tbuckley/cabot-search huggingface dataset:
Doxorubicin-induced cardiac dysfunction in unselected patients with a history of early-stage breast cancer.
Authors: Megan Veresh Caram, Monika Leja, Jeffrey B. Smerage, Cui Guo, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2015)

e17653 Background: Cardiomyopathy is a serious but rare side effect seen in patients participating in clinical trials investigating anthracyclines for the treatment of breast cancer, but is far more frequently reported in studies of population-based samples of breast cancer survivors. Differences in methods for ascertaining cardiac toxicity, duration of follow up, and patient selection are likely to account for the discrepancy. Methods: The objectives of this study were to prospectively evaluate the prevalence of abnormal cardiac biomarkers in a group of unselected patients who had been treated with doxorubicin for early-stage breast cancer at least 12 months before enrollment and to use the biomarkers to guide echocardiographic evaluation to determine the prevalence of cardiac dysfunction. All participants underwent a physical exam, symptom inventory, medical record review, and gave a blood and urine specimen for evaluation of serum brain natriuretic peptide (BNP), N-terminal (NT)-proBNP, troponin, and urine NT-proBNP. Analyses were performed to investigate the impact of age, cumulative dose of doxorubicin, diabetes, hypertension, left-sided radiation therapy, and other patient factors that could affect the risk for developing left ventricular dysfunction. Results: Among 246 patients who completed participation, 166 had an abnormal biomarker and underwent an echocardiogram. The median time since last anthracycline among the patients who completed an echocardiogram was 68 months (range 13-264). Among the 166 patients who had an echocardiogram, 11.5% had a left ventricular ejection fraction < 55%. The median serum NT-proBNP in patients who had an EF ≥ 55% was 225 while the median value for patients with an EF < 55% was 316. (p = 0.18). Only 5% of patients with a normal NT-proBNP had an EF < 55%. (p = 0.05) Troponin BNP, and urine NT-proBNP were not associated with decreased ejection fraction. Conclusions: Serum NT-proBNP may be a useful biomarker to rule out subclinical cardiac dysfunction in breast cancer survivors treated with an anthracycline. Subclinical cardiac dysfunction is an infrequent complication of treatment with anthracyclines but may be more prevalent than reported in clinical trials.
Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis
Authors: Victor G. Puelles, David Fleck, Lena Ortz, Stella Papadouri, Thiago Strieder, Alexander M.C. Böhner, James W. van der Wolde, Michael Vogt, Turgay Saritas, Christoph Kuppe, Astrid Fuss, Sylvia Menzel, Barbara M. Klinkhammer, Gerhard Müller-Newen, Felix Heymann, Leon Decker, Fabian Braun, Oliver Kretz, Tobias B. Huber, Etsuo A. Susaki, Hiroki R. Ueda, Peter Boor, Jürgen Floege, Rafael Kramann, Christian Kurts, John F. Bertram, Marc Spehr, David J. Nikolic-Paterson, Marcus J. Moeller
Journal: Kidney International (2019)

Recent developments in optical tissue clearing have been difficult to apply for the morphometric analysis of organs with high cellular content and small functional structures, such as the kidney. Here, we establish combinations of genetic and immuno-labelling for single cell identification, tissue clearing and subsequent de-clarification for histoimmunopathology and transmission electron microscopy. Using advanced light microscopy and computational analyses, we investigated a murine model of crescentic nephritis, an inflammatory kidney disease typified by immune-mediated damage to glomeruli leading to the formation of hypercellular lesions and the rapid loss of kidney function induced by nephrotoxic serum. Results show a graded susceptibility of the glomeruli, significant podocyte loss and capillary injury. These effects are associated with activation of parietal epithelial cells and formation of glomerular lesions that may evolve and obstruct the kidney tubule, thereby explaining the loss of kidney function. Thus, our work provides new high-throughput endpoints for the analysis of complex tissues with single-cell resolution.
Abstract 16283: The Usefulness of a Fragmented QRS Complex in Patients With Myocardial Ischemia
Authors: Myung Hwan Bae, Se Yong Jang, Hong Nyun Kim
Journal: Circulation (2017)

