Cost-Effectiveness Analysis of the Oncotype DX Breast Recurrence Score® Test from a US Societal Perspective.

Background and Objectives: The 21-gene assay (the Oncotype DX Breast Recurrence Score® test) estimates the 10-year risk of distant recurrence in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early-stage breast cancer to inform adjuvant chemotherapy decisions. The cost-effectiveness of the 21-gene assay compared against standard clinical-pathological risk tools alone for HR+/HER2- early-stage breast cancer was assessed using an economic model informed by evidence from randomized controlled trials. Materials and Methods: A cost-effectiveness model consisted of a decision-tree to stratify patients according to their Recurrence Score (RS) results and the use of adjuvant chemotherapy, followed by a Markov component to estimate the long-term costs and outcomes of the chosen treatment. Distributions of patients and distant recurrence probabilities were derived from the TAILORx (N0) and RxPONDER (N1) trials. The model was evaluated from a healthcare payer and societal perspective. Endocrine therapy and chemotherapy use were informed using clinical expert opinion to reflect US clinical practice and were combined with Medicare drug costs (2021) to estimate the cost of treatment. Societal costs included lost productivity and patient out-of-pocket costs obtained from literature. Results: The Oncotype DX test generated more quality-adjusted life-years (QALYs) (N0: 0.25; N1: 0.08) at a lower cost (N0: -$13,395; N1: -$2526) compared to clinical-pathological risk alone from a societal cost perspective. The overall conclusions from the model did not change when considering a payer perspective. The main cost drivers were avoidance of distant recurrence for N0 (-$12,578), and the cost of adjuvant chemotherapy for N1 (-$2133). Lost productivity had a major impact in the societal perspective analysis (N0: -$4607; N1: -$1586). Conclusion: Adjuvant chemotherapy decisions based on the RS result led to more life year gains and lower healthcare costs (dominant) compared to using clinical-pathological risk factors alone among patients with HR+/HER2- N0 and N1 early-stage breast cancer.

The budget impact of utilizing the Oncotype DX Breast Recurrence Score test from a US healthcare payer perspective.

BACKGROUND AND OBJECTIVES: The Oncotype DX Breast Recurrence Score test is used to estimate distant recurrence risk of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer and inform decisions on the use of adjuvant chemotherapy. A model-based budget impact analysis compared the Oncotype DX test in combination with clinical-pathological risk against using clinical-pathological risk alone for HR+/HER2- node-negative (N0) and node-positive (N1; 1-3 axillary lymph nodes) early-stage breast cancer patients. MATERIALS AND METHODS: Test and medical costs associated with treatment of breast cancer were assessed through a US healthcare payer perspective. Distributions of patients by Recurrence Score result and distant recurrence probabilities with chemo-endocrine and endocrine therapy were derived from the TAILORx (N0) and RxPONDER (N1) trials. Changes in budget impact were evaluated over a 5-year horizon for a 1,000,000-member hypothetical health plan. RESULTS: With the Oncotype DX test, there was an incremental budget impact of $261,067 (per member per month (PMPM): $0.004), in the N0 population, and $56,143 (PMPM: $0.001) in the N1 population over the 5-year period. The largest budget impact reduction in the N0 population was attributed to reduced breast cancer recurrence costs (incremental: -$633,457, PMPM: -$0.011), while chemotherapy sparing reduced costs in the N1 population (incremental: -$94,884, PMPM: -$0.002). CONCLUSION: The clinical benefit of using the Oncotype DX test to inform adjuvant chemotherapy decisions has been shown in multiple randomized controlled trials. This analysis demonstrated that while using the Oncotype DX test to inform adjuvant chemotherapy decisions may slightly increase US healthcare costs over an initial 5-year time horizon (driven by a cost increase in the first year with cost savings reflected in remaining 4 years), there is significant scope for cost savings when assessing beyond this period due to avoided downstream costs of distant recurrence and long-term chemotherapy adverse events. PMPM costs also remain low across all populations examined, demonstrating a close-to-neutral budget impact.

Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), characterized by atrophic lesions that first start in the outer retina and progressively expand to cover the macula and the fovea, the center of the macula, leading to irreversible loss of vision over time. GA is distinct from wet or neovascular AMD (nAMD), the other form of advanced AMD. Neovascular AMD is characterized by new invading leaky blood vessels in the macula that can lead to acute vision loss. GA and nAMD may coexist in the same eye. The underlying pathophysiology of GA is complex and thought to involve chronic inflammation due to overactivation of the complement system that leads to the loss of photoreceptors, retinal pigment epithelium (RPE), and the underlying choriocapillaris. The disappearance of these structures appears as sharply demarcated atrophic lesions that are typical of GA. Researchers have reported about 1 million reported cases of GA in the United States, and about 160,000 cases occur per year. The most important risk factors for GA are increasing age and family history. Diagnosis of GA is usually made by using multimodal imaging techniques. Lesions associated with GA are highly heterogeneous, and the growth rate may differ from patient to patient. Despite the progressive nature of GA, the fovea may be spared until much later in the disease, thereby retaining central vision in patients. With time, atrophic lesions may progressively grow to involve the fovea, thereby severely impairing central vision. Vision loss can happen rapidly once the lesions reach the fovea. However, even without the involvement of the fovea, ongoing vision impairment impacting daily life may be present. Median time from GA not involving the center of the fovea (without subfoveal involvement) to GA with lesion boundary affecting the foveal center (subfoveal involvement) ranges from 1.4 to 2.5 years. GA can greatly impact patients' functioning and quality of life and limit their independence by interfering with activities of daily living, including difficulties with reading, driving, watching television, recognizing faces, and being unable to do household chores. No treatments have been available until intravitreal pegcetacoplan was recently approved by the US Food and Drug Administration for GA secondary to AMD. DISCLOSURES: Dr Bakri serves as a consultant to Apellis Pharmaceuticals, as well as AbbVie, Adverum, Eyepoint, iLumen, Iveric Bio, Genentech, Novartis, Outlook Therapeutics, Pixium, Regeneron, Roche, and Regenxbio. Drs Sharp, Luo, and Sarda are employees of Apellis Pharmaceuticals. Dr Bektas and Ms Khan are employees of RTI Health Solutions. Apellis developed and led the concept design of this publication, review and interpretation, approval, and decision to publish. This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. This supplement is to describe the disease of geographic atrophy and was funded by Apellis. Apellis Pharmaceuticals has developed Syfovre (pegcetacoplan), the first and only treatment for geographic atrophy.

Rates of Follow-up Colonoscopy After a Positive Stool-Based Screening Test Result for Colorectal Cancer Among Health Care Organizations in the US, 2017-2020.

