Polypharmacy among medicaid-insured children with and without documented obesity.

OBJECTIVE: Polypharmacy increases the risk of drug-drug interactions and adverse drug events. As obesity and rates of obesity-associated comorbid chronic conditions continue to rise, an improved understanding of whether children with obesity experience higher risk of polypharmacy is needed. This study aimed to compare chronic medication polypharmacy prevalence among children with and without a diagnosis of obesity. METHODS: We performed a cross-sectional examination of prescription data for children aged 2-18 years prescribed ≥1 chronic medication using the 2019 Marketscan Medicaid database. Children with documented obesity were identified using medical visit diagnosis codes. Chronic medications included any ≥30-day prescription with ≥2 dispensed refills. Polypharmacy was defined as the prescription of ≥2 chronic medications for ≥1 overlapping days. Chi-squared tests compared polypharmacy prevalence and the distribution of chronic medication classes between children with and without obesity. Logistic regression determined the adjusted odds ratio (aOR) of polypharmacy for children with obesity, adjusting for relevant demographic and clinical differences. RESULTS: Of 634,671 included children, 12.2% had documented obesity. More than one-half (52.7%) of children with obesity experienced polypharmacy compared with 47.6% of children without obesity (aOR 1.06 [95% confidence interval 1.04-1.08]). Chronic medication prescriptions, particularly for psychiatric and asthma medications, were more commonly prescribed among children with obesity than those without obesity. CONCLUSIONS: Children with documented obesity have higher polypharmacy prevalence than children without obesity. Clinicians must be aware of this risk and minimize inappropriate polypharmacy whenever possible. Future work should examine the consequences of polypharmacy, including drug-drug interactions and adverse drug events in children with obesity.

Identifying Acute Neuropsychiatric Events in Children and Adolescents.

OBJECTIVES: The objective of this study was to develop and validate an approach to accurately identify incident pediatric neuropsychiatric events (NPEs) requiring hospitalization by using administrative data. METHODS: We performed a cross-sectional, multicenter study of children 5 to 18 years of age hospitalized at two US children's hospitals with an NPE. We developed and evaluated 3 NPE identification algorithms: (1) primary or secondary NPE International Classification of Diseases, 10th Revision diagnosis alone, (2) NPE diagnosis, the NPE was present on admission, and the primary diagnosis was not malignancy- or surgery-related, and (3) identical to algorithm 2 but without requiring the NPE be present on admission. The positive predictive value (PPV) of each algorithm was calculated overall and by diagnosis field (primary or secondary), clinical significance, and NPE subtype. RESULTS: There were 1098 NPE hospitalizations included in the study. A total of 857 confirmed NPEs were identified for algorithm 1, yielding a PPV of 0.78 (95% confidence interval [CI] 0.76-0.80). Algorithm 2 (n = 846) had an overall PPV of 0.89 (95% CI 0.87-0.91). For algorithm 3 (n = 938), the overall PPV was 0.86 (95% CI 0.83-0.88). PPVs varied by diagnosis order, NPE clinical significance, and subtype. The PPV for critical clinical significance was 0.99 (0.97-0.99) for all 3 algorithms. CONCLUSIONS: We identified a highly accurate method to identify neuropsychiatric adverse events in children and adolescents. The use of these approaches will improve the rigor of future studies of NPE, including the necessary evaluations of medication adverse events, infections, and chronic conditions.

Impact of multimorbidity subgroups on the health care use of early pediatric cancer survivors.

BACKGROUND: Although pediatric cancer survivors in the United States are at an increased risk of developing chronic conditions, to the authors' knowledge there is limited information regarding the types and combinations of conditions they experience in the years immediately after the completion of cancer therapy. METHODS: An observational cohort study of early pediatric cancer survivors (children who were ≥2 years from the end of therapy and aged ≤18 years) was conducted using the Truven Health MarketScan (r) Commercial Claims and Encounters database (2009-2014). Latent class analysis was used to identify comorbidity groups among the subset with ≥2 conditions. Group-level health care use was compared with survivors without chronic conditions using multivariate regression. RESULTS: A total of 3687 early survivors were identified, of whom approximately 41.2% had no chronic conditions, 22.5% had 1 chronic condition, and 36.3% had ≥2 chronic conditions. Among those with ≥2 chronic conditions, 5 groups emerged: 1) general pediatric morbidity (35.4%); 2) central nervous system (CNS) (22.4%); 3) mental health conditions (22.2%); 4) endocrine (26.2%); and 5) CNS with endocrine (3.8%). The CNS group experienced the highest expenditures, at $17,964 more per year (95% CI, $1446-$34,482) compared with survivors without chronic conditions. The CNS group also had the highest odds of an emergency department visit (adjusted odds ratio, 1.71; 95% CI, 1.15-2.56). The endocrine group had the highest odds of hospitalization (odds ratio, 2.29; 95% CI, 1.24-4.22). CONCLUSIONS: Multimorbidity is common among pediatric cancer survivors. The current study identified 5 distinct comorbidity subgroups, all of which experienced high, yet differential, rates of health care use. The results of the current study highlight the complex health care needs of early survivors and provide evidence for the design of targeted survivorship services and interventions.

