Early Switch Research Articles

Actualités sur la prise en charge des kératoses actiniques chez les patients transplantés d’organes: Management of actinic keratoses in organ transplant recipients: an update

Transplant recipients are at high risk of developing actinic keratosis (AK) and skin cancer. For this reason, initiating treatment at an early stage is crucial. Topical and systemic therapeutic options for AK have widely been described in studies of immunocompetent patients. However, little is known about AK management in organ transplant recipients (OTR). Photodynamic therapy (PDT), along with imiquimod, topical NSAIDs and topical 5-fluorouracil have been used on ORT patients in small non randomized studies. Although these studies seem to suggest that PDT offers best results, solid evidence is lacking. Nicotinamide and oral retinoids have also been described as reasonably effective preventive treatments in ORT patients. Management of immunosuppressive drugs is also considered as a key point for reducing the number of AK in ORT patients; an early switch for m-tor inhibitors has been shown to be protective while azathioprine, ciclosporin and tacrolimus have been shown to heighten the risk of developing AKs and skin cancer in this population. © 2019 Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Kératoses actiniques : comprendre et traiter réalisé avec le soutien institutionnel de Galderma International.

The Outcomes of Chronic Myeloid Leukemia Patients With Molecular Warning Responses During Imatinib Treatment According to the European LeukemiaNet 2013 Recommendations

BackgroundIn the European LeukemiaNet (ELN) 2013 recommendations, chronic myeloid leukemia (CML) patients with warning response (WR) were suggested to be monitored closely continuing with the same tyrosine kinase inhibitor (TKI). Differently, the guidelines of the National Comprehensive Cancer Network considers switching to another TKI as an option. Patients and MethodsWe retrospectively evaluated 73 CML patients receiving first-line imatinib, who were followed and managed in accordance with ELN recommendations. We compared patients with molecular WR with patients with optimal response (OR) and failure regarding short- and long-term outcomes. ResultsThe cumulative major molecular response (MMR) rates in patients with OR were significantly higher at any time point than those achieved by the WR group. Patients with WR at 3 months had significantly inferior failure-free survival (FFS) than optimal responders, but overall survival (OS) was similar. For 6 and 12 months, the WR and OR groups had similar FFS and OS. Twenty of 23 patients with WR at 12 months achieved MMR during imatinib treatment. ConclusionIt takes longer to get to ELN time points with imatinib than second-generation TKIs (2GTKIs). Treatment might fail in a small proportion of the patients with WR during imatinib treatment, but close and careful monitoring and timely switching to 2GTKIs might translate into favorable outcomes. Avoiding early switch to 2GTKIs would prevent patients from experiencing potential toxicities. There is still a need for prospective comparative studies (ie, continuing imatinib treatment vs. switching to 2GTKIs) in patients with WR, to justify the validity of this response category and to explore the benefit of treatment change in these patients.

186TiP - An open-label, randomized phase III study of early switch maintenance vs delayed second-line nivolumab in advanced stage squamous non-small cell lung cancer (NSCLC) patients after standard first-line platinum-based chemotherapy: EDEN trial

186TiP - An open-label, randomized phase III study of early switch maintenance vs delayed second-line nivolumab in advanced stage squamous non-small cell lung cancer (NSCLC) patients after standard first-line platinum-based chemotherapy: EDEN trial

Combination of Mac-2 Binding Protein Glycosylation Isomer and Up-To-Seven Criteria as a Useful Predictor for Child-Pugh Grade Deterioration after Transarterial Chemoembolization for Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage hepatocellular carcinoma (HCC). In patients who became refractory to TACE, a treatment switch to tyrosine kinase inhibitors (TKIs) needs to be considered. However, TACE could worsen liver function, thereby narrowing the time window for a switch to TKIs because TKIs are recommended for patients with Child-Pugh grade A (CP-A). We investigated the factors associated with CP grade deterioration after TACE. Among patients who underwent TACE, 125 patients with CP-A were enrolled. The cumulative CP grade deterioration rates were 20.3%, 27.1%, and 41.4% at six months, one year, and two years, respectively. Multivariate analysis revealed that factors associated with CP grade deterioration included high Mac-2 binding protein glycosylation isomer (M2BPGi) levels (>2.00 cut-off index) and beyond the up-to-seven criteria. The cumulative CP grade deterioration rates of patients with high M2BPGi and beyond the up-to-seven criteria were 50.6% and 59.2% at six months and one year, respectively, which were significantly higher than for those in any other groups. The combination of M2BPGi and up-to-seven criteria could be a surrogate marker for predicting CP grade deterioration after TACE. In patients with intermediate-stage HCC, elevated M2BPGi levels, and beyond the up-to-seven criteria, an early treatment switch to TKIs should be considered to improve their prognosis.

