tbuckley/cabot-search huggingface dataset:
PP01. TARGETING MYC/MYCN BY INHIBITION OF CHECKPOINT KINASE 1 (CHK1) SENSITIZES PAEDIATRIC GLIOBLASTOMA (PGBM) CELLS TO TEMOZOLOMIDE
Authors: Dr Meera Nandhabalan
Journal: Neuro-Oncology (2017)

Paediatric glioblastomas (pGBM) are biologically distinct from adults, and are in part defined by highly recurrent mutations in the H3F3A gene which encodes the histone variant H3.3. This causes amino acid substitutions at or close to the residues K27 and K36 whose methylation is key to the regulation of transcription. We found that these subgroups have distinct age of incidence, anatomical location, and clinical outcomes. Specifically, through differential binding of the activating mark trimethylated H3K36me3, the G34 mutation causes upregulation of MYCN, a known oncogenic driver in other paediatric diseases. These tumours were mutually exclusive of those harbouring gene amplification of MYCN, which represent a distinct subgroup of pGBM by methylation profiling. Increased copies of MYC/MYCN occur via complex rearrangements on chromosomes 2 and 8, often co-amplifying ID2, PVT1 and other genes. MYC/MYCN amplifications are observed in 13/851 (1.5%) and 36/851 (4.2%) pHGGs respectively and correlate with poorer survival (p<0.0485). These tumours are most common in children peaking at an age of 5.4 years, thus appearing to define a specific subset of paediatric glioblastoma. A synthetic lethality kinome screen in vitro identified H3.3G34 cells to be differentially sensitive to checkpoint kinase 1 inhibition, known to interfere with the stabilisation of MYCN protein. Screening a panel of pGBM cell lines and primary cultures with a series of CHK1 inhibitors (AZD7762, LY2603618, CCT244747) demonstrated a dose-dependent degradation of MYC/MYCN protein which correlated with in vitro GI50 values. Transduction of pGBM cells with stabilised MYCN (T58A) lead to enhanced sensitivity to CHK1 inhibition in both cell viability and clonogenic assays. Combining CHK1 inhibitors with temozolomide produced significant synergy in cells whose resistance is both independent and dependent on MGMT, resulting in combination indices of 0.3–0.6. These data identify a significant proportion of pGBM to be amenable to CHK1 inhibition by virtue of MYC/MYCN dependency. In addition, CHK1 inhibition may play a role in chemosensitisation of paediatric glioblastoma cells to temozolomide regardless of mechanism of alkylating agent resistance. Therefore, combining temozolomide with CHK1 inhibition may be of particular therapeutic benefit in patients whose tumours amplify and/or express MYC/MYCN.
Reduced Frizzled Receptor 4 Expression Prevents WNT/β-Catenin–driven Alveolar Lung Repair in Chronic Obstructive Pulmonary Disease
Authors: Wioletta Skronska-Wasek, Kathrin Mutze, Hoeke A. Baarsma, Ken R. Bracke, Hani N. Alsafadi, Mareike Lehmann, Rita Costa, Mariano Stornaiuolo, Ettore Novellino, Guy G. Brusselle, Darcy E. Wagner, Ali Ö. Yildirim, Melanie Königshoff
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. Wingless and INT-1 (WNT)/β-catenin signaling is reduced in COPD; however, the mechanisms thereof, specifically the role of the frizzled (FZD) family of WNT receptors, remain unexplored.To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD.FZD expression was analyzed in lung homogenates and alveolar epithelial type II (ATII) cells of never-smokers, smokers, patients with COPD, and two experimental COPD models by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on FZD4, WNT/β-catenin signaling, and elastogenic components were investigated in primary ATII cells in vitro and in three-dimensional lung tissue cultures ex vivo. Gain- and loss-of-function approaches were applied to determine the effects of FZD4 signaling on alveolar epithelial cell wound healing and repair, as well as on expression of elastogenic components.FZD4 expression was reduced in human and experimental COPD lung tissues as well as in primary human ATII cells from patients with COPD. Cigarette smoke exposure down-regulated FZD4 expression in vitro and in vivo, along with reduced WNT/β-catenin activity. Inhibition of FZD4 decreased WNT/β-catenin-driven epithelial cell proliferation and wound closure, and it interfered with ATII-to-ATI cell transdifferentiation and organoid formation, which were augmented by FZD4 overexpression. Moreover, FZD4 restoration by overexpression or pharmacological induction led to induction of WNT/β-catenin signaling and expression of elastogenic components in three-dimensional lung tissue cultures ex vivo.Reduced FZD4 expression in COPD contributes to impaired alveolar repair capacity.
The Prognostic Impact of Inflammatory Factors for Survival in Patients with Newly Diagnosed Multiple Myeloma Who Were Treated with Thalidomide Containing Induction Chemotherapy Underwent Autologous Stem Cell Transplantation
Authors: Cheolsu Kim, Ho Sup Lee, Yang Soo Kim, Chang-Ki Min, Je-Jung Lee, Kihyun Kim, Dok Hyun Yoon, Hyeon Seok Eom, Hyewon Lee, Won Sik Lee, Ho-Jin Shin, Ji Hyun Lee, Yong Park, Jae-Cheol Jo, Young Rok Do, Yeung-Chul Mun
Journal: Blood (2014)
Abstract OT2-04-01: Study on the usefulness of the skin wound therapeutic agent 'Neo dermal activator' in breast cancer surgery
Authors: JH Kim, SM Lim, SI Kim, SH Park, HS Park, JY Kim
Journal: Cancer Research (2017)