Patterns of Electrolyte Testing at Children's Hospitals for Common Inpatient Diagnoses.

BACKGROUND: Overuse of laboratory testing contributes substantially to health care waste, downstream resource use, and patient harm. Understanding patterns of variation in hospital-level testing across common inpatient diagnoses could identify outliers and inform waste-reduction efforts. METHODS: We conducted a multicenter retrospective cohort study of pediatric inpatients at 41 children's hospitals using administrative data from 2010 to 2016. Initial electrolyte testing was defined as testing occurring within the first 2 days of an encounter, and repeat testing was defined as subsequent testing within an encounter in which initial testing occurred. To examine if testing rates correlated across diagnoses at the hospital level, we compared risk-adjusted rates for gastroenteritis with a weighted average of risk-adjusted rates in other diagnosis cohorts. For each diagnosis, linear regression was performed to compare initial and subsequent testing. RESULTS: In 497 719 patient encounters, wide variation was observed across hospitals in adjusted, initial, and repeat testing rates. Hospital-specific rates of testing in gastroenteritis were moderately to strongly correlated with the weighted average of testing in other conditions (initial: r = 0.63; repeat r = 0.83). Within diagnoses, higher hospital-level initial testing rates were associated with significantly increased rates of subsequent testing for all diagnoses except gastroenteritis. CONCLUSIONS: Among children's hospitals, rates of initial and repeat electrolyte testing vary widely across 8 common inpatient diagnoses. For most diagnoses, hospital-level rates of initial testing were associated with rates of subsequent testing. Consistent rates of testing across multiple diagnoses suggest that hospital-level factors, such as institutional culture, may influence decisions for electrolyte testing.

Chronic Medication Use in Children Insured by Medicaid: A Multistate Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Little is known about the use of chronic medications (CMs) in children. We assessed the prevalence of CM use in children and the association of clinical characteristics and health care resource use with the number of CMs used. METHODS: This is a retrospective study of children ages 1 to 18 years using Medicaid from 10 states in 2014 grouped by the annual number of CMs (0, 1, 2-4, 5-9, and ≥10 medications), which are defined as a dispensed ≥30-day prescription with ≥2 dispensed refills. Trends in clinical characteristics and health care use by number of CMs were evaluated with the Cochran-Armitage trend test. RESULTS: Of 4 594 061 subjects, 18.8% used CMs. CM use was 44.4% in children with a complex chronic condition. Across all children, the most common CM therapeutic class was neurologic (28.9%). Among CM users, 48.8% used multiple CMs (40.3% used 2-4, 7.0% used 5-9, and 0.5% used ≥10). The diversity of medications increased with increasing number of CMs: for 1 CM, amphetamine stimulants were most common (29.0%), and for ≥10 CMs, antiepileptics were most common (7.1%). Of $2.3 billion total pharmacy spending, 59.3% was attributable to children dispensed multiple CMs. Increased CM use (0 to ≥10 medications) was associated with increased emergency department use (32.1% to 56.2%) and hospitalization (2.3% to 36.7%). CONCLUSIONS: Nearly 1 in 5 children with Medicaid used CMs. Use of multiple CMs was common and correlated with increased health care use. Understanding CM use in children should be fundamentally important to health care systems when strategizing how to provide safe, evidence-based, and cost-effective pharmaceutical care to children.

Multimorbidity and healthcare utilization among early survivors of pediatric cancer.

