Impact of guided weight-based medication dosing in pediatric patients with obesity.

BACKGROUND: Obesity is a common disease state within pediatrics, with 19.7% of children in the United States classified as obese. Medication dosing in this population is a challenge not commonly examined in clinical drug trials. Dosing based on total body weight may not always be appropriate; therefore, ideal body weight (IBW) and adjusted body weight (AdjBW) may provide more effective dosing. OBJECTIVE: The goal was to implement a dosing protocol for pediatric patients with obesity to improve adherence. The primary endpoint was to evaluate adherence to evidence-based dosing recommendations and the secondary endpoints included cost saving analysis for immune globulin and accurate charting of IBW and AdjBW. METHODS: This was a single center, quality improvement project composed of pre- and post-implementation groups. An IBW and AdjBW calculator were implemented in our electronic health record, as customized enhancements, along with specific weight ordering options. A literature search of pharmacokinetic and pharmacodynamic dosing recommendations based on IBW and AdjBW was conducted. For both groups, patients were included if they were 3-18 years old, had a body mass index greater than or equal to the 95th percentile, and if they received a specified medication. RESULTS: A total of 618 patients were identified with 24 and 56 patients included for the pre- and post-implementation groups. There were no statistically significant differences in baseline characteristics of the comparator groups. The usage of correct body weight increased from 1.2% to 24.2% after implementation and education (P < 0.001). Cost savings was analyzed for immune globulin with the potential for a net savings of $9423 ± 3626.92. CONCLUSION: Dosing medications for our pediatric patients with obesity improved with the implementation of calculated dosing weights in the electronic health record, provision of an evidence-based dosing chart, and education of providers.

Cefepime Dosing in Neonates: What is the Evidence?

OBJECTIVE: Recommended cefepime dosing strategies in neonates varies in commonly utilized dosing references with regard to dose and frequency. The objective of this review is to summarize and evaluate the available literature describing cefepime dosing in neonatal patients. STUDY DESIGN: We performed a literature review in MEDLINE using the keyword cefepime. The search was limited to the English language, humans, and patients <2 months of age. We evaluated four pharmacokinetic studies and two studies describing the use of cefepime in clinical practice. RESULTS: The available studies assessing cefepime serum concentrations in neonatal patients demonstrated maintenance of adequate pharmacokinetic parameters when utilizing a dosing frequency of every 12 hours, specifically for organisms with a minimum inhibitory concentration (MIC) ≤ 8 mg/L. In studies evaluating clinical outcomes of cefepime use in neonates, the most frequent adverse effects reported included seizures and hypophosphatemia. Microbiologic cure was demonstrated with a dosing regimen of 50 mg/kg per dose every 12 hours. CONCLUSION: Cefepime dosed 30 to 50 mg/kg per dose every 12 hours may be appropriate to achieve a concentration two to four times above an MIC ≤ 8 mg/L for at least 60% of the dosing interval in neonatal patients.

Novel prostate acid phosphatase-based peptide vaccination strategy induces antigen-specific T-cell responses and limits tumour growth in mice.

Treatment options for patients with advanced prostate cancer remain limited and rarely curative. Prostatic acid phosphatase (PAP) is a prostate-specific protein overexpressed in 95% of prostate tumours. An FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE® (sipuleucel-T), has been shown to prolong survival, however the precise sequence of the PAP protein responsible for the outcome is unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, preclinical studies using PAP have the potential to be directly relevant to clinical setting. Here, we show three PAP epitopes naturally processed and presented in the context of HHDII/DR1 (114-128, 299-313, and 230-244). The PAP-114-128 epitope elicits CD4(+) and CD8(+) T-cell-specific responses in C57BL/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody®), PAP-114-128 prevents and reduces the growth of transgenic adenocarcinoma of mouse prostate-C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect is associated with infiltration of CD8(+) tumour-infiltrating lymphocytes and the generation of high avidity T cells secreting elevated levels of IFN-γ. PAP-114-128 therefore appears to be a highly relevant peptide on which to base vaccines for the treatment of prostate cancer.

Standardized neonatal continuous infusion concentrations: A quality improvement initiative.

