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1.
Ilse M. Boudewijn Alen Faiz Katrina Steiling Erica van der Wiel Eef D. Telenga Susan J. M. Hoonhorst Nick H. T. ten Hacken Corry-Anke Brandsma Huib A. M. Kerstjens Wim Timens Irene H. Heijink Marnix R. Jonker Harold G. de Bruin J. Sebastiaan Vroegop Henk R. Pasma Wim G. Boersma Pascal Wielders Frank van den Elshout Khaled Mansour Avrum Spira Marc E. Lenburg Victor Guryev Dirkje S. Postma Maarten van den Berge 《Respiratory research》2017,18(1):213
Background
Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium.Methods
Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls.Results
In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate?<?0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDRGSEA <?0.001).Conclusion
We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD.Trial registration
ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008).2.
Background
The prevalence of atrial fibrillation (AF) is growing as the population ages, and at least 15% of ischemic strokes are attributed to AF. However, many high-risk AF patients are not offered guideline-recommended stroke prevention therapy due to a variety of system, provider, and patient-level barriers.Methods
We will conduct a pragmatic, cluster-randomized controlled trial randomizing primary care clinics to test a “toolkit” of quality improvement interventions in primary care. In keeping with the recommendations of the chronic care model to simultaneously activate patients and facilitate proactive care by providers, the toolkit includes provider-focused strategies (education, audit and feedback, electronic decision support, and reminders) plus patient-directed strategies (educational letters and reminders). The trial will include two feedback cycles at baseline and approximately 6 months and a final data collection at approximately 12 months. The study will be powered to show a difference of 10% in the primary outcome of proportion of patients receiving guideline-recommended stroke prevention therapy. Analysis will follow the intention-to-treat principle and will be blind to treatment allocation. Unit of analysis will be the patient; models will use generalized estimating equations to account for clustering at the clinical level.Discussion
Stroke prevention therapy using anticoagulation in patients with AF is known to reduce strokes by two thirds or more in clinical trials, but most studies indicate under-use of this treatment in real-world practice. If the toolkit successfully improves care for patients with AF, stakeholders will be engaged to facilitate broader application to maximize the potential to improve patient outcomes. The intervention toolkit tested in this project could also provide a model to improve quality of care for other chronic cardiovascular conditions managed in primary care.Trial registration
ClinicalTrials.gov (NCT01927445). Registered August 14, 2014 at https://clinicaltrials.gov/.3.
Jeff Kirk Svane Shu-Ti Chiou Oliver Groene Milena Kalvachova Mirna Zagrajski Brkić Isao Fukuba Tiiu Härm Jerneja Farkas Yen Ang Mikkel Østerheden Andersen Hanne Tønnesen 《Implementation science : IS》2018,13(1):153
Background
Implementation of clinical health promotion (CHP) aiming at better health gain is slow despite its effect. CHP focuses on potentially modifiable lifestyle risks such as smoking, alcohol, diet, and physical inactivity. An operational program was created to improve implementation. It included patients, staff, and the organization, and it combined existing standards, indicators, documentation models, a performance recognition process, and a fast-track implementation model.The aim of this study was to evaluate if the operational program improved implementation of CHP in clinical hospital departments, as measured by health status of patients and staff, frequency of CHP service delivery, and standards compliance.Methods
Forty-eight hospital departments were recruited via open call and stratified by country. Departments were assigned to the operational program (intervention) or usual routine (control group). Data for analyses included 36 of these departments and their 5285 patients (median 147 per department; range 29–201), 2529 staff members (70; 10–393), 1750 medical records (50; 50–50), and standards compliance assessments.Follow-up was measured after 1 year. The outcomes were health status, service delivery, and standards compliance.Results
No health differences between groups were found, but the intervention group had higher identification of lifestyle risk (81% versus 60%, p?<?0.01), related information/short intervention and intensive intervention (54% versus 39%, p?<?0.01 and 43% versus 25%, p?<?0.01, respectively), and standards compliance (95% versus 80%, p?=?0.02).Conclusions
The operational program improved implementation by way of lifestyle risk identification, CHP service delivery, and standards compliance. The unknown health effects, the bias, and the limitations should be considered in implementation efforts and further studies.Trial registration
ClinicalTrials.gov: NCT01563575. Registered 27 March 2012. https://clinicaltrials.gov/ct2/show/NCT015635754.