Importance: Noninvasive stool-based screening tests (SBTs) are effective alternatives to colonoscopy. However, a positive SBT result requires timely follow-up colonoscopy (FU-CY) to complete the colorectal cancer screening paradigm. Objectives: To evaluate FU-CY rates after a positive SBT result and to assess the association of the early COVID-19 pandemic with FU-CY rates. Design, Setting, and Participants: This mixed-methods cohort study included retrospective analysis of deidentified administrative claims and electronic health records data between June 1, 2015, and June 30, 2021, from the Optum Labs Data Warehouse and qualitative, semistructured interviews with clinicians from 5 health care organizations (HCOs). The study population included data from average-risk primary care patients aged 50 to 75 years with a positive SBT result between January 1, 2017, and June 30, 2020, at 39 HCOs. Main Outcomes and Measures: The primary outcome was the FU-CY rate within 1 year of a positive SBT result according to patient age, sex, race, ethnicity, insurance type, Charlson Comorbidity Index (CCI), and prior SBT use. Results: This cohort study included 32 769 individuals (16 929 [51.7%] female; mean [SD] age, 63.1 [7.1] years; 2092 [6.4%] of Black and 28 832 [88.0%] of White race; and 825 [2.5%] of Hispanic ethnicity). The FU-CY rates were 43.3% within 90 days of the positive SBT result, 51.4% within 180 days, and 56.1% within 360 days (n = 32 769). In interviews, clinicians were uniformly surprised by the low FU-CY rates. Rates varied by race, ethnicity, insurance type, presence of comorbidities, and SBT used. In the Cox proportional hazards regression model, the strongest positive association was with multitarget stool DNA use (hazard ratio, 1.63 [95% CI, 1.57-1.68] relative to fecal immunochemical tests; P < .001), and the strongest negative association was with the presence of comorbidities (hazard ratio, 0.64 [95% CI, 0.59-0.71] for a CCI of >4 relative to 0; P < .001). The early COVID-19 pandemic was associated with lower FU-CY rates. Conclusions and Relevance: This study found that FU-CY rates after a positive SBT result for colorectal cancer screening were low among an average-risk population, with the median HCO achieving a 53.4% FU-CY rate within 1 year. Socioeconomic factors and the COVID-19 pandemic were associated with lower FU-CY rates, presenting opportunities for targeted intervention by clinicians and health care systems.

Prevalence of Lumbosacral Transitional Vertebrae in Patients With Symptomatic Femoroacetabular Impingement Requiring Hip Arthroscopy.

PURPOSE: The primary aim of this study was to determine the prevalence of lumbosacral transitional vertebrae (LSTVs) in patients with symptomatic femoroacetabular impingement (FAI) requiring hip arthroscopy. The secondary aim was to determine whether there is an association between LSTV anatomy and patient-reported outcomes. METHODS: This retrospective study included patients aged 18 to 45 years with symptomatic FAI who underwent arthroscopy between March 2010 and March 2016 and had anteroposterior pelvic radiographs. The exclusion criteria included lack of an FAI diagnosis, hip osteoarthritis (Tönnis grade ≥ 2), prior spinal fusion surgery, prior total hip arthroplasty, indications for total hip arthroplasty, and revision surgery on the affected hip. All radiographs were assessed by an interventional spine and sports fellow. The primary outcome was the prevalence of LSTVs, classified using the criteria of Castellvi et al. Secondary outcomes included the modified Harris Hip Score, Hip Outcome Score, and International Hip Outcome Tool 33 score. RESULTS: A total of 1,880 patients were included. Review of the patients' radiographs yielded 262 LSTVs, for an overall prevalence of 13.9% (type IA in 104 [5.5%], type IB in 53 [2.8%], type IIA in 60 [3.2%], type IIB in 25 [1.3%], type IIIA in 8 [0.4%], type IIIB in 0 [0%], and type IV in 12 [0.64%]). The prevalence of type II, III, and IV LSTVs was 5.6% (n = 105). Unilateral LSTV sidedness did not correlate with symptom laterality (κ = 0.07). There were no differences in patient-reported outcomes between patients with LSTV anatomy and those without it. CONCLUSIONS: In this large cohort of 1,880 patients with symptomatic FAI, the prevalence of LSTVs was 13.9%. There was no correlation between sidedness of unilateral LSTVs and the symptomatic hip. Furthermore, there was no association between LSTV anatomy and patient-reported outcomes. The prevalence of LSTVs in this cohort was similar to the prevalence rates previously reported in patients with low-back pain. LEVEL OF EVIDENCE: Level IV, case series.

Pretreatment costs of care and time to initial treatment for patients with cancer of unknown primary.