Early survivors of pediatric cancer are at increased risk of experiencing chronic conditions; however, little is known about the morbidity burden in this population. In this observational cohort study of commercially insured pediatric cancer survivors in the United States (2009-2014), we find that 22.5% of survivors had one chronic condition, and 36.3% had multiple. Compared with survivors without chronic conditions, the presence of multiple conditions significantly increased the odds of an emergency department visit by 70% (odds ratios [OR], 1.7; 95% confidence interval [CI], 1.4-2.1) and of a hospitalization almost four-fold (OR, 3.8; 95% CI], 2.5-5.5). Findings are important for informing pediatric survivorship care plans in the years following completion of therapy.

Etiology and Resource Use of Fever of Unknown Origin in Hospitalized Children.

BACKGROUND: Fever of unknown origin (FUO) is a well-known pediatric presentation. The primary studies determining the causes of prolonged fever in children were performed 4 decades ago, before major advances in laboratory and diagnostic testing. Given that the distribution of diagnosed causes of adult FUO has changed in recent decades, we hypothesized that the etiology of FUO in children has concordantly changed and also may be impacted by a definition that includes a shorter required duration of fever. METHODS: A single-center, retrospective review of patients 6 months to 18 years of age admitted to the North Carolina Children's Hospital from January 1, 2002, to December 21, 2012, with an International Classification of Diseases, Ninth Revision diagnosis of fever, a documented fever duration >7 days before admission, and a previous physician evaluation of each patient's illness. RESULTS: A total of 1164 patients were identified, and of these, 102 met our inclusion criteria for FUO. Etiologic categories included "infectious" (42 out of 102 patients), "autoimmune" (28 out of 102 patients), "oncologic" (18 out of 102 patients), and "other" or "unknown" (14 out of 102 patients). Several clinical factors were statistically and significantly different between etiologic categories, including fever length, laboratory values, imaging performed, length of stay, and hospital costs. CONCLUSIONS: Unlike adult studies, the categorical distribution of diagnoses for pediatric FUO has marginally shifted compared to previously reported pediatric studies. Patients hospitalized with FUO undergo prolonged hospital stays and have high hospital costs. Additional study is needed to improve the recognition, treatment, and expense of diagnosis of prolonged fever in children.

Evans Syndrome Secondary to Common Variable Immune Deficiency.

Evans syndrome is an underdiagnosed condition consisting of simultaneous or sequential combination of autoimmune hemolytic anemia and immune-mediated thrombocytopenia. We report a case of severe Evans syndrome presenting as altered mental status, a rare presenting sign of the disease. This case highlights the difficulty in diagnosing Evans syndrome and provides a review of the literature and management strategies for treating the disorder.

Endogenous lipoid pneumonia preceding diagnosis of pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is an under-reported and under-diagnosed condition, with a high percentage of cases found on autopsy or late stage disease. The etiology of PAP includes genetic, primary (anti-granulocyte-macrophage colony-stimulating factor antibodies) and secondary (oncologic, rheumatologic, infectious, chemical and immunologic) causes. Here, we present the first reported pediatric case of endogenous lipoid pneumonia and non-specific interstitial pneumonitis preceding the development of PAP.

Inhibition of sphingosine kinase-2 ablates androgen resistant prostate cancer proliferation and survival.

BACKGROUND: Endogenous sphingolipid signaling has been shown to play an important role in prostate cancer endocrine resistance. METHODS: The novel SphK2 inhibitor, ABC294640, was used to explore SphK signaling in androgen resistant prostate cancer cell death signaling. RESULTS: It dose-dependently decreased PC-3 and LNCaP cell viability, IC(50) of 28 ± 6.1 µM (p < 0.05) and 25 ± 4.0 µM (p < 0.05), respectively. ABC294640 was more potent in long-term clonogenic survival assays; IC(50) of 14 ± 0.4 µM (p < 0.05) in PC-3 cells and 12 ± 0.9 µM (p < 0.05) in LNCaP cells. Intrinsic apoptotic assays failed to demonstrate increased caspase-9 activity. Ki-67 staining demonstrated decreased proliferation by 50 ± 8.4% (p < 0.01) in PC-3 cells. CONCLUSIONS: SphK2 inhibition decreases androgen resistant prostate cancer viability, survival, and proliferation independently of the intrinsic apoptotic pathway. Findings are in contrast to recent observations of ABC29460 acting dependently on the intrinsic pathway in other endocrine resistant cancer cell lines.

3-Ketone-4,6-diene ceramide analogs exclusively induce apoptosis in chemo-resistant cancer cells.

Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to anticancer ceramide analogs. In this work we designed five new ceramide analogs with different backbones, in order to test the hypothesis that extending the conjugated system in ceramide analogs would lead to an increase of their anticancer activity and selectivity towards resistant cancer cells. The analogs with the 3-ketone-4,6-diene backbone show the highest apoptosis-inducing efficacy. The most potent compound, analog 406, possesses higher pro-apoptotic activity in chemo-resistant cell lines MCF-7TN-R and NCI/ADR-RES than the corresponding chemo-sensitive cell lines MCF-7 and OVCAR-8, respectively. However, this compound shows the same potency in inhibiting the growth of another pair of chemo-sensitive and chemo-resistant cancer cells, MCF-7 and MCF-7/Dox. Mechanism investigations indicate that analog 406 can induce apoptosis in chemo-resistant cancer cells through the mitochondrial pathway. Cellular glucosylceramide synthase assay shows that analog 406 does not interrupt glucosylceramide synthase in chemo-resistant cancer cell NCI/ADR-RES. These findings suggest that due to certain intrinsic properties, ceramide analogs' pro-apoptotic activity is not disrupted by the normal drug-resistance mechanisms, leading to their potential use for overcoming cancer multidrug-resistance.

Preferential star strand biogenesis of pre-miR-24-2 targets PKC-alpha and suppresses cell survival in MCF-7 breast cancer cells.

microRNAs (miRNA) are regulators of cellular pathways and alterations of normal miRNA expression levels have been shown to increase tumorigenesis. miR-24 has been demonstrated as having both tumor suppressive and oncogenic properties depending on cell context. Here, we demonstrate a possible role for pre-miR-24-2 as a tumor suppressor in the MCF-7 breast cancer cell line through the preferential processing of mature miR-24-2* over miR-24. Specifically, we show that the ectopic expression of miR-24-2* in MCF-7 breast cancer cells results in a suppression of cellular survival both in vivo and in vitro. Notably, the overexpression of miR-24-2* results in a dampening of cell survival through the targeted suppression of PKCα. In addition, a similar biological change is observed in vivo where MCF-7 cells overexpressing pre-miR-24-2 have decreased tumorigenicity and tumor incidence. Taken together our data demonstrate that when overexpressed biogenesis of the pre-miR-24-2 favors miR-24-2* in the MCF-7 breast cancer cell line and suggests a tumor suppressive role for miR-24-2* observed through the inhibition of PKCα-mediated cellular survival.

Targeting ovarian cancer and chemoresistance through selective inhibition of sphingosine kinase-2 with ABC294640.

ABC294640, a selective inhibitor of sphingosine kinase-2, inhibits the formation of sphingosine 1-phosphate (S1P), a signaling lipid implicated in promoting tumor survival. We investigated the anticancer activity of ABC294640 in two ovarian cancer cell lines, BG-1 and Caov-3. ABC294640 dose-dependently inhibited clonogenic survival and cell viability of both ovarian cancer lines in vitro. Using enzyme-linked immunosorbant assays and western blot detection in chemoresistant Caov-3 cells, treatment with ABC294640 alone also potentiated bcl-2-associated X-protein and caspase-9 transcription levels, although it did not significantly increase apoptotic cell death. Interestingly, ABC294640 administered to Caov-3 ovarian cancer cells in conjunction with paclitaxel induced apoptotic cell death through activation of caspase-9. Induction of apoptosis may mediate the anticancer effect of ABC294640 in ovarian cancer, although its precise antitumor mechanism is unclear. Ultimately, through its inhibition of S1P formation and subsequent effects on critical survival signaling cascades, ABC294640 may prove to be a useful adjunct to help re-sensitize tumors to standard therapy.

MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis.

Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-ß protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(-), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.

Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition.

Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF­κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N­cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR­200, miR­303, miR­302, miR­199 and miR­328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.

Sphingosine kinase isoforms as a therapeutic target in endocrine therapy resistant luminal and basal-A breast cancer.

Sphingosine kinase signaling has become of increasing interest as a cancer target in recent years. Two sphingosine kinase inhibitors, sphingosine kinase inhibitor (SKI)-II and ABC294640, are promising as potential breast cancer therapies. However, evidence for their therapeutic properties in specific breast cancer subtypes is currently lacking. In this study, we characterize these drugs in luminal, endocrine-resistant (MDA-MB-361) and basal-A, triple-negative (MDA-MB-468) breast cancer cells and compare them with previously published data in other breast cancer cell models. Both SKI-II and ABC294640 demonstrated greater efficacy in basal-A compared with luminal breast cancer. ABC294640, in particular, induced apoptosis and blocked proliferation both in vitro and in vivo in this triple-negative breast cancer system. Furthermore, Sphk expression promotes survival and endocrine therapy resistance in previously sensitive breast cancer cells. Taken together, these results characterize sphingosine kinase inhibitors across breast cancer cell systems and demonstrate their therapeutic potential as anti-cancer agents.

