Lineage-specific detection of residual disease predicts relapse in patients with chronic myeloid leukemia stopping therapy.

ABSTRACT: Patients with chronic myeloid leukemia who are eligible for treatment-free remission (TFR) may still relapse after tyrosine kinase inhibitor (TKI) cessation. There is a need for accurate predictors of outcome to enable patients with a favorable profile to proceed while avoiding futile attempts. Sensitive detection of residual disease in total leukocytes at treatment cessation is associated with relapse but is not highly discriminatory, likely because it is a composite measure of residual leukemia derived from different cell lineages, whereas only some lineages are relevant for relapse. We prospectively measured BCR::ABL1 DNA as a predictive yes/no binary test in 5 cellular fractions from 48 patients meeting conventional criteria for TKI discontinuation. The median BCR::ABL1 DNA level was higher in granulocytes and T cells, but not in other lineages, in patients who relapsed. Among the 40 patients undergoing their first TFR attempt, we defined 3 groups with differing relapse risk: granulocyte-positive group (100%), granulocyte-negative/T-cell-positive group (67%), and granulocyte-negative /T-cell-negative group (25%). These data show the critical importance of lineage-specific assessment of residual disease in the selection of patients who can attempt to achieve TFR with a high expectation of success and, concurrently, defer patients who have a high probability of relapse.

Real-time navigation guidance with intraoperative CT imaging for pedicle screw placement using an augmented reality head-mounted display: a proof-of-concept study.

OBJECTIVE: Augmented reality (AR) has the potential to improve the accuracy and efficiency of instrumentation placement in spinal fusion surgery, increasing patient safety and outcomes, optimizing ergonomics in the surgical suite, and ultimately lowering procedural costs. The authors sought to describe the use of a commercial prototype Spine AR platform (SpineAR) that provides a commercial AR head-mounted display (ARHMD) user interface for navigation-guided spine surgery incorporating real-time navigation images from intraoperative imaging with a 3D-reconstructed model in the surgeon's field of view, and to assess screw placement accuracy via this method. METHODS: Pedicle screw placement accuracy was assessed and compared with literature-reported data of the freehand (FH) technique. Accuracy with SpineAR was also compared between participants of varying spine surgical experience. Eleven operators without prior experience with AR-assisted pedicle screw placement took part in the study: 5 attending neurosurgeons and 6 trainees (1 neurosurgical fellow, 1 senior orthopedic resident, 3 neurosurgical residents, and 1 medical student). Commercially available 3D-printed lumbar spine models were utilized as surrogates of human anatomy. Among the operators, a total of 192 screws were instrumented bilaterally from L2-5 using SpineAR in 24 lumbar spine models. All but one trainee also inserted 8 screws using the FH method. In addition to accuracy scoring using the Gertzbein-Robbins grading scale, axial trajectory was assessed, and user feedback on experience with SpineAR was collected. RESULTS: Based on the Gertzbein-Robbins grading scale, the overall screw placement accuracy using SpineAR among all users was 98.4% (192 screws). Accuracy for attendings and trainees was 99.1% (112 screws) and 97.5% (80 screws), respectively. Accuracy rates were higher compared with literature-reported lumbar screw placement accuracy using FH for attendings (99.1% vs 94.32%; p = 0.0212) and all users (98.4% vs 94.32%; p = 0.0099). The percentage of total inserted screws with a minimum of 5° medial angulation was 100%. No differences were observed between attendings and trainees or between the two methods. User feedback on SpineAR was generally positive. CONCLUSIONS: Screw placement was feasible and accurate using SpineAR, an ARHMD platform with real-time navigation guidance that provided a favorable surgeon-user experience.

Development of a Spatial Decision Support System for Real-Time Flood Early Warning in the Vu Gia-Thu Bon River Basin, Quang Nam Province, Vietnam.

