Objective To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low ...gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). Study design Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). Results Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit RB 1.28 95% CI 1.07-1.55). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. Conclusion Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. Trial registration ClinicalTrials.gov : NCT01022580
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Objective To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, ...safely improves survival without bronchopulmonary dysplasia (BPD). Study design Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. Results A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. Conclusion Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. Trial registration ClinicalTrials.gov : NCT01022580.
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Summary Background Population and study design heterogeneity has confounded previous meta-analyses, leading to uncertainty about effectiveness and safety of elective high-frequency oscillatory ...ventilation (HFOV) in preterm infants. We assessed effectiveness of elective HFOV versus conventional ventilation in this group. Methods We did a systematic review and meta-analysis of individual patients' data from 3229 participants in ten randomised controlled trials, with the primary outcomes of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age, death or severe adverse neurological event, or any of these outcomes. Findings For infants ventilated with HFOV, the relative risk of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 0·95 (95% CI 0·88–1·03), of death or severe adverse neurological event 1·00 (0·88–1·13), or any of these outcomes 0·98 (0·91–1·05). No subgroup of infants (eg, gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids) benefited more or less from HFOV. Ventilator type or ventilation strategy did not change the overall treatment effect. Interpretation HFOV seems equally effective to conventional ventilation in preterm infants. Our results do not support selection of preterm infants for HFOV on the basis of gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids. Funding Nestlé Belgium, Belgian Red Cross, and Dräger International.
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Continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV) hold much promise as means to protect the lungs of newborn infants who have respiratory distress from many causes. A wide ...variety of options are available to the clinician, including CPAP, bilevel CPAP, and both synchronized and unsynchronized noninvasive mechanical breaths. Limited data are available regarding the best ways to use CPAP and NIV in today's NICU environment. This article reviews current information on these modalities, including available options, possible risks, and unanswered questions.
To assess demographic characteristics and perceptions of female physicians in attendance at a medical conference for women with content focused on growth, resilience, inspiration, and tenacity to ...better understand major barriers women in medicine face and to find solutions to these barriers.
A Likert survey was administered to female physicians attending the conference (September 20 to 22, 2018). The survey consisted of demographic data and 4 dimensions that are conducive to women’s success in academic medicine: equal access, work-life balance, freedom from gender biases, and supportive leadership.
All of the 228 female physicians surveyed during the conference completed the surveys. There were 70 participants (31.5%) who were in practice for less than 10 years (early career), 111 (50%) who were in practice for 11 to 20 years (midcareer), and 41 (18.5%) who had more than 20 years of practice (late career). Whereas participants reported positive support from their supervisors (mean, 0.4 SD 0.9; P<.001), they did not report support in the dimensions of work-life balance (mean, −0.2 SD 0.8; P<.001) and freedom from gender bias (mean, −0.3 SD 0.9; P<.001).
Female physicians were less likely to feel support for work-life balance and did not report freedom from gender bias in comparison to other dimensions of support. Whereas there was no statistically significant difference between career stage, trends noting that late-career physicians felt less support in all dimensions were observed. Future research should explore a more diverse sample population of women physicians.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The standard of care for myelodysplastic syndromes is hypomethylating agents such as azacitidine. However, responses to azacitidine are generally temporary, and outcomes after hypomethylating agent ...failure are dismal. Therefore, the development of more effective treatments is crucial to improve outcomes in patients with myelodysplastic syndromes. We aimed to assess azacitidine and lenalidomide in patients with high-risk myelodysplastic syndromes and acute myeloid leukaemia.
We did this single-arm phase 1/2 study at the University of Texas MD Anderson Cancer Center, TX, USA. Patients of any age were eligible for phase 1 and 2a if they had relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome with bone marrow blasts more than 10%. For phase 2b, eligible participants were previously untreated with myelodysplastic syndrome with an International Prognostic Scoring System (IPSS) score of intermediate-1 or higher with up to 30% blasts. All participants received 75 mg/m(2) azacitidine once a day for days 1-5 for each 28 day cycle. We gave patients oral lenalidomide for 5 or 10 days starting on day 6. We assessed seven lenalidomide doses in a 3 + 3 phase 1 design (n=28). The primary endpoint in phase 1 was the maximum tolerated dose, and the primary endpoint in phase 2 was overall survival. Outcome analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01038635.
