≥100?IU/ml. Patients taking antidepressants were less likely to have poor compliance than those not on anti-depressants (6.3% vs. 22.3%, p?=?0.04). A similar association was found for patients taking any psychiatric drug (7.0% vs. 23.5%, p?=?0.02). On multivariable analysis, the odds of poor compliance were 6.3 times higher in patients who stopped HIV therapy for greater than one week between visits (p?=?0.004) and 3.6 times lower in patients taking any psychiatric medication (p?=?0.05).     

Surgery for Acute Presentation of Thoracoabdominal Aortic Disease

1. Download high-res image (159KB)
2. Download full-size image

     

Pivarubicin Is More Effective Than Doxorubicin Against Triple-Negative Breast Cancer In Vivo

Triple-negative breast cancer (TNBC) is unresponsive to antiestrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide, and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20–40%, a consequence of drug resistance and cumulative dose limitations necessitated by the reversible cardiotoxic effects of drug therapy. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanistic analyses of the novel anthracycline, pivarubicin, and its in vivo efficacy against human primary TNBC. Pivarubicin directly activates PKCd, triggers rapid mitochondrial-dependent apoptosis, and circumvents resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X_L, and Bcr-Abl. As a consequence, pivarubicin is more cytotoxic than doxorubicin against MDA-MB-231, and SUM159 TNBC cell lines grown in both monolayer culture and tumorspheres. Comparative in vivo efficacy of pivarubicin and doxorubicin was performed in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses (MTDs) of pivarubicin and doxorubicin. Tumor growth was monitored by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity was assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Primary tumors treated with multiple rounds of doxorubicin at MTD failed to inhibit tumor growth compared with vehicletreated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at a therapeutic dose. These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.     

Guest editors’ introduction

Journal of Thrombosis and Thrombolysis -