tbuckley/cabot-search huggingface dataset:
A phase 2 open-label study of the efficacy of ABT-199 (GDC-0199) in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) harboring 17p deletion.
Authors: William G. Wierda, John Francis Seymour, Andrew Warwick Roberts, Soham Puvvada, Matthew Steven Davids, Shekman Wong, Ming Zhu, Elisa Cerri, Rod Humerickhouse, Stephan Stilgenbauer
Journal: Journal of Clinical Oncology (2014)

TPS7121 Background: Evasion of apoptosis is a hallmark of cancer. Overexpression of the anti-apoptotic Bcl-2 protein is associated with tumorigenesis and resistance to chemotherapy. ABT-199 is a selective, potent, orally bioavailable small molecule Bcl-2 antagonist that works by directly relieving the inhibition of apoptosis, downstream of p53. Preliminary phase 1 data with ABT-199 indicate promising therapeutic activity, with a greater than 80% overall response rate in patients (pts) with heavily pretreated CLL, independent of poor prognostic indicators including 17p deletion [del(17p)]. This Phase 2 multinational study is designed to evaluate ABT-199 monotherapy in patients with R/R CLL harboring del(17p). Methods: ABT-199 treatment starts with a lead-in 20mg daily dosing period with weekly dose increases up to 400 mg daily as the study final dose. Treatment continues once daily until progression or discontinuation for toxicity. Study visits are weekly through week 4 or 5, every 4 weeks until week 36, and every 12 weeks thereafter. Key eligibility criteria include relapsed or refractory CLL harboring del(17p) in ≥7% of cells, as determined by central diagnostics; clinically measurable disease; and no previous allogeneic hematopoietic cell transplant (alloHCT), evidence of Richter’s transformation, or uncontrolled autoimmune cytopenias. The primary objective of this study is to evaluate overall response rate (ORR), using IWCLL 2008 criteria. Secondary objectives are to evaluate the complete remission rate, partial remission rate, duration of response, progression-free survival, time to progression, overall survival, and the percentage of pts who are able to proceed to alloHCT. Minimal residual disease status in the peripheral blood and bone marrow will be assessed as an exploratory objective. Pharmacokinetic data will be evaluated using a population approach. The ORR for ABT-199 will be tested to reject the null hypothesis of a 40% ORR once 70 pts have completed 6 months of treatment or after all enrolled pts have discontinued ABT-199, whichever is earlier. The study began in June, 2013 and is currently enrolling patients. (NCT01889186) Clinical trial information: NCT01889186.
T1 MAPPING ASSESSES DIAGNOSIS, SEVERITY AND PROGNOSIS IN ACUTE MYOCARDITIS
Authors: Chirag Agarwal, Carlos Santos-Gallego, Juan Antonio Requena-Ibanez, Allen Weiss, Rebecca Smoller, Valentin Fuster, Juan Badimon, Angel Sanz Salvo
Journal: Journal of the American College of Cardiology (2017)
POOR AGREEMENT BETWEEN TRANSTHORACIC ECHOCARDIOGRAPHY AND RIGHT HEART CATHETERIZATION FOR ASSESSMENT OF PULMONARY HYPERTENSION SEVERITY: CLINICAL APPLICATIONS IN THE TAVR ERA
Authors: Islam Abdelkarim, Jeffrey Xu, Michael Sharbaugh, Andrew Althouse, William Katz, Frederick Crock, Matthew Harinstein, Dustin Kliner, Forozan Navid, Joon Lee, John Schindler, Thomas Gleason, Joao L. Cavalcante
Journal: Journal of the American College of Cardiology (2017)
Trends in Suicide by Level of Urbanization — United States, 1999–2015
Authors: Scott R. Kegler, Deborah M. Stone, Kristin M. Holland
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Suicide is a major and continuing public health concern in the United States. During 1999-2015, approximately 600,000 U.S. residents died by suicide, with the highest annual rate occurring in 2015 (1). Annual county-level mortality data from the National Vital Statistics System (NVSS) and annual county-level population data from the U.S. Census Bureau were used to analyze suicide rate trends during 1999-2015, with special emphasis on comparing more urban and less urban areas. U.S. counties were grouped by level of urbanization using a six-level classification scheme. To evaluate rate trends, joinpoint regression methodology was applied to the time-series data for each level of urbanization. Suicide rates significantly increased over the study period for all county groupings and accelerated significantly in 2007-2008 for the medium metro, small metro, and non-metro groupings. Understanding suicide trends by urbanization level can help identify geographic areas of highest risk and focus prevention efforts. Communities can benefit from implementing policies, programs, and practices based on the best available evidence regarding suicide prevention and key risk factors. Many approaches are applicable regardless of urbanization level, whereas certain strategies might be particularly relevant in less urban areas affected by difficult economic conditions, limited access to helping services, and social isolation.