Abstract Background : Wound infection after breast cancer surgery is considered to be factors that increase the discomfort of the patient and increase of the extension and the use of antibiotics in the treatment time period, in particular breast cancer postoperative wound infection resulting slow the implementation of adjunctive therapy such as radiation therapy or chemotherapy after surgery can cause, it is important to effectively prevent, there has been a development of a variety of skin wound therapeutic agent to reduce them. The purpose of this study was to evaluate the effects of the wound dressing with existing wound dressing Neo dermal activator compared to the patients receiving preoperative chemotherapy. Methods : A total of 54 breast cancer patients who recieved BCS &amp; mastectomy devided two group(each 27 patients) through the random assignment between Jan, 2016 and June, 2016. Day one weeks after surgery to examine the wound infection rate (surgical site infection, SSI rate). After six months of outpatient surgery visits to check the wounds of patients, using the VAS records the scar of the wound satisfaction. For patients who underwent radiation therapy, check out the time it took to begin radiation therapy after surgery. All tests were two-sided. All statistical analyses were performed using SPSS version 20.0 (SPSS Inc., Chicago, Illinois, USA). Eligbility criteria is : - one side breast cancer - not inflammatory breast cancer - recieved BCS and mastectomy only (without immediate reconstruction surgery) - stage IV breast cancer. Citation Format: Kim JH, Lim SM, Kim SI, Park SH, Park HS, Kim JY. Study on the usefulness of the skin wound therapeutic agent 'Neo dermal activator' in breast cancer surgery [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-04-01.
A phase II trial of trastuzumab and low dose interleukin-2 in patients with metastatic breast cancer who have previously failed trastuzumab
Authors: A. Mani, J. Roda, M. Caligiuri, G. Fleming, P. Kaufman, A. Brufsky, W. Carson, C. Shapiro
Journal: Journal of Clinical Oncology (2007)