Pharmacology and anti-tumor activity of RWJ67657, a novel inhibitor of p38 mitogen activated protein kinase.

Endocrine therapy resistance is a primary cause of clinical breast cancer treatment failure. The p38 mitogen activated protein kinase (MAPK) signaling pathway is known to promote ligand independent tumor growth and resistance to endocrine therapy. In this study, we investigated the therapeutic potential of the p38 inhibitor RWJ67657 in the treatment of tamoxifen resistant MDA-MB-361 cells. RWJ67657 dose-dependently decreased both basal and stimulated activation of p38 MAPK signaling in this drug resistant cell system. Decreased activation of p38 by RWJ67657 resulted in inhibition of the downstream p38 targets hsp27 and MAPKAPK. Diminished p38 signaling resulted in inhibition of p38-medated gene transcription. Furthermore, pharmacological inhibition of p38 by RWJ67657 decreased biological effects of p38, including ER-mediated gene expression and clonogenic survival in a dose-dependent manner. Animal studies revealed significantly decreased p38 signaling in vivo following exposure to RWJ67657. Treatment with the inhibitor markedly decreased phosphorylation of p38 in MDA-MB-361 tumors, leading to decreased transcription of both Fra-1 and progesterone receptor. Utilizing well-established xenograft tumor models, we demonstrated that RWJ67657 exhibits potent anti-tumor properties. Treatment with RWJ67657 markedly decreased tamoxifen resistant tumor growth, both in the presence and absence of estrogen. Taken together, our findings demonstrate the therapeutic potential of targeting the p38-MAPK signaling cascade in the treatment of endocrine resistant breast cancer.

Altered death receptor signaling promotes epithelial-to-mesenchymal transition and acquired chemoresistance.

Altered death receptor signaling and resistance to subsequent apoptosis is an important clinical resistance mechanism. Here, we investigated the role of death receptor resistance in breast cancer progression. Resistance of the estrogen receptor alpha (ER)-positive, chemosensitive MCF7 breast cancer cell line to tumor necrosis factor (TNF) was associated with loss of ER expression and a multi-drug resistant phenotype. Changes in three major pathways were involved in this transition to a multidrug resistance phenotype: ER, Death Receptor and epithelial to mesenchymal transition (EMT). Resistant cells exhibited altered ER signaling, resulting in decreased ER target gene expression. The death receptor pathway was significantly altered, blocking extrinsic apoptosis and increasing NF-kappaB survival signaling. TNF resistance promoted EMT changes, resulting in a more aggressive phenotype. This first report identifying specific mechanisms underlying acquired resistance to TNF could lead to a better understanding of the progression of breast cancer in response to chemotherapy treatment.

Inhibition of p38-MAPK alters SRC coactivation and estrogen receptor phosphorylation.

The p38 mitogen activated protein kinase pathway (MAPK) is known to promote cell survival, endocrine therapy resistance and hormone independent breast cancer cell proliferation. Therefore, we utilized the novel p38 inhibitor RWJ67657 to investigate the relevance of targeting this pathway in the ER (+) breast cancer cell line MCF-7. Our results show that RWJ67657 inhibits both basal and estrogen stimulated phosphorylation of p38α, resulting in decreased activation of the downstream p38α targets hsp27 and MAPAPK. Furthermore, inhibition of p38α by RWJ67657 blocks clonogenic survival of MCF-7 cells with little effect on non-cancerous breast epithelial cells. Even though p38α is known to phosphorylate ERα at residue within ER's hinge region at Thr311, resulting in increased ERα transcriptional activation, our results suggest RWJ67657 inhibits the p38α-induced activation of ER by targeting both the AF-1 and AF-2 activation domains within ERα. We further show that RWJ67657 decreases the transcriptional activity of the ER coactivators SRC-1, SRC-2 and SRC-3. Taken together, our results strongly suggest that in addition to phosphorylating Thr311 within ERα, p38α indirectly activates the ER by phosphorylation and stimulation of the known ERα coactivators, SRC-1, -2 and-3. Overall, our data underscore the therapeutic potential of targeting the p38 MAPK pathway in the treatment of ER (+) breast cancer.