tbuckley/cabot-search huggingface dataset:
Long-term Benefits of Intensive Glucose Control for Preventing End-Stage Kidney Disease: ADVANCE-ON
Authors: Muh Geot Wong, Vlado Perkovic, John Chalmers, Mark Woodward, Qiang Li, Mark E. Cooper, Pavel Hamet, Stephen Harrap, Simon Heller, Stephen MacMahon, Giuseppe Mancia, Michel Marre, David Matthews, Bruce Neal, Neil Poulter, Anthony Rodgers, Bryan Williams, Sophia Zoungas
Journal: Diabetes Care (2016)

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that intensive glucose control prevents end-stage kidney disease (ESKD) in patients with type 2 diabetes, but uncertainty about the balance between risks and benefits exists. Here, we examine the long-term effects of intensive glucose control on risk of ESKD and other outcomes.Survivors, previously randomized to intensive or standard glucose control, were invited to participate in post-trial follow-up. ESKD, defined as the need for dialysis or kidney transplantation, or death due to kidney disease, was documented overall and by baseline CKD stage, along with hypoglycemic episodes, major cardiovascular events, and death from other causes.A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years. In-trial HbA1c differences disappeared by the first post-trial visit. The in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering on the risks of death, cardiovascular death, or major cardiovascular events did not differ by levels of kidney function (P > 0.26).Intensive glucose control was associated with a long-term reduction in ESKD, without evidence of any increased risk of cardiovascular events or death. These benefits were greater with preserved kidney function and with well-controlled blood pressure.
Inhibition of Protease–Epithelial Sodium Channel Signaling Improves Mucociliary Function in Cystic Fibrosis Airways
Authors: James A. Reihill, Brian Walker, Robert A. Hamilton, Timothy E. G. Ferguson, J. Stuart Elborn, M. Jackson Stutts, Brian J. Harvey, Vinciane Saint-Criq, Siobhan M. Hendrick, S. Lorraine Martin
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

In cystic fibrosis (CF) a reduction in airway surface liquid (ASL) height compromises mucociliary clearance, favoring mucus plugging and chronic bacterial infection. Inhibitors of the epithelial sodium channel (ENaC) have therapeutic potential in CF airways to reduce hyperstimulated sodium and fluid absorption to levels that can restore airway hydration.To determine whether a novel compound (QUB-TL1) designed to inhibit protease/ENaC signaling in CF airways restores ASL volume and mucociliary function.Protease activity was measured using fluorogenic activity assays. Differentiated primary airway epithelial cell cultures (F508del homozygotes) were used to determined ENaC activity (Ussing chamber recordings), ASL height (confocal microscopy), and mucociliary function (by tracking the surface flow of apically applied microbeads). Cell toxicity was measured using a lactate dehydrogenase assay.QUB-TL1 inhibits extracellularly located channel activating proteases (CAPs), including prostasin, matriptase, and furin, the activities of which are observed at excessive levels at the apical surface of CF airway epithelial cells. QUB-TL1-mediated CAP inhibition results in diminished ENaC-mediated Na(+) absorption in CF airway epithelial cells caused by internalization of a prominent pool of cleaved (active) ENaCγ from the cell surface. Importantly, diminished ENaC activity correlates with improved airway hydration status and mucociliary clearance. We further demonstrate QUB-TL1-mediated furin inhibition, which is in contrast to other serine protease inhibitors (camostat mesylate and aprotinin), affords protection against neutrophil elastase-mediated ENaC activation and Pseudomonas aeruginosa exotoxin A-induced cell death.QUB-TL1 corrects aberrant CAP activities, providing a mechanism to delay or prevent the development of CF lung disease in a manner independent of CF transmembrane conductance regulator mutation.
Brief Report: Secukinumab Provides Significant and Sustained Inhibition of Joint Structural Damage in a Phase III Study of Active Psoriatic Arthritis
Authors: Désirée van der Heijde, Robert B. Landewé, Philip J. Mease, Iain B. McInnes, Philip G. Conaghan, Luminita Pricop, Greg Ligozio, Hanno B. Richards, Shephard Mpofu
Journal: Arthritis & Rheumatology (2016)

