tbuckley/cabot-search huggingface dataset:
Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation
Authors: Tom Greene, Jian Ying, Edward F. Vonesh, Hocine Tighiouart, Andrew S. Levey, Josef Coresh, Jennifer S. Herrick, Enyu Imai, Tazeen H. Jafar, Bart D. Maes, Ronald D. Perrone, Lucia del Vecchio, Jack F.M. Wetzels, Hiddo J.L. Heerspink, Lesley A. Inker
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Randomized controlled trials of CKD traditionally use clinical events that happen late in the course of CKD progression as study end points. Doing this requires large sample sizes and long follow-up periods that can make the studies very costly. The authors use statistical simulations to investigate circumstances in which using the change in GFR over time or GFR slope as a study end point reduces the required sample size or trial duration compared with clinical end points. They found that GFR slope performs better than clinical end points when patients’ initial GFRs are high and the treatment has no acute effect on GFR. The results along with other recent studies suggest GFR is a valid surrogate end point for CKD clinical trials that may allow for more efficient trials and help speed the development of new CKD therapies. Background Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. Methods We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up. Results In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients’ GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions. Conclusions Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.
Clinical-grade computational pathology using weakly supervised deep learning on whole slide images
Authors: Gabriele Campanella, Matthew G. Hanna, Luke Geneslaw, Allen Miraflor, Vitor Werneck Krauss Silva, Klaus J. Busam, Edi Brogi, Victor E. Reuter, David S. Klimstra, Thomas J. Fuchs
Journal: Nature Medicine (2019)
Sugary drink consumption and risk of cancer: results from NutriNet-Santé prospective cohort
Authors: Eloi Chazelas, Bernard Srour, Elisa Desmetz, Emmanuelle Kesse-Guyot, Chantal Julia, Valérie Deschamps, Nathalie Druesne-Pecollo, Pilar Galan, Serge Hercberg, Paule Latino-Martel, Mélanie Deschasaux, Mathilde Touvier
Journal: BMJ (2019)

Abstract Objective To assess the associations between the consumption of sugary drinks (such as sugar sweetened beverages and 100% fruit juices), artificially sweetened beverages, and the risk of cancer. Design Population based prospective cohort study. Setting and participants Overall, 101 257 participants aged 18 and over (mean age 42.2, SD 14.4; median follow-up time 5.1 years) from the French NutriNet-Santé cohort (2009-2017) were included. Consumptions of sugary drinks and artificially sweetened beverages were assessed by using repeated 24 hour dietary records, which were designed to register participants’ usual consumption for 3300 different food and beverage items. Main outcome measures Prospective associations between beverage consumption and the risk of overall, breast, prostate, and colorectal cancer were assessed by multi-adjusted Fine and Gray hazard models, accounting for competing risks. Subdistribution hazard ratios were computed. Results The consumption of sugary drinks was significantly associated with the risk of overall cancer (n=2193 cases, subdistribution hazard ratio for a 100mL/d increase 1.18, 95% confidence interval 1.10 to 1.27, P&lt;0.0001) and breast cancer (693, 1.22, 1.07 to 1.39, P=0.004). The consumption of artificially sweetened beverages was not associated with the risk of cancer. In specific subanalyses, the consumption of 100% fruit juice was significantly associated with the risk of overall cancer (2193, 1.12, 1.03 to 1.23, P=0.007). Conclusions In this large prospective study, the consumption of sugary drinks was positively associated with the risk of overall cancer and breast cancer. 100% fruit juices were also positively associated with the risk of overall cancer. These results need replication in other large scale prospective studies. They suggest that sugary drinks, which are widely consumed in Western countries, might represent a modifiable risk factor for cancer prevention. Study registration ClinicalTrials.gov NCT03335644 .
Randomised trial of cetuximab every 2 weeks with FOLFIRI or cetuximab with alternating FOLFIRI/FOLFOX in patients with RAS and BRAF wild type metastatic colorectal cancer: Nordic 8 results
Authors: P. Pfeiffer, B. Glimelius, S. Winther, C. Qvortrup, M. Yilmaz, À Berglund, K. Vistisen, C. Kersten, G. Liposits, H. Sorbye
Journal: Annals of Oncology (2019)
Real-time informatics to collect data, toxicities, image response assessments, and patient-reported outcomes (PROs) in a phase II clinical trial.
Authors: Maria Catherine Pietanza, Ethan M. Basch, Alex Lash, Lawrence H. Schwartz, Michelle S. Ginsberg, Binsheng Zhao, Marwan Shouery, Mary Shaw, Lauren J. Rogak, Manda Wilson, Aaron Gabow, Marcia Latif, Quinfei Wu, Samantha Lindsay Kass, Claire Miller, Leslie B. Tyson, Dyana K. Sumner, Alison Berkowitz, Camelia S. Sima, Mark G. Kris
Journal: Journal of Clinical Oncology (2012)