3028 Background: Trastuzumab (TZB) mediates lysis of Her2-pos. breast cancer cells by interleukin-2 (IL2) primed natural killer (NK) cells. We hypothesized that IL2 would augment the effects of TZB. The objective of this study was to determine the response rate to and toxicity of low dose IL2 plus TZB in patients with Her2-pos. metastatic breast cancer who had progressed within 12 months of receiving TZB. Also, we measured the ability of patient (pt) peripheral blood mononuclear cells (PBMC) to produce cytokines and conduct antibody-directed cellular cytotoxicity (ADCC) against Her2-pos. target cells. Methods: Pts received low (1 million IU/m 2 ) and intermediate dose (12 million IU/m 2 ) IL2 plus TZB (4 mg/kg) in each cycle. Low dose IL2 was given on days 2–7 and days 12–21 of cycle 1, and days 4–14 of later cycles. Intermediate dose IL2 was given on days 9–11 of cycle 1, and on days 1–3 of later cycles. TZB was given on day 1 and 8 of cycle 1, and on day 1 of later cycles. Pt plasma and PBMCs were analyzed for levels of serum cytokines and ADCC against a TZB-coated cell line, respectively. Results: Thirteen pts with median age of 52 (range 30–71), and a median of 1 (range 1–2) prior TZB-containing regimens were enrolled. The median number of cycles completed was 4. Five pts had grade 3 or greater toxicities, including fever, nausea, vomiting, diarrhea, dyspnea, and hypercalcemia. Twelve pts had progression of disease, and 1 pt withdrew consent. ADCC of pt PBMCs against a TZB-coated cell line was enhanced in only 1 pt. Two pts had elevated plasma levels of interferon-gamma (IFNg), and one of these pts had a 20-fold increase in IFNg transcript levels. The antiangiogenic chemokines MIG and IP-10 rose significantly over baseline in 11 pts. Conclusions: TZB given with low and intermediate pulse-dose IL2 did not produce a robust immune or clinical response in this pt population. A clinical trial in a TZB-naive population may help to determine the immune effects of this combination of IL2 plus TZB. No significant financial relationships to disclose.
Cell-Cycle Regulation Accounts for Variability in Ki-67 Expression Levels
Authors: Michal Sobecki, Karim Mrouj, Jacques Colinge, François Gerbe, Philippe Jay, Liliana Krasinska, Vjekoslav Dulic, Daniel Fisher
Journal: Cancer Research (2017)

The cell proliferation antigen Ki-67 is widely used in cancer histopathology, but estimations of Ki-67 expression levels are inconsistent and understanding of its regulation is limited. Here we show that cell-cycle regulation underlies variable Ki-67 expression in all situations analyzed, including nontransformed human cells, normal mouse intestinal epithelia and adenomas, human cancer cell lines with or without drug treatments, and human breast and colon cancers. In normal cells, Ki-67 was a late marker of cell-cycle entry; Ki-67 mRNA oscillated with highest levels in G2 while protein levels increased throughout the cell cycle, peaking in mitosis. Inhibition of CDK4/CDK6 revealed proteasome-mediated Ki-67 degradation in G1 After cell-cycle exit, low-level Ki-67 expression persisted but was undetectable in fully quiescent differentiated cells or senescent cells. CDK4/CDK6 inhibition in vitro and in tumors in mice caused G1 cell-cycle arrest and eliminated Ki-67 mRNA in RB1-positive cells but had no effect in RB1-negative cells, which continued to proliferate and express Ki-67. Thus, Ki-67 expression varies due to cell-cycle regulation, but it remains a reliable readout for effects of CDK4/CDK6 inhibitors on cell proliferation. Cancer Res; 77(10); 2722-34. ©2017 AACR.
Final Results of a Randomized Phase 2 Multicenter Study of Two Bortezomib Schedules In Patients with Recurrent or Refractory Follicular Lymphoma. Groupe d'Etude Des Lymphomes De l'Adulte (GELA) Study FL-05
Authors: Vincent Ribrag, Herve Tilly, Olivier Casasnovas, Andre Bosly, Reda Bouabdallah, Richard Delarue, Francois Boue, Dominique Bron, Pierre Feugier, Corinne Haioun, Fritz C Offner, Bertrand Coiffier
Journal: Blood (2010)
FDA Policies Should Be Amended To Allow Pharmaceutical Manufacturers To Disseminate Information Regarding Potentially Fatal Toxicities That Occur with Off-Label Use of Oncology Agents: A Policy Recommendation Based on Review of Thalidomide-Associated Thromboembolism Cases by the RADAR Project.
Authors: Andrew M. Evens, Martin S. Tallman, Seema Singhal, June M. McKoy, E. Allison Lyons, Dennis W. Raisch, Paul R. Yarnold, Hau Kwaan, Timothy M. Kuzel, Jayesh Mehta, Charles L. Bennett
Journal: Blood (2004)
A randomized phase II trial of bevacizumab (BV) plus oral everolimus (EV) versus bevacizumab alone for recurrent or persistent epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal cancer (PPC).
Authors: William P. Tew, Michael Sill, D. Scott McMeekin, Angeles Alvarez Secord, Albert J. Bonebrake, Jeanne Schilder, Ashley Stuckey, Laurel Rice, Krishnansu Sujata Tewari, Carol Aghajanian
Journal: Journal of Clinical Oncology (2014)

