tbuckley/cabot-search huggingface dataset:
LCCC 1025: Phase II study of everolimus, trastuzumab, and vinorelbine for HER2+ breast cancer brain metastases (BCBM).
Authors: Carey K. Anders, Allison Mary Deal, Amanda Elyse Day Van Swearingen, Marni Siegel, David N. Hayes, Heejoon Jo, Paul Little, Elizabeth Claire Dees, Hyman B. Muss, Trevor Augustus Jolly, Timothy Zagar, J Keith Smith, Julie Gottlieb Fisher, Nikita C. Shah, Lisle Nabell, Rita Nanda, Patrick Michael Dillon, Shannon Puhalla, Vandana Gupta Abramson, Lisa A. Carey
Journal: Journal of Clinical Oncology (2017)

1011 Background: HER2+ BC is an aggressive subset of BC with high rates of BM and poor survival. Two-thirds of BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy (Rx). This phase II study evaluated everolimus (E), a brain permeable mTOR inhibitor, added to trastuzumab (T) and vinorelbine (V) in patients (pts) with HER2+ BCBM. Methods: Eligible pts had progressing HER2+ BCBM. Pts received E (5mg PO QD), T (2mg/kg IV weekly) and V (25mg/m 2 IV d1, 8 of 21d cycle). The primary endpoint was intracranial response rate (RR [CR+PR], modified RECIST); secondary objectives (CNS clinical benefit rate [CBR, CR+PR+SD], extracranial RR, time to progression (TTP), overall survival (OS), and correlative studies). Targeted DNA sequencing of 20 tissues from 18 pts was performed. We used a two-stage design to distinguish ORR of 5% vs 20%. Results: 32 pts were evaluable for toxicity; 26 for efficacy. Median age was 53 (28–70 yrs). 31/32 pts had prior radiation: 13 (42%) WBRT, 8 (26%) radiosurgery, 9 (29%) both. Median prior lines of metastatic Rx was 2 (0–7). 30 (94%) received anti-HER2 Rx: 91% T, 69% lapatinib, 38% pertuzumab, 25% TDM1. Intracranial RR was 4% (1 PR, 6 SD &gt; 6 mos, 10 SD &gt; 3 mos, 9 PD). CNS CBR (6 mos) was 27%; CNS CBR (3 mos) was 65%. Extracranial RR was 46%. Median TTP was 4 mos (95% CI, 2.2 –5). OS was 12.2 mos (95% CI, 0.6 – 20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). DNA sequencing showed heterogeneous HER2 copy number amplification (CN amp): only 11/20 show HER2 CN amp (median 40X v 0.7X; 5/11 BC, 4/4 BCBM, 1/2 liver mets, 1/3 LN). BCBM exhibited high-level HER2 CN amp (median 49X) vs other sites (16X). While 11/20 show both HER2 CN amp and PI3K pathway mutation, this was not associated TTP; RAD21 CN amp was associated with TTP &lt; 3 mos. Lack of HER2 CN amp plus a HER2 Tyr-kinase domain mutation was seen in a pt with nonresponse and short OS. Conclusions: While intracranial RR to ETV was low in pts with HER2+ BCBM, a substantial proportion had CNS CBR; OS was 1 year for this pt population. No new toxicity signals were observed. Further evaluation of DNA heterogeneity, including degree of HER2 CN amp in HER2+ BCBM, and association with outcome is warranted. Clinical trial information: NCT01305941.
Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma
Authors: Huynh Hung, Chow Pierce, Palanisamy Nallasivam, Salto-Tellez Manuel, Goh Cher, Lee Kuen, Somani Anaji, Lee Sung, Kalpana Ramnarayanan, Yu Kun, Tan Hoon, Wu Jeanie, Soong Richie, Lee Hui, Hor Henley, Soo Chee, Toh Chong, Tan Patrick
Journal: Clinical Cancer Research (2007)

A32  Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality, with standard chemotherapy being minimally effective in prolonging survival. VEGF regulates angiogenesis and the mTOR pathway regulates VEGF expression in HCC. Here, we investigated if combined targeting of VEGF protein and expression might affect HCC growth and tumor angiogenesis. We treated patient-derived HCC xenografts with i) bevacizumab (BEV), a VEGF monoclonal antibody; ii) rapamycin (RAPA), an inhibitor of mTOR pathway; and iii) a RAPA/BEV combination. We report that HCC growth was inhibited by the combination RAPA/BEV treatment to a significantly greater degree than RAPA or BEV monotherapy. Reductions in tumor growth by RAPA/BEV were associated with inhibition of downstream targets of the mTOR pathway, reductions in VEGF expression, and tumor microvessel density (MVD). Potentially additive effects of RAPA/BEV included reductions in VEGF expression, cyclin D1 and cyclin B1. In an intra-peritoneal model of HCC, RAPA/BEV potently inhibited both intra-liver and intra-abdominal tumor growth, reduced ascites levels, and significantly prolonged mouse survival. Our results suggest that RAPA/BEV, which are both clinically approved drugs, may represent a novel molecularly-targeted combination treatment for HCC.
Impact of breast magnetic resonance imaging (MRI) on long-term outcome after breast conservation therapy (BCT).
Authors: Carolyn J. Kushner, Neha Vapiwala, Wei-Ting Hwang, Gary M. Freedman, Lawrence J. Solin
Journal: Journal of Clinical Oncology (2016)

1053 Background: For women undergoing BCT, the role of breast MRI at the time of initial diagnosis and treatment remains controversial. This study was performed to determine the long-term outcomes after BCT for women with vs. without breast MRI. We have previously reported 8-year outcomes (J Clin Oncol 16:386, 2008), and we herein report updated results to 15 years. Methods: Between 1992 and 2001, 755 women with AJCC stage 0-II breast cancer underwent BCT with radiotherapy. All patients underwent breast-conserving surgery (with axillary lymph node staging for invasive carcinoma) followed by definitive breast radiotherapy. Evaluation at initial diagnosis included conventional mammography in all subjects and breast MRI in 215 (28%) of the study cohort. Clinical and pathologic characteristics were generally comparable for patients with vs. without breast MRI. Systemic therapy (chemotherapy and/or hormonal therapy) was given to 73% of the patients. The median follow-up is 13.8 years. Outcomes were determined using the Kaplan-Meier method, and were compared using the log-rank method. Results: There were 49 local failures (15 for women with and 34 for women without breast MRI). The 15-year rates of local failure were 8% (95% confidence interval [CI]: 4%, 13%) with an MRI and 8% (95% CI: 5%, 11%) without an MRI (P= 0.59). There were also no differences between women with vs without MRI for 15-year rates of overall survival 77% (95% CI: 70%, 82%) vs 71% (95% CI: 66%, 75%) (P= 0.24), freedom from distant metastases 83% (95% CI: 76%, 88%) vs 89% (95% CI: 85%, 91%) (P= 0.08), and contralateral breast cancer 10% (95% CI: 6%, 15%) vs 8% (95% CI: 5%, 11%) (P= 0.11). Conclusions: Breast MRI during initial evaluation for BCT had no significant impact on 15-year rates of local control and other outcomes. The routine use of breast MRI does not appear to be indicated for patients undergoing BCT.
H-Ferritin Subunit Overexpression in Erythroid Cells Reduces the Oxidative Stress Response and Induces Multidrug Resistance Properties
Authors: Silvina Epsztejn, Hava Glickstein, Virginie Picard, Itzchak N. Slotki, William Breuer, Carole Beaumont, Z. Ioav Cabantchik
Journal: Blood (1999)
Risk of arterial thromboembolism in patients with colorectal cancer.