AIM: Time to treatment and pretreatment costs may be affected by unknown primary tumor site. METHODS: This retrospective study used electronic medical record data from patients in ten US community oncology practices. Eligible patients were ≥18 years, diagnosed with cancer of unknown primary (CUP) or known metastatic solid tumor, and presented between 1 January 2012 and 30 June 2014. RESULTS: Patients with CUP (n = 294) had a longer interval than non-CUP patients (n = 92) from presentation to treatment initiation (1.18 vs 0.49 months, p < 0.0001), and had higher pretreatment costs (US$27,882 vs US$20,449, p = 0.0075). When analyzed as monthly cost, the difference between groups in log-cost per month was nonsignificant. CONCLUSION: Higher pretreatment costs in CUP patients appeared attributable to significantly longer time to initiation of therapy.

The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment.

Chromosome rearrangements involving the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPCs) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development. Cells expressing MLL-AF9 efficiently developed AML in NSGS mice. In contrast, MLL-Af4 cells, which were fully oncogenic under lymphoid conditions present in NSG mice, displayed compromised transformation capacity in a myeloid microenvironment. MLL-Af4 activated a self-renewal program in a lineage-dependent manner, showing the leukemogenic activity of MLL-Af4 was interlinked with lymphoid lineage commitment. The C-terminal homology domain (CHD) of Af4 was sufficient to confer this linkage. Although the MLL-CHD fusion protein failed to immortalize HSPCs in myeloid conditions in vitro, it could successfully induce ALL in NSG mice. Our data suggest that defective self-renewal ability and leukemogenesis of MLL-Af4 myeloid cells could contribute to the strong B-cell ALL association of MLL-AF4 leukemia observed in the clinic.

Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia.

The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+ cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. Such incongruity was also observed in t(4;11) patients in whom leukemia evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.

Drug-eluting Balloon Versus Second Generation Drug Eluting Stents in the Treatment of In-stent Restenosis: A Systematic Review and Meta-analysis.

BACKGROUND: In-stent restenosis (ISR) remains a significant mode of stent failure following PCI. The optimal treatment strategy, however, remains undefined and the role of drug-eluting balloons (DEB) in the management of ISR is also unclear. METHODS: A meta-analysis was performed to compare the efficacy of DEB in the treatment of ISR against second generation drug eluting stents (DES). RESULTS: Seven studies comprised of 1,065 patients were included for analysis. The follow-up period ranged from 12-25 months. The use of DEB was associated with an inferior acute gain in minimal luminal diameter (MLD) (0.36, 95% CI: 0.16-0.57mm), higher late loss in MLD (0.11, 0.02-0.19mm) and a higher binary restenosis rate at follow-up (risk ratio: 2.24, 1.49-3.37). No significant differences were noted in the overall incidence of the analysed clinical parameters between the two groups. When only the randomised controlled trials (RCT) were considered however, there was a strong trend towards higher target lesion revascularisation (TLR; 9.9% vs. 3.6%; RR: 2.5, p=0.07) and a significantly higher major adverse cardiovascular event (MACE) rate (15.7% vs. 8.8%; RR 1.78; p=0.02) with DEB. CONCLUSION: While equipoise has been demonstrated in selected clinical outcomes between DEB and second generation DES in the treatment of ISR, the suboptimal angiographic outcome at follow-up and the higher TLR and MACE rates associated with DEB observed in the RCT are concerning. The results of the present analysis should be regarded as preliminary, although the generalised adoption of DEB in the treatment of ISR currently cannot be recommended.

Translational research in oncology research & development and its impact on early development in China: report of the 5th Annual Meeting of the US Chinese Anti-Cancer Association (USCACA) at 2013 AACR Annual Meeting.