Mengyuan Liu Xin Zhen Hongyan Song Junhao Chen Xiaoling Sun Xiaoqin Li Jianjun Zhou Guijun Yan Lijun Ding Haixiang Sun 《Reproductive biology and endocrinology : RB&E》2017,15(1):95
Background
The published results regarding lymphocytes immunotherapy for unexplained recurrent miscarriage (uRM) patients are conflicting due to different screening criteria and therapeutic protocols. The objective of the present study is to evaluate the effectiveness of immunotherapy using low-dose lymphocytes in patients with uRM and Th1/Th2/Treg paradigm disorders.Methods
Sixty-four uRM patients who received low-dose lymphocytes immunotherapy served as the immunotherapy group, while the other 35 women who did not receive the treatment served as the control group. The proportions of peripheral blood Th1 cells, Th2 cells and Treg cells; and the concentration of TGF-β1 in serum were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, before and after the immunotherapy.Results
The proportion of Th1 cells was significantly decreased while the proportions of Th2 cells and Treg cells were significantly increased in immunotherapy group patients after treatment. In addition, the concentration of TGF-β1 in serum was significantly higher after immunotherapy than before. Forty-three uRM patients achieved pregnancy after receiving immunotherapy and 5 patients underwent miscarriages in the immunotherapy group (11.6%, 5/43), while 8 of the 23 pregnant patients experienced a miscarriage in the control group (34.8%, 8/23; p?<?0.05).Conclusions
Low-dose lymphocyte immunotherapy is beneficial for restoring balance in the Th1/Th2/Treg paradigm and improving pregnancy outcome in uRM patients.5.
Bernadette G Dijkman Jason W Busse Stephen D Walter Mohit Bhandari the TRUST Investigators 《Trials》2011,12(1):237
Background
Radiographic healing is a common outcome measure in orthopedic trials and adjudication by outcome assessors is often conducted on the basis of plain films alone. The degree to which this process reflects clinical practice, in which both plain films and clinical notes are available, is uncertain. We explored the effect of adding clinical notes to radiographs in the adjudication process of a feasibility trial of tibial shaft fractures.Methods
Radiographic and clinical data from a multicenter randomized controlled trial of 51 patients with operatively treated tibial fractures formed the basis of the study data. At the completion of the trial, serial radiographs (anteroposterior and lateral) were independently evaluated for progression of fracture healing, defined as bridging of at least 3 of 4 cortices, by an adjudication committee comprised of 3 blinded orthopaedic trauma surgeons. Immediately after determination of radiographic time to healing, each surgeon was provided with clinical notes associated with each radiographic follow up visit and asked to re-visit their initial impression. Consensus was achieved for both adjudications. We calculated the percentage of time to healing consensus decisions that changed after evaluation of clinical notes. We further examined the contents of clinical notes and their relative influence on the committee's decisions.Results
47 of 51 patients were determined to have healed radiographically during the trial follow-up period, and consideration of clinical notes resulted in a change of 40% (19 of 47) of time to healing consensus decisions; however, revised decisions were equally likely to support an earlier or a later time to healing. Clinical notes that resulted in a change to either a 'healed' or a 'not healed' decision contained significantly more comments of either pain resolution or deterioration, respectively, resumption of or failure to resume weightbearing, or either return or no return to work/pre-injury activities (p < 0.001).Conclusions
The addition of clinical notes to the adjudication of radiographic fracture healing changed the outcome decision in a substantial number of cases. Orthopedic trialists should consider the addition of clinical notes to adjudication material in studies of fracture healing in order to enhance the generalizability of their results.Trial Registration
The TRUST trial was registered [ID NCT00667849] at http://clinicaltrials.gov/ct2/show/NCT006678496.