Introduction: Fragmented QRS (fQRS) represents myocardial conduction abnormalities due to myocardial scar in patients with coronary artery disease. Hypothesis: However, the implication of the fQRS ...
Randomized phase II trial of intravenous ascorbic acid (AA) as an adjunct to pazopanib for metastatic and unresectable clear cell renal cell carcinoma (ccRCC): A study of Academic and Community Cancer Research United (ACCRU) GU1703.
Authors: Niraj Konchady Shenoy, Fang-Shu Ou, John C. Cheville, Tushar Bhagat, Benjamin Adam Gartrell, Amit Verma, Mark Levine, Lance C. Pagliaro
Journal: Journal of Clinical Oncology (2019)

TPS679 Background: AA has re-emerged as a promising anti-cancer agent based on recent knowledge of pharmacokinetics, discovery of unexpected mechanisms of action, and early phase trials with IV AA.(Shenoy et al, Cancer Cell 34: 2018, in press) We hypothesized that ccRCC would be particularly susceptible to anti-cancer effects of IV AA due to: a. TET dependent demethylation of the hypermethylated genome of ccRCC causing re-expression of tumor suppressors (Shenoy et al, AACR 2018 Targeting DNA methylation conf. A11; Hu et al, Clin Cancer Res 20:4349-60, 2014) b. H2O2 production causing intra-tumoral oxidative damage, hypothesized to be enhanced by high iron content in RCC microenvironment c. Intracellular accumulation of dehydroascorbic acid secondary to high HIF activity in ccRCC. Animal data and case reports support the hypothesis. Methods: Trial design: Patients (pts) with newly diagnosed metastatic/ unresectable ccRCC are randomized 1:1 to arm A (pazopanib 800 mg/d plus IV AA 1g/kg 3 times/week) or arm B (pazopanib 800 mg/d). Protocol treatment is for 10 cycles (unless PD, unacceptable AE, alternative therapy, or pt refusal), each cycle being 28 days. Primary endpoint is Treatment Failure-Free rate at 40 weeks (TFF40). Treatment Failure is defined as: Radiographic disease progression, off-protocol treatment due to AE, alternative therapy initiation (except metastasectomy post clinical benefit), or death. Secondary endpoints include OS, PFS, ORR and AE. Statistical methods: 82 eligible pts (41 in each in arm) will provide 81% power to detect a 19% increase of TFF40 from 45% in arm B to 64% in arm A assuming a one-sided type I error rate of 0.19 (EAST 6.4). Correlatives: Epigenetic mechanism: 5mC, 5hmC and H3K27me3 IHC, MeDIP/ hMeDIP seq, RNA seq. H2O2 mechanism: tumor microenvironment iron, tumor catalase IHC. Dehydroascorbic acid mechanism: HIF-1 alpha, HIF-2 alpha, GLUT-1 IHC. Key exclusion criteria: G6PD deficiency, renal disease (Cockcroft Gault CrCl &lt; 55 ml/min). ClinicalTrials.gov Identifier: NCT03334409 Status: Open for accrual in 9/10 planned sites. Funding Source: Foundation. Clinical trial information: NCT03334409.
Abstract P370: Minor Electrocardiographic Abnormalities and Cardiovascular Mortality
Authors: Krupal J Hari, Matthew J Singleton, Muhammad Imtiaz Ahmad, Elsayed Z Soliman
Journal: Circulation (2019)