Authors: Babak B. Navi, Anne S. Reiner, Hooman Kamel, Peter M. Okin, Costantino Iadecola, Mitchell S.V. Elkind, Katherine Panageas, Lisa Marie DeAngelis
Journal: Journal of Clinical Oncology (2016)

1572 Background: Colorectal cancer is one of the most common cancers in the world and clearly increases the risk of venous thromboembolism. However, its association with arterial thromboembolism is less certain. We aimed to determine the short-term cumulative incidence and relative hazard of arterial thromboembolism in patients with incident colorectal cancer. Methods: Using the Surveillance Epidemiology and End Results-Medicare linked database, we identified patients with a new primary diagnosis of colorectal cancer from 2002 through 2011. These patients were individually matched by age, sex, race, registry, and comorbidities to a group of Medicare enrollees without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify a primary composite outcome of arterial thromboembolism defined as any ischemic stroke or myocardial infarction. Secondary outcomes included ischemic stroke and myocardial infarction alone. Cumulative incidence rates were calculated using competing risk survival statistics. The Gray test and Cox proportional hazard analysis at discrete time points were used to compare rates between groups. Results: We identified 82,722 pairs of colorectal cancer patients and matched controls. Median age was 77 years (IQR 72-83) and 39% of cancers were stage 3 or 4 at diagnosis. The 6-month cumulative incidence of arterial thromboembolism was 7.6% (95% CI 7.4-7.8%) in cancer patients compared to 3.5% (95% CI 3.4-3.6%) in controls (HR 2.3, 95% CI 2.2-2.4, p < 0.01). The short-term risk of each secondary outcome was heightened in the cancer group, although the relative hazard for myocardial infarction was higher than for ischemic stroke. The 6-month cumulative incidence of ischemic stroke was 4.3% (95% CI 4.1-4.4%) in cancer patients compared to 2.4% (95% CI 2.3-2.5%) in controls (HR 1.8, 95% CI 1.7-1.9, p < 0.01), and the 6-month cumulative incidence of myocardial infarction was 3.8% (95% CI 3.7-4.0%) in cancer patients compared to 1.2% (1.2-1.3%) in controls (HR 3.1, 95% CI 2.9-3.4, p < 0.01). Excess risks attenuated over time but were still present at 2 years. Conclusions: Patients with incident colorectal cancer face an increased short-term risk of ischemic stroke and myocardial infarction.
Huge heterogeneity of patient characteristics, treatment patterns, hospital costs exists in non-small cell lung cancer surgeries among different centers of China: A study of 5060 patients based on the Chinese national NSCLC outcome registry.
Authors: Jian Zhou, Fan Yang, Yanguo Liu, Yin Li, Lin Xu, Lingbin Du, Xianzhen Liao, Xiaotao Zhang, Aishan Jin, Chenlong Xu, Junfeng Liu, Hui Qiu, Lin Zhu, Yongzhen Zhang, Naiquan MAO, Changjun He, Yunchao Huang, Hao Li, Xun Wang, Jun Wang
Journal: Journal of Clinical Oncology (2016)

e13074 Background: Lung cancer is the leading cause of death of all tumors in China. Due to imbalanced development of different provinces, the surgical treatments of NSCLC in different areas of China diverse. The Chinese National NSCLC outcome registry was founded in 2013, which covers 17 provinces across China. We analyze the data of 5060 NSCLC patients retrieved from this registry to reveal the imbalanced circumstances. Methods: Data of 5060 stage I-III patients during 2013-2014 were obtained from the registry . Baseline data, surgical treatment pattern parameters, pathology, number of lymph nodes dissected, and total hospital costs were analyzed. Results: Among the patients, the mean age was 59.7 , while 3204 were male. Mean pre-op forced expiratory volume in 1 second (FEV1) was 2.23L, FEV1/FVC was 81.8%. 64.6% patients combined with at least one comorbidity. The average diameter of the tumor was 3.28cm. Mean operation time was 181.2 minutes. The post-operative pathology confirmed 59.8% as adenocarcinoma while 30.2% as squamous carcinoma. 88.5%(mean,50% to 100%) patients who were pathologically confirmed as stage III received neo-adjuvant therapy before surgery. The rate of minimally invasive lobectomy surgery was 49.9(mean, 2.31 to 90.2)% in different regions. The number of lymph nodes stations harvested in lobectomy was 5.9(mean, 3.0 to 7.4). Mean hospital cost was 57757 (mean, 42205 to 100113 ) RMB. Conclusions: The heterogeneity of surgical treatment is quite huge in different centers of China. The baseline status before surgery，pre-operative therapy strategy, surgical technique, and health economic data submitted to the registry showed imbalanced development of NSCLC surgical treatment in different regions of China. Results of center 1-8. Center No. of lymph nodes in lobectomy Cost (RMB) VATS % Neo-ajuvant of Stage III% No. of patients submitted 1 6.3 46861 90.2 99.3% 838 2 6.4 52891 27.5 98.8 788 3 4.5 47516 59.0 84.8 729 4 5.6 70875 60.3 50.3 676 5 5.3 51742 78.9 98.6 392 6 7.4 65409 26.1 100.0 387 7 6.8 50696 8.5 100.0 293 8 4.8 42206 8.3 98.6 265 Total 5.9 57757 50.07 88.45 5060
The role of post-mastectomy radiotherapy among 3,437 women with pathologic T3N0M0 breast cancer in the national cancer data base.