Daphnée Lamarche Jennie Johnstone Nicole Zytaruk France Clarke Lori Hand Dessi Loukov Jake C. Szamosi Laura Rossi Louis P. Schenck Chris P. Verschoor Ellen McDonald Maureen O. Meade John C. Marshall Dawn M. E. Bowdish Tim Karachi Diane Heels-Ansdell Deborah J. Cook Michael G. Surette for the PROSPECT Investigators Canadian Critical Care Trials Group Canadian Critical Care Translational Biology Group 《Respiratory research》2018,19(1):245
Background
Host-associated microbial communities have important roles in tissue homeostasis and overall health. Severe perturbations can occur within these microbial communities during critical illness due to underlying diseases and clinical interventions, potentially influencing patient outcomes. We sought to profile the microbial composition of critically ill mechanically ventilated patients, and to determine whether microbial diversity is associated with illness severity and mortality.Methods
We conducted a prospective, observational study of mechanically ventilated critically ill patients with a high incidence of pneumonia in 2 intensive care units (ICUs) in Hamilton, Canada, nested within a randomized trial for the prevention of healthcare-associated infections. The microbial profiles of specimens from 3 anatomical sites (respiratory, and upper and lower gastrointestinal tracts) were characterized using 16S ribosomal RNA gene sequencing.Results
We collected 65 specimens from 34 ICU patients enrolled in the trial (29 endotracheal aspirates, 26 gastric aspirates and 10 stool specimens). Specimens were collected at a median time of 3?days (lower respiratory tract and gastric aspirates; interquartile range [IQR] 2–4) and 6?days (stool; IQR 4.25–6.75) following ICU admission. We observed a loss of biogeographical distinction between the lower respiratory tract and gastrointestinal tract microbiota during critical illness. Moreover, microbial diversity in the respiratory tract was inversely correlated with APACHE II score (r?=???0.46, p?=?0.013) and was associated with hospital mortality (Median Shannon index: Discharged alive; 1.964 vs. Deceased; 1.348, p?=?0.045).Conclusions
The composition of the host-associated microbial communities is severely perturbed during critical illness. Reduced microbial diversity reflects high illness severity and is associated with mortality. Microbial diversity may be a biomarker of prognostic value in mechanically ventilated patients.7.
Joost?Swart Gabriella?Giancane Gerd?Horneff Bo?Magnusson Michael?Hofer Еkaterina?Alexeeva Violeta?Panaviene Brigitte?Bader-Meunier Jordi?Anton Susan?Nielsen Fabrizio?De Benedetti Sylvia?Kamphuis Valda?Sta?ēvi?a Maria?Tracahana Laura?Marinela?Ailioaie Elena?Tsitsami Ariane?Klein Kirsten?Minden Ivan?Foeldvari Johannes?Peter?Haas Jens?Klotsche Anna?Carin?Horne Alessandro?Consolaro Francesca?Bovis Francesca?Bagnasco Angela?Pistorio Alberto?Martini Nico?Wulffraat Nicolino?Ruperto for the Paediatric Rheumatology International Trials Organisation BiKeR the board of the Swedish Registry 《Arthritis research & therapy》2018,20(1):285
8.
Leslie Amass Huihua Li Balarama K. Gundapaneni Jeffrey H. Schwartz Denis J. Keohane 《Orphanet journal of rare diseases》2018,13(1):225
Background
Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN.Methods
A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score–Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment.Results
The T-T (n?=?64) and P-T (n?=?61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p?<?0.0001). Neurologic progression in the T-T group was less than in the P-T group across all levels of baseline NIS-LL (p?=?0.0088), and the degree of separation increased over the 18-month period. Similar results were seen with the NIS-LL muscle weakness subscale.Conclusions
This analysis of patients with Val30Met ATTR-PN demonstrates that neurologic disease progression strongly depends on baseline neurologic severity and illustrates the disease-modifying effect of tafamidis relative to placebo across a range of baseline levels of neurologic severity and treatment durations. These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression in ATTR-PN.Trial Registration
NCT00409175, NCT00791492 and NCT00925002 registered 08 December 2006, 14 November 2008 (retrospectively registered), and 19 June 2009, respectively.9.
Michael Wang Stephen J. Schuster Tycel Phillips Izidore S. Lossos Andre Goy Simon Rule Mehdi Hamadani Nilanjan Ghosh Craig B. Reeder Evelyn Barnett Marie-Laure Casadebaig Bravo Peter Martin 《Journal of hematology & oncology》2017,10(1):171
Background
The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance.Methods
The primary endpoint was investigator-assessed overall response rate based on the 2007 International Working Group criteria.Results
Of 58 enrolled patients (median age, 71 years; range, 50–89), 13 received lenalidomide monotherapy, 11 lenalidomide plus rituximab, and 34 lenalidomide plus other treatment. Most patients (88%) had received ≥?3 prior therapies (median 4; range, 1–13). Median time from last dose of ibrutinib to the start of lenalidomide was 1.3 weeks (range, 0.1–21.7); 45% of patients had partial responses or better to prior ibrutinib. Primary reasons for ibrutinib discontinuation were lack of efficacy (88%) and ibrutinib toxicity (9%). After a median of two cycles (range, 0–11) of lenalidomide-based treatment, 17 patients responded (8 complete responses, 9 partial responses), for a 29% overall response rate (95% confidence interval, 18–43%) and a median duration of response of 20 weeks (95% confidence interval, 2.9 to not available). Overall response rate to lenalidomide-based therapy was similar for patients with relapsed/progressive disease after previous response to ibrutinib (i.e., ≥PR) versus ibrutinib-refractory (i.e., ≤SD) patients (30 versus 32%, respectively). The most common all-grade treatment-emergent adverse events after lenalidomide-containing therapy (n = 58) were fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each). At data cutoff, 28 patients have died, primarily due to mantle cell lymphoma.Conclusion
Lenalidomide-based treatment showed clinical activity, with no unexpected toxicities, in patients with relapsed/refractory mantle cell lymphoma who previously failed ibrutinib therapy.Trial registration
Clinicaltrials.gov identifier NCT02341781. Date of registration: January 14, 201510.
