tbuckley/cabot-search huggingface dataset:
Dose linearity of inhaled fentanyl (FT) with comparative pharmacokinetics to transmucosal fentanyl (A)
Authors: A. P. Jekunen, C. Cotterill-Jones, P. Dewlan, T. Tanner, H. Sikorska, L. Asking, T. Jouhikainen
Journal: Journal of Clinical Oncology (2006)

8629 Background: Cancer patients frequently experience breakthrough pain which is a transitory flare of moderate or severe pain occurring on top of otherwise controlled, persistent pain. Fentanyl TAIFUN (FT), a novel breath-actuated dry powder inhaler is being developed for the treatment of breakthrough cancer pain in patients with ongoing opiate therapy. Methods: A randomized, open-label, crossover phase I study with 5 periods derived pharmacokinetics after fentanyl oromucosal (Actiq, A) and pulmonary (FT) administration in 30 healthy volunteers. Each single dose of study medication (200 mcg A; or 100, 200, 400 or 800 mcg FT) was administered following premedication with 50 mg of naltrexone with a minimum of 7 days between doses. Pharmacokinetic parameters were calculated from the plasma concentrations using a non-compartmental model. Results: The plasma concentrations of FT increased proportionally to the increasing dose and t 1/2 was independent of the dose. FT had a linear elimination phase. FT had a substantially faster absorption and higher peak fentanyl concentration (Cmax) than A. Median Tmax was 1 and 60 min for FT and A, respectively. Moreover, there was an 8-fold increase in bioavailability of fentanyl during the first 20 min when 200 mcg FT is compared to 200 mcg A. Conclusions: The plasma concentrations from FT increases proportionally to the increasing dose while t 1/2 is independent of the dose, and there is a linear elimination phase. Overall, FT is substantially more bioavailable than A during the important first 20–30 minutes after administration. Inhalation of FT allows an immediate and comparable availability of fentanyl suggesting potential for rapid pain relief. [Table: see text] [Table: see text]
Addition of ATG to Myeloablative Haplo Conditioning with Post-Transplantation Cyclophosphamide Might Decrease the Risk of Gvhd and TRM without Increasing the Risk of Relapse
Authors: Ghuzayel Al Dawsari, Mona Fawzy Ramadan Hassanein, Walid Rasheed, Fahad Almohareb, Naeem A. Chaudhri, Fahad Alsharif, Hazza Al Zahrani, Said Y Mohamed, Amr Hanbali, Syed Osman Ahmed, Marwan Shaheen, Feras Alfraih, Shahrukh Hashmi, Noura Al Hashim, Shad Ahmed, Ghada el Gohary, Wahiba Chebbo, Abdul Mannan, Maamoun Alsermani, Farhan Anjum, Muhamad Hitham Almahayni, Mahmoud Aljurf, Riad O. El Fakih
Journal: Blood (2016)
IMPACT OF FLOW, GRADIENT, AND LEFT VENTRICULAR FUNCTION ON OUTCOMES AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Edward T. Carreras, Tsuyoshi Kaneko, Fernando Ramirez-Del Val, Marc P. Pelletier, Piotr Sobieszczyk, Deepak Bhatt, Pinak Shah
Journal: Journal of the American College of Cardiology (2017)
A phase II study of foretinib in triple-negative, recurrent/metastatic breast cancer: NCIC CTG trial IND.197 (NCT01147484).