Background: Although minor electrocardiographic (ECG) abnormalities are common in clinical practice, their prognostic significance remains unclear due to inconsistent reports. Such inconsistent reports may be related to the focus on the presence vs. absence of minor ECG abnormalities and ignoring the number of abnormalities. Hypothesis: The number of minor abnormalities is associated with cardiovascular disease (CVD) mortality in a dose-response fashion. Methods: This analysis included 6,467 participants (mean age 59 years 53% women, 49% non-Hispanic whites) from the NHANES-III who were free of CVD and major ECG abnormalities. ECG abnormalities were defined from digitally recorded and centrally processed standard 12-lead ECGs using the Minnesota Code ECG Classification. Cause of death was identified using the National Death Index. Cox proportional hazards analysis was used to examine the association between baseline minor ECG abnormalities (presence of at least 1 abnormality vs. normal ECG, and presence of 1, or ≥2 abnormalities vs. normal ECG, separately) with CVD mortality. Results: About 38% (n=2,438) of the participants had at least 1 minor abnormality at baseline. During a median follow-up of 13.9 years, 755 CVD deaths occurred. Compared to normal ECG, presence of minor ECG abnormally was marginally associated with CVD mortality (HR(95%CI):1.16 (1.00, 134); p= .0045). When the number of abnormalities was taken into account, the association with CVD mortality showed a dose-response relationship. While presence of only 1 minor abnormality was not associated with CVD mortality, presence of ≥ 2 abnormalities was associated with a 39% increased risk. Also, each additional minor ECG abnormality was associated a 13% increased risk of CVD mortality ( Table ). Conclusions: The number of minor ECG abnormalities, not only their mere presence, should be taken into account to both understand the prognostic significance of these common findings and to enhance the potential role of ECG to identify individuals at risk for CVD.
Major Events in the Life Course of New Drugs, 2000–2016
Authors: Reed F. Beall, Thomas J. Hwang, Aaron S. Kesselheim
Journal: New England Journal of Medicine (2019)

This interactive graphic allows viewers to explore data on the time it takes for investigational drugs to reach important U.S. milestones, such as NDAs, FDA approval, and market entry of generics. Data may be viewed in aggregate or by individual drug, therapeutic class, approval pathway, and year.
An observational study of a team management approach for first-line XELOX therapy in patients with advanced/recurrent colorectal cancer: The SMILE study (the study of metastatic colorectal cancer to investigate impact of learning effect).
Authors: Michio Nakamura, HIroshi Matsuoka, Yoshihisa Shibata, Yoshinori Munemoto, Hiroyuki Okuda, Hiroshi Uchida, Yutaka Ogata, Genichi Nishimura, Takeru Shiroiwa, Junji Kishimoto, Kotaro Maeda
Journal: Journal of Clinical Oncology (2015)

554 Background: Although oral chemotherapies such as XELOX are widely favored for convenience and flexibility, these have several disadvantages such as drug non-compliance and delayed discovery of adverse events. So we designed a multicenter, prospective, observational study to evaluate the efficacy of supportive interventions in first-line XELOX for colorectal cancer (CRC) patients (pts). Methods: CRC pts undergoing first-line XELOX (+Bevacizumab) therapy practicing one or more of supportive interventions as follows: 1) a telephone follow-up (TF), 2) instruction on dosage and administration by a pharmacist, 3) skin care instruction by a nurse, and 4) pts education by a doctor were eligible. The objective was to evaluate the incident rate of grade 2 or worse hand-foot syndrome (HFS), QoL, safety, and efficacy. QoL was assessed at baseline, 2, 4, 5 and 8 cycles after the treatment started, using the Hospital Anxiety and Depression Scale (HADS) and the Mental adjustment to cancer scale (MAC). Results: From April 2011 to September 2012, 80 pts were enrolled from 14 institutes. The characteristics were as follows: male/female: 46/34, age median: 63 (36-75), and supportive intervention 1)/2)/3)/4): 36/68/73/78. The incidence of grade 2 or worse HFS during 6 months were 11.1% (n=4) for those received TF (n=36), and 20.5% (n=9) for those received other intervention except TF (n=44). Relative dose intensity (RDI) was 75.7% (TF+/-: 77.7/74.3%) in oxaliplatin and 77.5% (TF+/-: 80.2/75.3%) in capecitabine, respectively. Although a tendency of the QoL score improvement about anxiety, fighting spirit and helplessness in a TF group was observed during the periods from start of therapy to 4 courses, there were no significant differences compared to other interventions except TF. Conclusions: We confirmed that HFS incidence was mitigated in a TF group. In regard to QoL, although we could not show the statistical differences due to some limitations of this study such as small sample size and non-randomized, it was indicated that TS had the potential to improve several QoL about anxiety, fighting spirit, and helplessness. Clinical trial information: UMIN000007185.
Proposed clinical guidelines for genetic gesting of polyposis patients based on Grover et al. (JAMA 308: 485, 2012): Study of prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas.
Authors: James T. Lin
Journal: Journal of Clinical Oncology (2015)

e14564 Background: Current guidelines for APC and MUTYH mutation testing have resulted in relatively large numbers of patients with adenomatous polyps (AP) but no personal or family history of colorectal cancer (CRC) being referred for evaluation. This is especially true in the VA system where there is a robust screening program for colorectal cancer starting at age 50. Re-analysis of Grover, et al. to provide absolute prevalence estimates suggests stricter guidelines can limit the degree of low yield testing. Methods: Using the odds ratio and patient numbers from Grover’s Table 3, along with the total number of positive test results, estimated prevalence percentages by age group were derived. Results: Estimated probability tables are below. Conclusions: Since the submitted samples were selected based on clinical suspicion, the data likely represent an upper bound to the true population prevalence. Based on the published odds ratios and calculated probabilities, patients who have their first AP at age 50 or older have a relatively low likelihood of a detecting a mutation in APC or MUTYH and testing may not be cost effective. Patients with first AP above age 50, no family history and a limited number of polyps probably should not be tested for APC or MUTYH outside of a clinical research protocol. Age at adenoma dx APC bivariable APC multivariable MUTYH bivariable MUTYH multivariable APC or MUTYH bivariable APR or MUTYH multivariable < 30 75% 63% 1.7% 3.6% 58% 53% 30-39 25% 25% 7.0% 8.6% 25% 25% 40-49 10% 11% 8.8% 7.8% 13% 15% 50 or over 3.3% 4.1% 4.6% 3.9% < 5% 6.1%
Abstract 027: The Menopausal Transition and Cerebrovascular Reactivity in the Coronary Artery Risk Development in Young Adults Study
Authors: Muna J Tahir, Pamela J Schreiner, Ilya M Nasrallah, Martine Elbejjani, Melissa F Wellons, R Nick Bryan, Lenore J Launer
Journal: Circulation (2019)

Background: Estrogen induces vasodilation in cerebral arteries and therefore increases perfusion to brain regions as needed. The menopausal transition, a state of variably declining endogenous estrogen levels, may be related to poorer cerebrovascular function. This study aims to investigate the association of menopausal status with cerebrovascular reactivity (CVR). Methods: The sample included women [N= 353] from the Coronary Artery Risk Development in Young Adults (CARDIA) Study who self-reported their reproductive histories and participated in the brain magnetic resonance imaging (MRI) sub-study at the year 25 follow-up examination. Menopausal status was classified as premenopause, perimenopause and postmenopause based on menstrual cycle regularity or cessation. CVR, a measure of vascular responsiveness to hypoxia, was calculated as mean percent change in blood-oxygen level dependent signals in activated voxels following a breath-hold test. Multiple linear regression models were used to examine the cross-sectional associations of menopausal status with total brain, gray matter and white matter CVR. Results: Women were mean age 50.4 ± 3.5 years; 42% were black; 56% were postmenopausal, 24% were perimenopausal and 20% were premenopausal. Following adjustment for hormone replacement therapy, and demographic, cardiovascular and behavioral risk factors, postmenopause versus premenopause was associated with less total, gray matter and white matter CVR (Table). Compared to premenopause, perimenopause showed no associations with CVR (Table). Conclusions: In this population-based sample of middle-aged women, postmenopausal status was associated with lower CVR, a marker for arterial stiffness and vascular aging, compared to premenopause; no difference was observed for perimenopause. While cross-sectional, these data suggest that interventions to prevent postmenopausal cerebrovascular function decline may still be initiated during perimenopause.
Clinical outcomes of a Dutch prospective observational registry of metastatic castration resistant prostate cancer (mCRPC) patients treated with radium-223 (Ra-223).
Authors: Rebecca Louhanepessy, Sushil Badrising, Vincent van der Noort, Jules L. L. M. Coenen, Paul Hamberg, Aart Beeker, Nils Wagenaar, Marnix G.E.H. Lam, Filiz Celik, Olaf Loosveld, Ad Oostdijk, Johanna Maria Zuetenhorst, Erik Vegt, Wilbert Zwart, Andre M. Bergman
Journal: Journal of Clinical Oncology (2019)