Objective To assess whether secukinumab treatment in patients with active psoriatic arthritis (PsA) is associated with sustained inhibition of radiographic progression. Methods In this phase III, double‐blind, placebo‐controlled study, 606 patients with PsA were randomized to receive intravenous (IV) secukinumab at a dose of 10 mg/kg (weeks 0, 2, 4) followed by subcutaneous secukinumab at a dose of 150 mg or 75 mg (the IV→150 mg and IV→75 mg groups, respectively) or placebo. Patients were stratified according to prior anti–tumor necrosis factor (anti‐TNF) exposure (71% were anti‐TNF naive). At week 16, placebo‐treated patients who had at least a 20% reduction in the tender and swollen joint counts (responders) continued to receive placebo until week 24; nonresponders were re‐randomized to receive secukinumab at a dose of 150 mg or 75 mg. The modified total Sharp/van der Heijde score (SHS) was determined at baseline, week 16 or 24, and week 52. Results In the overall population, radiographic progression was inhibited through 52 weeks; efficacy was demonstrated for both erosion and joint space narrowing scores and in patients who switched from placebo to secukinumab at week 24. Subgroup analyses showed that secukinumab reduced radiographic progression at week 24, regardless of previous anti‐TNF treatment. Among anti‐TNF–naive patients, the mean changes from baseline to week 24 in the modified total SHS were 0.05 in the pooled secukinumab group and 0.57 in the placebo group; among patients with an inadequate response or intolerance to anti‐TNF treatment, the mean changes were 0.16 and 0.58, respectively. Anti‐TNF–naive patients showed negligible progression through week 52. Inhibition of structural damage was observed through week 52 irrespective of concomitant methotrexate use. A high proportion of patients receiving secukinumab showed no progression (change in SHS of ≤ 0.5) from baseline to week 24 (82.3% of the IV→150 mg group and 92.3% of the IV→75 mg group) and from week 24 to week 52 (85.7% of the IV→150 mg group and 85.8% of the IV→75 mg group). Conclusion Secukinumab inhibited radiographic progression over 52 weeks of treatment in patients with active PsA.
Bone Complications in Patients With Cancer
Authors: Vivek Subbiah, Howard L. West
Journal: JAMA Oncology (2016)

Bone Complications in Patients With CancerWhen cancer spreads to bones, it can make them weak and fragile.What Bone Complications Can Be Caused by Cancer?How do medications used to treat bone-related cancer complications work?Denosumab decreases osteoclast maturation.Bisphosphonates decrease osteoclast activity.
A pilot study utilizing molecular profiling to find potential targets and select individualized treatments for patients with metastatic breast cancer.
Authors: Gayle S. Jameson, Emanuel Petricoin, Jasgit C. Sachdev, Lance A. Liotta, David Loesch, Stephen Patrick Anthony, Manpreet Chadha, Mariaelena Pierobon, Alex Reeder, Monica Fulk, Linda Vocila, Nina Cantafio, Bryant Dunetz, Nicholas J. Robert
Journal: Journal of Clinical Oncology (2013)