Report of first-stage accrual for NCI 5886, a phase II study of erlotinib, carboplatin and paclitaxel as first-line treatment of ovarian cancer
Authors: S. V. Blank, J. P. Curtin, N. A. Goldman, C. D. Runowicz, J. L. Speyer, A. D. Tiersten, J. Dancey, S. Wadler, F. M. Muggia
Journal: Journal of Clinical Oncology (2006)

5076 Background: Abnormalities in the EGFR pathway are thought to play a major role in the dysregulated growth of ovarian and related epithelial cancers. The purpose of this study is to determine whether the addition of erlotinib (erl) to the standard first line regimen of paclitaxel (T) and carboplatin (CB) encourages pathologic complete response (pCR) in patients (pts) with ovarian (OC), fallopian tube (FTC) or primary peritoneal (PPC) cancers. Tolerability and toxicity data have been previously reported (ASCO 2005). Correlative studies of EGFR and related pathways are being performed, but data is insufficient currently for presentation. Methods: Pts with a histologic diagnosis of OC, FTC or PPC Stage III or IV with either optimal (≤ 1 cm) or suboptimal residual disease within 12 weeks of initial surgery were eligible for enrollment. Pts received T (175 mg/m 2 ) and CB (AUC 6) every 21 days, along with erl (150 mg) by mouth, daily, continuously, for a planned 6 cycles, after which pts underwent surgical reassessment to determine pCR. Data were analyzed as two parallel phase II trials in the strata of Stage III optimal (Op) and Stage III suboptimal/Stage IV (S). Both trials followed Simon’s two-stage design, with planned first stage sample sizes of 28 (Op) and 19 (S). Early stopping rules applied for ≤ 11 pCR in Op pts, and ≤3 responses in S pts. Results: Since June 2003, 47 pts have been accrued, 29 Op and 18 S. In the Op stratum, 19 second looks (SL) were performed: 10 negative, revealing pCR, and 9 positive. Two patients elected not to have SL. Six Op pts discontinued treatment prior to completion, and four pts in this group continue treatment. In the S stratum, 7 pts were treated neoadjuvantly, and 1 pt is Stage IV. Surgical reassessment was performed in 5 of the 18 S pts, all of whom had dramatic responses, but not pCR. One pt’s disease did not respond enough to the regimen to warrant surgical reassessment. One pt was ineligible, 8 discontinued treatment, and 3 continue treatment. Conclusions: First stage accrual goals have been met, and demonstrate enough activity of erl, T and Cb in OC, FTC and PPC to proceed with second stage accrual. In the S cohort, criteria for proceeding with the study are being reassessed to account for early dropouts and neoadjuvant treatment. No significant financial relationships to disclose.
Predictors of pathologic complete response (pCR) after neoadjuvant chemoradiation (Neo CRT) for rectal cancer: A multicenter population-based study.