Authors: Daniel Rayson, Sasha M. Lupichuk, Stephen K. L. Chia, Kylea R. Potvin, Susan Dent, Ming Sound Tsao, Catherine Prady, Susan Ellard, Muhammad Salim, Ghassan Allo, Olga Ludkovski, Rachel Anne Goodwin, Nancy Wainman, Wendy Walsh, Pat Farmer, Elizabeth A. Eisenhauer
Journal: Journal of Clinical Oncology (2012)

1036 Background: Met, a receptor tyrosine kinase, is preferentially expressed in basal-like compared to luminal breast cancer. In murine models, overexpression of the oncogenic Met receptor transgene induces tumors with human basal gene expression characteristics supporting Met inhibition as a treatment strategy for triple negative (TN) breast cancer. Foretinib is an oral multi-kinase inhibitor of Met, RON, AXL, TIE-2 and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Methods: Patients (pts) with TN breast cancer and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. Tumor samples were centrally reviewed to confirm ER/PR/HER2 status and for correlative studies including Met, PTEN and EGFR expression. Stage 1 accrual required 23 response-evaluable Met unselected patients with accrual continuing if &gt;/= 1 response or &lt; 17 early progressions (PD &lt;= 8 weeks on study) were observed. Results: Accrual is 29 pts to date; 24 are eligible, 22 evaluable for toxicity and 15 for response. Median age is 56 y (43-81), ECOG PS 0-1 in 23/24. Grade 3 laboratory adverse events were: lymphopenia (9%), elevations in ALT (5%), GGT (5%) and INR (5%). Treatment-related non-hematologic toxicities included (all/grade 3-4) fatigue (64%/5%), nausea (55%/5%), diarrhea (41%/5%), hypertension (32%/14%), vomiting (27%/0%), anorexia (23%/5%) and rash (14%/0%). Three SAEs possibly related to foretinib included; asymptomatic pulmonary embolism, reversible CHF and pleural effusion with QTc prolongation. One PR (7%), 8 early PD (53%) and 6 SD (40%) have been observed to date with median SD duration of 5.4 months (range 2.7-5.5). Preliminary correlative results (IHC): 5/8 (62.5%) evaluable Met positive cases had SD and 4/5 (80%) Met negative cases had PD as best response. Met IHC was negative in the pt with PR. Conclusions: Foretinib shows preliminary evidence of activity and tolerability in metastatic, TN breast cancer. Stage 2 of accrual will include 15 pts with pre-treatment biopsies of metastases and circulating tumor cell collection.
Molecular profiles of prostate cancer versus today’s diagnostic tools
Authors: V. Vuaroqueaux, P. Diener, S. Eppenberger-Castori, M. Labuhn, C. Horica, T. Németh, M. Sulmoni, G. Fürstenberger, U. Eppenberger, R. Morant
Journal: Journal of Clinical Oncology (2006)

14659 Background: Tumor size, nodal status, the Gleason grading system and serum PSA values are today’s available prognostic tools of localized prostate cancer and the only help for adjuvant therapy. Based on the results of a feasibility study we continued the evaluation of the recently developed prognostic molecular signature. Methods: Of 60 CaP patients, who underwent primary prostatectomy in 2003 to 2005, fresh frozen samples of the tumor were asserved. The RNA extracted from cryocuts was tested. The quantitative RNA expression levels of 90 relevant genes involved in the different tumor hallmarks were simultaneously assessed. Results: Unsupervised agglomerative clustering of the obtained molecular profiles revealed different signatures. Correlations between these groups and the known TNM staging as well as Gleason scores were strongly present. Of interest was that all recurrences observed within this short period of time were found in a single cluster expressing higher levels of proliferation markers. Conclusions: The molecular profile of primary prostate cancer by quantitative RT-PCR is a powerful tool describing the biology of an individual tumor. Gene expression profiling can be precisely quantified and seems to be better reproducible than pathological judgments of the Gleason scores. Moreover, the gene panel is partially based on drug target genes and therefore of predictive value. Finally the method could be applied also in core biopsies. [Table: see text]
BMP Pathway Alterations in Chronic Myelogenous Leukemia Lead to the Amplification of Primitive Progenitors Output in Chronic Phase
Authors: Franck E. Nicolini, Bastien Laperoussaz, Sandrine Jeanpierre, Karen Sagorny, Bastien Kaniewski, Stephane Morisset, Stéphanie Salesse, Thibault Voeltzel, Véronique maguer-Satta
Journal: Blood (2012)
Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS).