Bo?Cai Mei?Guo Yao?Wang Yajing?Zhang Jun?Yang Yelei?Guo Hanren?Dai Changlin?Yu Qiyun?Sun Jianhui?Qiao Kaixun?Hu Hongli?Zuo Zheng?Dong Zechuan?Zhang Mingxing?Feng Bingxia?Li Yujing?Sun Tieqiang?Liu Zhiqing?Liu Yi?Wang Yajing?Huang Bo?Yao Weidong?Han Huisheng?Ai
Background
Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined.Case presentation
We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy.Conclusions
Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned.Trial registration
Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT0279955011.
Catriona Graham Steff Lewis John Forbes Gillian Mead Maree L. Hackett Graeme J. Hankey John Gommans Huy Thang Nguyen Erik Lundström Eva Isaksson Per Näsman Ann-Sofie Rudberg Martin Dennis 《Trials》2017,18(1):627
Background
Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients’ functional outcome.Methods/Design
The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2–15 days after stroke onset. Patients are randomised centrally via each trials’ web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months.Discussion
Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020.Trial registration
FOCUS: ISRCTN, ISRCTN83290762. Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012.AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Registered on 22 July 2011.EFFECTS: ISRCTN, ISRCTN13020412. Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213. Registered on 2 February 2016. EudraCT, 2011-006130-16. Registered on 8 August 2014.12.
Balbino Rivail Ventura NepomucenoJr. Naniane Cidreira Almeida Caroline Ferreira Guerreiro Eveline Xavier-Souza Mansueto Gomes Neto 《Trials》2017,18(1):626
Background
The early institution of inspiratory muscle training on hospitalised patients with no established respiratory deficits could prevent in-hospital adverse outcomes that are directly or indirectly associated to the loss of respiratory muscle mass inherent to a prolonged hospital stay. The objective of the clinical trial is to assess the impact of inspiratory muscle training on hospital inpatient complications.Methods
This is a double-blind randomised controlled trial. Subjects in the intervention group underwent an inspiratory muscle training loaded with 50% maximum inspiratory pressure twice daily for 4 weeks from study enrolment. Patients were randomly assigned to an inspiratory muscle training group or a sham inspiratory muscle training group. All patients received conventional physiotherapy interventions. Baseline and post-intervention respiratory and peripheral muscle strength, functionality (performance of activities of daily living), length of hospital stay, and death were evaluated. Clinical outcomes were assessed until hospital discharge. This study was approved by the Institutional Hospital Ethics Committee (03/2014).Results
Thirty-one patients assigned to the inspiratory muscle training group and 34 to the sham inspiratory muscle training group were analysed. Patients in the inspiratory muscle training group had a shorter mean length of hospital stay (35.3?±?2.7 vs. 41.8?±?3.5 days, p?<?0.01) and a lower risk of endotracheal intubation (relative risk (RR)?=?0.36; 95% confidence interval (CI) 0.27–0.97; p?=?0.03) as well as muscle weakness (RR?=?0.36; 95% CI 0.19–0.98; p?=?0.02) and mortality (RR?=?0.23; 95% CI 0.2–0.94; p?=?0.04). The risk of adverse events did not differ significantly between groups.Conclusion
Inspiratory muscle training was a protective factor against endotracheal intubation, muscle weakness, and mortality.Trial registration
ClinicalTrials.gov, ID: NCT02459444. Registered on 19 May 2015.13.