Vu Gia-Thu Bon (VGTB) river basin is an area where flash flood and heavy flood events occur frequently, negatively impacting the local community and socio-economic development of Quang Nam Province. In recent years, structural and non-structural solutions have been implemented to mitigate damages due to floods. However, under the impact of climate change, natural disasters continue to happen unpredictably day by day. It is, therefore, necessary to develop a spatial decision support system for real-time flood warnings in the VGTB river basin, which will support in ensuring the area's socio-economic development. The main purpose of this study is to develop an online flood warning system in real-time based on Internet-of-Things (IoT) technologies, GIS, telecommunications, and modeling (Soil and Water Assessment Tool (SWAT) and Hydrologic Engineering Center's River Analysis System (HEC-RAS)) in order to support the local community in the vulnerable downstream areas in the event of heavy rainfall upstream. The structure of the designed system consists of these following components: (1) real-time hydro-meteorological monitoring network, (2) IoT communication infrastructure (Global System for Mobile Communications (GSM), General Packet Radio Service (GPRS), wireless networks), (3) database management system (bio-physical, socio-economic, hydro-meteorological, and inundation), (4) simulating and predicting model (SWAT, HEC-RAS), (5) automated simulating and predicting module, (6) flood warning module via short message service (SMS), (7) WebGIS, application for providing and managing hydro-meteorological and inundation data, and (8) users (citizens and government officers). The entire operating processes of the flood warning system (i.e., hydro-meteorological data collecting, transferring, updating, processing, running SWAT and HEC-RAS, visualizing) are automated. A complete flood warning system for the VGTB river basin has been developed as an outcome of this study, which enables the prediction of flood events 5 h in advance and with high accuracy of 80%.

The Design and Rationale of a Pilot Study: A COmmunity and Tech-Based ApproaCh for Hypertension Self-MANagement (COACHMAN).

African-Americans with hypertension continue to demonstrate poor blood pressure (BP) control and have markedly lower rates of hypertension self-management compared to non-African-Americans. Innovative and practical solutions such as mHealth technology are promising and can be leveraged to promote self-management of hypertension. Substantial evidence has demonstrated the importance of community support in improving patients' management of chronic illnesses. Unfortunately, such programs do not offer technology-based interventions (TBI) as a delivery method. Thus, this paper describes the design and rationale of an ongoing pilot study that incorporates TBI using a community-based participatory approach.

BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia.

Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, BCR-ABL1 mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of BCR-ABL1 mRNA are proportional to the depletion of leukemic cells.

Dietary Supplement Ingredient Database (DSID) and the Application of Analytically Based Estimates of Ingredient Amount to Intake Calculations.

OBJECTIVE: We describe the purpose of the Dietary Supplement Ingredient Database (DSID), the statistical methodology underlying online calculators of analytically verified supplement content estimates, and the application and significance of DSID label adjustments in nutritional epidemiology. BACKGROUND AND HISTORY: During dietary supplement (DS) manufacturing, many ingredients are added at higher than declared label amounts, but overages are not standardized among manufacturers. As a result, researchers may underestimate nutrient intakes from DSs. The DSID provides statistical tools on the basis of the results of chemical analysis to convert label claims into analytically predicted ingredient amounts. These adjustments to labels are linked to DS products reported in NHANES. RATIONALE: Tables summarizing the numbers of NHANES DS products with ingredient overages and below label content show the importance of DSID adjustments to labels for accurate intake calculations. RECENT DEVELOPMENTS: We show the differences between analytically based estimates and labeled content for vitamin D, calcium, iodine, caffeine, and omega-3 (n-3) fatty acids and their potential impact on the accuracy of intake assessments in large surveys. Analytical overages >20% of label levels are predicted for several nutrients in 50-99% of multivitamin-mineral products (MVMs) reported in NHANES: for iodine and selenium in adult MVMs, for iodine and vitamins D and E in children's MVMs, and for iodine, chromium, and potassium in nonprescription prenatal MVMs. Predicted overages of 10-20% for calcium can be applied to most MVMs and overages >10% for folic acid in the vast majority of adult and children's MVMs. FUTURE DIRECTIONS: DSID studies are currently evaluating ingredient levels in prescription prenatal MVMs and levels of constituents in botanical DSs. CONCLUSIONS: We estimate that the majority of MVM products reported in NHANES have significant overages for several ingredients. It is important to account for nonlabeled additional nutrient exposure from DSs to better evaluate nutritional status in the United States.

Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells.