Early Switch to Oral Treatment of Endocarditis: No Delayed Treatment Failure

The POET study (NEJM JW Infect Dis Oct 2018 and N Engl J Med 2019; 380:415) challenged the dogma that endocarditis must be treated exclusively with

Early switch/early discharge opportunities for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections in Brazil

BackgroundEarly antibiotic switch and early discharge protocols have not been widely studied in Latin America. Our objective was to describe real-world treatment patterns, resource use, and estimate opportunities for early switch from intravenous to oral antibiotics and early discharge for patients hospitalized with methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections. Materials/methodsThis retrospective medical chart review recruited 72 physicians from Brazil to collect data from patients hospitalized with documented methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections between May 2013 and May 2015, and discharged alive by June 2015. Data collected included clinical characteristics and outcomes, hospital length of stay, methicillin-resistant Staphylococcus aureus-targeted intravenous and oral antibiotic use, and early switch and early discharge eligibility using literature-based and expert-validated criteria. ResultsA total of 199 patient charts were reviewed, of which 196 (98.5%) were prescribed methicillin-resistant Staphylococcus aureus -active therapy. Only four patients were switched from intravenous to oral antibiotics while hospitalized. The mean length of methicillin-resistant Staphylococcus aureus-active treatment was 14.7 (standard deviation, 10.1) days, with 14.6 (standard deviation, 10.1) total days of intravenous therapy. The mean length of hospital stay was 22.2 (standard deviation, 23.0) days. The most frequent initial methicillin-resistant Staphylococcus aureus-active therapies were intravenous vancomycin (58.2%), intravenous clindamycin (19.9%), and intravenous daptomycin (6.6%). Thirty-one patients (15.6%) were discharged with methicillin-resistant Staphylococcus aureus -active antibiotics of which 80.6% received oral antibiotics. Sixty-two patients (31.2%) met early switch criteria and potentially could have discontinued intravenous therapy 6.8 (standard deviation, 7.8) days sooner, and 65 patients (32.7%) met early discharge criteria and potentially could have been discharged 5.3 (standard deviation, 7.0) days sooner. ConclusionsOnly 2% of patients were switched from intravenous to oral antibiotics in our study while almost one-third were early switch eligible. Additionally, one-third of hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections were early discharge eligible indicating opportunity for reducing intravenous therapy and days of hospital stay. These results provide insight into possible benefits of implementation of early switch/early discharge protocols in Brazil.

Early Switch to Mammalian Target of Rapamycin Inhibitors Is a Sustainable Treatment Approach in Renal Transplant Recipients: 7-Year Results

ObjectiveThe aim of this study was to investigate the safety and sustainability of mammalian target of rapamycin inhibitor (m-TORi)-based treatment protocols in renal transplant patients. MethodsWe retrospectively evaluated a total of 206 patients who were switched to low-dose calcineurin inhibitors (CNI) + m-TORi or mycophenolate mofetil (MMF) + m-TORi treatment protocols in the first 3 months of renal transplantation between January 2010 and August 2011 in our center. Demographic and laboratory features of the patients were recorded. ResultsOf the patients included in the study, 89 (43.2%) were female and 117 (56.8%) were male. The mean age was 41.9 ± 13.8 years. Panel reactive antibody was negative in 95% of the recipients. One hundred thirty-four (65%) patients received anti-thymocyte globulin induction therapy. Initially, 108 patients were treated with cyclosporine and 98 (47.6%) were treated with tacrolimus-based regimens. One hundred thirty-five patients (65.5%) were switched to low-dose CNI + m-TORi and 71 patients (34.5%) were switched to MMF + m-TORi. The mean switching time was 3 months. At the end of the study, 161 patients (78.2%) were still continuing the m-TORi treatment protocol and 45 patients (21.8%) could not continue for various reasons (11.4% proteinuria, 5.5% edema, 2.9% acute rejection, 1% acne + oral aphthae, 1% neuropathy). The biopsy-proven acute rejection rate was 4.5% (n = 9). The mean duration of sustainability of m-TORi treatment protocol was 84.15 ± 6.79 months. Mean serum creatinine of patients who were still continuing m-TORi was 1.42 ± 1.09 mg/dL. ConclusionSwitching to m-TORi in the early posttransplant period is a safe and sustainable treatment approach.

