Clinical effectiveness outcomes and healthcare resource utilization of patients diagnosed with small-cell lung cancer.

Background: Real-world data are lacking on patients with small-cell lung cancer (SCLC) with extensive-stage SCLC (eSCLC) and poor performance status (PS). Patients & methods: Eligible patients diagnosed with eSCLC between 1 January 2008 and 31 December 2017 were included in this retrospective, observational study. Results: The study included 406 patients, with 14.3% impaired PS. Progression-free survival and overall survival were not significantly different between impaired (Eastern Cooperative Oncology Group ≥2) and not impaired patients (median, 4.5 vs 5.3 months, and 7.2 vs 8.4 months, respectively). Impaired patients used more supportive care drugs (mean, 3.0 vs 2.0; p = 0.033). Conclusion: Effectiveness outcomes among patients with and without impaired PS did not differ in the real-world setting. Progression-free survival and overall survival were similar to data from clinical trials.

Treatment patterns and clinical outcomes of palbociclib-based therapy received in US community oncology practices.

Background: Limited studies have evaluated palbociclib-based therapy use in patients with advanced/metastatic breast cancer in the real world. This retrospective study used medical records from US community oncology practices to address the gap. Materials & methods: Eligible patients receiving palbociclib-based therapy per label indication from 3 February 2015 to 31 December 2017 were included. Descriptive analyses were conducted for patient characteristics, treatment patterns and clinical outcomes. Results: The study included 233 patients who received palbociclib + aromatase inhibitor (P+AI) and 48 who received palbociclib + fulvestrant (P+F). Real-world progression-free rate for P+AI was 69.8% (46.8%) at 12 (24) months (P+F: 43.5% [39.9%]) months. Real-world survival rate was 89.8% (71.4%) at 12 (24) months (P+F: 76.3% [65.0%]). Conclusion: The study findings are consistent with previous studies of palbociclib-based therapy.

Real-world utilization of darbepoetin alfa in cancer chemotherapy patients.

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.

Cost per response analysis of strategies for chronic immune thrombocytopenia.

OBJECTIVES: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the "watch-and-rescue" (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP). STUDY DESIGN: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder. METHODS: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed. RESULTS: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case. CONCLUSIONS: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue.

Using multiple sources of data for surveillance of postoperative venous thromboembolism among surgical patients treated in Department of Veterans Affairs hospitals, 2005-2010.

BACKGROUND: There are limitations to using administrative data to identify postoperative venous thromboembolism (VTE). We used a novel approach to quantify postoperative VTE events among Department of Veterans Affairs (VA) surgical patients during 2005-2010. METHODS: We used VA administrative data to exclude patients with VTE during 12 months prior to surgery. We identified probable postoperative VTE events within 30 and 90 days post-surgery in three settings: 1) pre-discharge inpatient, using a VTE diagnosis code and a pharmacy record for anticoagulation; 2) post-discharge inpatient, using a VTE diagnosis code followed by a pharmacy record for anticoagulation within 7 days; and 3) outpatient, using a VTE diagnosis code and either anticoagulation or a therapeutic procedure code with natural language processing (NLP) to confirm acute VTE in clinical notes. RESULTS: Among 468,515 surgeries without prior VTE, probable VTEs were documented within 30 and 90 days in 3,931 (0.8%) and 5,904 (1.3%), respectively. Of probable VTEs within 30 or 90 days post-surgery, 47.8% and 62.9%, respectively, were diagnosed post-discharge. Among post-discharge VTE diagnoses, 86% resulted in a VA hospital readmission. Fewer than 25% of outpatient records with both VTE diagnoses and anticoagulation prescriptions were confirmed by NLP as acute VTE events. CONCLUSION: More than half of postoperative VTE events were diagnosed post-discharge; analyses of surgical discharge records are inadequate to identify postoperative VTE. The NLP results demonstrate that the combination of VTE diagnoses and anticoagulation prescriptions in outpatient administrative records cannot be used to validly identify postoperative VTE events.

Progenitor expansion in apc mutants is mediated by Jak/Stat signaling.

BACKGROUND: Mutations in APC, a negative regulator of the Wnt/ß-catenin pathway, can cause cancer as well as profound developmental defects. In both cases, affected cells adopt a proliferative progenitor state and fail to differentiate. While the upregulation of some target genes of Wnt/ß-catenin signaling has been shown to mediate these phenotypes in individual tissues, it is unclear whether a common mechanism underlies the defects in APC mutants. RESULTS: Here we show that stat3, a known oncogene and a target of ß-catenin in multiple tissues, is upregulated in apc mutant zebrafish embryos. We further demonstrate that Jak/Stat signaling is necessary for the increased level of proliferation and neural progenitor gene expression observed in apc mutants. CONCLUSIONS: Together, our data suggest that the regulation of Jak/Stat signaling may represent a conserved mechanism explaining the expansion of undifferentiated cells downstream of APC mutations.