323 Background: In 2012 the ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit of mCRPC patients treated with Ra-223 over placebo. To date clinical outcomes of Ra-223 treatment in a non-study population have not been prospectively evaluated. Methods: The ROTOR registry aimed to include 300 patients in 20 Dutch hospitals prior to Ra-223 treatment at the physician’s discretion. Clinical parameters collected included: positioning of Ra-223, Adverse Events (AE’s; CTCAE v4.03), Skeletal Related Events (SRE) and survival data. SRE was defined as radiotherapy to a bone metastasis, a new pathological fracture, spinal cord compression and/or bone surgery. Progression-Free Survival (PFS) was defined as survival until radiological or clinical progression, subsequent treatment or death. Results: Between April 2014 and September 2017, 305 patients were included of whom 300 were evaluable. The mean age of patients was 72.6 (range 46.3-91.5) years, 255 (85%) had ≥ 6 bone metastases and 197 (65.5%) were pretreated with taxanes and/or abiraterone or enzalutamide (214 (71.3%)). Two-hundred and ninety (96.7%) patients were treated with Ra-223. Twenty-nine (9.7%), 104 (34.7%), 96 (32%) and 66 (22%) patients received Ra-223 as a first, second, third, ≥ fourth mCRPC treatment line, respectively. Patients received an average of 4.6 (SD 1.8) cycles of Ra-223, while 140 (46.7%) completed all six cycles. After a median follow-up of 13.2 months, PFS was 5.1 (CI 4.5-5.8) months and OS 15.2 (CI 12.8-17.6) months. Eighty-two (27.3%) patients were hospitalized during Ra-223 treatment (Serious AE). Grade ≥ 3 anemia, neutropenia and thrombocytopenia was found in 54 (18.0%), 8 (2.7%) and 11 (3.7%) patients, respectively. Other frequent AE’s (all grades) were nausea (90 (30%)), diarrhea (83 (27.7%)) and fatigue (178 (59.3%)). SREs were observed in 46 (15.3%) patients; 22 (7.3%) received radiotherapy, 6 (2%) developed pathologic fractures, 17 (5.6%) spinal cord compression and 1 (0.3%) received bone surgery during Ra-223 therapy. Conclusions: The non-study ROTOR population had characteristics, all grade AEs and OS comparable with the treatment arm of ALSYMPCA. Clinical trial information: NCT03223597.
Variability in functional outcome and treatment practices by treatment center after out-of-hospital cardiac arrest: analysis of International Cardiac Arrest Registry
Authors: Teresa L. May, Christine W. Lary, Richard R. Riker, Hans Friberg, Nainesh Patel, Eldar Søreide, John A. McPherson, Johan Undén, Robert Hand, Kjetil Sunde, Pascal Stammet, Stein Rubertsson, Jan Belohlvaek, Allison Dupont, Karen G. Hirsch, Felix Valsson, Karl Kern, Farid Sadaka, Johan Israelsson, Josef Dankiewicz, Niklas Nielsen, David B. Seder, Sachin Agarwal
Journal: Intensive Care Medicine (2019)
Genomic profiling of variant urinary tract tumor histologies.
Authors: Amin Nassar, Kent William Mouw, Catherine Curran, Archana Agarwal, Andres Acosta, Mark A. Preston, Matthew Mossanen, Arvind Ravi, Michelle S. Hirsch, Toni K. Choueiri, David J. Kwiatkowski, Guru Sonpavde
Journal: Journal of Clinical Oncology (2019)