Between Dec 30, 2009, and June, 17, 2013, we enrolled 88 patients (28 in phase 1 and 60 in phase 2). One patient unexpectedly died in the phase 1 study at the highest dose level, six more patients were recruited with no further serious adverse events. We recorded no dose-limiting toxic effects, and the maximum tolerated dose of lenalidomide in combination with azacitidine in patients with acute myeloid leukaemia and myelodysplastic syndrome was initially established at 50 mg per day for 10 days. In the first 20 patients in phase 2, we noted a high rate of myelosuppression and myelosuppression-related toxic effects; therefore, we amended the lenalidomide dose to 25 mg per day for 5 days. We also adjusted the inclusion criteria to include patients with less than 30% blasts to focus mainly on patients with myelodysplastic syndromes. Median overall survival was 75 weeks (IQR 25-not reached) for the 40 patients in phase 2b. The most common grade 3-4 adverse events overall were neutropenic fever (n=27) and pneumonia (n=18).
We have identified a safe and active sequential treatment combination of azacitidine and lenalidomide for patient with myelodysplastic syndrome and have preliminary evidence that this dose is also safe for patients with acute myeloid leukaemia.
MD Anderson Cancer Center and Celgene.
Background: Ponatinib, a third-generation pan-tyrosine kinase inhibitor (TKI), was found to be effective in heavily pretreated patients (pts) with chronic myeloid leukemia (CML). With the ...availability of multiple TKI, these agents are used in different sequences, and there is limited information on the value of various TKI in different lines of therapy. Since ponatinib has been effective in 3rd and subsequent lines of therapy, we performed an analysis of a cohort of pts with CML who received ponatinib as a different line of treatment.
Method: A total of 80 pts with chronic phase of CML and received ponatinib from 2009 to 2018 were analyzed. Only pts who received ponatinib as a second or subsequent line of therapy of CML were included. Major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), molecular response (MR) 4, and MR 4.5 were assessed. Event-free (EFS), transformation-free (TFS), failure-free (FFS) and overall survival (OS) were also analyzed.
Results: Nine pts (11%) received ponatinib as a 2nd line therapy (prior TKI imatinib in 6, dasatinib in 1, and nilotinib in 2 pts); 21 (26%) as a 3rd line, 26 (33%) as a 4th line, and 24 (30%) as a 5th and above line. The median age was over 50 years (Y) in all the groups except for pts who received ponatinib as a 3rd line 38 Y (23-76). Among pts who received ponatinib as 2nd line, 9 (100%) achieved CCyR and MR 4.5; the median time to achieve CCyR and MR 4.5 was 3 and 6.8 months (mo), respectively (Table 1). In pts treated in 3rd line CCyR and MR 4.5 were 67% and 57%, respectively and the median time to response was 4.8 and 19.3 mo, respectively. Of the 26 pts treated in 4th line, 13 (50%) achieved CCyR (median time to CCyR 3 mo) and 7 (27%) achieved MR 4.5 (median time 11.6 mo). In 5th line and above 14 (58%) achieved CCyR (median time 6.4 mo) and 8 (33%) achieved MR 4.5 (median time 12.3 mo) (Figure 1). After a median follow-up of 59.8 months (range, 4.7 to 114.3) for all pts, the median OS was not reached in pts treated in 2nd to 4th line and 81.4 mo in ≥5th line. The median FFS was not reached in 2nd line, and was 45.6, 20.2, and 17.8 mo in 3rd, 4th, and ≥5th line, respectively. The median EFS and TFS was not reached in any line of treatment. The TFS was significantly better in pts who received ponatinib as a 2nd-4th line therapy as compared to ≥5th p=0.0026, HR-55.97 (4.076-768.7) (Figure 2).
Conclusion: Our results suggest that CCyR and MR 4.5 were higher when ponatinib was used in up to 4th line of therapy for resistant CML, and it was particularly effective in 2nd or 3rd line where high rates of MR4.5 can be achieved. These results underscore the efficacy of ponatinib in these settings.
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Sasaki:Otsuka Pharmaceutical: Honoraria. Ravandi:Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Kadia:Takeda: Consultancy; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. DiNardo:Agios: Consultancy; Bayer: Honoraria; Medimmune: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Konopleva:Stemline Therapeutics: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Immunogen: Research Funding. Pemmaraju:stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; samus: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; abbvie: Research Funding. Daver:ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Consultancy; Incyte: Research Funding; Karyopharm: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; Alexion: Consultancy; ImmunoGen: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.
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