Imatinib is actively transported by organic cation transporter-1 (OCT-1) influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Herein we report that, in diagnostic chronic myeloid leukemia mononuclear cells and BCR-ABL1+ cell lines, peroxisome proliferator-activated receptor γ agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor γ antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to BCR-ABL kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor γ-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor γ transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84; P<0.0001), suggesting that peroxisome proliferator-activated receptor γ activation has a negative impact on the intracellular uptake of imatinib and consequent BCR-ABL kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor γ activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor γ agonist pioglitazone was reported to act synergistically with imatinib, targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor γ ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor γ activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor γ transcriptional activity.

Immobilization of D-Amino Acid Oxidase (DAAO) Enzyme on Hybrid Mesoporous MCF, SBA-15 and MCM-41 Nanomaterial.

Hybrid mesoporous materials as carriers for immobilization of D-amino acid oxidase (DAAO) were prepared via three steps: (i) hydrothermal synthesis of nanoporous MCF, SBA-15 and MCM-41 powders, (ii) functionalization with 3-aminopropyltriethoxysilane (APTES) by post-synthesis grafting; and (iii) activation with glutardialdehyde. The resulting mesostructured solids were characterized by various techniques: XRD, IR, TGA-DTA and N2 adsorption­desorption (BET). The characterization results indicated that these materials still maintained their structure after functionalization. IR data and TGA-DTA analysis demonstrated the existence of amine functional groups on the surface of APTES-functionalized samples. The DAAO immobilized on these materials exhibited higher catalytic activity and stability of enzyme for conversion of cephalosporin C (CPC) as compared to those of the non-functionalized ones. The catalytic activity and stability of enzyme decreased in the order MCF > SBA-15 > MCM-41.

Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study.

Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months, the actuarial estimate of stable treatment-free remission was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib, a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up, 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse.

Multilayered Inorganic Microparticles for Tunable Dual Growth Factor Delivery.

There is an increasing need to control the type, quantity, and timing of growth factors released during tissue healing. Sophisticated delivery systems offering the ability to deliver multiple growth factors with independently tunable kinetics are highly desirable. Here, a multilayered, mineral coated micro-particle (MCMs) platform that can serve as an adaptable dual growth factor delivery system is developed. Bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) are bound to the mineral coatings with high binding efficiencies of up to 80%. BMP-2 is firstly bound onto a 1st mineral coating layer; then VEGF is bound onto a 2nd mineral coating layer. The release of BMP-2 is sustained over a period of 50 days while the release of VEGF is a typical two-phase release with rapid release in the first 14 days and more sustained release for the following 36 days. Notably, the release behaviors of both growth factors can be independently tailored by changing the intrinsic properties of the mineral coatings. Furthermore, the release of BMP-2 can be tuned by changing the thickness of the 2nd layer. This injectable microparticle based delivery platform with tunable growth factor release has immense potential for applications in tissue engineering and regenerative medicine.

Lymph node management in patients with paratesticular rhabdomyosarcoma: a population-based analysis.

BACKGROUND: Paratesticular rhabdomyosarcoma (PTRMS) is the most common primary solid tumor arising from the mesenchymal tissue of the testis. Traditionally, retroperitoneal lymph node dissection is not recommended for children aged <10 years because of the morbidity of the procedure and low risk of retroperitoneal lymph node involvement. In the current study, the authors analyzed the patient and tumor characteristics of PTRMS as well as survival outcomes associated with lymph node dissection status. METHODS: A total of 255 cases of PTRMS were identified from the patient data reported by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute from 1973 through 2009. RESULTS: Among 173 patients aged ≥ 10 years, lymph node dissection was found to improve the 5-year overall survival (OS) rate from 64% to 86% (P < 0.01). Conversely, patients aged <10 years fared extremely well regardless of lymph node dissection status; the 5-year OS rate was 100% and 97%, respectively, for patients who did versus those who did not undergo lymph node dissection (P = .37). The yield of positive lymph nodes was approximately ≥ 20% when < 11 lymph nodes were removed. The incidence of lymph node involvement was also higher in older patients compared with younger patients (40% vs 8%). Radiotherapy improved the OS rate in patients with lymph node involvement (5-year OS rate: 90% with vs 36% without radiation; P < .0001). CONCLUSIONS: Lymph node dissection is recommended in patients aged ≥10 years. Radiotherapy is beneficial in patients with lymph node-positive disease.

Clinically relevant variation in FLT3-ITD quantitation as a result of PCR cycle number and ITD insertion size.