Authors: Dawn Elizabeth Armstrong, Haider Ali, Erin Diana Powell, Julie A. Price Hiller, Patricia Tang, D. Gwyn Bebb, Scot D. Dowden, Vincent Channing Tam, Sasha M. Lupichuk, Anthony MacLean, Jacob C. Easaw, Janine Marie Davies, Daniel Yick Chin Heng, Michael M. Vickers
Journal: Journal of Clinical Oncology (2012)

e14073 Background: pCR to Neo CRT for rectal cancer is associated with better outcomes and used as an early indicator of response. To assess the rate and predictors of pCR, as well as access to care, we performed a retrospective study in two Canadian provinces. Methods: Cancer registries identified consecutive patients with clinical stage I-III rectal cancer from the Tom Baker Cancer Center, Cross Cancer Institute, and Dr. H. Bliss Murphy Cancer Centre who received Neo CRT and had curative intent surgery (Sx) from 2005 to 2011. Patient, tumor and therapy characteristics were correlated with response. Results: 301 patients were included of which 59 (19.6%) had a pCR to Neo CRT. At a median follow-up of 17 months, disease free survival was 96.7% for pCR vs 82.3% for non-pCR (p=0.005). 43 (73%) patients with pCR received adjuvant chemotherapy including bolus FU 27 (63%), capecitabine 10 (23%) and oxaliplatin-based 6 (14%). Median time from diagnosis to consult was 4 weeks (wks), from consult to start of Neo CRT 3.3 wks and start of CRT to Sx 13 wks. On multivariate analysis a low pre-op CEA (p=0.0323) was a significant independent predictor of pCR while statin use at initial consult (p=0.077) and higher pre-op hemoglobin (p=0.0974) trended toward significance when adjusted for clinical stage. Conclusions: Rates of pCR in a population based setting are substantial. A lower pre-op CEA is associated with a pCR to Neo CRT. Statin use and pre-op hemoglobin require further investigation. Our access to care data provides a baseline for future comparisons. [Table: see text]
PRECISELY CONTROLLED ARTERIAL CO2 CAN POTENTIATE MYOCARDIAL BLOOD FLOW TO THE SAME EXTENT AS ADENOSINE: A PRECLINICAL STUDY IN CANINES WITH 13N-AMMONIA PET
Authors: Hsin-Jung Yang, Damini Dey, Jane Sykes, Michael Klein, John Butler, Michael Kovacs, Olivia Sobczyk, Behzad Sharif, Xiaoming Bi, Avinash Kali, Ivan Cokic, Richard Tang, Roya Yumul, Antonio Conte, Sotirios Tsaftaris, Mourad Tighiouart, Debiao Li, Piotr Slomka, Daniel Berman, Frank Prato, Joseph Fisher, Rohan Dharmakumar
Journal: Journal of the American College of Cardiology (2017)
The Host Genetic Background of DNA Repair Mechanisms Represents An Independent Predictor of Progression and Survival in Diffuse Large B-Cell Lymphoma Treated with R-CHOP.