TPS11123 Background: The objective of this prospective pilot study was to determine if treatment selected by molecular profiling (MP) of metastatic breast cancer (MBC) tumors at time of disease progression provides greater clinical benefit than empiric treatment selection. Methods: Eligible pts had MBC, ≥ 3 prior lines of therapy, and &gt; 6 wks - &lt; 6 months time to progression on last treatment prior to study entry. Fresh core biopsy samples were taken from the metastatic site for MP. Analysis by IHC, FISH, DNA microarray and reverse phase protein microarray (RPMA) a quantitative protein pathway activation mapping technique using laser capture micro dissected tumor cells was done, with results in ≤14 days reviewed by a Treatment Selection Committee. The primary objective was to compare the progression-free survival (PFS) using a MP selected treatment regimen to the preceding PFS. Clinical benefit for the pt is defined by PFS ratio (PFS on MP selected therapy/PFS on prior therapy) is ≥ 1.3, (JCO,28:4877-83:2010). N= 25 was determined (exact single-stage design for phase II studies, type I error rate of 5% [one-sided], power of 90%). MP selected therapy would warrant further investigation if ≥ 35% of the pts demonstrate a PFS ratio of ≥ 1.3. Results: Three U.S. sites enrolled 25 evaluable pts who were treated based on MP results. Pts were heavily pretreated with 4 -11 prior therapies (median 7.24). Ten pts (40%) met or exceeded the PFS ratio of 1.3. The most common targets used in drug treatment selection were TOPO1, TS, ER/PR, TOP2A, HER2. Sixty percent of pts’ samples had activation of drug targets determined by RPMA in 3 major clusters: pan-HER-AKT; EGFR/SRC/ERK/mTOR; IGFR/RAF/MEK/PLK1. Days on MP selected treatments range from 9 - 816+. 3 pts continue on treatment for 199, 254 and 816 days. Conclusions: This study demonstrates the feasibility of a highly multiplexed genomic and proteomic MP study for treatment selection in a timely fashion. Patient-specific target driven treatment selection based on MP of a metastatic lesion provided clinical benefit for 10 of 25 heavily pretreated MBC pts. Thus, this approach merits further investigation in future studies. Funded by The Side-Out Foundation. Clinical trial information: NCT01074814.
Apolipoprotein E epsilon 4 allele and pupillary response to tropicamide
Authors: S Higuchi, S Matsushita, Y Hasegawa, T Muramatsu, H Arai, M Hayashida
Journal: American Journal of Psychiatry (1997)

This study was designed to investigate in cognitively normal subjects the possible association between hypersensitive pupil dilation response to the cholinergic antagonist tropicamide and the presence of the apolipoprotein E epsilon 4 (APOE4) allele, a well-defined genetic risk factor for Alzheimer's disease.The authors measured tropicamide-induced changes in pupil area in 44 cognitively normal Japanese subjects with and without the APOE4 allele.The subjects with the APOE4 allele had significantly greater increases in pupil area than the others. The significant correlation of changes in pupil area with age for the subjects with the APOE4 allele was lacking for those without this allele.The results suggest that a hypersensitive pupil dilation response to tropicamide is already present in cognitively normal individuals with the APOE4 allele. This association also suggests the potential involvement of APOE4 in the mechanism of pupil dilation.
Cetuximab (C225) in the first-line treatment of advanced colorectal cancer (CRC) patients (Pts) with<i> K-ras</i> wild-type (WT) tumors: Does the choice and schedule of fluoropyrimidine (Fp) matter?
Authors: Geoffrey Yuyat Ku, Benjamin Haaland, Gilberto de Lima Lopes
Journal: Journal of Clinical Oncology (2012)

576 Background: C225, a monoclonal antibody against the epidermal growth factor receptor, has been shown to inconsistently improve response rates (RR), progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced CRC Pts with K-ras WT tumors. Methods: We performed a meta-analysis of four trials where K-ras WT Pts received a Fp (capecitabine (C) or bolus (b) or infusional (CI) 5-fluorouracil (5-FU)) and oxaliplatin (oxali) or irinotecan (CPT) ± C225 (CRYSTAL, OPUS, COIN and NORDIC VII trials) and one trial, where K-ras WT and mutant Pts received C225 with capecitabine (C) and oxali or CPT (AIO study). We sought to determine if the choice of Fp affects the response to C225. A mixed effects model similar to that of DerSimonian and Laird was fit by restricted maximum likelihood and used to obtain an overall estimate of the effect of C225 in the presence of CI 5-FU, an indirect estimate of the decrease in the effect of C225 in the presence of C/b5-FU relative to CI 5-FU, and an estimate of the study-to-study variability. Results: Only Pts treated with CI 5-FU based chemo derived benefit from C225. Relative to CI 5-FU, Pts treated with C or b5-FU based doublet chemo had a decrease in RR, PFS and OS. The choice of oxali or CPT did not affect responses to C225. Conclusions: The lack of benefit for C225 with C or b5-FU chemo is unexpected. A possible explanation is increased toxicity with C225, which led to dose reduction of C only in the C225-arm of the COIN study; however, increased toxicity was not seen in the NORDIC VII study. Pending further study, only CI 5-FU regimens should be used with C225. [Table: see text]
ATNT-15MIBEFRADIL DIHYDROCHORIDE WITH HYPOFRACTIONATED RADIATION FOR RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS OF A PHASE I DOSE EXPANSION TRIAL
Authors: Nataniel H. Lester-Coll, Jeannie Kluytenaar, Kira F. Pavlik, James B. Yu, Joseph N. Contessa, Jennifer Moliterno, Joseph M. Piepmeier, Kevin P. Becker, Joachim M. Baehring, Anita J. Huttner, Alexander O. Vortmeyer, Ramachandran Ramani, Rachel J. Lampert, Xiaopan Yao, Ranjit S. Bindra
Journal: Neuro-Oncology (2015)

