Comparison of the Transcriptomic Signatures in Pediatric and Adult CML.

Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients.

Scholarly Productivity and Rank in Academic Hospital Medicine.

Despite the rapid growth of academic hospital medicine, scholarly productivity remains poorly characterized. In this cross-sectional study, distribution of academic rank and scholarly output of academic hospital medicine faculty are described. We extracted data for 1,554 hospitalists on faculty at the top 25 internal medicine residency programs. Only 11.7% of faculty had reached associate (9.0%) or full professor (2.7%). The median number of publications was 0.0 (interquartile range [IQR], 0.0-4.0), with 51.4% without a single publication. Faculty 6 to 10 years post residency had a median of 1.0 (IQR, 0.0-4.0) publication, with 46.8% of these faculty without a publication. Among men, 54.3% had published at least one manuscript, compared to 42.7% of women (P < .0001). Predictors of promotion included H-index, number of years post residency graduation, completion of chief residency, and graduation from a top 25 medical school. Promotion remains uncommon in academic hospital medicine, which may be partially due to low rates of scholarly productivity.

Availability of Palliative Care in Long-Term Acute Care Hospitals.

OBJECTIVE: To determine the availability of palliative care programs in long-term acute care hospitals (LTACHs) DESIGN: Cross-sectional analysis using the 2016 American Hospital Association (AHA) Annual Survey. SETTING AND PARTICIPANTS: LTACHs in the United States. METHOD: We used descriptive analyses to compare the prevalence of palliative care programs in LTACHs across the United States in 2016. For LTACHs without a program, we also examined palliative care physician capacity in regions where those LTACHs resided to evaluate if expertise existed in those regions. RESULTS: One-third (36.5%) of 405 LTACHs (50.6% response rate) self-reported having a palliative care program. Among LTACHs without palliative care, 42.4% were in regions with the highest palliative care physician capacity nationwide. CONCLUSIONS AND IMPLICATIONS: LTACHs care for patients with serious and prolonged illnesses, many of whom would benefit from palliative care. Despite this, our study finds that specialty palliative care is limited in LTACHs. The limited palliative care availability in LTACHs is mismatched with the needs of this seriously ill population. Greater focus on increasing palliative care in LTACHs is essential and may be feasible as 40% of LTACHs without a palliative care program were located in regions with the highest palliative care physician capacity.

RSK inhibitor BI-D1870 inhibits acute myeloid leukemia cell proliferation by targeting mitotic exit.

The 90 kDa Ribosomal S6 Kinase (RSK) drives cell proliferation and survival in cancers, although its oncogenic mechanism has not been well characterized. Phosphorylated level of RSK (T573) was increased in acute myeloid leukemia (AML) patients and associated with poor survival. To examine the role of RSK in AML, we analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK. BI-D1870 treatment increased the G2/M population and induced apoptosis in AML cell lines and patient AML cells. Characterization of mitotic phases showed that the metaphase/anaphase transition was significantly inhibited by BI-D1870. BI-D1870 treatment impeded the association of activator CDC20 with APC/C, but increased binding of inhibitor MAD2 to CDC20, preventing mitotic exit. Moreover, the inactivation of spindle assembly checkpoint or MAD2 knockdown released cells from BI-D1870-induced metaphase arrest. Therefore, we investigated whether BI-D1870 potentiates the anti-leukemic activity of vincristine by targeting mitotic exit. Combination treatment of BI-D1870 and vincristine synergistically increased mitotic arrest and apoptosis in acute leukemia cells. These data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit, providing a novel approach to overcoming vincristine resistance in AML cells.

Economic Burden Associated With Extended-Release vs Immediate-Release Drug Formulations Among Medicare Part D and Medicaid Beneficiaries.

Importance: The United States spends more money on medications than any other country. Most extended-release drugs have not consistently shown therapeutic or adherence superiority, and switching these medications to less expensive, generic, immediate-release formulations may offer an opportunity to reduce health care spending. Objective: To evaluate Medicare Part D and Medicaid spending on extended-release drug formulations and the potential savings associated with switching to generic immediate-release formulations. Design, Setting, and Participants: This cross-sectional study used the 2012 to 2017 Medicare Part D Drug Event and Medicaid Spending and Utilization data sets to analyze 20 extended-release drugs with 37 Medicare formulations and 36 Medicaid formulations. Only cardiovascular, diabetes, neurologic, and psychiatric extended-release drugs saving at most 1 additional daily dose compared with their immediate-release counterparts were included. Extended-release drugs with therapeutic superiority were excluded. Analyses were conducted from January to December 2019. Main Outcomes and Measures: Estimated Medicare Part D and Medicaid savings from switching extended-release to immediate-release drug formulations between 2012 and 2017. Results: Of the 6252 drugs screened for eligibility from the 2017 Medicaid Drug Utilization database and the 2017 Medicare Part D database, 67 drugs with extended-release formulations that were identified in the Medicare data set (20 distinct drugs with 37 formulations [19 brand, 18 generic]) were included in the analysis. In 2017, Medicare Part D spent $2.2 billion and Medicaid spent $952 million (a combined $3.1 billion) on 20 extended-release drugs. Between 2012 and 2017, Medicare Part D and Medicaid spent $12 billion and $5.9 billion, respectively, on extended-release formulations. Switching from brand-name to generic extended-release formulations was estimated to be associated with a $247 million reduction in Medicare spending and $299 million reduction in Medicaid spending in 2017, whereas switching all brand-name and generic extended-release formulations to immediate-release formulations in both Medicare and Medicaid was estimated to reduce spending by $2.6 billion ($1.8 billion for Medicare and $836 million for Medicaid) in 2017. During the study period, the estimated spending reduction associated with switching all patients receiving extended-release formulations (brand name extended-release and generic extended-release) to generic immediate-release formulations was $13.7 billion ($8.5 billion from Medicare and $5.2 billion from Medicaid). Conclusions and Relevance: The findings suggest that switching from extended-release drug formulations to therapeutically equivalent immediate-release formulations when available represents a potential option to reduce Medicare and Medicaid spending.

Epigenetic Targeting of TERT-Associated Gene Expression Signature in Human Neuroblastoma with TERT Overexpression.

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-sequencing data from 498 patients with neuroblastoma and revealed a differentially overexpressed gene signature in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. Brd4 and cyclin-dependent kinases (CDK) had critical regulatory roles in the expression and chromatin activation of TERT and multiple TERT-associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of TERT and multiple TERT-associated genes in neuroblastoma with TERT overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with TERT overexpression and an epigenetically targeted novel therapeutic strategy. SIGNIFICANCE: Epigenetically cotargeting Brd4 and Cdks suppresses human neuroblastoma with TERT overexpression by inhibiting the TERT-associated gene expression networks.