Dasatinib Versus Imatinib in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Not Achieved an Optimal Response to 3 Months of Imatinib Therapy: Dascern

Introduction: Treatment with dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has resulted in high rates of cytogenetic and molecular responses for pts with CML-CP, both as initial therapy and after failure of other therapies. A reduction in BCR-ABL1 transcript levels to ≤ 10% on the International Scale (IS) at 3 mo is associated with an improved probability of deep molecular responses and superior progression-free and overall survival (PFS and OS). In DASISION, considerably more pts treated with dasatinib achieved BCR-ABL1 ≤ 10% IS compared to imatinib. BCR-ABL1 ≤ 10% IS at 3 mo is considered an optimal response by international guidelines; however, approximately one-third of pts with CML-CP on first-line (1L) imatinib will not achieve this threshold. Clinical studies exploring the potential benefit of early switching to dasatinib in pts with less than optimal responses on initial imatinib treatment have not been reported.Methods: DASCERN (NCT01593254) is a randomized, open-label, international phase 2b trial in adult pts with CML-CP who had achieved complete hematologic response (CHR) but who had BCR-ABL1 > 10% IS at 3 mo after initial treatment with 400 mg imatinib once daily (QD). Imatinib must have been started within 6 mo of the initial CML-CP diagnosis. Pts were randomized 2:1 to receive 100 mg dasatinib QD or continue imatinib at ≥ 400 mg daily with the option for dose escalation. Pts initially randomized in the imatinib cohort who met European LeukemiaNet 2013 failure criteria after randomization and without dasatinib-resistant mutations were crossed over to the dasatinib arm. The primary endpoint in DASCERN is the rate of MMR (BCR-ABL1 < 0.1% IS) at 12 mo after day 1 initiation of 1L imatinib (9 mo after randomization). Secondary endpoints include time to MMR, OS, and PFS (progression was defined as transformation to accelerated/blast phase or death). Tertiary endpoints include safety and tolerability profile of both treatment arms and cytogenetic response over time.Results: All 260 randomized pts (dasatinib: n = 174; imatinib: n = 86) had a minimum follow-up of ≥ 12 mo from the last pts 1st visit (Sokal scores: 28% low, 30% intermediate, 24% high, 18% unknown; median age 37 y [range 18-82, 95% were < 65 y]; 78% male; 73% Asian). All pts had e13a2 or e14a2 transcript types. At the time of analysis, 84% of pts were continuing in the study. Median daily dose was 100 mg QD (range 26-142) for dasatinib and 400 mg QD (range 129-825) for imatinib. Median treatment duration was 111 wk (774 d) in the dasatinib arm and 68 wk (477 d) in the imatinib arm; 42 (49%) imatinib-randomized pts crossed over to dasatinib. Rate of MMR at 12 mo in the intent-to-treat population was 29% (95% confidence interval [CI] 22, 36) for dasatinib and 13% (95% CI 7, 22) for imatinib (P = 0.005); median time to MMR was 14 mo (range 12-18) for dasatinib vs 20 mo (range 14-26) for imatinib (P = 0.053). No differences in the rate of progression or OS were observed between treatment arms. No new safety signals were observed for either treatment arm and the early switch to dasatinib did not increase the toxicity rate. Treatment-emergent pleural effusion (PE; any grade) occurred in 11 (6%) pts randomized to dasatinib and 3 (7%) imatinib-randomized pts who crossed over to dasatinib; treatment-emergent PE grade 3/4 occurred in 1 (1%) pt randomized to dasatinib and 2 (5%) pts randomized to imatinib who crossed over to dasatinib. Hematologic toxicity was similar between treatment arms: neutropenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and 12 (29%) pts randomized to imatinib who crossed over to dasatinib; thrombocytopenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and in 7 (17%) pts randomized to imatinib who crossed over to dasatinib. Two dasatinib-treated pts discontinued due to hematologic toxicity (1 neutropenia, 1 thrombocytopenia).Conclusions: Early results from DASCERN show that pts with suboptimal responses to imatinib at 3 mo who switched to dasatinib had a significantly increased rate of MMR at 12 mo compared to pts who remained on imatinib. Longer follow-up is required to assess the impact of early switching on PFS and OS, and achievement of deep molecular responses. DisclosuresCortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding. Kim:BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Gurnani:Bristol-Myers Squibb: Employment.