PURPOSE: Medication errors are a significant and preventable source of patient harm, especially in the neonatal population. Standardized infusion concentrations increase patient safety and streamline the workflow for pharmacists, nurses, and physicians. METHODS: Neonatal continuous infusion concentrations were standardized and implemented into the electronic health record using an automated order panel. Pre- and postimplementation data were collected to assess the impact of this quality improvement initiative. The primary endpoint was the proportion of neonatal intensive care unit infusion orders that were compatible with "bolus from infusion" functionality in the syringe pump. RESULTS: Before implementation, only 40% of eligible infusions were compatible with the "bolus from infusion" function, compared to 93% after implementation (P < 0.00001). Within the syringe pump, the ratio of total options to the number of concentrations per medication was reduced by 31%. CONCLUSION: Implementation of an order panel with defaulted standard infusion concentration selection improved workflow and optimized technology in the neonatal intensive care unit.

Dexmedetomidine - An emerging option for sedation in neonatal patients.

Dexmedetomidine is a sedative agent with limited dosing, safety, and efficacy information in the neonatal population. This comprehensive review describes the available evidence summarizing the use of dexmedetomidine in various neonatal populations. We identified 21 studies and 1 case report supporting the efficacy and short-term safety of DEX in neonates. Reported dosing ranges from 0.5-1.5 mcg/kg/h with or without loading doses. Clinically relevant adverse effects include bradycardia and hypotension. Future studies are needed to determine long-term safety and facilitate clinical applicability.

Vedolizumab: An Emerging Treatment Option for Pediatric Inflammatory Bowel Disease.

Vedolizumab is a humanized α4ß7-integrin antagonist that is currently FDA-approved for adult inflammatory bowel disease. Limited evidence is available to guide use in pediatric patients, though off-label use is described in the form of retrospective reviews and case series. Collectively these publications begin to establish safety and efficacy data in pediatric patients < 18 years of age. Additionally, dosing regimens described in the literature serve to guide weight-based dosing, which is not established at this time. This narrative review aims to summarize the available literature and provide recommendations for vedolizumab use in the pediatric population. A literature search was performed in PubMed (January 2014-December 2020) using the keyword vedolizumab. Based on the available evidence, vedolizumab appears to be a safe and moderately effective agent for treatment of refractory pediatric inflammatory bowel disease. Prospective, randomized trials are warranted to optimize dosing regimens and to establish long-term safety.

Association of Performance Status With Survival in Patients With Advanced Non-Small Cell Lung Cancer Treated With Pembrolizumab Monotherapy.

Importance: Despite approximately 40% of patients having Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of at least 2 in the real world, most landmark clinical trials that led to the use of pembrolizumab as standard of care in advanced non-small cell lung cancer (NSCLC) excluded this group. Objective: To evaluate whether an ECOG PS score of at least 2 at the start of therapy is associated with progression-free survival (PFS) and overall survival (OS) in advanced NSCLC treated with pembrolizumab monotherapy. Design, Setting, and Participants: This cohort study included all consecutive patients with advanced NSCLC who underwent treatment with palliative pembrolizumab monotherapy from February 2016 to October 2019 at a single academic cancer center, with data censoring on January 15, 2020. Exposures: ECOG PS score at start of therapy, with 0 and 1 indicating fully active or restricted in strenuous activity and scores of 2 and higher indicating increasing disability. Main Outcomes and Measures: PFS and OS, measured from initiation of pembrolizumab monotherapy. Results: Of 74 patients (median [range] age, 68.5 [33-87] years; 36 [48.7%] women; 53 [71.6%] White individuals) with median follow-up of 19.5 (95% CI, 13.4-27.8) months, 45 (60.8%) had an ECOG PS of 0 or 1, while 29 (39.2%) had an ECOG PS of at least 2. There were no significant differences in the baseline characteristics, except in age. Compared with patients with PS scores of 0 or 1, those with PS scores of at least 2 had significantly lower disease control rates (38 [88.4%] vs 15 [53.6%]; P = .002), shorter median PFS (7.9 [95% CI, 4.6-15.4] months vs 2.3 [95% CI, 1.8-4.8] months; P = .004), and shorter median OS (23.2 [14.0 vs 35.7] months vs 4.1 [95% CI, 2.1-6.9] months; P < .001). Among those potentially eligible for subsequent cancer-directed therapy beyond pembrolizumab monotherapy, patients in the group with PS scores of at least 2 were less likely to receive it than those with PS scores of 0 or 1 (2 [8.3%] vs 14 [45.2%]; P = .003). Multivariable adjustment for baseline characteristics confirmed ECOG PS of at least 2 as an independent risk factor for worse PFS (HR, 2.02; 95% CI, 1.09-3.74; P = .03) and worse OS (HR, 2.87; 95% CI, 1.40-5.89; P = .004). Conclusions and Relevance: In this cohort study, having an ECOG PS score of at least 2 was associated with poorer prognosis for treatment of advanced NSCLC with palliative pembrolizumab monotherapy. Further prospective studies are needed to evaluate more objective and consistent measures of functional status to facilitate identification of patients with borderline performance status who may achieve durable clinical benefit from treatment with pembrolizumab monotherapy.