Authors: Richard John Cassidy, Shannon Kahn, Xi Liu, Theresa Wicklin Gillespie, Yuan Liu, Mylin Ann Torres
Journal: Journal of Clinical Oncology (2016)

1018 Background: The role of postmastectomy radiotherapy (PMRT) in breast cancer patients with pathologic T3N0M0 disease remains controversial. The purpose of this study was to determine the impact of PMRT on overall survival among pT3N0M0 breast cancer patients in the National Cancer Data Base (NCDB). Methods: Using the NCDB, 3,437 women diagnosed with pT3N0M0 breast cancer between 2003 and 2011 were identified. All received initial treatment with mastectomy. 1,644 (47.8%) received PMRT. Univariable and multivariable analyses (MVA) were performed to identify patient, tumor, and treatment characteristics associated with PMRT and factors predictive of overall survival (OS). Tests of interaction between PMRT and relevant variables were performed. Additionally, propensity score matching (PSM) was employed to reduce treatment selection bias. Results: On MVA, treatment with PMRT was associated with age < 40 (p = 0.02), private insurance coverage (p < 0.01), increasing tumor size (p = 0.04), use of chemotherapy (p < 0.01) and/or endocrine therapy (p < 0.01). In our cohort, PMRT was associated with significantly higher 5 year overall survival rates (86.3% PMRT vs. 66.4% non-PMRT patients; p < 0.01). In addition to PMRT [HR = 0.73 (.60-.89), p < 0.01], age ≤ 50, chemotherapy, and endocrine therapy were all independently predictive of better OS on MVA (all p < 0.01). In the same model, Charlson Comorbidity Score of ≥ 1, poorly differentiated tumors and/or tumor size ≥ 7.0cm were associated with worse OS (all p < 0.01). Interaction tests revealed that the influence of PMRT on OS did not differ among levels of factors associated with PMRT with the exception of insurance status (p < 0.03). There was no significant interaction between PMRT and Charlson Comorbidity Score, margin status, tumor size, and treatment with chemotherapy or endocrine therapy (all p > 0.20). Finally, PSM analysis confirmed that PMRT is associated with improved OS (p = 0.01). Conclusions: In this large study of NCDB breast cancer patients with pT3N0M0 disease treated with initial mastectomy, PMRT is independently associated with improved overall survival regardless of margin status, tumor size, and systemic therapy treatment.
Abstract 16362: Early Cardiology Assessment and Intervention Reduces Mortality Following Myocardial Injury After Non-Cardiac Surgery (MINS)
Authors: Alina X Hua, Holly Pattenden, Maria Leung, Simon Davies, David A George, Hilgart Raubenheimer, Zakiyah Niwaz, Eric Lim
Journal: Circulation (2014)

Myocardial injury after non-cardiac surgery (MINS) has been recently defined as troponin elevation ≥0.03ng/ml, associated with 3.87 fold increase in early mortality (1). We sought to determine the impact of early cardiology intervention on 30-day mortality in patients who underwent general thoracic surgery and developed MINS. Methods: A retrospective review of patients who underwent thoracic surgery over a 5-year period where troponin levels were routinely measured on the first post-operative day was performed. Data acquisition and mortality status was obtained via medical records and NHS tracing systems. Thirty-day mortality was compared on the MINS cohort using Fisher’s exact square testing and logistic regression analysis. Actuarial survival was calculated using Kaplan Meier method and Cox proportional hazards regression was utilized to determine risk adjusted impact of MINS on post-operative survival. Results: Troponin levels were measured in 492 (96%) of 511 patients and 80 (16%) had troponin elevation fulfilling MINS criteria. Of the MINS positive patients, 61 (76%) received early cardiology consult and a formal diagnosis of “myocardial infarction” stated in 4 (5%). Risk assessment for Acute Myocardial Infarction was performed in all patients and 20 (25%) commenced on anti-platelet agents, 4 (5%) on β-blockers and 1 (1%) underwent primary coronary intervention. In total, 49 (61%) received primary risk factor modification and 26 (33%) had further cardiology outpatient follow-up. There were no significant differences in the proportion who died within the first 30 days in the MINS group (2.6%) compared to the non-MINS group (1.6%; P=0.625). The odds ratio for 30-day mortality in the MINS group was 1.69 (95% CI 0.34 to 8.57, P=0.522). On follow up there were no significant difference on the impact of MINS on survival between the two groups (HR 1.06 95% CI 0.67 to 1.68; P=0.799). Conclusion: Our results confirm MINS is common after general thoracic surgery. We observed that early cardiology intervention reduced the expected hazard ratio of early death from 3.87 to an odds ratio of 1.69 with no significant difference in either early or longer term mortality for patients who developed MINS.