e19647 Background: In clinical trials, delayed and disorganized data reporting due to traditional toxicity symptom monitoring methods, paper documentation and out-dated collection systems lead to inaccuracies of critical study information and inefficiencies in the process. Electronic systems offer an opportunity to collect this information in real-time from various sources. The feasibility of such an approach is unknown. Methods: We created a computer software system to collect PROs of symptomatic toxicities, automated RECIST-based tumor response, and lab data, and made this information available to investigators in real-time at the point of care during a phase II lung cancer trial. We assessed data completeness within 48hrs of each visit. Clinician satisfaction was measured. Results: We enrolled 44 patients from 1/23/09 to 09/20/11. There were a total of 725 visits, with mean and median being 13 (range, 1-64) and 10, respectively. At each visit, patients completed self-reports using a dedicated wireless laptop 99.6% of the time; only 3 reports were not completed due to lack of a laptop or technical issues with the institutional Intranet. All PROs were completely distributed in batch throughout the system within 24hrs of the visit, and similarly lab data were available for review with a mean of 26hrs from the time the laboratory received the specimen. Manual attribution to lab toxicities in the system took a median of 1 day. Automated RECIST tumor measurements were available to clinicians online with a median of 2 days from the time of imaging; only 8% obtained &gt;7 days after scans were performed. Throughout the trial, there was improvement in data acquisition times (i.e., a “learning curve”). 89% (16/18) of clinicians and research study assistants felt there was greater accuracy in collection of PROs, radiographic responses and trial data. Conclusions: Existing data management systems can be harnessed to enable real-time collection and review of clinical information during trials. This approach facilitates reporting of information closer to the time of events and may improve accuracy and efficiency, as well as ability to make earlier clinical decisions.
Detection of DNA stool mutations in colorectal cancer patients.
Authors: Nora Manoukian Forones, Jacqueline Miranda Lima, Yolanda Teixeira, Celia Aparecida Marques Pimenta, Helena Murray, Tiago Donizetti, Aledson Vitor Felipe, Juliana Oliveira, Veronica Vidigal, Ermelindo Della Libera, Sidney Sahran Saad
Journal: Journal of Clinical Oncology (2013)