Association of Extended Dosing Intervals or Delays in Pembrolizumab-based Regimens With Survival Outcomes in Advanced Non-small-cell Lung Cancer.

BACKGROUND: Besides modeling/simulation-based analysis, no post-approval studies have evaluated the optimal administration frequency of pembrolizumab in non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a multicenter retrospective cohort study to evaluate the association between survival outcomes and treatment extensions/delays of pembrolizumab-based regimens in patients with advanced NSCLC. Those who had received at least 4 cycles in routine practice were divided into 2 groups: nonstandard (Non-Std, ≥ 2 cycles at intervals > 3 weeks + 3 days) and standard (Std, all cycles every 3 weeks or 1 cycle > 3 weeks + 3 days). RESULTS: Among 150 patients, 92 (61%) were eligible for the study (Non-Std, 27; Std, 65). The reasons for patients with extensions/delays in the Non-Std group included: immune-related adverse events (irAEs) (33%), non-irAE-related medical issues (26%), and patient-physician preference (41%). The Non-Std group was more likely to have a higher programmed death-ligand 1 tumor proportion score, a higher number of treatment cycles, and pembrolizumab monotherapy. Univariate and 6-month landmark analyses showed longer median overall survival and progression-free survival in the Non-Std group compared with the Std group. After multivariable adjustment for confounding factors, there was no significant difference in overall survival (hazard ratio, 1.2; 95% confidence interval, 0.3-4.8; P = .824) or progression-free survival (hazard ratio, 2.6; 95% confidence interval, 0.7-9.6; P = .157) between the 2 groups. CONCLUSION: Our study shows that a significant proportion of patients with advanced NSCLC receive pembrolizumab-based regimens with extended intervals or delays in routine clinical practice and with similar outcomes to those receiving treatment at label-specified 3-week intervals. Given the durability of benefit seen and the potential for cost reduction and decreased infusion frequency in these patients, this requires validation in prospective trials.

Impact of a Rapid Diagnostic Meningitis/Encephalitis Panel on Antimicrobial Use and Clinical Outcomes in Children.

Rapid molecular diagnostic assays are increasingly used to guide effective antimicrobial therapy. Data on their effectiveness to decrease antimicrobial use in children have been limited and varied. We aimed to assess the impact of the implementation of the FilmArray Meningitis Encephalitis Panel (MEP) on antimicrobial use and outcomes in children. In an observational retrospective study performed at Atlantic Health System (NJ), we sought to evaluate the duration of intravenous antibiotic treatment (days of therapy (DoT)) for patients <21 years of age hospitalized and evaluated for presumptive meningitis or encephalitis before and after the introduction of the MEP. A secondary analysis was performed to determine if recovery of a respiratory pathogen influenced DoT. The median duration of antibiotic therapy prior to the implementation of the MEP was 5 DoT (interquartile range (IQR): 3-6) versus 3 DoT (IQR: 1-5) (p < 0.001) when MEP was performed. The impact was greatest on intravenous third-generation cephalosporin and ampicillin use. We found a reduction in the number of inpatient days associated with the MEP. In the regression analysis, a positive respiratory pathogen panel (RPP) was not a significant predictor of DoT (p = 0.08). Furthermore, we found no significant difference between DoT among patients with negative and positive RPP (p = 0.12). Our study supports the implementation of rapid diagnostics to decrease the utilization of antibiotic therapy among pediatric patients admitted with concerns related to meningitis or encephalitis.