5546 Background: BV monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in persistent mTOR activation, which if blocked, may circumvent resistance to anti-VEGF therapy.We evaluated the efficacy and tolerability of combining BV and oral everolimus (EV), an mTOR kinase inhibitor, in women with EOC/FTC/PPC. Methods: Eligible pts had persistent or recurrent EOC/FTC/PPC, measurable (RECIST 1.1) or detectable (CA125 ≥ 2x upper limit normal), 1-3 prior regimens, performance status (PS) 0-2, and no prior m-TOR inhibitor. All pts received BV 10 mg/kg IV every 2wks in 4wk cycles. Pts were randomized (1:1) to oral EV (10 mg daily) or placebo with stratification for platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response evaluated every 8wks. Results: 150 evaluable pts were randomized to BV with (n=75) and without (n=75) EV. Arms were well-balanced for age (median 63: range 28-92), PS (0: 73%, 1-2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV+EV vs BV median PFS was 5.9 vs 4.5 mos, respectively (hazard for progression 0.95 (95% CI, 0.66-1.37, p=0.39); pts with PFI>6mos had HR 0.615 (95% CI 0.33~1.15, p=NS). Median OS was 16.6 vs 17.3 mos (hazard of death 1.16 (95% CI, 0.72~1.87, p=NS). Among pts with measureable disease, objective responses were higher with BV+EV (19% vs 9%). Study removal due to toxicity was high with BV+EV (29%) compared to BV alone (12%). Toxicity (≥g3) most significantly associated with addition of EV were “other GI” (17 vs 1pts) and “metabolic/nutrition” (14 vs. 5pt). Most common toxicities ( ≥g2) were anemia (24 vs 6pt), neutropenia (20 vs 1pts), oral mucositis (22 vs 0pts), nausea (24 vs 9pts), fatigue (24 vs 15pts), and hypertension (20 vs. 21pts). Conclusions: The combination regimen (BV+EV) is active in this population but did not significantly reduce the hazard of progression or death and was associated with higher rates of study discontinuation for tolerability when compared to BV alone.
A 55-Year-Old Man With a Painful Rash on the Sole of His Foot
Authors: Ramya Vangipuram, Stephen K. Tyring
Journal: JAMA (2017)

A 55-year-old man presented with 2- to 3-mm grouped vesicles on an erythematous base in a discrete area on the sole of his foot. He reported no fevers, chills, or malaise and denied history of human immunodeficiency virus, hepatitis, chickenpox, or recurrent infections. What would you do next?
Effects of patient mindset raise a legal dilemma
Authors: Dieneke Hubbeling, Manhal Zarroug, Robert Bertram
Journal: BMJ (2017)

Crum and colleagues1 argue that mindsets are important in medical treatment. They refer to several empirical studies indicating that the way patients are informed about their condition and treatment influences the outcome. Giving information about risk and side effects is not a wholly neutral act: it …
Correction: Progress in gene therapy for neurological disorders
Authors: Michele Simonato, Jean Bennett, Nicholas M. Boulis, Maria G. Castro, David J. Fink, William F. Goins, Steven J. Gray, Pedro R. Lowenstein, Luk H. Vandenberghe, Thomas J. Wilson, John H. Wolfe, Joseph C. Glorioso
Journal: Nature Reviews Neurology (2013)
Role of Selective HDAC6 Inhibition On Multiple Myeloma Bone Disease
Authors: Loredana Santo, Diana Cirstea, Bin Wang, Tso-Pang Yao, Joy Y. Wu, Peter Waterman, Derrick Jeon, Mary Bouxsein, Leeann Louis, Sutada Lotinun, Roland Baron, Homare Eda, Neeharika Nemani, Anuj Mahindra, Andrew J. Yee, Teru Hideshima, Kenneth C. Anderson, Simon S Jones, Noopur Raje
Journal: Blood (2012)
Prognostic Value of Pretreatment Metabolic Tumor Volume and Total Lesion Glycolysis Using 18F-FDG PET/CT in Patients With Metastatic Renal Cell Carcinoma Treated With Anti–Vascular Endothelial Growth Factor–Targeted Agents
Authors: Sang Hyun Hwang, Arthur Cho, Mijin Yun, Young Deuk Choi, Sun Young Rha, Won Jun Kang
Journal: Clinical Nuclear Medicine (2017)