e22074 Background: Colorectal cancer (CRC) is the third leading cause of cancer in the world. Noninvasive screening tests have higher compliance. Changes in tumoral cells are also found in the stools after cancer cell exfoliation. Aim: to detect mutations in the stools of CRC patients and compare to mutations found in CRC tissue Methods: Patients referred for colonoscopy were divided into 3 groups: control, cancer, and polyp. The DNA was extracted from tissue and stool and it was analysed by two microarrays, the KRAS/BRAF/PIK3CA Array and the RanplexCRC Array (Randox Laboratories Ltd). Both based on the simultaneous detection of 20 mutations in KRAS, BRAF and PIK3CA and 28 mutations in KRAS, BRAF, TP53 and APC respectively. Positive tissue sample mutations were confirmed by Sanger sequencing. Results: 90 stools and 112 tissue biopsies were studied. Analysis of tissue samples was initially performed using the KRAS/BRAF/PIK3CA Array. In total mutations were detected in 16(55%) CRC, 12(45%) polyp and 2(6%) control samples. Mutations were confirmed via Sanger sequencing (76%). In the stool the frequency were 17(35%) in CRC, 10(71%) in polyp and 1(4%) in the control. Inconclusive tests were higher among the controls (32.5%) and polyps (22%), being less frequent in the CRC patients (6%). Excluding the inconclusive tests, WT genes were common in the controls (96%). The most common mutation was within KRAS codon 12. Stools samples from 48 subjects were compared to the results obtained by the RanplexCRC Array and mutations were found in 50% of CRC. KRAS/BRAF/PIK3CA Array stool results had a correlation with RanplexCRC Array in 64% of CRC patients and in 47% of polyp patients. The average human DNA in the stools was 15ng/ul in CRC patients and 0.46ng/ul in the controls (p=0.0001). Conclusions: Both arrays had a good correlation and a sensitivity between 30-50% with a high specificity (95-100%). The KRAS/BRAF/PIK3CA Array is currently optimized and recommended for assessment of tissue samples. This initial set of data however does indicate its potential applicability to stool specimens. Inconclusive tests are likely as a result of limited human DNA content within stool control samples. FAPESP (Sao Paulo Research Foundation) project 09/16618-8.
Abstract 21385: Presenting Features in Suspected Cardiac Sarcoid
Authors: Gayatri Acharya, John Bois, Martin Rodriguez-Porcel, Panithaya Chareonthaitawee
Journal: Circulation (2017)

Background: Sarcoidosis is multi-system disease characterized by non-caseating granulomas, often presenting with pulmonary involvement. However, in the United States at least one-fourth of sarcoid patients have cardiovascular involvement. Sarcoid can also present as isolated cardiac sarcoidosis (CS), with symptoms that include heart failure (HF), advanced atrioventricular (AV) nodal block, ventricular tachycardia (VT), or sudden cardiac death. Consequently, it has been suggested that CS should be considered in patients presenting with high grade AV block, VT, or heart failure, with a non-ischemic presentation. Here, we present the CS experience at a tertiary medical center. Methods: Patients who underwent 18 F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) PET/CT to assess perfusion and inflammation for clinical suspicion of CS between 2009-2015 at a tertiary referral center were included in the study. These patients were retrospectively assessed for frequency of presenting features. Results: Inclusion criteria were met by 71 patients. VT was the most common presenting symptom seen in 40 of 71 patients (56%). High grade AV block was seen in 24 of 71 patients (34%). VT and high grade AV block was seen concomitantly in 9 (13%). An abnormal PET result was seen in 51 out of 71 patients (72%) with 30 of 51 having VT (59%) and 21 of 51 having AV block (41%). Of the patients with both VT and AV block, 8 of 9 had abnormal PET studies. In 34 of 71 (47%) patients with known extracardiac sarcoid, 18 (53%) had VT and 11 (32%) had AV block. HF symptoms (New York Heart Association class II-IV) were seen in 24 (34%). An abnormal resting ECG was seen in 64 out of 71 patients (90%). Conclusions: In our retrospective cohort VT is the most common presenting symptom in patients with suspicion of CS, and the combination of AV block with VT should raise concerns for an infiltrative process. In patients with extracardiac sarcoid and rhythm disturbance, cardiac involvement should be suspected and screened. Early identification of cardiovascular involvement is critical to ensure that appropriate management of the source of rhythm disturbance or heart failure is addressed before cardiovascular dysfunction is sustained.
Epimutations in Developmental Genes Underlie the Onset of Domestication in Farmed European Sea Bass
Authors: Dafni Anastasiadi, Francesc Piferrer
Journal: Molecular Biology and Evolution (2019)