A Rare Case of Levetiracetam and Drug-Induced Idiopathic Aseptic Meningitis in a Pediatric Patient.

Levetiracetam (LEV) is a pyrrolidine derivative antiepileptic medication used for the treatment of seizures in pediatric and adult patients. We report a case of probable LEV-induced aseptic meningitis in a 13-year-old girl. The patient received LEV for a generalized seizure disorder and presented with symptoms 5 days after medication initiation. Ten days after LEV initiation, the patient presented to the hospital for further management. During her hospital course, infectious etiologies were ruled out with clinical and diagnostic testing. Upon discontinuation of LEV, the patient's symptoms resolved. Although select antiepileptic medications have been associated with drug-induced aseptic meningitis (DIAM), to date, no reports have been published about DIAM following the administration of LEV. We describe and categorize the probability of DIAM in association with LEV, as observed in a patient case.

Effect of Nursing Education on Optimization of Medication Reconciliation in the Pediatric Emergency Department.

OBJECTIVE: This study was conducted to evaluate the impact of education on optimizing medication histories in a single-center pediatric emergency department. METHODS: This was a prospective, 2-phase study of 200 patients ages 21 years and younger who presented to the pediatric emergency department in January and February 2017. In phase I of the study, 100 patients were interviewed by both a nurse and a pharmacist. Between phases I and II, the pharmacist educated each nurse and disseminated standardized education materials. In phase II, 100 additional patients were interviewed by both a nurse and a pharmacist. Discrepancies were quantified in both phases of the study. The primary outcome was the distribution of total discrepancies in medications identified. Total discrepancies were defined as a composite of medication name, dose, route, frequency, and time of last dose. RESULTS: A total of 200 medication histories were collected over phases I and II. In phase I (n = 79), the pharmacist identified 185 medications, 88 of which were also identified by the nurse. In phase II (n = 82), the pharmacist identified 180 medications, 95 of which were also identified by the nurse. The distribution of discrepancies per patient and per medication was significantly reduced in regard to dose, route, and frequency documentation. CONCLUSION: Although improvement was observed, barriers beyond a knowledge deficit exist to limit accuracy of medication histories collected by nurses.

Tumor biomarker testing in non-small-cell lung cancer: A decade of change.

INTRODUCTION: Although a growing list of essential genomic/immune-based biomarkers are linked to approved non-small-cell lung cancer (NSCLC) therapies worldwide, few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice. METHODS: We retrospectively reviewed the first one thousand plus NSCLC patient specimens from our institution analyzed for predictive biomarkers from 2004 to 2017 and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics. RESULTS: The majority of 1009 NSCLC patients had advanced stages of adenocarcinoma with most tissues obtained from the lung, mediastinal/hilar nodes, or pleura. The majority of testing was performed on cytology or small biopsy specimens. All were tested for EGFR mutations, 895 for ALK rearrangement, 841 for KRAS mutation, 537 for ROS1 rearrangement, and 179 using comprehensive genomic profiling. Implementation of near-universal genomic biomarker testing at our institution for EGFR, ALK, ROS1 and PD-L1 all occurred within the first year following evidence of clinical activity or regulatory body approval of an associated inhibitor. The overall testing failure rate after use of the best specimen for the most common tests was ≤5.5%. A quarter of tumors had a driver oncogene identified (EGFR/ALK/ROS1/BRAF V600E) with an approved oral targeted therapy, with the highest prevalence in those patients with no or light (≤15 pack-years) history of tobacco use. CONCLUSIONS: Tumor biomarker testing using clinical NSCLC specimens in routine oncologic care evolves rapidly following approval of targeted therapies linked to diagnostic assays. Our practice's decade plus experience highlights the rapid evolution of biomarker testing and confirms the therapeutic relevance of such testing in all patients-particularly those patients with light/no history of tobacco use.

EGFR Testing in Advanced Non-Small-Cell Lung Cancer, A Mini-Review.