The aim of this study was to evaluate the prognostic value of pretreatment metabolic tumor volume (MTV) and total lesion glycolysis (TLG) using F-FDG PET/CT in patients with metastatic renal cell carcinoma (RCC) after treatment with anti-vascular endothelial growth factor-targeted agents.Fifty-six patients with metastatic RCC who underwent F-FDG PET/CT for staging and recurrence evaluation were retrospectively enrolled. SUVmax, MTV, and TLG were measured using F-FDG PET/CT in all patients. The highest SUV in all the metastatic RCC lesions of each patient was defined as SUVmax. Metabolic tumor volume was defined as the total tumor volume greater than 40% of SUVmax. Total lesion glycolysis was calculated as (MTV) · (SUVmean). The prognostic significance of PET/CT parameters and clinical factors for progression-free survival (PFS) and overall survival (OS) were evaluated by univariate and multivariate analyses, along with other clinical factors.The most common organ for metastases was lung (35 patients). In the univariate analysis, hypercalcemia, time from diagnosis to treatment, SUVmax, MTV, and TLG were significant prognostic factors affecting PFS (P < 0.05), and Karnofsky score, hypercalcemia, time from diagnosis to treatment, SUVmax, MTV, and TLG were significant prognostic factors affecting OS (P < 0.05). In the multivariate analysis, hypercalcemia, MTV, and TLG were independent prognostic factors affecting PFS (P < 0.05), and hypercalcemia, time from diagnosis to treatment, MTV, and TLG were independent prognostic factors affecting OS (P < 0.05). In subgroup analyses, the high MTV or TLG groups showed poor prognosis for PFS and OS in patients with intermediate or poor risk.Metabolic tumor volume and TLG are independent prognostic factors for predicting PFS and OS in patients with metastatic RCC. Furthermore, MTV and TLG could provide additional prognostic information in patients with clinically high-risk metastatic RCC treated with anti-vascular endothelial growth factor-targeted therapies.
OP02. MOLECULAR CONVERGENCE OF CHD7 AND BMI1 IN MEDULLOBLASTOMA PATHOGENESIS
Authors: Prof Silvia Marino, Dr Adrian Dubuc, Prof Michael Taylor, Dr Xinyu Zhang
Journal: Neuro-Oncology (2017)