BACKGROUND: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Our group recently performed a high-throughput drug screen for novel DNA repair inhibitors which identified mibefradil dihydrochloride, a T-type calcium channel blocker. Follow-up studies by our group and others subsequently revealed that mibefradil is active as a glioma radiosensitizer. Based on these findings, we sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and hypofractionated radiation (RT), in a Phase I study of patients with recurrent GBM. A subset of patients are enrolled on a molecular biomarker sub-study, in which the drug is administered prior to surgical re-resection, and the tissue is analyzed for tumor penetration and in situ activity. METHODS: The inclusion criteria are histologically proven GBM progressive or recurrent following RT and temozolomide treatment. Patients receive mibefradil, in escalating dose from 150mg/day until the maximum tolerated dose (MTD) or a dose of 350 mg/day is reached using a standard 3 + 3 design. RT consists of 5 fractions of 600 cGy each, delivered over 2 weeks for a total of 3,000 cGy using stereotactic, intensity-modulated RT. RESULTS: To date, eight patients have been enrolled including two patients on the molecular biomarker sub-study, and seven have been successfully treated. The first dose level cohort has completed accrual. Median progression-free survival was 2.5 months. One patient experienced a complete radiographic response on MRI and one had grade 3 or higher drug-related toxicity. CONCLUSIONS: This Phase I dose-escalation study assesses the safety and determines the MTD of mibefradil dihydrochloride as a novel radiosensitizer in patients with recurrent GBM. Our preliminary data suggest that mibefradil and RT can be safely co-administered with the potential to improve disease response as a novel radiosensitizer.
Multicenter, randomized, phase III trial comparing radical retropubic prostatectomy with conventional external beam radiotherapy for localized prostate cancer: An interim report
Authors: S. M. Di Stasi, A. Giannantoni, M. Valenti, L. Storti, F. Attisani, T. Palloni, E. A. Jannini, M. Bibas, G. Zampa
Journal: Journal of Clinical Oncology (2006)

4607 Background: We report the outcomes of a randomised trial comparing radical retropubic prostatectomy (RP) with conventional external beam radiotherapy (EBRT) in patients with clinically localized prostate cancer. Methods: Between January 1997 and September 2001, 137 patients with clinically localized diagnosed prostate cancer were randomly assigned to RP (n = 70) or EBRT (n = 67). Data collected at follow-up included evidence of clinical disease progression, survival rates and general and disease specific health-related quality of life. All data were measured by physical examination, digital rectal examination, PSA, annual TC and bone scan and questionnaire. Analysis was by intention to treat. Results: After a median follow-up of 67 months (range 24–88) 35 patients (32.8%) had evidence of biochemical disease progression, 22 (31.4%) in RP group and 23 (32.8%) in EBRT group respectively. The median time to biochemical failure was 55.5 months (range 1–86) in RP group and 56 (range 3–88) in EBRT group. A local progression was observed in 11 patients (15.79%) of RP group and 12 (17.9%) of EBRT group. The median time to local progression was 65 months (range 6–86) in RP group and 64 (range 6–88) in EBRT group. Distant metastases were observed in 4 patients (5.7%) in RP group and 6 (8.9%) in EBRT group. The median time to distant failure was 67 months (range 12–86) in RP group and 66 (range 12–88) in EBRT group. Death due to prostate cancer occurred in 3/70 of patients assigned to RP (4.3%) and in 1/67 of those assigned to EBRT (1.5%). A significant decrease in general HRQOL was evident only in the first month after RP (p &lt; 0.001). At 2 years, patients undergoing RP report significantly worse urinary function (p &lt; 0.001), but better bowel function than those treated with EBRT (p &lt; 0.001). Sexual dysfunction was more prevalent in the RP than in the EBRT group (70.2% versus 61.2%). Conclusions: This interim analysis indicates that there was no significant difference between RP and EBRT in terms of clinical disease progression and survival rates in patients with clinically localized prostate cancer. However, additional larger sample size accrual and long-term follow-up data are warranted to confirm these results. No significant financial relationships to disclose.
Perfusion and diffusion MRI in the assessment of the antivascular effect of arsenic trioxide combined with radiotherapy for glioblastoma multiforme: NABTT phase I study
Authors: S. Ryu, I. Crocker, V. Stieber, X. Ye, J. D. Fisher, S. Grossman
Journal: Journal of Clinical Oncology (2005)