Abstract 268: Epigenetic Regulation Of Canonical Tnfa Pathway By Hdac1 Determines Survival Of Cardiac Myocytes
Authors: Agnieszka Biala, Lorrie A Kirshenbaum, Hongying Gang, Rimpy Dhingra
Journal: Circulation Research (2013)

Gene transcription is regulated by post-translation modifications. Histone deacetylases (HDACs) remove acetyl-groups from histone and non-histone factors inhibiting transcription. Pro-inflammatory cytokines such as TNFα activate the canonical Nuclear Factor -κB (NF-κB) pathway. Earlier we established a cytoprotective role for NF-κB in the heart. Though a causal relationship for HDAC1 and NF-κB has been established, the impact of HDAC1 on TNFα signaling is unknown. Herein, we demonstrate HDAC1 provides a molecular switch for determining cell survival in the TNFα pathway. In contrast to vehicle treated control cells, TNFα treated cells displayed a marked increase in NF-κB gene transcription. Notably, cells treated with TNFα were indistinguishable from vehicle controls cells with respect to viability. Interestingly, HDAC activity was reduced in cells treated with TNFα. Conversely, in the presence of HDAC1, NF-κB gene transcription by TNFα was repressed, resulting in mitochondrial perturbations and widespread cell death. Heterologous fusion proteins comprised of yeast Gal4 DNA binding domain fused in frame to the NF-κB p65 transactivation domain were preferentially repressed by HDAC1. Moreover, transcription mediated by Gal4VP16 protein from herpes virus was unaffected by HDAC1 in cardiac myocytes. Mutations that abrogate known catalytic activities of HDAC1, small interference RNA or pharmacological inhibition of HDAC1, restored NF-κB signaling and suppressed cell death induced by TNFα. These data provide the first evidence for an obligate link between HDAC1 and canonical TNFα pathway for cell survival of cardiac myocytes.
Extrahepatic cancer risk among patients with liver cirrhosis in Taiwan: A nationwide population-based study.
Authors: Chia-Jen Liu, San-Chi Chen, Chueh-Chuan Yen, Ming-Huang Chen, Chun-Yu Liu, Ta-Chung Chao, Po-Min Chen, Tzeon-Jye Chiou, Jin-Hwang Liu
Journal: Journal of Clinical Oncology (2016)

1564 Background: Cirrhosis is a well-known risk factor of hepatocellular carcinoma. However, the risk of extra-hepatic cancers (EHCs) is not clear in cirrhotic patients. This study is aimed to identify the risk and sites of EHCs among cirrhotic patients. Methods: Newly diagnosed cirrhotic patients between 2000 and 2011 were recruited from Taiwan's nationwide health insurance database. Patients aged < 20 years and those with antecedent malignancies were excluded. To avoid surveillance bias, EHCs that developed within one year were also excluded in further analysis. Standardized incidence ratios (SIRs) of EHCs in these patients were calculated by comparing to the EHC incidence in the general population. Univariate and multivariate Cox proportional hazards models were applied to find the predictors of EHCs development among patients with cirrhosis. Results: During the 12-year study period, 859 EHCs developed among 13,729 cirrhotic patients, with a median follow-up period of 4.44 years. The SIR for all patients was 2.17 (95% confidence interval [CI] 2.03-2.32), for cirrhosis due to alcohol 3.43 (95% CI 3.02-3.89), for hepatitis B 1.81 (95% CI 1.51-2.15) and for hepatitis C 1.83 (95% CI 1.52-2.19). The SIRs for cancers of esophagus (4.60), head and neck (2.43), skin (1.99), stomach (1.95), bladder (1.66), breasts (1.46), and lung and mediastinum (1.42) were significantly increased. Multivariate analysis showed that age ≥ 50 years (adjusted hazard ratio [HR] 2.26, 95% CI 1.85-2.75), being male (HR 1.57, 95% CI 1.29-1.90), and chronic obstructive pulmonary disease (HR 1.29, 95% CI 1.06-1.56) were independent factors. Conclusions: This largest cohort study demonstrated an increasing risk of EHCs among cirrhotic patients, especially cirrhosis due to alcohol. Risk factors for cancer development in patients with cirrhosis. Variables Multivariate analysis HR (95% CI) P Value Age ≥ 50 2.26 (1.85-2.75) < 0.001 Sex (male) 1.57 (1.29-1.90) < 0.001 Comorbidities Diabetes mellitus 1.15 (0.94-1.40) 0.165 COPD 1.29 (1.06-1.56) 0.011 Autoimmune diseases 0.86 (0.61-1.21) 0.382 Dyslipidemia 1.00 (0.82-1.22) 0.998 Chronic kidney disease 0.95 (0.74-1.21) 0.658 COPD: chronic obstructive pulmonary disease
Metformin for the treatment of endometrial hyperplasia.
Authors: Emily Meichun Ko, Stephanie Sullivan, Brooke Rambally, Siobhan O'Connor, Ruth Everett, Dhiren Thakker, Dominic T. Moore, John Byron, Victoria Lin Bae-Jump
Journal: Journal of Clinical Oncology (2016)

5592 Background: We sought to evaluate the short-term response rate, toxicity and potential molecular changes following treatment with metformin for simple (SEH) and complex endometrial hyperplasia without atypia (CEH). Methods: Women with newly diagnosedsimple or complex endometrial hyperplasia without atypia by endometrial biopsy or dilation & curettage were enrolled onto a prospective multi-institutional single arm clinical trial, and treated with metformin for 3 months (850 mg daily x 4 weeks, then twice daily for 8 weeks), followed by repeat biopsy. Pathologic response and toxicity (CTCAE 4.1) were assessed. Expression of the estrogen (ER) and progesterone (PR) receptor and the metformin transporters (OCT1, OCT3, PMAT, MATE1, MATE2) were evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded endometrial specimens pre- and post-treatment. Slides were scanned using the Aperio ScanScope, and digital images were analyzed using Aperio ImageScope software. We report proportions as %, along with their exact 95% confidence intervals. Pre- and post- comparisons were done using the Wilcoxon signed-rank test. Reported p-values were nominal, or unadjusted for multiple testing. Results: 18 patients enrolled, with 16 evaluable, of whom all completed treatment. 56% (9/16, 95% CI 30%, 80%) showed pathologic response (6/9 SEH, 2/5 CEH, 1/2 SEH/CEH). Common toxicities included diarrhea (67%), nausea (39%), flatulence (28%); all were grade 1 except for grade 2 diarrhea (n = 2), GERD (n = 1), and nausea (n = 1). Before metformin, the median % positive staining cells was 98.9% for ER, 89.9% for PR, 50.8% for MATE2, 98.4% for MATE1, 26.5% for PMAT, 87.5% for OCT1 and 68.6% for OCT3. Expression of MATE2 (50.8 to 60.4% positive cells; 86.1 to 120.6 H-score, p = 0.048) and OCT3 (68.6 to 91.7% positive cells; 116.8 to 136.5 H-score, p = 0.017, 0.057 respectively) increased after metformin treatment, whereas expression of MATE1, PMAT, OCT1, ER, PR did not change. Conclusions: Approximately half of the patients with endometrial hyperplasia without atypia responded to short-term metformin treatment. Preliminary exploratory comparisons seem to indicate that MATE2 and OCT3 expression (by % positive cells and H-score) increases with metformin treatment. Clinical trial information: NCT01685762.