Prognostic Implication of Early Molecular Response at 3 Months in Chronic Myeloid Leukemia Patients: A Comparison of Imatinib and Second Generation Tyrosine Kinase Inhibitors

Background: Although several studies have demonstrated that BCR-ABL1 transcript levels at 3 months were prognostically significant in patients treated with frontline imatinib (IM) and second-generation tyrosine kinase inhibitors (2G-TKIs), the decision to change treatment based on early molecular response (EMR) status remain under investigaiton. Because CML patients currently have multiple treatment options, the impact of early molecular milestones on long-term outcomes needs to be determined in each agent treated patients.Aims: The aim of this study is to evaluate the impact of 3-month early molecular response (EMR) on long-term outcomes of CML patients treated with IM and different 2G-TKIs, as additional information to guide clinical decisions on switching to a different TKI.Methods: 734 new CP CML patients who were treated with frontline IM (n = 366) or 2G TKIs (n = 368) were analyzed. Molecular responses were monitored using qRT-PCR assay in 3 month intervals by achieving major molecular response (MMR), and then 6 month intervals after achieving MMR. Main study objectives were to evaluate the long-term outcomes, including failure-free survival (FFS), progression-free survival (PFS), and overall survival (OS), according to 3-month EMR. FFS was measured from the date of treatment start until death, progression to AP or BP, or ELN failure on treatment, whichever came first. PFS and OS collected survivals on patients who were treated with other TKIs after frontline therapy discontinuation.Results: A total of 734 patients were treated with imatinib (IM; n = 366), dasatinib (DAS; n = 141), nilotinib (NIL; n = 89), and radotinib (RAD; n = 138). The median age was 43 years (range, 11-87). The percentages of patients with low, intermediate, and high Sokal risk scores were 37%, 38% and 23%, respectively, with 2% unknown risk. With a median follow-up of 85.6 (IM; range, 4.4-207.5) and 38.9 (2G-TKIs; range, 11.6-130.2) months, 460 (62.7%; 182 IM and 218 2G-TKIs) patients continue on the frontline therapy and 274 (37.3%) patients were permanently discontinued or changed to other TKIs due to intolerance (73 IM, 38 DAS, 2 NIL, 28 RAD), ELN failure (32 IM, 3 DAS, 2 NIL, 3 RAD), progression (3 IM, 1 DAS, 1 RAD), and others (60 warning, 3 pregnancy, 14 treatment-free remission study, and 9 follow-up loss). In 366 patients treated with IM, patients achieving BCR-ABL1 ≤ 10% at 3 months (n = 275, 75.1%) had a better outcomes in terms of 8-y OS (97.4% vs 89.7%, P <0.001), 8-y PFS (96.3% vs 88.6, P=0.002), and 8-y FFS (91.5% vs 74.6%, P<0.001) compared with those of the patients with BCR-ABL1 >10%. In 368 patients treated with 2G-TKIs, achievement of 3-month EMR (n = 331, 90.0%) was associated with a higher 8-y OS (98.6% vs 91.9%, P <0.001), 8-y PFS (98.2% vs 91.7, P=0.001), and 8-y FFS (96.5% vs 82.7%, P<0.001). The prognostic impact of 3-month EMR was observed in both IM and 2G-TKIs treated groups.Conclusions: Our data showed that EMR failure at 3 months could translate into poor survival outcomes in patients treated with frontline IM and 2G-TKIs.However, to confirm the benefit of an early switch of therapy, further investigations in a larger patient population with longer follow-up are needed. DisclosuresKim:Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding; Ilyang: Research Funding.

Integration of Multiple Bioassays Using Machine Learning to Identify High-Risk CP-CML Patients Treated with Frontline Imatinib