Expert consensus guidelines have defined minimum requirements for routine testing and identification of classical epidermal growth factor (EGFR) mutations (ie, exon 19 deletions and exon 21 L858R substitution) and anaplastic lymphoma kinase (ALK) rearrangements in advanced non-small-cell lung cancers of adenocarcinoma histology, with the intent of permitting use of these predictive biomarkers to select patients who will derive maximal benefit from approved oral tyrosine kinase inhibitors (TKIs) directed against EGFR and ALK, respectively. However, the practice of precision medicine is incumbent upon optimal tumor sampling, accurate tumor testing, and informed application of results to patient care. We report on a brief review of EGFR testing methodologies (Sanger sequencing, allele-specific polymerase chain reaction, and targeted next-generation sequencing) to identify classical and other (ie, exon 18 G719X, exon 19 insertions, exon 20 insertions, exon 21 L861Q) EGFR mutations; practical considerations (type of tissue/biopsies with different success rates of DNA isolation, and timeliness of result-reporting to facilitate therapeutic decision-making); role of rebiopsy (to identify mechanisms of acquired resistance to first- and second-generation EGFR TKIs, most importantly EGFR-T790M); and clinical vignettes highlighting the nuances of testing in day-to-day practice.

Rapidly fatal advanced EGFR-mutated lung cancers and the need for rapid tumor genotyping in clinical practice.

Use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is associated with dramatic, durable, and tolerable responses and side effect profiles when applied for palliation of advanced EGFR-mutated non-small-cell lung cancers (NSCLCs). Expert guidelines recommend that EGFR mutation testing results should be available within 10 working days of receipt of tumor specimen by the testing laboratory; in circumstances where the tumor specimen needs to be sent to an external laboratory for testing, the sample should be sent within 3 working days of receiving the request for testing. We report here 2 cases, out of 109 EGFR-mutated (exon 19 deletion or L858R) NSCLCs seen at our institution, experiencing rapid clinical deterioration and death within the window of time prescribed by consensus testing guidelines. We hypothesize that a faster turn-around time may have changed the clinical outcome. Improving rapid turnaround times for tumor genotyping may afford more optimal palliation vis-à-vis early initiation of oral targeted therapy in patients with advanced EGFR-mutated NSCLC.

Patterns of care for non-small-cell lung cancer at an academic institution affiliated with a national cancer institute-designated cancer center.

PURPOSE: Evidence-based treatment guidelines for non-small-cell lung cancer (NSCLC) exist to improve the quality of care for patients with this disease. However, how often evidence-based decisions are used for care of NSCLC is poorly understood. PATIENTS AND METHODS: We examined patterns of care and rate of adherence to evidence-based guidelines for 185 new NSCLC patients seen between 2007 and 2009. Evidence-based care status was determined for 150 patients. RESULTS: Eighty-one percent of the patients were white, the mean age was 66 years, 49% were women, 11% were never smokers, 83% had Eastern Cooperative Oncology Group performance status 0 to 1, 49.7% of tumors were adenocarcinomas, 57.1% of never smokers had tumors genotyped (EGFR, ALK, KRAS), and 13.3% participated in clinical trials. The rate of evidence-based treatment adherence was 94.1% (16 of 17), 100% (21 of 21) and 100% (36 of 36) in patients with stages I, II, and III NSCLC, respectively. Stage IV disease, with adherence of 76.3% (58 of 76), was correlated with a higher rate of nonadherence when compared with stages I-III (odds ratio 16.33; 95% CI, 1.94 to 137.73). In patients with stage IV disease, the rate of evidence-based adherence was 95% (72 of 76) for first-line therapy, 95.2% (40 of 42) for second-line therapy, and only 33.3% (6 of 18) for third-line therapy (P < .001). There was no significant correlation between evidence-based adherence status and the patient's age, sex, performance status, smoking history, ethnicity, or the treating physician. CONCLUSION: These data point toward the need for improved evidence-based use of resources in the third-line setting of stage IV NSCLC.

Subdivision of the T1 size descriptor for stage I non-small cell lung cancer has prognostic value: a single institution experience.

BACKGROUND: Non-small cell lung cancer (NSCLC) staging is currently being revised by the International Association for the Study of Lung Cancer (IASLC). Among other changes, the revised staging system proposes the subdivision of the T1 tumor ( 2 cm but