In April 2013, the US Chinese Anti-Cancer Association (USCACA) held its 5th annual meeting in conjunction with the American Association for Cancer Research (AACR) 2013 Annual Meeting in Washington DC. The USCACA executive committee reported activities and programs and highlighted the partnership and collaboration between USCACA and other major organizations. The key initiatives and programs of USCACA included 1) USCACA-TIGM Esophageal Cancer Program that funds translational research of esophageal cancer prevention and treatment at the Xinxiang Medical University in Henan province, China; 2) the USCACA-NFCR-AFCR Scholarship Program, which has supported 10 young outstanding Chinese cancer researchers and will award 4 fellowships at the Guangzhou International Symposium on Oncology in November this year; 3) USCACA-Hengrui Training Program for Early Phase Clinical Research, which has supported the training of a Chinese scholar at two major cancer centers in the US; and 4) USCACA has continued its partnership with the Chinese Journal of Cancer, which has reached significant international impact.

The discriminatory cost of ICD-10-CM transition between clinical specialties: metrics, case study, and mitigating tools.

OBJECTIVE: Applying the science of networks to quantify the discriminatory impact of the ICD-9-CM to ICD-10-CM transition between clinical specialties. MATERIALS AND METHODS: Datasets were the Center for Medicaid and Medicare Services ICD-9-CM to ICD-10-CM mapping files, general equivalence mappings, and statewide Medicaid emergency department billing. Diagnoses were represented as nodes and their mappings as directional relationships. The complex network was synthesized as an aggregate of simpler motifs and tabulation per clinical specialty. RESULTS: We identified five mapping motif categories: identity, class-to-subclass, subclass-to-class, convoluted, and no mapping. Convoluted mappings indicate that multiple ICD-9-CM and ICD-10-CM codes share complex, entangled, and non-reciprocal mappings. The proportions of convoluted diagnoses mappings (36% overall) range from 5% (hematology) to 60% (obstetrics and injuries). In a case study of 24 008 patient visits in 217 emergency departments, 27% of the costs are associated with convoluted diagnoses, with 'abdominal pain' and 'gastroenteritis' accounting for approximately 3.5%. DISCUSSION: Previous qualitative studies report that administrators and clinicians are likely to be challenged in understanding and managing their practice because of the ICD-10-CM transition. We substantiate the complexity of this transition with a thorough quantitative summary per clinical specialty, a case study, and the tools to apply this methodology easily to any clinical practice in the form of a web portal and analytic tables. CONCLUSIONS: Post-transition, successful management of frequent diseases with convoluted mapping network patterns is critical. The http://lussierlab.org/transition-to-ICD10CM web portal provides insight in linking onerous diseases to the ICD-10 transition.

MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome.

MLL encodes a histone methyltransferase that is critical in maintaining gene expression during embryonic development and hematopoiesis. 11q23 translocations result in the formation of chimeric MLL fusion proteins that act as potent drivers of acute leukemia. However, it remains unclear what portion of the leukemic genome is under the direct control of MLL fusions. By comparing patient-derived leukemic cell lines, we find that MLL fusion-bound genes are a small subset of that recognized by wild-type MLL. In an inducible MLL-ENL model, MLL fusion protein binding and changes in H3K79 methylation are limited to a specific portion of the genome, whereas wild-type MLL distributes to a much larger set of gene loci. Surprisingly, among 223 MLL-ENL-bound genes, only 12 demonstrate a significant increase in mRNA expression on induction of the fusion protein. In addition to Hoxa9 and Meis1, this includes Eya1 and Six1, which comprise a heterodimeric transcription factor important in several developmental pathways. We show that Eya1 has the capacity to immortalize hematopoietic progenitor cells in vitro and collaborates with Six1 in hematopoietic transformation assays. Altogether, our data suggest that MLL fusions contribute to the development of acute leukemia through direct activation of a small set of target genes.

Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia.