Introduction. Imatinib has revolutionised the treatment of chronic phase-chronic myeloid leukemia (CP-CML), with up to 70% of patients (pts) achieving major molecular response (MMR, BCR-ABL1 < 0.1% IS). Achievement of MMR by 2 years (yrs) is associated with an excellent prospect of long term survival. Currently, three baseline prognostic scoring systems - the Sokal, Hasford (Euro) and EUTOS risk scores - have all been used to identify pts with a poor response and/or an adverse prognosis in CP-CML. Recently, the EUTOS long-term survival (ELTS) score is shown to have strong predictive power for overall survival in CML pts. We have previously reported bioassays that have significant value for predicting MMR. Combinations of these biomarkers, together with clinical risk score, may provide a better indicator of high risk pts at the time of diagnosis.Aim. To identify high-risk pts by combining selected predictive bioassay, determine whether the ELTS score is more discriminating, and determine whether it provides additional predictive value when combined with the biomarker score.Methods. Bioassays including CRKL IC50 imatinib (White, Blood, 2005), OCT-1 Activity (OA)(White, JCO, 2010), leves of 39 plasma cytokines (Nievergall, Leukemia, 2016), expression of 20 most prognostic gene by qPCR TLDA (Kok, ASH abstract, 2015), ABCB1 gene expression (Eadie, Leukemia, 2016), KIR2DL5B genotype (Yeung, Blood, 2015), BIM and ASXL1 polymorphisms (Marum, Blood advances, 2017) were used in this study. High-risk by biomarker score (HR) was defined as pts who did not achieve MMR by 2 yrs. 210 TIDEL-II pts (frontline imatinib with early switch to nilotinib for failure to meet optimal time-dependent molecular targets) were used in this study (Yeung, Blood, 2015). Only 201 pts had ELTS scores. The Recursive Partitioning and Regression Trees (rpart) algorithm was used to identify important bioassays in predicting high-risk pts. Fisher's-exact test was used for statistical analysis.Results. In the TIDEL-II cohort, there were 21 high ELTS and 180 low/intermediate ELTS pts. Pts with high ELTS had significantly lower rates of MMR by 2 yrs compared to those pts with low/intermediate ELTS (57% vs 81%, p=0.02). We constructed a predictive model using multiple different bioassays as variables to predict high-risk pts. The rpart based model used in this analysis yielded four variables (IGFBP2 gene expression, KIR2DL5B genotype, OA, and MCP-1 cytokine plasma level) as most important for predicting high-risk pts. The accuracy of the model was 84%. Pts predicted as high-risk (HR, n=27) had significantly lower MMR achievement rate compared to those predicted as low-risk (LR), (26% vs 86%, n=183, p<0.0001, OR:17.3). Importantly, pts with HR had significantly higher rate of blast-crisis progression (15%, n=4/27) compared to those with LR (1.6%, n=3/183, p=0.006, OR:10.4) and pts with high ELTS (5%, n=1/21). Interestingly, there were two categories of HR patient groups based on the model: 1) Patient with high IGFBP2 gene expression and low OA, and 2) pts with low IGFBP2, KIR2DL5B positive genotype and high MCP-1 cytokine level. When combined with ELTS, the bioassays model improved ELTS performance in predicting HR pts. For instance, within the low/intermediate ELTS pts group, our assays could futher distinguish HR pts with inferior MMR (n=20, 2 yrs MMR of 30%) versus LR pts (n=160, 2 yrs MMR 87%). Similarly, pts with high ELTS in combination with HR also had lower MMR rate (n=1/5, 20%) compared to pts with high ELTS in combination with LR (n=11/16, 69%, p=0.11, OR:8.8).Conclusion. We developed a combined bioassays model that is predictive of MMR failure and adverse clinical outcomes for pts who receive optimised frontline imatinib therapy. This model performs well even without adding clinical parameters. Our model has additional predictive value when used together with the ELTS score, and can distinuguish HR pts within the low/intermediate ELTS group, as well as LR patients within the high ELTS category. Further confirmation of the predictive performance of this model, using a large independent patient cohort is now indicated. We postulate that this bioassay-based model could be used, in combination with ELTS, for identifying HR pts who would benefit from intensified therapeutic approaches to obtain optimal clinical outcome. [Display omitted] DisclosuresYeung:Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Specialised Therapeutics Australia: Honoraria. Yong:Celgene: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:BMS: Research Funding; Novartis: Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees.