Authors: Sant P. Chawla, Jean-Yves Blay, Antoine Italiano, Martin Gutierrez, Axel Le Cesne, Carlos Alberto Gomez-Roca, Launce G. Gouw, Margaret von Mehren, Andrew Wagner, Robert G. Maki, Brian Higgins, Steven Middleton, Gwen L. Nichols, David Geho, Steven Blotner, Jianguo Zhi, Lin Chi Chen
Journal: Journal of Clinical Oncology (2013)

10514 Background: Preclinical data demonstrate p53-dependent MIC-1 activation by both D and the MDM2 inhibitor RG7112. This study evaluated the tolerability of combining D with RG7112 in ASTS patients (pts) and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the combination. Methods: A phase 1b 3+3 dose escalation study was designed. Pts with ASTS in whom D was considered appropriate were eligible. D was administered IV at either 50 mg/m 2 or 60 mg/m 2 on day 1 with RG7112 administered orally 500 or 1000 mg QD for 3 or 5 days (d1-3 or d1-5) in 28-d treatment cycles. Safety, PK and PD, including serum MIC-1 (an indicator of p53 activation), were assessed. Results: As of January 15, 2013, enrollment was complete with 23 pts with ASTS accrued; safety data for cycle 1 was available for preliminary review in 20 pts. Growth factor support was mandated following the first dosing group (D 60 mg/m 2 and RG7112 500 mg x 5d) due to febrile neutropenia or grade 4 neutropenia. Of the 20 pts for which cycle 1 safety data is available, 13 pts reported neutropenia (12 grade 3/4); 5 reported grade 3/4 febrile neutropenia (3 following mandatory GCSF prophylaxis); 12 pts developed thrombocytopenia (9 grade 3/4). PK parameters of the combination therapy are similar to single agent values and did not demonstrate evidence of drug-drug interactions. Serum MIC-1 rapidly increased to levels greater than for either agent alone. Best response to date is stable disease in 8/16 pts who have had interim evaluations. Conclusions: Combination therapy with D and RG7112 resulted in a high rate of grade 3/4 neutropenia (60%) or thrombocytopenia (45%). PK analysis does not suggest this is due to changes in the metabolism of either drug. This combination demonstrates apparent potentiation of p53 activation demonstrated by increased MIC-1 levels greater than additive effects of the single agents. Biomarker analyses, safety, PK, and MIC-1 data will be presented. Clinical trial information: NCT01605526. [Table: see text]
Dual anti-HER2 treatment of patients with HER2-positive metastatic colorectal cancer: The HERACLES trial (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification).
Authors: Silvia Marsoni, Andrea Bertotti, Andrea Sartore-Bianchi, Francesco Leone, Sara Lonardi, Fortunato Ciardiello, Carmine Pinto, Massimo Aglietta, Vittorina Zagonel, Marcello Gambacorta, Walter Franco Grigioni, Massimo Rugge, Mauro Risio, Cosimo Martino, Emanuele Valtorta, Alberto Bardelli, Livio Trusolino, Paolo M. Comoglio, Salvatore Siena
Journal: Journal of Clinical Oncology (2013)

TPS3648 Background: We identified HER2 amplification as a potential onco-driver and marker of de novo resistance to anti-EGFR therapy in mCRC PTS for which other known genetic alterations conferring resistance to anti EGFR antibodies were excluded. Exploiting direct transfer xenografts of mCRC surgical samples in mice (xenoPTS), we conducted a multi-arm study in HER2-amplified xenoPTS showing that combinations of lapatinib (L) and trastuzumab (T), or L and pertuzumab (P) induced long-lasting tumor regressions while monotherapy with L led to stabilization and either monotherapy with T or P were ineffective (Bertotti et al. Cancer Discov 2011). The combination of P+T has a strong rationale for treatment of HER2-amplified mCRC, since combining the two agents is synergic in HER2+ breast cancers failing T (Baselga et al. JCO 2010), suggesting a cooperative mechanism of inhibition. On these findings we designed the HERACLES trial. Methods: HERACLES is an independent Phase II, 2-sequential cohort trial, assessing the response rate (RR) of T combined with either L (Cohort A) or P (Cohort B), in m CRC PTS harbouring an amplified HER2 tumor (SISH). Endpoints are RR and PFS. For each cohort sample size was calculated according to the Fleming &amp; Hern 1- stage design under identical assumptions: H0 = RR 10%, H1= RR 30%. With a =0.05, power=0.85, 27 patient are required in each cohort (54 patients overall). A or B will be considered positive if ≥ 6 responses/27 PTS are observed. Detection and quantitation of genetic alterations in circulating tumor DNA (liquid biopsy) and Her2 ECD in plasma as potential markers of secondary resistance will be done q14 days until relapse. Eligibility: CRC histology with KRAS WT, HER2 IHC 3+ ≥50% cells, prior treatment with fluoropirimidines, oxaliplatin, irinotecan, anti EGFR moABs based regimens ± Bevacizumab; measurable disease (RECIST v1.0), ECOG PS ≤1, adequate organ function. Response is assessed q8w. Treatment: L 1000 mg daily po + T 4 mg/kg iv load, then 2 mg/kg iv weekly. Enrollment: since trial start (8/12/12) 198 PTS have been HER2 screened, 10 found positive and 7 are in treatment. EudraCT number : 2012-002128-33. Clinical trial information: 2012-002128-33.