MicroRNA (miRNA)-17-92 cluster (miR-17-92), containing seven individual miRNAs, is frequently amplified and overexpressed in lymphomas and various solid tumors. We have found that it is also frequently amplified and the miRNAs are aberrantly overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Furthermore, we show that MLL fusions exhibit a much stronger direct binding to the locus of this miRNA cluster than does wild-type MLL; these changes are associated with elevated levels of histone H3 acetylation and H3K4 trimethylation and an up-regulation of these miRNAs. We further observe that forced expression of this miRNA cluster increases proliferation and inhibits apoptosis of human cells. More importantly, we show that this miRNA cluster can significantly increase colony-forming capacity of normal mouse bone marrow progenitor cells alone and, particularly, in cooperation with MLL fusions. Finally, through combinatorial analysis of miRNA and mRNA arrays of mouse bone marrow progenitor cells transfected with this miRNA cluster and/or MLL fusion gene, we identified 363 potential miR-17-92 target genes that exhibited a significant inverse correlation of expression with the miRNAs. Remarkably, these potential target genes are significantly enriched (P < 0.01; >2-fold) in cell differentiation, hematopoiesis, cell cycle, and apoptosis. Taken together, our studies suggest that overexpression of miR-17-92 cluster in MLL-rearranged leukemias is likely attributed to both DNA copy number amplification and direct up-regulation by MLL fusions, and that the miRNAs in this cluster may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation, by regulating relevant target genes.

The impact of proton pump inhibitor compliance on health-care resource utilization and costs in patients with gastroesophageal reflux disease.

OBJECTIVE: Standard pharmacotherapy for patients with gastroesophageal reflux disease (GERD) includes treatment with proton pump inhibitors (PPIs). This study examined the effect of GERD patients' compliance with PPI therapy on health-care resource utilization and costs. METHODS: This was a retrospective study of more than 25 million managed care lives in the United States from January 2000 through February 2005. Administrative claims data were obtained from the National Managed Care Benchmarks database, developed by Integrated Health Care Information Solutions. GERD-diagnosed patients who had at least two PPI dispensings were extracted and grouped into two treatment categories based on their PPI medication possession ratio (MPR): compliant (MPR > 0.8) and noncompliant. A regression-based difference-in-differences approach was used to estimate the effect of compliance on the frequency and costs of inpatient and outpatient visits and pharmacy costs. Statistical controls included health plan type, patient age, baseline use of nonsteroidal antiinflammatory drugs, and comorbidities. RESULTS: Of the total 41,837 patients studied, 68% were compliant. On an annual, per-patient basis, PPI compliance resulted in 0.47 fewer outpatient visits (P = 0.040), 0.03 fewer inpatient visits (P = 0.015), and 0.47 fewer hospitalization days (P = 0.001) from the pre-PPI use period, compared to noncompliance. PPI therapy increased pharmacy costs for both groups, but the total annual health-care costs were reduced for both groups. Compliant patients experienced a greater decline in total cost from the pre-PPI period compared to noncompliant patients (declines of $3261 vs. $2406 per patient per year, P = 0.012). CONCLUSIONS: Both health-care resource use and costs were reduced after initiation of PPI therapy. Additional reductions from the pre-PPI period were further observed by compliance with PPI therapy.

Impact of compliance with proton pump inhibitors on NSAID treatment.

OBJECTIVE: To assess the impact of patient compliance with proton pump inhibitor (PPI) therapy on nonsteroidal anti-inflammatory drug (NSAID) treatment duration and upper-gastrointestinal (GI) complications in patients with gastroesophageal reflux disease (GERD). STUDY DESIGN: Retrospective cohort study. METHODS: Study subjects were GERD patients receiving cotherapy with a PPI and a cyclooxygenase-2-selective (COX-2-selective) or nonselective NSAID. Patients compliant and noncompliant with PPI therapy were compared on NSAID treatment duration and incidence of upper-GI events. Kaplan-Meier analysis and a multivariate Cox proportional hazards model were used to compare durations of NSAID treatment, controlling for baseline characteristics. The incidences of GI events were compared using incidence rate and Poisson regression models. The analyses were conducted separately for patients taking COX-2-selective NSAIDs and those taking nonselective NSAIDs. RESULTS: In both patient groups taking a COX-2-selective agent (n = 12,562; 70.9% compliant) and nonselective NSAID (n = 17,487; 69.9% compliant), mean NSAID treatment duration was significantly longer (84.0 days and 20.8 days longer, respectively) in PPI-compliant patients than in noncompliant patients. Compliance with PPI therapy was associated with a greater reduction in the incidence of GI events than noncompliance in both patients taking a COX-2-selective NSAID (6-fold vs 5-fold; P = .026) and patients taking a nonselective NSAID (8-fold vs 6-fold; P = .002). CONCLUSIONS: In GERD patients receiving NSAIDs, those who were compliant with PPI therapy had a longer NSAID treatment duration and better GI tolerability than those who were noncompliant.

Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.

Important biological and pathologic properties are often conserved across species. Although several mouse leukemia models have been well established, the genes deregulated in both human and murine leukemia cells have not been studied systematically. We performed a serial analysis of gene expression in both human and murine MLL-ELL or MLL-ENL leukemia cells and identified 88 genes that seemed to be significantly deregulated in both types of leukemia cells, including 57 genes not reported previously as being deregulated in MLL-associated leukemias. These changes were validated by quantitative PCR. The most up-regulated genes include several HOX genes (e.g., HOX A5, HOXA9, and HOXA10) and MEIS1, which are the typical hallmark of MLL rearrangement leukemia. The most down-regulated genes include LTF, LCN2, MMP9, S100A8, S100A9, PADI4, TGFBI, and CYBB. Notably, the up-regulated genes are enriched in gene ontology terms, such as gene expression and transcription, whereas the down-regulated genes are enriched in signal transduction and apoptosis. We showed that the CpG islands of the down-regulated genes are hypermethylated. We also showed that seven individual microRNAs (miRNA) from the mir-17-92 cluster, which are overexpressed in human MLL rearrangement leukemias, are also consistently overexpressed in mouse MLL rearrangement leukemia cells. Nineteen possible targets of these miRNAs were identified, and two of them (i.e., APP and RASSF2) were confirmed further by luciferase reporter and mutagenesis assays. The identification and validation of consistent changes of gene expression in human and murine MLL rearrangement leukemias provide important insights into the genetic base for MLL-associated leukemogenesis.

Distinct microRNA expression profiles in acute myeloid leukemia with common translocations.

MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.

Loss of MLL PHD finger 3 is necessary for MLL-ENL-induced hematopoietic stem cell immortalization.

Reciprocal chromosomal translocations at the MLL gene locus result in expression of novel fusion proteins, such as MLL-ENL, associated with leukemia. The three PHD finger cassette, one of the highly conserved domains in MLL, is absent in all fusion proteins. This domain has been shown to interact with Cyp33, a cyclophilin which enhances the recruitment of histone deacetylases (HDAC) to the MLL repression domain and mediates HOX gene repression. Insertion of the third PHD finger of MLL into MLL-ENL allows the recruitment of Cyp33 and, subsequently, HDAC1 to the fusion protein. Furthermore, expression of the fusion protein with the PHD finger insertion mediates the down-regulation of the HOXC8 gene expression in a Cyp33-dependent manner. Finally, the addition of the PHD finger domain or the third PHD finger alone into MLL-ENL blocks the hematopoietic stem cell immortalization potential of the fusion protein in serial plating colony assays. Insertion of only the first and second PHD fingers has no such effect. These data support the hypothesis that the binding of Cyp33 to the MLL third PHD finger switches the MLL function from transactivation to repression. In the immortalizing MLL fusion protein, the loss of the PHD fingers, in combination with the gain of the activation domain of ENL or of other partner proteins, makes the fusion protein a constitutive transactivator. This leads to constitutive overexpression of MLL target genes that block stem cell commitment and promote stem cell renewal, probably the first step in MLL-related leukemogenesis.

Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

Metabolism and disposition of dasatinib after oral administration to humans.

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC(50) for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.