Domestication of wild animals induces a set of phenotypic characteristics collectively known as the domestication syndrome. However, how this syndrome emerges is still not clear. Recently, the neural crest cell deficit hypothesis proposed that it is generated by a mildly disrupted neural crest cell developmental program, but clear support is lacking due to the difficulties of distinguishing pure domestication effects from preexisting genetic differences between farmed and wild mammals and birds. Here, we use a farmed fish as model to investigate the role of persistent changes in DNA methylation (epimutations) in the process of domestication. We show that early domesticates of sea bass, with no genetic differences with wild counterparts, contain epimutations in tissues with different embryonic origins. About one fifth of epimutations that persist into adulthood are established by the time of gastrulation and affect genes involved in developmental processes that are expressed in embryonic structures, including the neural crest. Some of these genes are differentially expressed in sea bass with lower jaw malformations, a key feature of domestication syndrome. Interestingly, these epimutations significantly overlap with cytosine-to-thymine polymorphisms after 25 years of selective breeding. Furthermore, epimutated genes coincide with genes under positive selection in other domesticates. We argue that the initial stages of domestication include dynamic alterations in DNA methylation of developmental genes that affect the neural crest. Our results indicate a role for epimutations during the beginning of domestication that could be fixed as genetic variants and suggest a conserved molecular process to explain Darwin's domestication syndrome across vertebrates.
Abstract 16563: Assessment of Reduced Left Ventricular Ejection Fraction Using Isovolumic Contraction dP/dt from HEMOTAG
Authors: Kaustubh Kale, Mark D Skowronski, Steven Borzak, Robert Chait
Journal: Circulation (2018)

Introduction: Approximately 16 million Americans have Stage B heart failure, and another 6 million Americans have Stages C and D heart failure. Annual management costs for heart failure patients ex...
A phase I trial of palbociclib in combination with dexamethasone in relapsed or refractory adult B-cell acute lymphoblastic leukemia (ALL).
Authors: Margaret T. Kasner, Lindsay Wilde, Gina Keiffer, Neil David Palmisiano, Bruno Calabretta
Journal: Journal of Clinical Oncology (2019)

TPS7065 Background: c-Myb is a DNA-binding transcription factor that is highly expressed in immature hematopoietic cells. c-Myb and its products are essential in regulating normal hematopoiesis and influencing leukemogenesis. Knockdown of c-Myb causes cell cycle arrest and apoptosis in pre-B-ALL cells. The effects of c-Myb depend on transcriptional regulation of CDK6 and Bcl-2. c-Myb-silenced Ph+ ALL cells exhibit Rb-dependent cell cycle arrest and apoptosis, both of which are rescued by ectopic expression of cyclin D3, CDK6, and Bcl-2 expression. Preclinical studies suggest that the cytotoxic activity of dexamethasone in ALL cells may be due to decreased c-Myb expression and reduced Bcl-2 levels. Thus, the novel combination of palbociclib, a small molecule CDK4/6 inhibitor, and dexamethasone is a logical approach for the treatment of B-cell ALL. Methods: This is a single arm, phase I, dose escalation study with a traditional 3+3 design. Adult patients with relapsed or refractory B-cell ALL are eligible. Patients with Ph+ ALL must be refractory to or intolerant of standard tyrosine kinase inhibitor therapy. Patients receive a 1-week lead-in of palbociclib alone followed by induction with 4 weeks of palbociclib and dexamethasone. If an adequate response is seen, patients move to maintenance therapy, which consists of 1 week of palbociclib plus dexamethasone followed by 3 weeks of palbociclib alone. Treatment continues until disease progression, dose limiting toxicity, or availability of an alternative therapy. The primary endpoints are dose limiting toxicity and maximum tolerated dose of palbociclib and dexamethasone. Correlative studies, which are performed on pretreatment, day +1 and day +8 samples, include RB phosphorylation and FOXM1 expression as measures of palbociclib activity; CD19+ cell gene expression profiling of (1) p21 expression as an indicator of cell cycle activity, (2) S-Phase, Annexin V/Caspase 3 activation as indicators of proliferation and apoptosis and (3) Myb and Bcl-2 expression as indicators of dexamethasone sensitivity. Cohort 1 is currently enrolling. Once a maximum tolerated dose is established, an expansion cohort is planned. Clinical trial information: NCT03472573.
The impact of prior therapy with ketoconazole (keto) on clinical outcomes after subsequent docetaxel treatment in metastatic castration-resistant prostate cancer (mCRPC) patients: Results from a randomized phase III trial (CALGB 90401).
Authors: Eric Jay Small, Susan Halabi, Michael Anthony Carducci, Charles J. Ryan, Daniel J. George, John Francis Mahoney, Walter Michael Stadler, Michael J. Morris, Philip Kantoff, J. P. Monk, William Kevin Kelly
Journal: Journal of Clinical Oncology (2012)