Wan-Hong Zhao Jie Liu Bai-Yan Wang Yin-Xia Chen Xing-Mei Cao Yun Yang Yi-Lin Zhang Fang-Xia Wang Peng-Yu Zhang Bo Lei Liu-Fang Gu Jian-Li Wang Nan Yang Ru Zhang Hui Zhang Ying Shen Ju Bai Yan Xu Xu-Geng Wang Rui-Li Zhang Li-Li Wei Zong-Fang Li Zhen-Zhen Li Yan Geng Qian He Qiu-Chuan Zhuang Xiao-Hu Fan Ai-Li He Wang-Gang Zhang 《Journal of hematology & oncology》2018,11(1):141
Background
Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).Methods
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80?years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300?mg/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5?×?106 cells/kg [range, 0.07 to 2.1?×?106]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.Results
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥?1 adverse events (AEs). Grade ≥?3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥?3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1?month (range, 0.4 to 3.5). At a median follow-up of 8?months, median progression-free survival was 15?months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.Conclusions
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.Trial registration
ClinicalTrials.gov, NCT03090659; Registered on March 27, 2017, retrospectively registered14.
Background
Pacritinib (SB1518) is a highly selective kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. This multicenter phase 1/2 study evaluated the maximum tolerated dose (MTD), safety, and clinical activity of pacritinib in patients with myelofibrosis (MF) and other advanced myeloid malignancies.Methods
In the phase 1 dose-escalation part of the study, 43 adults with advanced myeloid malignancies received pacritinib 100 to 600 mg once daily (QD). In the phase 2 part of the study, 31 adults with refractory or intermediate- or high-risk newly diagnosed MF and any degree of cytopenia received pacritinib 400 mg QD. The primary endpoint is a ≥35% reduction in spleen volume at week 24 as determined by magnetic resonance imaging.Results
Five patients (11.6%) experienced a dose-limiting toxicity during cycle 1 of phase 1. The clinical benefit rate was 86.0% (13 patients achieving clinical improvement and 24 patients having stable disease). The MTD was established at 500 mg QD, and the recommended phase 2 dose was 400 mg QD. In phase 2, the primary endpoint was achieved by 23.5% of evaluable patients (4/17), with 47.4% (9/19) achieving a ≥50% spleen length reduction at week 24 as measured by physical examination. At week 24, 38.9% of evaluable patients (7/18) achieved a ≥50% decrease in MF Quality of Life and Symptom Assessment total score. Gastrointestinal toxicities were the most common adverse events and were predominantly grade 1/2 in severity. Grade 3/4 anemia was reported in 5/31 patients and grade 3/4 thrombocytopenia was reported in 3/31 patients. The most frequent AEs considered to be treatment related were diarrhea (28/31), nausea (15/31), vomiting (9/31), and fatigue (4/31). Grade 3 treatment-related AEs were reported in seven patients (22.6%), four of whom had diarrhea. No grade 4/5 treatment-related AEs were reported. No leukopenia, neutropenia, or lymphopenia were reported.Conclusions
Pacritinib was well tolerated and demonstrated clinical activity in MF. The study suggests that pacritinib has unique characteristics, namely a lack of substantial myelosuppression and manageable side effects, making it an attractive target for further evaluation in MF.Trial registration
Retrospectively registered at www.clinicaltrials.gov (#NCT00719836) on July 20, 2008.15.
Srdan Verstovsek Jason Gotlib Ruben A. Mesa Alessandro M. Vannucchi Jean-Jacques Kiladjian Francisco Cervantes Claire N. Harrison Ronald Paquette William Sun Ahmad Naim Peter Langmuir Tuochuan Dong Prashanth Gopalakrishna Vikas Gupta 《Journal of hematology & oncology》2017,10(1):156
Background
Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.Methods
This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.Results
A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n?=?155; COMFORT-II, n?=?146) and 227 to control (n?=?154 and n?=?73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54–0.91]; P?=?0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23–0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36–0.78]; P?=?0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.Conclusions
These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.16.
Background
Software applications (apps) could potentially promote exercise adherence. However, it is unclear whether adolescents with painful hyperkyphosis will use an app designed for a home exercise program. The purpose of this study is to assess factors regarding adherence to an app-based home exercise program in adolescents with hyperkyphosis and back pain who were provided a one-time exercise treatment.Methods
Twenty-one participants were instructed in a one-time exercise treatment and asked to complete a home exercise program 3 times a week for 6 months using an app called PT PAL. At a 6-month follow-up, 14 participants completed a survey assessing factors related to their experiences using the app and their treatment engagement.Results
Although most participants did not use the app, they reported performing their exercises a few times per week. The adolescent participants considered the app to be more of a barrier than a supportive measure for promoting exercise adherence. Most participants still reported bothersome back pain.Conclusions
Although adherence to the 6-month app-based home exercise program was not successful, adolescents still viewed technology support such as text reminders as a potential solution.Trial registration
ClinicalTrials.gov Identifier: NCT03212664. Registered 11 July 2017. Retrospectively registered.17.