Development of a quantitative immunofluorescent method for analysis of nuclear and cytoplasmic p53 and p21 in circulating tumor cells (CTC) as biomarkers of response to p53-targeted therapy.
Authors: Jacky Woo, Weiguo Wu, Vladislava O. Melnikova, Kenna Lynn Anderes, Darren W. Davis
Journal: Journal of Clinical Oncology (2012)

e13575 Background: The tumor suppressor p53 is involved in many aspects of cell cycle control and p53 mutations are the most common genetic abnormality in solid tumors. Several diverse approaches targeting p53 signaling including activators of p53, cell cycle checkpoint inhibitors and MdM2 inhibitors are under development and will require determination of p53 status to demonstrate proof of concept and ultimately drive patient selection. Measurement of p53 status in tumor biopsies is often hindered by limited availability of tissues. Detection of p53 status in CTCs offers an alternative to biopsy. Methods: A multiplex immunofluorescent (IF) method for identification of CTCs was developed using cytokeratin, CD45 and DAPI. DO7, a p53 specific antibody, and total and phospho-p21 antibodies were optimized for multiplex detection. Bleomycin (50 mU/mL) was used to activate p53 in A549 p53 wt cells, HT29 and SkBr3 p53 mutant cells. Single cell-based IF analysis was performed pre and post treatment by quantitative Laser Scanning Cytometry (LSC). Results: Wild type A549 cells expressed lower baseline levels of nuclear p53 compared to mutant p53 cell lines HT29 and SKBr3. Total and phosphorylated p21 was also lower in A549 cells compared to HT29 and SKBr3 cells. Bleomycin treatment of wt A549 cells led to a transient increase in p53 expression by 30% while mutant HT29 and SKBr3 cells did not show any change in p53. Treatment of A549 cells with bleomycin led to a 100% increase in total p21and a 70% increase in phosphorylated p21. No change in p21 was observed in p53 mutant HT29 and SKBr3 cell lines. Conclusions: We developed a sensitive, quantitative method for detection of nuclear and cytoplasmic p53 and p21 protein in cell lines that functionally discriminates between p53 wt and p53 mutant status. The method is transferable to circulating tumor cells (CTCs) and may have utility in selecting patients based on functional p53 status and predicting responses to p53 pathway targeted agents.
Wireless Power Transfer Strategies for Implantable Bioelectronics
Authors: Kush Agarwal, Rangarajan Jegadeesan, Yong-Xin Guo, Nitish V. Thakor
Journal: IEEE Reviews in Biomedical Engineering (2017)

Neural implants have emerged over the last decade as highly effective solutions for the treatment of dysfunctions and disorders of the nervous system. These implants establish a direct, often bidirectional, interface to the nervous system, both sensing neural signals and providing therapeutic treatments. As a result of the technological progress and successful clinical demonstrations, completely implantable solutions have become a reality and are now commercially available for the treatment of various functional disorders. Central to this development is the wireless power transfer (WPT) that has enabled implantable medical devices (IMDs) to function for extended durations in mobile subjects. In this review, we present the theory, link design, and challenges, along with their probable solutions for the traditional near-field resonant inductively coupled WPT, capacitively coupled short-ranged WPT, and more recently developed ultrasonic, mid-field, and far-field coupled WPT technologies for implantable applications. A comparison of various power transfer methods based on their power budgets and WPT range follows. Power requirements of specific implants like cochlear, retinal, cortical, and peripheral are also considered and currently available IMD solutions are discussed. Patient's safety concerns with respect to electrical, biological, physical, electromagnetic interference, and cyber security from an implanted neurotech device are also explored in this review. Finally, we discuss and anticipate future developments that will enhance the capabilities of current-day wirelessly powered implants and make them more efficient and integrable with other electronic components in IMDs.