Identification of proteins binding to E-Box/Ku86 sites and function of the tumor suppressor SAFB1 in transcriptional regulation of the human xanthine oxidoreductase gene.

The xanthine oxidoreductase gene (XOR) encodes an important source of reactive oxygen species and uric acid, and its expression is associated with various human diseases including several forms of cancer. We previously reported that basal human XOR (hXOR) expression is restricted or repressed by E-box and TATA-like elements and a cluster of transcriptional proteins, including AREB6-like proteins and DNA-dependent protein kinase (DNA-PK). We now demonstrate that the cluster contains the tumor suppressors SAFB1, BRG1, and SAF-A. We further demonstrate that SAFB1 silencing increases hXOR expression and that SAFB1 directly binds to the E-box. Multiple studies in vitro and in vivo including pulldown, immunoprecipitation and chromatin immunoprecipitation analyses indicate that SAFB1, Ku86, and BRG1 associate with each other. The results suggest that the SAFB1 complex binds to the hXOR promoter in a chromatin environment and plays a critical role in restricting hXOR expression via its direct interaction with the E-box, DNA-PK, and tumor suppressors. Moreover, we demonstrate that the cytokine, oncostatin M (OSM), induces the phosphorylation of SAFB1 and that the OSM-induced hXOR mRNA expression is significantly inhibited by silencing the DNA-PK catalytic subunit or SAFB1 expression. The present studies for the first time demonstrate that hXOR is a tumor suppressor-targeted gene and that the phosphorylation of SAFB1 is regulated by OSM, providing a molecular basis for understanding the role of SAFB1-regulated hXOR transcription in cytokine stimulation and tumorigenesis.

NSSR1 promotes neuronal differentiation of mouse embryonic carcinoma P19 cells.

We generated the small interference RNAs to specifically silence the expression of neural salient serine/arginine rich protein 1 (NSSR1) and showed that the inhibition of NSSR1 expression in mouse embryonic carcinoma cells (P19) reduces neuronal differentiation. By contrast, its over-expression promotes the differentiation. Neither inhibition nor over-expression shows distinct effect on cell proliferation. The over-expression increases the inclusion of NCAM L1 exon2 while the inhibition reduces the inclusion. The splicing of kinase insert free isoform of TrkC (TrkC-K1) is increased by the over-expression. The results demonstrate that NSSR1 promotes neuronal differentiation and the splicing of NCAML1 exon2 and TrkC-K1.

Neural expression and regulation of NSSR1 proteins.

Neural salient serine-/arginine-rich protein 1 (NSSR1) is a newly identified SR protein that regulates pre-mRNA splicing. In the present study, we demonstrated the neural specialization of NSSR1 protein expression in humans and mice. Strong immunoreactive signals to NSSR1 were observed in mouse cerebral neurons, cerebellar Purkinje cells, pyramidal neurons in CA1, CA2 and CA3 regions of the hippocampus and granule cells in the dentate gyrus. In primarily cultured mouse neural progenitor cells (NPCs), at the undifferentiated status, NSSR1 transcripts were detected, but not the proteins. In comparison, in differentiated NPCs both NSSR1 transcripts and proteins were expressed and significantly up-regulated. The results suggest that NSSR1 is important in regulation of brain function and neural differentiation, possibly via regulating the neural-specific alternative splicing of genes.

Upregulation of Ku expression in human neuroectodermal tumor cells after retroviral DNA integration.

OBJECTIVE: To examine the expression of DNA-dependent protein kinase (DNA-PK); including DNA-PKcs, Ku70 and Ku80 in human neuroectodermal tumor cells with or without retroviral DNA integration. METHODS: RT-PCR assay was used to examine the transcript of DNA-PK. Western blot and immunocytochemistry assays were used to examine the protein level of DNA-PK. RESULTS: The expression of DNA-PKcs was similar in the cells with or without retroviral DNA integration, but the expression of Ku (both mRNA and protein for Ku70 and only protein for Ku80) was higher in cells with retroviral DNA integration than in cells without retroviral DNA integration. CONCLUSION: The expression of Ku but not the expression of DNA-PKcs is induced by retroviral DNA integration. Ku70 may play an important role in the regulation of Ku function in response to retroviral DNA integration.