Angela M. Feraco

Usefulness of Various Plasma Biomarkers for Diagnosis of Heart Failure in Children With Single Ventricle Physiology

Children with single ventricle physiology have increased ventricular work and are at greater risk of developing heart failure than other children with congenital heart disease. However, the diagnosis of heart failure is difficult because few objective measures have been validated for this cohort. Plasma proteins have been identified as biomarkers of heart failure in adults with structurally normal hearts. However, whether these correlate similarly with heart failure in children with single ventricle physiology is unknown, because the etiology of adult heart failure is typically ischemic heart disease, but heart failure in these children is presumed to be due to primary myocardial dysfunction. We conducted a single-site, cross-sectional observational study of young, single-ventricle patients. Clinical heart failure was defined as a Ross score >2. The association of several candidate biomarkers with heart failure was assessed using logistic regression analysis and receiver operating characteristic curves. Of the 29 included children, 9 (31%) were in clinical heart failure. A doubling of plasma B-type natriuretic peptide was associated with an odds ratio for heart failure of 2.17. The area under the receiver operating characteristic curve was 80.3%. A threshold value of > or =30 pg/ml showed both sensitivity and specificity for heart failure. Three other candidate biomarkers were not associated with clinical heart failure in this sample. In conclusion, plasma B-type natriuretic peptide is a sensitive biomarker for clinical heart failure in young children with single-ventricle heart disease. The use of this plasma biomarker might facilitate detection of heart failure in these complex patients.

Pediatric Resident Burnout and Attitudes Toward Patients.

Burnout is highly prevalent among pediatric residents across multiple programs, and is associated with negative self-reported patient care attitudes and behaviors. BACKGROUND AND OBJECTIVES: Burnout occurs in up to 75% of resident physicians. Our study objectives were to: (1) determine the prevalence of burnout, and (2) examine the association between burnout and self-reported patient care attitudes and behaviors among pediatric residents. METHODS: A total of 258 residents (53% response rate) from 11 pediatric residency programs completed a cross-sectional Web-based survey. Burnout was measured with 2 items from the Maslach Burnout Inventory. Patient care attitudes and behaviors were measured with 7 questions from a standardized qualitative survey. χ2 and logistic regression tested the association between burnout and self-reported patient care attitudes and behavior. RESULTS: A total of 39% of respondents (mean age, 29.4 years ± 2.3 SD; 79% female; 83% white; 35% postgraduate year [PGY] -1, 34% PGY-2, and 31% PGY-3), endorsed burnout. Residents with burnout had significantly greater odds (P < .01) of reporting suboptimal patient care attitudes and behaviors, including: discharging patients to make the service more manageable (adjusted odds ratio [aOR] 4.2; 95% confidence interval [CI], 1.6–11.1), not fully discussing treatment options or answering questions (aOR 3.5; 95% CI, 1.7–7.1), making treatment or medication errors (aOR 7.1; 95% CI, 2.0–25.8), ignoring the social or personal impact of an illness (aOR 9.6; 95% CI, 3.2–28.9), and feeling guilty about how a patient was treated (aOR 6.0; 95% CI, 1.6–22.1). CONCLUSIONS: Burnout is highly prevalent among pediatric residents and is associated with self-reported negative patient care attitudes and behaviors. Residency programs should develop interventions addressing burnout and its potential negative impact on patient care.

Communication Skills Training in Pediatric Oncology: Moving Beyond Role Modeling.

Communication is central to pediatric oncology care. Pediatric oncologists disclose life‐threatening diagnoses, explain complicated treatment options, and endeavor to give honest prognoses, to maintain hope, to describe treatment complications, and to support families in difficult circumstances ranging from loss of function and fertility to treatment‐related or disease‐related death. However, parents, patients, and providers report substantial communication deficits. Poor communication outcomes may stem, in part, from insufficient communication skills training, overreliance on role modeling, and failure to utilize best practices. This review summarizes evidence for existing methods to enhance communication skills and calls for revitalizing communication skills training within pediatric oncology.

Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study

BACKGROUND Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. METHODS This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. FINDINGS Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4·5 years (IQR 1·3-13·3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 mg per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. No grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib-related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. INTERPRETATION The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age. FUNDING Loxo Oncology Inc.

The Creation of Standard-Setting Videos to Support Faculty Observations of Learner Performance and Entrustment Decisions.

Entrustable professional activities (EPAs) provide a framework to standardize medical education outcomes and advance competency-based assessment. Direct observation of performance plays a central role in entrustment decisions; however, data obtained from these observations are often insufficient to draw valid high-stakes conclusions. One approach to enhancing the reliability and validity of these assessments is to create videos that establish performance standards to train faculty observers. Little is known about how to create videos that can serve as standards for assessment of EPAs. The authors report their experience developing videos that represent five levels of performance for an EPA for patient handoffs. The authors describe a process that begins with mapping the EPA to the critical competencies needed to make an entrustment decision. Each competency is then defined by five milestones (behavioral descriptors of performance at five advancing levels). Integration of the milestones at each level across competencies enabled the creation of clinical vignettes that were converted into video scripts and ultimately videos. Each video represented a performance standard from novice to expert. The process included multiple assessments by experts to guide iterative improvements, provide evidence of content validity, and ensure that the authors successfully translated behavioral descriptions and vignettes into videos that represented the intended performance level for a learner. The steps outlined are generalizable to other EPAs, serving as a guide for others to develop videos to train faculty. This process provides the level of content validity evidence necessary to support using videos as standards for high-stakes entrustment decisions.

Development of the “Day 100 Talk”: Addressing existing communication gaps during the early cancer treatment period in childhood cancer

Families’ communication needs during the early cancer treatment period (ECTP) may not be optimally met by current practices. We sought to identify potential communication gaps and to ameliorate these by developing a novel in‐depth conversation between families and their pediatric oncologists, the “Day 100 Talk” (D100), during the ECTP.

Considerations for Cancer-Directed Therapy in Advanced Childhood Cancer

Cancer-directed therapy encompasses any modality utilized with the goal of controlling cancer. Research among adults with advanced cancer suggests that adults who understand that their cancer is incurable are less likely to continue cytotoxic cancer-directed therapy. However, novel classes of targeted and immunologic therapies are rapidly changing treatment paradigms in advanced malignancies. These agents may alter previously accepted prognostic estimates for some advanced cancers by facilitating life extension through cancer control without achieving cancer eradication. Similarly, our understanding of illness trajectories in advanced childhood cancers is increasingly complex and necessitates nuanced and serial prognostic discussions. Research among families of children with advanced cancer suggests that preferences and priorities vary and that cancer-directed therapy may convey benefits as well as burdens. In summary, detailed understanding of tumor biology, available therapies and healthcare system constraints, careful symptom monitoring, and repeated assessments of patient and parent understanding, preferences, and goals should guide decision-making with regard to selecting, continuing, or discontinuing cancer-directed therapy.