Authors: Davide Rossi, Silvia Rasi, Alberto Fabbri, Francesco Forconi, Marco Fangazio, Alessio Bruscaggin, Silvia Franceschetti, Lorenzo De Paoli, Alessia Puma, Ricardo Bruna, Annalisa Chiappella, Enrico M. Pogliani, Francesco Lauria, Umberto Vitolo, Gianluca Gaidano
Journal: Blood (2009)
THE PRESENCE OF FRAGMENTED QRS COMPLEXES EARLY AFTER ACUTE MYOCARDIAL INFARCTION IS ASSOCIATED WITH SUBSEQUENT LACK OF FAVORABLE LEFT VENTRICULAR REMODELING
Authors: Derek Chew, Rozsa Sas, Haris Vaid, Katherine Kavanagh, Caroline Liong Eng Tan-Mesiatowsky, Danielle Southern, Andrew Howarth, James White, Stephen Wilton, Derek Exner
Journal: Journal of the American College of Cardiology (2017)
INFERIOR VENA CAVA THROMBOSIS COMPLICATING VENA CAVA FILTER RETRIEVAL IN THE SETTING OF VENA CAVA PSEUDO-ANEURYSM AND HEPARIN INDUCED THROMBOCYTOPENIA
Authors: Harish Jarrett, Ganesh Athappan, Scott Golarz, Riyaz Bashir
Journal: Journal of the American College of Cardiology (2017)
DERIVATION AND VALIDATION OF A SIMPLE INFLAMMATION BASED RISK SCORE FOR PREDICTING IN-HOSPITAL MORTALITY IN ACUTE CORONARY SYNDROME
Authors: Hector Gonzalez-Pacheco, Rafael Bojalil, Luis Amezcua-Guerra, Julio Sandoval, Guering Eid-Lidt, Alexandra Arias-Mendoza, Francisco Azar Manzur, Amada Alvarez, Alfredo Altamirano, Jose Luis Briseño De La Cruz, Carlos Martinez-Sanchez
Journal: Journal of the American College of Cardiology (2017)
CARDIAC DIFFUSION WEIGHTED IMAGE IN PATIENTS WITH CARDIAC SARCOIDOSIS: COMPARISON TO 18F-FLUDEOXYGLCOSE PET
Authors: Kenji Fukushima, Yasuhiro Goto, Michinobu Nagao, Mitsuru Momose, Masami Yoneyama, Yamato Shimomiya, Naoki Serizawa, Eri Watanabe, Nobuhisa Hagiwara, Shuji Sakai
Journal: Journal of the American College of Cardiology (2017)
GUIDELINES ALLOWING CONTROL OF HYPERTENSION IN NON-DIABETICS GREATER THAN 60 YEARS OLD AT UP TO 150 MMHG AVERAGE SYSTOLIC BLOOD PRESSURE INCREASES PATIENT MORTALITY IN VETERANS
Authors: Ross Fletcher, Hans Moore, Richard Amdur, Raya Kheirbek, Farrokh Alemi, David Maron, Charles Faselis, Vasilios Papademetriou, Ronald E. Jones
Journal: Journal of the American College of Cardiology (2017)
INCREMENTAL ROLE OF RESTING MYOCARDIAL COMPUTED TOMOGRAPHY PERFUSION FOR PREDICTING PHYSIOLOGICALLY SIGNIFICANT CORONARY ARTERY DISEASE: A MACHINE LEARNING METHOD APPROACH
Authors: Donghee Han, Ji Hyun Lee, Asim Rizvi, Kimberly Elmore, Heidi Gransar, Briain O. Hartaigh, Fay Lin, James Min, Guanglei Xiong
Journal: Journal of the American College of Cardiology (2016)
A phase I trial of the farnesyltransferase (FT) inhibitor, BMS-214662 (B) in combination with paclitaxel (P) and carboplatin (C) in patients with advanced cancer
Authors: G. K. Dy, L. M. Bruzek, G. A. Croghan, S. Mandrekar, P. Peethambaram, L. J. Hanson, C. Erlichman, S. Cheng
Journal: Journal of Clinical Oncology (2004)

3066 Background: FT, has emerged as an important target for cancer therapy. B, a parenterally-administered FT inhibitor, has enhanced potency against quiescent cells in vitro. The combination of P and C is broadly active and exhibited cytotoxic synergy with P in human tumor xenograft models. Methods: A phase I study was performed to define the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and clinical activity of the combination of escalating doses of P(IV d1) and C(IV d1) followed by B(IV d1), on a 21-day cycle in patients (pts) with advanced cancers. In vivo target inhibition was evaluated by FT enzyme assays and inhibition of HDJ2 farnesylation in peripheral blood mononuclear cells. Results: 32 pts received 141 cycles of treatment through 6 dose levels. Significant treatment-related toxicities in all cycles of treatment graded by NCI CTC (cumulative events in all cycles, CTC grade) were neutropenia (33 grade 3, 26 grade 4), thrombocytopenia ( 4 grade 3), leukopenia (34 grade 3, 12 grade 4), peripheral neuropathy ( 1 grade 3), nausea (3 grade 3), vomiting (1 grade 3) fatigue (4 grade 3) and diarrhea (1 grade 3). DLTs were neutropenia, severe nausea and vomiting. Two PRs were documented (relapsed ovarian cancer, taxane-resistant esophageal cancer). Regression of evaluable endometrial cancer was seen. Stable disease (> 4 cycles) occurred in 10 pts. MTD was defined at dose level 4. B Clp and t1/2 were not significantly altered by prior administration of P. Dose-dependent reversible FT inhibition occurred. Conclusions: The combination of B with P and C is biologically effective and well-tolerated. No significant financial relationships to disclose.