1538 Background: Significant tumor control and prolongation of survival have been demonstrated by combined use of radiosurgery and antivascular agent, Arsenic Trioxide (ATO), in rodent gliosarcoma model in rats. This agent is now undergoing clinical evaluation in the NABTT Brain Tumor Consortium in a Phase I trial with ATO dose escalation in combination with fractionated radiation therapy. Since this agent showed rapid effect on the tumor vasculature in the animal studies, MRI perfusion and diffusion studies were performed shortly following ATO administration. Methods: The patients were treated with external beam radiotherapy 60 Gy in 6 weeks with ATO at a starting dose of 0.25 mg/kg once a week during the course radiotherapy. ATO dose was escalated by 0.05 mg. The perfusion images were acquired using a Echo Planar Image (EPI) sequence. Perfusion parameters were Mean Transit Time (MTT), relative Cerebral Blood Volume (rCBV), and relative Cerebral Blood Flow (rCBF). The perfusion parameter values under regions of interest (ROI) from the enhancing and non-enhancing portions of the lesion were then followed serially during treatment. Results: There was a delay on mean transit time (MTT) and relative cerebral flow (rCBF) by ATO and radiotherapy, compared to counterpart normal brain. This effect was apparent within 24 hours of ATO infusion. The extent and duration of these changes will be correlated with conventional measures of outcome, such as lesion volumes, response, and time to tumor progression (TTP). There were no dose limiting toxicities with doses of ATO as high as 0.35 mg/kg once a week. Conclusions: A total of 12 patients were treated with this phase I trial. At the doses studied thus far, ATO combined with radiotherapy appears safe in the treatment of glioblastoma multiforme. ATO induced a differential delay of blood flow in the tumor compared to the normal brain. ATO showed the immediate effects and serial evaluation highlights the dynamic nature of the intratumoral vasculature in response to ATO, antivascular agent. No significant financial relationships to disclose.
Nivolumab (N) (Anti-Pd-1; Bms-936558, Ono-4538) in Combination with Sunitinib (S) or Pazopanib (P) in Patients (Pts) with Metastatic Renal Cell Carcinoma (Mrcc)
Authors: A. Amin, E.R. Plimack, J.R. Infante, M. Ernstoff, B.I. Rini, D.F. McDermott, J. Knox, S.K. Pal, M. Voss, P. Sharma, C.K. Kollmannsberger, D. Heng, J. Spratlin, Y. Shen, J. Kurland, P. Gagnier, H. Hammers
Journal: Annals of Oncology (2014)
Modern Approaches to Localized Cancer of the Esophagus
Authors: Robert E. Glasgow, David H. Ilson, James A. Hayman, Hans Gerdes, Mary F. Mulcahy, Jaffer A. Ajani
Journal: Journal of the National Comprehensive Cancer Network (2011)

The clinical spectrum of esophageal cancer has changed dramatically over the past couple of decades. Most notably, a profound rise in esophageal adenocarcinoma and decrease in the incidence of squamous carcinomas have occurred. An understanding of the factors that influence survival for patients with localized esophageal cancer has evolved concomitantly with these changes in epidemiology. Significant advancement in endoscopic and radiographic staging allows for more selective use of treatment modalities. The treatment of localized esophageal cancer mandates a multidisciplinary approach, with treatment tailored to disease extent, location, histology, and an accurate assessment of pretreatment staging. Despite these improvements in the staging and use of multimodality therapy, only modest improvements in patient survival have been observed. This article summarizes these modern approaches to localized cancer of the esophagus.