450 Background: Little is known about the genomic features of rare histologic variants of urinary tract (UT) tumors. The purpose of this study is to compare the pattern of genetic alterations in UT tumors with adenocarcinoma (AD), small cell (SC), or squamous cell (SQ) histology to UT tumors with urothelial carcinoma (UC) histology. Methods: We identified patients with pure variant (AD, SC, or SQ) or UC histology evaluated at Dana Farber Cancer Institute (DFCI). Tumors with mixed histology were excluded. We employed Oncopanel, which assesses 275-447 cancer genes for somatic mutations and copy number variations (CNVs). Alterations observed at an allele frequency &gt; 0.1% in the ExAC database were assumed to be germline variants and were excluded. Mutation frequencies, CNVs, and tumor mutation burden (TMB) were determined for AD, SC, SQ, and UC, and were compared using the Fisher’s Exact test and Kruskall Wallis Test. Nominal p values were obtained, and fdr correction was employed (q &lt; 0.1). Results: Genetic data was available for 11 AD, 6 SC, 9 SQ, and 120 UC tumors. All patients had muscle-invasive disease. The mean age was 67.8 years and 74% of patients were male. Overall, UC had significantly higher TMB than AD (median = 9.5 vs median = 6 respectively, p = 0.03). There were no significant differences in the CNV count among the four subtypes. Statistically significant differences in genetic alterations by subtype are shown in the Table. ARID1A and KDM6A mutations were less common in the variant histologies; while DICER1, FBXW7, MAP2K4, and MYB alterations were higher in ≥1 variant histology. RB1 and TP53 mutations were enriched in SC tumors while SMAD4 alterations were enriched in AD tumors. Conclusions: Genetic features of variant histology UT tumors differ from those seen in UC, suggesting biological differences and possibly different therapies. Validation in larger datasets is warranted. [Table: see text]
Angiogenic and immunomodulatory biomarkers in axitinib-treated patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Brian I. Rini, Bernard Escudier, Danielle Murphy, Panpan Wang, Jamal Christo Tarazi, Robert J. Motzer
Journal: Journal of Clinical Oncology (2019)

614 Background: Axitinib (axi) is approved for 2nd-line treatment of aRCC. In AXIS trial, median progression-free survival (PFS) was significantly longer in axi- vs sorafenib (sor)-treated pts (hazard ratio [HR] 0.67, 95% CI 0.54–0.81, P&lt;0.0001). Association between mRNA/miRNA expression and clinical outcomes in a subset of axi- or sor-treated pts from AXIS was assessed. Methods: mRNA/miRNA analyses were performed on archival tumor samples. Expression was summarized for responders (complete and partial response) vs non-responders (stable and progressive disease), and for maximum percent tumor change. PFS and overall survival (OS) were analyzed by Kaplan-Meier. Results: Pt characteristics were similar between axi (n=34) and sor (n=33) arms. Association with outcomes is shown in the Table. A correlation was observed for CD68 protein and mRNA expression in axi-treated pts (R=0.4774 P=0.0043 and R=0.3985 P=0.0196, respectively). Both CXCR4 and TLR3 showed differences between treatment arms and association with PFS. TNFSF10 &lt;median, and CD163, CSF1R and miR-221-5p ≥median were associated with shorter OS with axi vs sor ( P&lt;0.05). Clinical trial information: NCT00678392. Conclusions: Immune-related biomarkers were associated with clinical outcomes in axi/sor-treated aRCC pts. Lower CCR7 expression was associated with better response and OS in axi-treated pts. CXCR4 and TLR3 may be predictive of response to axi. Analysis in a larger cohort is warranted.[Table: see text]