International, Prospective Study Comparing Nilotinib Versus Imatinib with Early Switch to Nilotinib to Obtain Sustained Treatment-Free Remission in Patients with Chronic Myeloid Leukemia. a GIMEMA and HOVON Study

BackgroundThe best front-line treatment of CML is not yet defined. Indeed, despite the higher activity of the second-generation TKIs respect to Imatinib and the higher rates of deep molecular remission (DMR), no clear superiority in term of long-term overall survival among the first and second TKIs for the initial treatment of CML has been shown in all the available studies. Furthermore, treatment free remission is emerging as one of the most important goal of the treatment of this disease, but no clinical trial has shown so far the best first line treatment to reach this aim.MethodsSince it is widely accepted that a sustained DMR is the pre-requisite to discontinue the TKI treatment for an extended duration of time, and since in patients who start treatment with imatinib (IM) and fail EMR, it is expected that a switch to NIL may improve the probability of achieving a DMR, we launched in November 2016 an international, prospective, interventional, randomized, two arms, phase IV study to evaluate both the depth of the molecular response and the rate of TFR in newly diagnosed CP-CML patients treated with a second generation TKI (Nilotinib, NIL) or with Imatinib (IM) followed by switch to NIL in absence of optimal response (defined according the ELN 2013 criteria (Clinical Trial number 02602314) The enrolled patients are randomized 1:1 between NIL and IM. Patients are stratified at randomization according to the Sokal risk score (high versus intermediate/low risk) and country (Italy, The Netherlands, Belgium). All the patients who obtain a reduction greater than 4.0 logs of residual disease (MR4.0) within the first three years of treatment, and maintain this level of response in all the subsequent tests up to the end of the fourth years of therapy qualify for the discontinuation phase of the study. The study has two primary end-points: a) the rates of molecular response (MR4.5) at 24 months, and b) the rate of patients who remain in sustained treatment free remission (≥MR3.0) without molecular relapse 12 months after entering the TFR phase. The molecular relapse is defined as loss of MMR, or confirmed loss of MR3.0. Differences in the patient-reported quality of life (QoL) were are investigated by QoL questionnaires (EORTC QLQ-C30 and EORTC CML-24) at baseline (before the randomization) and at 3, 6, 12, 18, 24, 30, 36, 42, 48, 60 months. A total of 165 patients will be enrolled. Enrollment will be concluded in 2019, and final results will be given in 2024.ResultsFrom November 2016 to the 15 July 15 2018, 165 patients with newly diagnosed CP-CML patients (mean age 54.6 years - range 20.0-85.8) were enrolled and randomized into the two arms of the study. Of those, 137 (83%) were classified as low/intermediate-risk Sokal, and the remaining 28 (17%) as high-risk. Additional chromosome abnormalities in the Philadelphia positive clone were detected in 20 (12.1%) patients, 7 (8.5%) in the IM group and 13 (15.9%) in the NIL group.Overall, 12 patients of the IM group switched to NIL; for absence of optimal response at 3 months in two cases, at 6 months in 7 patients and at 12 months in one case. The remaining two patients switched to NIL for IM related toxicity. Among NIL treated patients, two patient stopped treatment, in one case at 1 month due to absence of hematological response and the other due to suboptimal response at 15 months. These patients were treated according to the principal investigator of the participating center and censored for final analysis.At a preliminary evaluation of patient-reported QoL questionnaires completed at baseline, women and elderly had a perception of higher symptom burden.ConclusionThis is the first and the unique prospective study comparing not only the rate of DMR but, more important, also the rate of TFR according to treatment: a second generation TKI frontline vs Imatinib frontline followed by the same second generation in case of non-optimal response to ImatinibAcknowledgmentsThe present study is a non-commercial study sponsored by Fondazione GIMEMA together with the HOVON that are responsible for the database of the study. Novartis Pharma supports the study with an unrestricted grant. DisclosuresPane:AMGEN: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Breccia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Soverini:Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Castagnetti:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Janssen:Pfizer: Consultancy, Speakers Bureau; Novartis: Research Funding; Incyte: Consultancy, Speakers Bureau; BMS: Research Funding; Abbvie: Consultancy; Jazz pharmaceuticals: Consultancy.

Early Oral Switch to Linezolid for Low-risk Patients With Staphylococcus aureus Bloodstream Infections: A Propensity-matched Cohort Study.

Oral switch to linezolid is a promising alternative to standard parenteral therapy (SPT) in Staphylococcus aureus bacteremia (SAB). We conducted a prospective cohort study of all adult cases of SAB between 2013 and 2017 in a Spanish university hospital. We compared the efficacy, safety, and length of hospital stay of patients receiving SPT and those where SPT was switched to oral linezolid between days 3 and 9 of treatment until completion. We excluded complicated SAB and osteoarticular infections. A k-nearest neighbor algorithm was used for propensity score matching with a 2:1 ratio. After propensity score matching, we included 45 patients from the linezolid group and 90 patients from the SPT group. Leading SAB sources were catheter related (49.6%), unknown origin (20.0%), and skin and soft tissue (17.0%). We observed no difference in 90-day relapse between the linezolid group and the SPT group (2.2% vs 4.4% respectively; P = .87). No statistically significant difference was observed in 30-day all-cause mortality between the linezolid group and the SPT group (2.2% vs 13.3%; P = .08). The median length of hospital stay after onset was 8 days in the linezolid group and 19 days in the SPT group (P < .01). No drug-related events leading to discontinuation were noted in the linezolid group. Treatment of SAB in selected low-risk patients with an oral switch to linezolid between days 3 and 9 of treatment until completion yielded similar clinical outcomes as SPT, allowing earlier discharge from the hospital.