FLT3 internal tandem duplication (ITD) quantitation is key to prognostication in acute myeloid leukaemia (AML). One potential source of variability in the allelic ratio (AR) is the number of polymerase chain reaction (PCR) cycles used. Using 30 archived samples of varying ITD lengths and AR, we compared two FLT3-ITD assays (Huang and RATIFY), evaluated the effect of PCR cycle number on each assay, and examined the potential clinical consequences. Huang and RATIFY assays at 35 and 27 PCR cycles, respectively, were highly concordant. A progressive decrease in AR (median 47%) was observed with the RATIFY assay when the PCR cycles were increased from 27 to 35 cycles, potentially impacting risk categorisation in 29% of patients. In contrast, minimal change in AR was observed with the Huang assay. Hence, both FLT3-ITD assays were almost identical using respective standard conditions, but the effect of PCR cycle number is assay-dependent, which may impact risk stratification in AML.

Longitudinal characterization of circulating extracellular vesicles and small RNA during simian immunodeficiency virus infection and antiretroviral therapy.

OBJECTIVES: Latent infection by HIV hinders viral eradication despite effective antiretroviral treatment (ART). Among proposed contributors to viral latency are cellular small RNAs that have also been proposed to shuttle between cells in extracellular vesicles. Thus, we profiled extracellular vesicle small RNAs during different infection phases to understand the potential relationship between these extracellular vesicle associated small RNAs and viral infection. DESIGN: A well characterized simian immunodeficiency virus (SIV)/macaque model of HIV was used to profile extracellular vesicle enriched blood plasma fractions harvested during preinfection, acute infection, latent infection/ART treatment, and rebound after ART interruption. METHODS: Measurement of extracellular vesicle concentration, size distribution, and morphology was complemented with qPCR array for small RNA expression, followed by individual qPCR validations. Iodixanol density gradients were used to separate extracellular vesicle subtypes and virions. RESULTS: Plasma extracellular vesicle particle counts correlated with viral load and peaked during acute infection. However, SIV gag RNA detection showed that virions did not fully explain this peak. Extracellular vesicle microRNAs miR-181a, miR-342-3p, and miR-29a decreased with SIV infection and remained downregulated in latency. Interestingly, small nuclear RNA U6 had a tight association with viral load peak. CONCLUSION: This study is the first to monitor how extracellular vesicle concentration and extracellular vesicle small RNA expression change dynamically in acute viral infection, latency, and rebound in a carefully controlled animal model. These changes may also reveal regulatory roles in retroviral infection and latency.

Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib.

Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (<11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% (p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients (n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.

Clinical Epidemiology Features and Risk Factors for Acute Diarrhea Caused by Rotavirus A in Vietnamese Children.

Introduction: Acute diarrhea caused by group A rotavirus (RVA) is a leading cause of morbidity and mortality globally in children less than 5 years old. Acute diarrhea caused by RVA is often manifested by loose/watery stool leading to different degrees of dehydration. The detection of risk factors, diagnosis, and prompt treatment of acute diarrhea caused by RVA is critical. We aimed to describe clinical epidemiological features of acute diarrhea caused by RVA and its associated risk factors. Subjects and Method. We conducted a cross-sectional study that included 321 children under 5 years old with acute diarrhea at Haiphong Children's Hospital, Vietnam, from 1 August 2019 to 31 July 2020. Results: Among the 321 children included in our analysis, 221 (68.8%) children were positive for RVA. Males represented 61.1% of cases, 41.2% of children were in the 12-<24-month age group, and the majority of cases were among children in suburban areas (71.5%). Clinical manifestations included loose and watery stool (100%), vomiting-fever-loose/watery stool (57.9%), vomiting-loose/watery stool (83.2%), fever-loose/watery stool (58.8%), dehydration (30%), hyponatremia (22.1%), hypernatremia (1.4%), and hypokalemia (15%). Risk factors for acute diarrhea caused by RVA included history of diarrhea, not exclusive breastfeeding in the first 6 months, living area, maternal education, and income. Conclusions: Acute diarrhea due to RVA was very prevalent in children under 5 years old. Clinical manifestations included a high prevalence of loose/watery stools/day and dehydration with electrolyte disorder. Mothers should exclusively breastfeed their children for the first 6 months to avoid the risk of acute diarrhea caused by RVA.