Phase II pharmacodynamic study of the fibroblast activation protein inhibitor Val-boro-Pro in patients with metastatic colorectal cancer
Authors: J. D. Cheng, S. J. Cohen, B. Stzempkowski-Brun, K. Magalong, V. J. Christiansen, P. A. McKee, R. K. Alpaugh, H. Lee, L. M. Weiner, N. J. Meropol
Journal: Journal of Clinical Oncology (2006)

3594 Background: Fibroblast activation protein (FAP) is selectively expressed by carcinoma stromal fibroblasts, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. FAP potentiates tumor growth in a murine model of human epithelial cancers. Val-boro-Pro, a boronic acid inhibitor of FAP protease activity, attenuates tumor growth in a mouse colorectal cancer model characterized by FAP expression by tumor-associated fibroblasts. We therefore initiated this first clinical trial of Val-boro-Pro in patients with colorectal cancer. Methods: Patients (pts) with previously treated, measurable metastatic colorectal cancer (CRC) were initially treated with 400 μg of Val-boro-Pro orally twice daily continuously. Due to unacceptable toxicities in the first 3 patients (including 1 grade 5 renal failure), the starting dose was reduced to 200 μg orally twice daily, with intrapatient dose escalation to 300 μg bid permitted after 4 weeks. The primary endpoint is response rate, with secondary endpoints including time to progression, and in vivo laboratory correlates of FAP inhibitory activity. Results: 20 patients (12 women, 8 men) with ECOG performance status 0–1 have been treated at 200 μg orally twice daily. The median age is 58 (range 41–80). At 200 μg bid, grade 1–2 adverse events include fatigue (12 pts), anorexia (7 pts), edema (7 pts), and fever (5 pts). The most common laboratory abnormalities are grade 1–2 anemia (7 pts), elevated alkaline phosphatase (4 pts), and hypoalbuminemia (3 pts). Grade 3–4 events are elevated alkaline phosphatase (1 pt, grade 3) and headache/syncope (1 pt, grade 3). Analyses of the first 9 patient plasma samples demonstrate a 92% (S.D. 2%) inhibition of dipeptidyl peptidase activity, and 22% increase in the FAP substrate α 2 -antiplasmin. Conclusions: Val-boro-Pro 200 μg orally bid is biologically active and well-tolerated, with toxicities likely related to cytokine upregulation. A planned interim analysis for clinical response will be conducted after treatment of 23 evaluable patients. The selectivity of FAP expression for tumor fibroblasts provides a unique opportunity to investigate and manipulate stromal contributions to tumor growth and invasion. No significant financial relationships to disclose.
IS VITAMIN D DEFICIENCY A RISK FACTOR FOR SEVERE CORONARY ARTERY DISEASE AND ACUTE CORONARY SYNDROME
Authors: Amar N. Patnaik, Pankajkumar A. Kasar, Raju V.R.C. Pusapati, K. Jagadishbabu, Naveenkrishna Kamana, Ramesh Gudapati
Journal: Journal of the American College of Cardiology (2017)
THE CLOSE RELATIONSHIP BETWEEN DRUG INTOLERANCE AND MAJOR CARDIAC AND CEREBROVASCULAR EVENTS AFTER AN ACUTE CORONARY SYNDROME OR CORONARY REVASCULARIZATION
Authors: Sara Doimo, Stefano Albani, Alessandro Altinier, Patrizia Maras, Giulia Barbati, Gianfranco Sinagra
Journal: Journal of the American College of Cardiology (2017)
A HOSPITAL LEVEL ANALYSIS OF 30-DAY READMISSION RATES FOR HEART FAILURE PATIENTS AND LONG-TERM SURVIVAL AMONG HIGHEST AND LOWEST PERFORMING HOSPITALS, FINDINGS FROM GET WITH THE GUIDELINES-HEART FAILURE
Authors: Sawan Jalnapurkar, Xin Zhao, Paul Heidenreich, Deepak Bhatt, Eric Smith, Adam DeVore, Adrian Hernandez, Roland Matsouaka, Clyde Yancy, Gregg Fonarow
Journal: Journal of the American College of Cardiology (2017)
HEALTH DISPARITIES AMONG PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA IN THE CASCADE-FH PATIENT REGISTRY
Authors: Stephen M. Amrock, Bart Duell, Thomas Knickelbine, Seth Martin, Peter Shrader, Emily O'Brien, Karol Watson, Joanna Mitri, Iris Kindt, Joshua Knowles, Zahid Ahmad
Journal: Journal of the American College of Cardiology (2017)
Pharmacokinetic (PK) guided optimization of 5-fluorouracil (5-FU) dosing in the treatment of patients with colorectal cancer (CRC).