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. Objectives: To identify prognostic factors for early switch after first therapy choice. Methods: Newly diagnosed relapsing–remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

A bimodal switch in global protein translation coupled to eIF4H relocalisation during advancing cell-cell transmission of herpes simplex virus.

We used the bioorthogonal protein precursor, homopropargylglycine (HPG) and chemical ligation to fluorescent capture agents, to define spatiotemporal regulation of global translation during herpes simplex virus (HSV) cell-to-cell spread at single cell resolution. Translational activity was spatially stratified during advancing infection, with distal uninfected cells showing normal levels of translation, surrounding zones at the earliest stages of infection with profound global shutoff. These cells further surround previously infected cells with restored translation close to levels in uninfected cells, reflecting a very early biphasic switch in translational control. While this process was dependent on the virion host shutoff (vhs) function, in certain cell types we also observed temporally altered efficiency of shutoff whereby during early transmission, naïve cells initially exhibited resistance to shutoff but as infection advanced, naïve target cells succumbed to more extensive translational suppression. This may reflect spatiotemporal variation in the balance of oscillating suppression-recovery phases. Our results also strongly indicate that a single particle of HSV-2, can promote pronounced global shutoff. We also demonstrate that the vhs interacting factor, eIF4H, an RNA helicase accessory factor, switches from cytoplasmic to nuclear localisation precisely correlating with the initial shutdown of translation. However translational recovery occurs despite sustained eIF4H nuclear accumulation, indicating a qualitative change in the translational apparatus before and after suppression. Modelling simulations of high multiplicity infection reveal limitations in assessing translational activity due to sampling frequency in population studies and how analysis at the single cell level overcomes such limitations. The work reveals new insight and a revised model of translational manipulation during advancing infection which has important implications both mechanistically and with regards to the physiological role of translational control during virus propagation. The work also demonstrates the potential of bioorthogonal chemistry for single cell analysis of cellular metabolic processes during advancing infections in other virus systems.

Correction: Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome

[This corrects the article DOI: 10.1371/journal.pone.0186603.].

Single-cell analysis of early progenitor cells that build coronary arteries.

SUMMARYArteries and veins are specified by antagonistic transcriptional programs. However, during development and regeneration, new arteries can arise from pre-existing veins through a poorly understood cell fate conversion. Using scRNA-Seq and mouse genetics, we discovered that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Prior to coronary blood flow, pre-artery cells appeared within the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein specifying transcription factor, Coup-tf2, blocked plexus cells from overcoming the pre-artery threshold through inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independent of blood flow upon the release of COUP-TF2/cell cycle factor-mediated inhibition.

De novo or early conversion to everolimus and long-term cancer outcomes in kidney transplant recipients: A trial-based linkage study.

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

Early BCR-ABL1 decline in imatinib-treated patients with chronic myeloid leukemia: results from a multicenter study of the Chinese CML alliance

An early molecular response is spectacularly predictive of outcome in chronic myeloid leukemia (CML) and early response landmarks may identify the high-risk patients likely to be benefit from an early therapy switch. In this study, we evaluated the most relevant cutoffs for early molecular response markers (BCR-ABL1 values at 3 months, log reduction and halving time between diagnosis and 3 months) in 476 first-line imatinib-treated Chinese patients with chronic phase CML. All outcomes were significantly superior for the 324 patients with 3-month BCR-ABL1 ≤10%, so did for the 270 patients with BCR-ABL1 >0.61 log reduction. BCR-ABL1 halving time ≤22 days was identified for patients with the most favorable outcome. Moreover, the prognosis was significantly poorest for patients with both halving time >44 days and BCR-ABL1 >10%. Importantly, multivariate regression analysis demonstrated that a BCR-ABL1 log reduction calculated at 3 months of 0.61 was the only variable that significantly predicted for OS. Our results highlight the importance of rapid initial decline of BCR-ABL1 in predicting satisfactory outcome. Our data support the evidence that monitoring BCR-ABL1 values at an early time point could contribute to accurately assess response and ultimately guide clinical decisions regarding the timing of therapeutic intervention.