Effectiveness and Safety of Glucosamine in Osteoarthritis: A Systematic Review.

Knee osteoarthritis is the most popular type of osteoarthritis that causes extreme pain in the elderly. Currently, there is no cure for osteoarthritis. To lessen clinical symptoms, glucosamine was suggested. The primary goal of our systematic review study is to evaluate the effectiveness and safety of glucosamine based on recent studies. Electronic databases such as PubMed, Scopus, and Cochrane were used to assess the randomized controlled trial (RCT). From the beginning through March 2023, the papers were checked, and if they fulfilled the inclusion criteria, they were then examined. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) and Visual Analog Scale (VAS) scales were considered the main outcome measures. A total of 15 studies were selected. Global pain was significantly decreased in comparison to placebo, as measured by the VAS index, with an overall effect size of standardized mean difference (SMD) of -7.41 ([95% CI] 14.31, 0.51). The WOMAC scale confirmed that pain, stiffness, and physical function had improved, however the effects were insufficient. A statistical update also revealed that there were no reports of serious medication interactions or significant adverse events. To summarize, glucosamine is more effective than a placebo at reducing pain in knee osteoarthritis patients. In long-term treatment, oral glucosamine sulfate 1500 mg/day is believed to be well tolerated.

Cost-Effectiveness of Glucosamine in Osteoarthritis Treatment: A Systematic Review.

Osteoarthritis (OA) is a chronic condition that most frequently affects older adults. It is currently the most common disability. The cost of treating an aging population places pressure on the healthcare budget. As a result, it is imperative to evaluate medicines' cost-effectiveness and, accordingly, their influence on health resource allocation. Our study aims to summarize the cost and outcome of utilizing glucosamine in OA treatment. Databases like Medline, Cochrane, and Scopus were searched as part of the identification process up until April 2023. Our primary inclusion criteria centered on the economic evaluation of glucosamine in OA treatments, providing an incremental cost-effectiveness ratio (ICER). The Quality of Health Economic Studies (QHES) instrument was applied to grade the quality of the studies. Seven qualified studies that discussed the cost-effectiveness of glucosamine with or without other formulations were selected. All of them demonstrated that glucosamine was cost-effective. There was an increase in quality-adjusted life years (QALYs) when incorporating glucosamine in conventional care. Moreover, patented crystalline glucosamine sulfate (pCGS) was more cost-effective than the other formulations of glucosamine (OFG). Overall, utilizing pCGS was more beneficial than using OFG in terms both of cost and quality of life.

Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib.

BACKGROUND: The functional activity of the organic cation transporter 1 (OCT-1) protein (OCT-1 activity) is an excellent predictor of molecular response and progression-free survival in patients with newly diagnosed chronic phase chronic myeloid leukemia treated with imatinib as front-line therapy. DESIGN AND METHODS: In this study the predictive value of OCT-1 activity in patients treated with imatinib 400 mg/day or 800 mg/day was evaluated in relation to trough imatinib plasma levels assessed in 100 patients enrolled in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial. RESULTS: The rate of major molecular responses by 24 months in patients on imatinib 400 mg/day was significantly higher in those with high OCT-1 activity than in those with low OCT-1 activity (low OCT-1 activity, 57% of patients; high OCT-1 activity, 100%; P < 0.001); the corresponding difference in patients treated with imatinib 800 mg/day did not reach statistical significance (low OCT-1 activity, 68%; high OCT-1 activity, 95%; P = 0.073). In addition, the combination of low trough imatinib levels (< 1200 ng/mL) and low OCT-1 activity defined a group of patients who had the lowest rates of major molecular response (47%) by 24 months compared to all other patients (81%, P = 0.009). These patients were also at the highest risk of failed imatinib therapy when compared to all other patients (P<0.001). CONCLUSIONS: High-dose imatinib leads to superior molecular responses in patients with low OCT-1 activity. In this group trough imatinib levels may define a group with inferior outcomes. Among patients with high OCT-1 activity, neither higher imatinib dose nor monitoring imatinib trough levels was found to be of significant clinical value. Hence OCT-1 activity determined prior to the start of therapy in newly diagnosed CML patients provides a valuable prognostic tool to determine the optimal up-front dose of imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia.