Refine
Year of publication
Document Type
- Article (78)
- Preprint (3)
- Doctoral Thesis (1)
Has Fulltext
- yes (82)
Is part of the Bibliography
- no (82)
Keywords
- breast cancer (13)
- Mammakarzinom (12)
- Behandlung (8)
- Metastasen (8)
- CDK4/6 (6)
- PD1/PDL1 (6)
- Prävention (6)
- Studien (6)
- prevention (6)
- treatment (6)
- metastases (5)
- Breast cancer (4)
- Risiko (4)
- risk (4)
- trials (4)
- metastatic (3)
- neoadjuvant therapy (3)
- Alpelisib (2)
- Atezolizumab (2)
- Diagnostik (2)
- Früherkennung (2)
- Galaktografie (2)
- Galaktomosynthese (2)
- HNSCC (2)
- Head and neck cancer (2)
- Katherine (2)
- Lokalrezidiv (2)
- MRI (2)
- MRT (2)
- Machine learning (2)
- Mamma (2)
- Nachsorge (2)
- PARP (2)
- PD1/ PDL1 (2)
- PD‑L1 (2)
- PI3K (2)
- Prognosefaktoren (2)
- Prädiktivfaktoren (2)
- Richtlinie (2)
- Supportivtherapie (2)
- Surgery (2)
- Tomosynthese (2)
- T‑DM1 (2)
- Ultraschall (2)
- adjuvant therapy (2)
- adjuvante Therapie (2)
- advanced (2)
- alpelisib (2)
- atezolizumab (2)
- breast (2)
- diagnosis (2)
- early breast cancer (2)
- follow‑up (2)
- fortgeschritten (2)
- frühes Mammakarzinom (2)
- galactography (2)
- galactomosynthesis (2)
- guideline (2)
- lapatinib (2)
- local recurrence (2)
- neoadjuvante Therapie (2)
- predictive factors (2)
- prognostic factors (2)
- screening (2)
- studies (2)
- supportive therapy (2)
- tomosynthesis (2)
- trastuzumab (2)
- treatment/therapy (2)
- ultrasound (2)
- ATXN2 (1)
- Active middle ear implants (1)
- Advanced breast cancer (1)
- Amyotrophic lateral sclerosis (1)
- Antihormone therapy (1)
- Arteria ophthalmica (1)
- Auditory system (1)
- B cell malignancies (1)
- BCOR (1)
- BCORL1 (1)
- Bibliometrics (1)
- Biomarker (1)
- Bipolar disorder (1)
- Blindness (1)
- Bone conduction devices (1)
- Bone metastases (1)
- Brain metastasis (1)
- C3M (1)
- C4M (1)
- CD74 (1)
- COVID-19 (1)
- CUP (1)
- CVID (1)
- Cancer of unknown primary (1)
- Capecitabine (1)
- Cellular stress (1)
- Central nervous system metastases (1)
- Cervical (1)
- Chemical biology (1)
- Chemical ecology (1)
- Citation analysis (1)
- Clinical Trials and Observations (1)
- Completed suicide (1)
- Consensus statement (1)
- Diagnostic markers (1)
- Digital breast tomosynthesis (DBT) (1)
- Digital mammography (1)
- Endocrinology (1)
- Environmental chemistry (1)
- Epilepsy (1)
- European Society for Immunodeficiencies (ESID) (1)
- Exosomes (1)
- Extended donor criteria (1)
- FDG-PET/CT (1)
- Filler (1)
- First site of metastatic disease (1)
- Gene regulation (1)
- German PID-NET registry (1)
- Glabella (1)
- Global protein synthesis rates (1)
- HER2 c-erbB2 (1)
- HER2-positive (1)
- HER2/neu (1)
- HLA class II (1)
- HLA peptidome (1)
- Head neck cancer (1)
- Health policy (1)
- Heregulin (1)
- Iceland (1)
- IgG substitution therapy (1)
- Immunophenotyping (1)
- Immunotherapy (1)
- Induction therapy (1)
- Isoflurane (1)
- KCGS (1)
- Kidney diseases (1)
- Loco-regional control (1)
- Lymph node (1)
- Lymphocyte subpopulations (1)
- MM-121 (1)
- Metastatic (1)
- Metastatic breast cancer (1)
- MicroRNAs (1)
- Mixed hearing loss (1)
- Molecular subtypes (1)