Antibiotic prescribing practices for hospitalised children with suspected bacterial infections in a paediatric hospital in Nigeria

Background: The burden of infectious diseases among Nigerian children is high. These children are often prescribed antibiotics during periods of hospitalisation. Unfortunately antibiotic resistance (ABR) threatens the availability and efficacy of antibiotics for use by vulnerable children and the future generations. Monitoring prescribing trends in our hospital as a means of identifying targets for improving prescribing is inevitable.Objective: The aim of the study was to evaluate antibiotic prescribing practices for hospitalised children with suspected bacterial infections in a Paediatric hospital in Nigeria.Methods: A retrospective survey was carried out using case notes of previously hospitalised patients admitted between January and June 2016. Data from 150 case notes of patients admitted for suspected bacterial infections were collected using a predesigned data collection form. Patients’ demographics, infection type, details of prescribed antibiotics, length of hospital stay and microbiological assessments were noted. Data were analysed using statistical package for social sciences (SPSS) version 22. Frequencies and percentages were calculated for categorical variables. Means and standard deviations were calculated for continuous (numerical) variables. Correlation was also employed in the analysis.Results: Of the 150 patients, 53.3% were males and 86% were children under 5 years of age. The mean duration of hospital stay was 7.59 (± 5.4) days. The most common infections were respiratory tract infection (32%) and sepsis (31.3%). The most common empirically prescribed antibiotics at the onset of admission were Gentamicin and a fixed dose combination of Ampicillin/Cloxacillin which were prescribed for 64.7% and 52.7% of the patients respectively. Cultures were ordered for only 7 (4.7%) of patients at the onset of hospitalisation. All antibiotics administered on admission were parenteral formulations and only 4% of the patients had their antibiotic switched to oral route on or before the third day of patients’ admission. Another 71.3% were converted to oral formulations on the day of discharge from the hospital. A total of 87.3% were discharged on antibiotics and the most commonly prescribed antibiotic at discharge was Cefixime (37.2% of antibiotics prescribed as take home medication).Conclusions: Antibiotics were started empirically in all cases and cultures were ordered for few patients at the start of antibiotic therapy. Cultures should be more frequently ordered in the hospital to guide antibiotic prescribing for patients admitted for suspected bacterial infections. In addition, timely intravenous (IV) to oral (PO) antibiotic switch should be practised whenever appropriate. Educating physicians on the benefits of early switch from IV to PO formulations when appropriate is also recommended. Initiatives such as the “Antibiotic Time out” or Start Smart-then Focus approach will be appropriate in the hospital. Introduction of an empiric antibiotic policy in the hospital is highly recommended.

Heterochronic opsin expression due to early light deprivation results in drastically shifted visual sensitivity in a cichlid fish: Possible role of thyroid hormone signaling.

During early ontogeny, visual opsin gene expression in cichlids is influenced by prevailing light regimen. Red light, for example, leads to an early switch from the expression of short-wavelength sensitive to long-wavelength sensitive opsins. Here, we address the influence of light deprivation on opsin expression. Individuals reared in constant darkness during the first 14 days post-hatching (dph) showed a general developmental delay compared with fish reared under a 12:12hr light-dark cycle (control group). Several characters including pigmentation patterns and eye development, appeared later in dark-reared individuals. Quantitative real-time PCR and fluorescent in situ hybridization at six time points during the 14 days period revealed that fish from the control group expressed opsin genes from 5dph on and maintained a short-wavelength sensitive phenotype (sws1, rh2b, and rh2a). Onset of opsin expression in dark-reared Midas cichlids was delayed by 4 days and visual sensitivity rapidly progressed toward a long-wavelength sensitive phenotype (sws2b, rh2a, and lws). Shifts in visual sensitivities toward longer wavelengths are mediated by thyroid hormone (TH) in many vertebrates. Compared to control fish, dark-reared individuals showed elevated dio3 expression levels - a validated proxy for TH concentration - suggesting higher circulating TH levels. Despite decelerated overall development, ontogeny of opsin gene expression was accelerated, resulting in retinae with long-wavelength shifted predicted sensitivities compared to light-reared individuals. Indirect evidence suggests that this was due to altered TH metabolism.