Authors: Gaurav Goel, Edward Chu, Min Sun, Dennis James Meisner, James J. Lee
Journal: Journal of Clinical Oncology (2014)

e14561 Background: 5-FU has been the backbone of systemic combination chemotherapy for treatment of CRC in the adjuvant and metastatic disease settings. The dosing of 5-FU has traditionally been based on body surface area (BSA). Growing evidence suggests that BSA-based 5-FU dosing has several limitations, and that PK-guided dosing of 5-FU improves clinical efficacy with reduced toxicity. We conducted this Quality Improvement project to evaluate the clinical feasibility of PK-guided 5-FU dose adjustment and its impact on clinical outcome. Methods: CRC patients treated with combination chemotherapy regimens containing infusional 5-FU at the UPMC Cancer Center who underwent PK-guided optimization of 5-FU dosing using an immunoassay (OnDose or MyCare) were included in the analysis. Results: A total of 21 patients (8 males, 13 females) meeting the entry criteria have been identified to date. The median age was 61 years (range, 41-82). Six patients had stage III disease, and the remaining 15 patients had stage IV disease. The 5-FU infusional regimens included FOLFOX6 (N=18) and FOLFIRI (N=3). A total of 49 5-FU PK tests were performed for these 21 patients. The median number of tests performed per patient was 2 (range, 1-4). On initial testing, only 19% (N=4) patients had 5-FU systemic exposure, measured as an area under the curve (AUC), within the suggested target range of 20-30 mg.hr/L (67% (N=14) patients were below while 14% (N=3) patients were above the target range). Of the 14 patients below the target range on initial testing, 5-FU doses were increased in 11 patients for the subsequent treatment cycle. The median number of dose modifications required to achieve the target PK levels in these patients was 1 (range, 1-2). The majority of these patients (82%, N=9) tolerated the increased 5-FU dose well without worsening of 5-FU related toxicity. Conclusions: Our data shows that 5-FU dosing based on BSA results in sub-optimal 5-FU exposure levels for the majority of patients (81%). PK-guided dose adjustment of 5-FU appears to be a practical and feasible approach to personalize optimal 5-FU exposure with potential for application in routine clinical practice.
LEFT VENTRICULAR GLOBAL LONGITUDINAL STRAIN PREDICTS ALL-CAUSE MORTALITY IN PATIENTS WITH MITRAL REGURGITATION AND ISCHEMIC HEART DISEASE BUT NOT IN NONISCHEMIC MITRAL REGURGITATION
Authors: Daniel Pu, Anthony Holmes, Ningxin Wan, Lili Zhang, Cynthia Taub
Journal: Journal of the American College of Cardiology (2017)
RELATIONSHIP BETWEEN CORONARY PHYSIOLOGICAL PARAMETERS AND CARDIAC BIOMARKERS IN PATIENTS UNDERGOING INVASIVE CORONARY ANGIOGRAPHY
Authors: Rikuta Hamaya, Taishi Yonetsu, Tadashi Murai, Yoshihisa Kanaji, Masahiro Hoshino, Masahiro Hada, Takayuki Niida, Sadamitsu Ichijo, Yoshinori Kanno, Tsunekazu Kakuta
Journal: Journal of the American College of Cardiology (2017)