- Multi-stakeholder approach (1)
- Myeloid Neoplasia (1)
- NK cell subsets (1)
- NPH insulin (1)
- Neoadjuvant therapy (1)
- Occlusion (1)
- Ophthalmoplegia (1)
- Organ allocation (1)
- PELICAN (1)
- PID prevalence (1)
- Paediatrics (1)
- Pancreas transplantation (1)
- Pandemic (1)
- Pathological complete response (1)
- Patterns of care (1)
- Pegylated liposomal doxorubicin (1)
- Population-based screening (1)
- Prediction of locoregional recurrence (1)
- RNA processing (1)
- Radiochemotherapy (1)
- Radiomics (1)
- Radiotherapy (1)
- Recall rate (1)
- Red blood cell transfusion (1)
- Rehabilitation (1)
- Rejection (1)
- Retinal diseases (1)
- Ribosomal S6 phosphorylation (1)
- Ribosomal translation (1)
- SARS-CoV2 (1)
- SCCHN (1)
- Salivary gland carcinoma (1)
- Scientific publishing (1)
- Scientists (1)
- Seribantumab (1)
- Spinocerebellar ataxia (1)
- Status epilepticus (1)
- Stem-cell therapies (1)
- Suicide attempt (1)
- T-DM1 (1)
- TGFB-induced factor homeobox 1 (1)
- TGIF (1)
- Technical data (1)
- Triple negative (1)
- Tumor heterogeneity (1)
- Tumor infiltrating lymphocytes (1)
- Type 2 diabetes (1)
- Validation (1)
- acute myeloid leukemia (1)
- advanced breast cancer (1)
- amblyopia (1)
- anaemia (1)
- anterior chamber depth changes (1)
- antibiotic therapy (1)
- antihormone therapy (1)
- ascites (1)
- basal insulin (1)
- biomarker (1)
- cataract surgery (1)
- chemogenomic set (1)
- chemotherapy (1)
- circadian variation (1)
- collagen degradation marker (1)
- continuous glucose monitoring (1)
- diabetes (1)
- diabetic macular edema (1)
- diclofenac (1)
- diffusion-weighted magnetic resonance imaging (1)
- drug discovery (1)
- druggable genome (1)
- effective lens position (1)
- elderly patients (1)
- everolimus (1)
- fluocinolone acetonide (1)
- gene signature (1)
- head and neck squamous cell carcinoma (1)
- hypoglycaemia (1)
- image-based risk modelling (1)
- iron deficiency (1)
- kinase inhibitor (1)
- liver cirrhosis (1)
- loss-of-function (1)
- machine learning (1)
- meta-analysis (1)
- metastasis (1)
- metastatic renal cell carcinoma (1)
- metformin (1)
- microdosing (1)
- multidrug resistance (1)
- multiplexed immunofluorescence (1)
- neoadjuvant chemoradiotherapy (1)
- oral cavity cancer (1)
- oral enzyme combination (1)
- osteoarthritis (1)
- patient blood management (1)
- pediatric eye screening (1)
- personalised therapy (1)
- pertuzumab (1)
- phase IV (1)
- phenotypic screening (1)
- postoperative radiochemotherapy (1)
- postoperative radiotherapy (1)
- predictive biomarker (1)
- pregnancy (1)
- preoperative anaemia management (1)
- preschool health examination (1)
- primary immunodeficiency (PID) (1)
- propensity score matching (1)
- protein kinase (1)
- pseudoexfoliative syndrome (1)
- radiation oncology (1)
- radiomic (1)
- randomized controlled trial (1)
- rat (1)
- registry for primary immunodeficiency (1)
- risk stratification (1)
- screening routine (1)
- second-line (1)
- small molecules (1)
- surgery (1)
- survival (1)
- understudied kinase (1)
Institute
- Medizin (82) (remove)
Background: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma.