Identification of a DNA Damage–Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers
Authors: Jing Chen, John Crutchley, Dadong Zhang, Kouros Owzar, Michael B. Kastan
Journal: Cancer Discovery (2017)

Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here, we identify and characterize a DNA-damage response (DDR) pathway that regulates alternative splicing of numerous gene products, including the human tumor suppressor TP53, and controls DNA damage-induced cellular senescence. In brief, ionizing radiation (IR) inhibits the activity of SMG1, a phosphoinositide-3-kinase-like kinase family member, reducing the binding of SMG1 to a specific region near exon 9 of p53 precursor mRNA and promoting the binding of ribosomal protein L26 (RPL26) to p53 pre-mRNA. RPL26, in turn, is required for the recruitment of the serine/arginine-rich splicing factor SRSF7 to p53 pre-mRNA and generation of alternatively spliced p53β RNA. Disruption of this pathway via selective knockout of p53β by CRISPR/Cas9 or downregulation of pathway constituents significantly reduces IR-induced senescence markers, and cells lacking p53β expression fail to transcriptionally repress negative regulators of cellular senescence and aging.Significance: We identified a new component of the DDR pathway that regulates alternative splicing of messenger RNAs, including human TP53 mRNA. Modulation of this regulatory pathway affects DNA-damage induction of cellular senescence markers. Cancer Discov; 7(7); 766-81. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.
IMPROVING PROCEDURAL SUCCESS AND REDUCING COMPLICATIONS IN ENDOVASCULAR TREATMENT OF SUPERFICIAL FEMORAL ARTERY IN-STENT RESTENOSIS IN THE PRESENCE OF OBSTRUCTIVE TIBIAL OUTFLOW DISEASE: RETROGRADE TRANSPEDAL ACCESS APPROACH
Authors: Apurva Patel, Roosha Parikh, John Coppola, Joseph Puma, Tak Kwan
Journal: Journal of the American College of Cardiology (2017)
Cdk5 links with DNA damage response and cancer
Authors: Wan Liu, Jun Li, Yu-Shu Song, Yue Li, Yu-Hong Jia, Hai-Dong Zhao
Journal: Molecular Cancer (2017)

As an atypical member of cyclin dependent kinase family, Cyclin dependent kinase 5 (Cdk5) is considered as a neuron-specific kinase in the past decade due to the abundant existence of its activator p35 in post-mitotic neurons. Recent studies show that Cdk5 participates in a series of biological and pathological processes in non-neuronal cells, and is generally dysregulated in various cancer cells. The inhibition or knockdown of Cdk5 has been proven to play an anti-cancer role through various mechanisms, and can synergize the killing effect of chemotherapeutics. DNA damage response (DDR) is a series of regulatory events including DNA damage, cell-cycle arrest, regulation of DNA replication, and repair or bypass of DNA damage to ensure the maintenance of genomic stability and cell viability. Here we describe the regulatory mechanisms of Cdk5, its controversial roles in apoptosis and focus on its links to DDR and cancer.