Medulloblastomas (MB) is the most common malignant brain tumour of childhood, and a common cause of pediatric morbidity and mortality. MB have recently been dissected into four distinct molecular subgroups (WNT, SHH, Group 3, Group 4) with divergent clinical and biological profiles. The Polycomb group protein Bmi1 is upregulated in a variety of cancers, has a positive correlation with clinical grade/stage and poor prognosis and it is a highly druggable molecule. Bmi1 is overexpressed across all MB subgroups; the growth of SHH and Group 4 MB is dependent on Bmi1 expression, as Bmi1 knockdown results in reduced tumour growth and invasion. Genome wide in vivo insertional mutagenesis (T2Onc2) driven by the Sleeping Beauty (SB11) transposase in glutamatergic progenitor cells engineered to over-express Bmi1 results in MB formation, while neither Bmi1 over-expression nor T2Onc2 transposition alone drives tumorigenesis. On the Bmi1 over-expressing background, we observe frequent T2Onc2 inactivating insertions in the chromatin remodelling factor Chd7 (Chromodomain helicase DNA binding factor 7), suggesting that Bmi1 overexpression and Chd7 loss of function cooperate to induce MB. High expression of BMI1 in combination with low expression of CHD7 is associated with a poor prognosis in human MB. Loss of function mutations of CHD7 are observed in MB, particularly in Group 4. Lentiviral mediated Chd7 knockdown (Chd7 kd) in patient-derived Group 4 MB cells led to increased proliferation and increased expression of markers of undifferentiated and highly proliferative progenitor cells both in vitro and in vivo. Importantly, we show the Bmi1-dependency of the phenotype observed upon Chd7 knockdown, as concomitant knock down of Bmi1 neutralised both increased proliferation and reversion to an undifferentiated state. We describe a novel molecular convergence between Bmi1 and Chd7 in the initiation and maintenance of MB. These finding raise the possibility that Bmi1 antagonists may be particularly indicated in a subgroup of MB with low expression level of Chd7.
A phase III trial of short-term androgen deprivation therapy in intermediate-risk prostate cancer treated with radiotherapy.
Authors: Abdenour Nabid, Nathalie Carrier, Eric Vigneault, Luis Souhami, Céline Lemaire, Marc-AndrÃƒÂ© Brassard, Boris Bahoric, Robert Archambault, François Vincent, Thu-Van Nguyen-Huynh
Journal: Journal of Clinical Oncology (2015)

5019 Background: The place of short term androgen deprivation therapy (STADT) in combination with radiotherapy (RT) for patients with intermediate risk prostate cancer (IRPC) remains controversial. The purpose of this prospective, randomized trial was to compare outcomes between patients with IRPC treated with different doses of RT with or without STADT, (PCS III trial, Clinical Trials.gov, #NCT00223145). Methods: From December 2000 to September 2010, 600 patients with IRPC were randomized to 6 months of STADT and two levels of prostate RT doses of 70 (arm 1) or 76 Gy (arm 2) versus prostate dose-escalated RT alone at 76 Gy (arm 3). STADT consisted of bicalutamide and gosereline for six months. RT (2 Gy per fraction) started four months after the beginning of STADT. Biochemical failure and disease-free survival (DFS) were primary end-points, with overall survival (OS) as secondary endpoint. DFS and OS rates were estimated with Kaplan-Meier and compared with log rank test and Cox regression. Results: Patient’s characteristics were well balanced among the 3 arms (median age 71 years, median PSA 10 ng/ml, median Gleason score 7 and clinical stage). At a median follow-up of 6.5 years, biochemical failure occurred in 96 (16%) patients (arms 1 to 3: 13.5%, 11%, 23.5%) with statistical difference between arm 1 and 3 (p = 0.01) and arm 2 and 3 (p < 0.001) but not between arm 1 and 2. A total of 130 (21.7%) patients died with only 7 deaths (1.2%) attributed to prostate cancer. The 5-/10-year DFS rates were 92.8%, 97.1% and 85.5%, and 78.4%, 78.3% and 65.9%, respectively. Significant differences in DFS between the treatment arms were observed at 5 and 10 years between arm 1 and 3 (p = 0.015, p = 0.012) and arm 2 and 3 (p < 0.001 at 5-/10-year) but not between arm 1 and 2 (p = 0.052, p = 0.385). The 5-/10-year OS rates were 90.9%, 93.6% and 90.8%, and 63.8%, 70.8% and 75%, respectively. There was no statistical difference in OS between arms at 5 and 10 years. Conclusions: In patients with IRPC, the use of STADT in association with RT, even at lower doses, leads to a superior biochemical control and DFS as compared to dose-escalated RT alone. These outcomes did not translate into an improved OS. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: #NCT00223145.
In left main CAD, CABG reduced major adverse cardiac or cerebrovascular events at 5 years compared with PCI
Authors: Eric R. Bates
Journal: Annals of Internal Medicine (2017)

Source Citation Mäkikallio T, Holm NR, Lindsay M, et al; NOBLE Study Investigators. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet. 2016;388:2743-52. 27810312