Methods: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics.
Results: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on "double-hit" MYC and BCL2 transformed lymphomas.
Conclusions: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.
Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).
Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).
Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).
Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.
Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.
We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.
We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.
In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March–December 2019 and March–December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.
Background: With the aging population and a rising incidence of squamous cell carcinoma of the head and neck (SCCHN), there is an emerging need for developing strategies to treat elderly patients.
Patients and Methods: We retrospectively analyzed 158 patients treated with definitive, concurrent chemoradiotherapy (CRT) for SCCHN. Clinicopathological characteristics, acute toxicities, and oncological outcomes were compared between patients younger and older than (or of age equal to) 65, 70, and 75 years.
Results: RT dose, chemotherapy regimen, and total chemotherapy dose were balanced between the groups. After a median follow-up of 29 months, overall survival (OS), progression-free survival (PFS), local control rate, and distant metastasis-free survival stratified by age of ≥65, ≥70, or ≥75 years revealed no differences. The rate of acute toxicities was also not higher for older patients. Worse ECOG performance score (ECOG 2-3) was associated with impaired OS () and PFS ().
Conclusion: Definitive treatment with CRT for SCCHN is feasible and effective; even in advanced age treatment decisions should be made according to general condition and comorbidity, rather than calendar age alone.
Purpose: To evaluate the efficacy of the virtual reality training simulator Eyesi to prepare surgeons for performing pars plana vitrectomies and its potential to predict the surgeons’ performance.
Methods: In a preparation phase, four participating vitreoretinal surgeons performed repeated simulator training with predefined tasks. If a surgeon was assigned to perform a vitrectomy for the management of complex retinal detachment after a surgical break of at least 60 hours it was randomly decided whether a warmup training on the simulator was required (n = 9) or not (n = 12). Performance at the simulator was measured using the built-in scoring metrics. The surgical performance was determined by two blinded observers who analyzed the video-recorded interventions. One of them repeated the analysis to check for intra-observer consistency. The surgical performance of the interventions with and without simulator training was compared. In addition, for the surgeries with simulator training, the simulator performance was compared to the performance in the operating room.
Results: Comparing each surgeon’s performance with and without warmup trainingshowed a significant effect of warmup training onto the final outcome in the operating room. For the surgeries that were preceeded by the warmup procedure, the performance at the simulator was compared with the operating room performance. We found that there is a significant relation. The governing factor of low scores in the simulator were iatrogenic retinal holes, bleedings and lens damage. Surgeons who caused minor damage in the simulation also performed well in the operating room.
Conclusions: Despite the large variation of conditions, the effect of a warmup training as well as a relation between the performance at the simulator and in the operating room was found with statistical significance. Simulator training is able to serve as a warmup to increase the average performance.
Background: Remodeling of extracellular matrix through collagen degradation is a crucial step in the metastatic cascade. The aim of this study was to evaluate the potential clinical relevance of the serum collagen degradation markers (CDM) C3M and C4M during neoadjuvant chemotherapy for breast cancer.
Methods: Patients from the GeparQuinto phase 3 trial with untreated HER2-positive operable or locally advanced breast cancer were enrolled between 7 November 2007, and 9 July 2010, and randomly assigned to receive neoadjuvant treatment with EC/docetaxel with either trastuzumab or lapatinib. Blood samples were collected at baseline, after four cycles of chemotherapy and at surgery. Cutoff values were determined using validated cutoff finder software (C3M: Low ≤9.00 ng/mL, high >9.00 ng/mL, C4M: Low ≤40.91 ng/mL, high >40.91 ng/mL).