4667 Background: Small retrospective reviews have suggested the possibility of a decreased benefit of docetaxel in mCRPC patients (pts) previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 was an intergroup (CALGB, ECOG) randomized phase 3 trial in which 1050 mCRPC pts were treated with docetaxel, which offered the opportunity to evaluate the effect of prior treatment with keto, an earlier generation ASI, on clinical outcomes following docetaxel treatment in mCRPC pts. Methods: Data from 1,050 men randomized on CALGB 90401 to treatment with docetaxel and prednisone with either bevacizumab or placebo were used. Pts were chemotherapy naïve, had evidence of progressive mCRPC, an ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function. Randomization was stratified by age, prior history of a thromboembolic event, and 24-month predicted survival using the CALGB nomogram. The effect of prior keto use on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (RR) was estimated using proportional hazards and logistic regression models. Results: 277/1050 pts (26%) had received prior keto. Baseline characteristics including the 3 stratification factors, race, performance status, measurable disease, and baseline alkaline phosphatase and Hgb were balanced between prior keto treated pts and keto untreated pts. LDH and PSA were higher in the keto treated patients (211 vs. 201, p = 0.01; and 121 vs. 73, p &lt; .0001; respectively.) There were no statistically significant differences in keto vs. non-keto treated patients with regards to OS (21.1 vs. 22.3 m, p = 0.643); PFS (8.1 vs. 8.6m p = 0.394 ); &gt;50% decline in PSA (61% vs. 66% p=.112); or objective response (39% vs. 43% p = 0.34). Conclusions: As measured by OS, PFS, PSA and RR, prior treatment with the ASI ketoconazole has no impact on the subsequent clinical impact of docetaxel in mCRPC pts.
The effect of adoptive transfer of <i>ex vivo</i> activated T cells on the efficacy and tumor penetrance of intravenously-administered CD3-engaging bispecific antibody.
Authors: Patrick C. Gedeon, Carter M. Suryadevara, Bryan D. Choi, John H. Sampson
Journal: Journal of Clinical Oncology (2019)

30 Background: Activated T cells are known to traffic throughout the body including past the blood-brain barrier where they perform routine immune surveillance. Whether activated T cells can be used to enhance the efficacy and delivery of intravenously-administered, immunotherapeutic antibodies has yet to be explored. Methods: To examine efficacy, T cell migration and antibody delivery in vivo, the invasive murine glioma, CT-2A-EGFRvIII, was implanted orthotopically in human CD3 transgenic mice. Cohorts of mice were given vehicle or 1x10 7 non-specifically activated, syngeneic T cells intravenously. Beginning the subsequent day, groups were treated with daily intravenous infusions of human-CD3-binding, tumor-lysis-inducing bispecific antibody (hEGFRvIII-CD3 bi-scFv) or control bispecific antibody. To block T cell extravasation, cohorts received natalizumab or isotype control via intraperitoneal injection every other day beginning on the day of adoptive cell transfer. T cell migration was assessed using whole body bioluminescence imaging of activated T cells transduced to express firefly luciferase. Bispecific antibody biodistribution was assessed using PET-CT imaging of iodine-124 labeled antibody. Results: Following intravenous administration, ex vivo activated T cells tracked to invasive, syngeneic, orthotopic glioma, reaching maximal levels on average four days following adoptive transfer. Administration of ex vivo activated T cells enhanced bispecific antibody efficacy causing a statistically significant increase in survival (p = 0.007) with 80% long-term survivors. Treatment with the T cell extravasation blocking molecule natalizumab abrogated the increase in efficacy to levels observed in cohorts that did not receive adoptive transfer of activated T cells (p = 0.922). Pre-administration with ex vivo activated T cells produced a statistically significant increase in tumor penetrance of radiolabeled bispecific antibody (p = 0.023). Conclusions: Adoptive transfer of non-specifically activated T cells enhances the efficacy and tumor penetrance of intravenously-administered CD3-binding bispecific antibody.