Safety and Efficacy of Total Dose Infusion of Low Molecular Weight (LMW) Iron Dextran in a Large Population of Anemic Patients Across a Broad Spectrum of Diagnoses Associated with Iron Lack
Authors: Tahir Mehmood, Khine Swe, Gopimohan Das, Aysegul Gozu, Michael Auerbach, Sein Aung
Journal: Blood (2014)
Updated survival results from a randomized, dose-ranging phase II study of nivolumab (NIVO) in metastatic renal cell carcinoma (mRCC).
Authors: Elizabeth R. Plimack, Hans J. Hammers, Brian I. Rini, David F. McDermott, Bruce Redman, Timothy Kuzel, Michael Roger Harrison, Ulka N. Vaishampayan, Harry A. Drabkin, Saby George, Theodore F. Logan, Kim Allyson Margolin, Li-an Xu, Ian Waxman, Robert Motzer
Journal: Journal of Clinical Oncology (2015)

4553 Background: NIVO, a programmed death-1 immune checkpoint inhibitor, demonstrated encouraging clinical activity in a randomized phase II study in pts with mRCC pretreated with targeted VEGF pathway agents. Here we present updated survival results. Methods: NIVO was administered at 0.3, 2, or 10 mg/kg IV Q3W until progression or toxicity to pts with clear-cell mRCC ( ≤ 3 prior systemic therapies, ≥ 1 agent targeting VEGF pathway). Treatment beyond progression was allowed in pts who tolerated NIVO and experienced clinical benefit. Primary endpoint (progression-free survival) was reported previously. Other endpoints included overall survival (OS), adverse event rate, and association of tumor PD-L1 expression with clinical outcomes. OS was calculated by Kaplan-Meier method. PD-L1 expression was measured in archival tumor tissue by immunohistochemistry (28-8 antibody; Dako). PD-L1 positivity was defined as ≥ 5% tumor membrane staining. Data cutoff, January 6, 2015. NCT01354431. Results: 168 pts were randomized.Of the treated pts (n = 59, 54, and 54 at 0.3, 2, and 10 mg/kg, respectively), 55 (33%) continue on study; 14 (8%) remain on treatment. Median doses given (range) was 6 (1–54), 7.5 (1–56), and 8 (1–59) for 0.3, 2, and 10 mg/kg, respectively. Median OS and OS rate are presented in the table. 64% of pts were evaluable for PD-L1 expression, 27% of whom had PD-L1 expression ≥ 5%. Median OS (80% CI) was 29.9 mo (13.4–not available [NA]) in the PD-L1+ subgroup and 18.2 mo (12.7–27.2) in the PD-L1– subgroup across doses. OS by MSKCC risk group and number of prior therapies, as well as long-term safety, will be presented. Conclusions: NIVO continues to demonstrate OS benefit across dose levels and in PD-L1+ and PD-L1– pts in this phase II mRCC study with 3 years minimum follow-up. Survival rates at 2 and 3 years compare favorably with other therapies in this setting of heavily pretreated pts with clear-cell mRCC and suggest potential for pts to achieve long-term survival with NIVO treatment. A phase III confirmatory study is underway. Clinical trial information: NCT01354431. NIVO, Q3W 0.3 mg/kg n = 59 2 mg/kg n = 54 10 mg/kg n = 54 Median OS, mo (80% CI) 18.5 (16.7–NA) 25.5 (19.8–31.2) 24.8 (15.3–26.0) OS rate, % 12 mo 63 72 70 24 mo 42 53 52 36 mo 33 40 32
Assessment of Stable Coronary Lesions
Authors: Deepak L. Bhatt
Journal: New England Journal of Medicine (2017)

In recent years, concerns have been raised about the appropriateness of performing percutaneous coronary intervention (PCI) in patients with stable coronary artery disease.1 One objective measure that is used to assess the potential benefit of revascularization is fractional flow reserve (FFR). FFR measurements, which allow for accurate assessment of stenosis severity, are obtained during an interventional procedure, in which the drop in pressure is measured across the lesion at rest and again after pharmacologic induction of hyperemia to increase flow through the lesion. Multiple randomized trials have established that lesions with normal FFR measurements can be managed medically without an . . .