Results: 157 patients were included in this analysis. At baseline, 11.7% and 14.8% of patients had high C3M and C4M serum levels, respectively. No correlation was observed between CDM and classical clinical-pathological factors. Patients with high levels of CDM were significantly more likely to achieve a pathological complete response (pCR, defined as ypT0 ypN0) than patients with low levels (C3M: 66.7% vs. 25.7%, p = 0.002; C4M: 52.7% vs. 26.6%, p = 0.031). Median levels of both markers were lower at the time of surgery than at baseline. In the multivariate analysis including clinical-pathological factors and C3M levels at baseline and changes in C3M levels between baseline and after four cycles of therapy, only C3M levels at baseline (p = 0.035, OR 4.469, 95%-CI 1.115–17.919) independently predicted pCR. In a similar model including clinical-pathological factors and C4M, only C4M levels at baseline (p = 0.028, OR 6.203, 95%-CI 1.220–31.546) and tumor size (p = 0.035, OR 4.900, 95%-CI 1.122–21.393) were independent predictors of pCR. High C3M levels at baseline did not correlate with survival in the entire cohort but were associated with worse disease-free survival (DFS; p = 0.029, 5-year DFS 40.0% vs. 74.9%) and overall survival (OS; p = 0.020, 5-year OS 60.0% vs. 88.3%) in the subgroup of patients randomized to lapatinib. In the trastuzumab arm, C3M did not correlate with survival. In the entire patient cohort, high levels of C4M at baseline were significantly associated with shorter DFS (p = 0.001, 5-year DFS 53.1% vs. 81.6%) but not with OS. When treatment arms were considered separately, the association with DFS was still significant (p = 0.014, 5-year DFS 44.4% vs. 77.0% in the lapatinib arm; p = 0.023, 5-year DFS 62.5% vs. 86.2% in the trastuzumab arm).
Conclusions: Collagen degradation markers are associated with response to neoadjuvant therapy and seem to play a role in breast cancer.
Background: It has been demonstrated that cognitive behavioural therapy (CBT) has a moderate effect on symptom reduction and on general well being of patients suffering from psychosis. However, questions regarding the specific efficacy of CBT, the treatment safety, the cost-effectiveness, and the moderators and mediators of treatment effects are still a major issue. The major objective of this trial is to investigate whether CBT is specifically efficacious in reducing positive symptoms when compared with non-specific supportive therapy (ST) which does not implement CBT-techniques but provides comparable therapeutic attention. Methods: The POSITIVE study is a multicenter, prospective, single-blind, parallel group, randomised clinical trial, comparing CBT and ST with respect to the efficacy in reducing positive symptoms in psychotic disorders. CBT as well as ST consist of 20 sessions altogether, 165 participants receiving CBT and 165 participants receiving ST. Major methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, analysis by intention to treat, data management using remote data entry, measures of quality assurance (e.g. on-site monitoring with source data verification, regular query process), advanced statistical analysis, manualized treatment, checks of adherence and competence of therapists. Research relating the psychotherapy process with outcome, neurobiological research addressing basic questions of delusion formation using fMRI and neuropsychological assessment and treatment research investigating adaptations of CBT for adolescents is combined in this network. Problems of transfer into routine clinical care will be identified and addressed by a project focusing on cost efficiency. Discussion: This clinical trial is part of efforts to intensify psychotherapy research in the field of psychosis in Germany, to contribute to the international discussion on psychotherapy in psychotic disorders, and to help implement psychotherapy in routine care. Furthermore, the study will allow drawing conclusions about the mediators of treatment effects of CBT of psychotic disorders. Trial Registration Current Controlled Trials ISRCTN29242879
Background: Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT. Methods: EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20–30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry. Results: Patients with non-recurrent SCCHN had significantly lower proportions of CD19+ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3+ T and CD3+/CD4+ T helper cells continuously decreased between t0 and t3, whereas that of CD8+ cytotoxic T cells and CD3+/CD56+ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4+/CD25+/FoxP3+ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4+ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56+/CD69+, CD3−/CD56+, CD3−/CD94+, CD3−/NKG2D+, CD3−/NKp30+, CD3−/NKp46+) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5). Conclusion: Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed. Trial registration: Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668.