N.H. M. Shukri J. Wells F. Mukhtar M.H.S. Lee M. Fewtrell 《International breastfeeding journal》2017,12(1):33
Background
The physiological and psychological signalling between mother and infant during lactation is one of the prominent mother-infant factors that may influence breastfeeding outcomes. The infant can ‘signal’ his needs through vocalisation, and the mother can respond by allowing or restricting nipple access, which might alter the breast milk composition or volume. This may lead to parent-offspring conflict during the lactation period. Challenging infant behaviour has also been associated with maternal psychological distress, which might affect breastfeeding performance. Most attempts to improve breastfeeding rates focus on providing additional support, yet many aspects of the breastfeeding process are poorly understood. Thus, our objective is to investigate mother-infant signalling during breastfeeding by manipulating maternal psychological state using a relaxation therapy intervention. The study will test the hypothesis that mothers who listen to the therapy will be more relaxed/less stressed and this will favourably alter breast milk composition and/or affect milk volume and hence influence infant outcomes.Methods
A randomised controlled trial will be conducted in first-time breastfeeding mothers and their new-born infants. Pregnant mothers will be recruited at antenatal clinics in Selangor, Malaysia, and four home visits will be carried out at 2, 6, 12 and 14 weeks postnatally. Participants will be randomised into a control and an intervention group in the early post-partum period. Mothers from the intervention group will be asked to listen daily to an audio recording with relaxation therapy during breastfeeding. Maternal psychological state, breastfeeding practices and infant behaviour will be assessed using validated questionnaires. Milk volume will be measured using stable isotopes. Breast milk samples will be collected to measure macronutrient content and hormone levels. Anthropometric measurements (weight, length and head circumference) will be performed during all home visits, including body composition at week 14.Discussion
The main outcomes will be the effect of the intervention on maternal psychological state, milk production, cortisol levels, and infant behaviour and growth. Secondary outcomes will be associations between breast milk composition and infant appetite and growth. This study aims to provide a greater understanding of maternal-infant factors which influence breastfeeding outcomes and which may be useful targets for future interventions.18.
You-Cheol Hwang Ari Kim Euna Jo Yeoree Yang Jae-Hyoung Cho Byung-Wan Lee 《BMC endocrine disorders》2017,17(1):68
Background
Randomized clinical trials have shown the efficacy and safety of short-acting exenatide in patients with type 2 diabetes mellitus (T2DM). The aim of this observational study was to investigate the effectiveness and safety of exenatide twice a day in Korean patients with T2DM who are suboptimally controlled with oral hypoglycemic agents.Methods
This study was a post hoc analysis of multi-center (71 centers), prospective, observational, single-arm, post-marketing study of short-acting exenatide 5 to 10 μg twice a day from March 2008 to March 2014 and analyzed those who finished the follow-up over 20 weeks of medication. Changes of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight values before and after exenatide treatment were analyzed. Adverse events and adverse drug reactions were estimated in patients who were treated with exenatide at least once and for whom follow-up for safety has been completed.Results
After 20 weeks treatment with exenatide, mean HbA1c and body weight were significantly reduced from 8.4% to 7.7% and from 83.4 kg to 80.2 kg, respectively (both p < 0.001). Subjects with higher baseline glucose and HbA1c levels showed an independent association with a greater reduction in glucose level. In addition, short duration of diabetes less than 5 years was an independent predictor for the improvement in glucose level. The majority of study subjects showed a reduction in both body weight and glucose level (63.3%) after exenatide treatment. In terms of safety profile, exenatide treatment was generally well-tolerated and the incidence of severe adverse event was rare (0.8%). The gastrointestinal side effects were most common and hypoglycemia was reported in 1.7% of subjects.Conclusion
In real clinical practice, 20 weeks treatment with short-acting exenatide was well tolerated and showed a significant body weight and glucose reduction in Korean patients with T2D who are suboptimally controlled with oral hypoglycemic agents.19.
20.
Mario H. Vargas Rosangela Del-Razo-Rodríguez Amando López-García José Luis Lezana-Fernández Jaime Chávez María E. Y. Furuya Juan Carlos Marín-Santana 《BMC pulmonary medicine》2017,17(1):206