Cost-utility analysis of percutaneous mitral valve repair in inoperable patients with functional mitral regurgitation in German settings.

BACKGROUND: To determine the cost-effectiveness of the percutaneous mitral valve repair (PMVR) using Carillon® Mitral Contour System® (Cardiac Dimensions Inc., Kirkland, WA, USA) in patients with congestive heart failure accompanied by moderate to severe functional mitral regurgitation (FMR) compared to the prolongation of optimal medical treatment (OMT). METHODS: Cost-utility analysis using a combination of a decision tree and Markov process was performed. The clinical effectiveness was determined based on the results of the Transcatheter Implantation of Carillon Mitral Annuloplasty Device (TITAN) trial. The mean age of the target population was 62 years, 77% of the patients were males, 64% of the patients had severe FMR and all patients had New York Heart Association functional class III. The epidemiological, cost and utility data were derived from the literature. The analysis was performed from the German statutory health insurance perspective over 10-year time horizon. RESULTS: Over 10 years, the total cost was €36,785 in the PMVR arm and €18,944 in the OMT arm. However, PMVR provided additional benefits to patients with an 1.15 incremental quality-adjusted life years (QALY) and an 1.41 incremental life years. The percutaneous procedure was cost-effective in comparison to OMT with an incremental cost-effectiveness ratio of €15,533/QALY. Results were robust in the deterministic sensitivity analysis. In the probabilistic sensitivity analysis with a willingness-to-pay threshold of €35,000/QALY, PMVR had a 84 % probability of being cost-effective. CONCLUSIONS: Percutaneous mitral valve repair may be cost-effective in inoperable patients with FMR due to heart failure.

Impact of maternal posture on fetal physiology in human pregnancy: a narrative review.

In numerous medical conditions, including pregnancy, gravity and posture interact to impact physiology and pathophysiology. Recent investigations, for example, pertaining to maternal sleeping posture during the third trimester and possible impact on fetal growth and stillbirth risk highlight the importance and potential clinical implications of the subject. In this review, we provide an extensive discussion of the impact of maternal posture on fetal physiology from conception to the postpartum period in human pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 242 studies from 1991 through 2021, inclusive, that met our inclusion criteria. Herein, we provide a synthesis of the resulting literature. In the first section of the review, we group the results by the impact of maternal posture at rest on the cervix, uterus, placenta, umbilical cord, amniotic fluid, and fetus. In the second section of the review, we address the impact on fetal-related outcomes of maternal posture during various maternal activities (e.g., sleep, work, exercise), medical procedures (e.g., fertility, imaging, surgery), and labor and birth. We present the published literature, highlight gaps and discrepancies, and suggest future research opportunities and clinical practice changes. In sum, we anticipate that this review will shed light on the impact of maternal posture on fetal physiology in a manner that lends utility to researchers and clinicians who are working to improve maternal, fetal, and child health.

Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families.

ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.

Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases.

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.

Navigating the Regulatory Pathway for Medical Devices-a Conversation with the FDA, Clinicians, Researchers, and Industry Experts.

Successful translation of new and innovative medical products from concept to clinical use is a complex endeavor that requires understanding and overcoming a variety of challenges. In particular, regulatory pathways and processes are often unfamiliar to academic researchers and start-ups, and even larger companies. Growing evidence suggests that the successful translation of ideas to products requires collaboration and cooperation between clinicians, researchers, industry, and regulators. A multi-stakeholder group developed this review to enhance regulatory knowledge and thereby improve translational success for medical devices. Communication between and among stakeholders is identified as a critical factor. Current regulatory programs and processes to facilitate communication and translation of innovative devices are described and discussed. Case studies are used to highlight the importance of flexibility when considering evidence requirements. We provide a review of emerging strategies, opportunities, and best practices to increase the regulatory knowledge base and facilitate medical device translation by all stakeholders. Clinicians, regulators, industry, and researchers require regulatory knowledge and collaboration for successful translation of innovative medical devices.

[18F]BTK-1: A Novel Positron Emission Tomography Tracer for Imaging Bruton's Tyrosine Kinase.

PURPOSE: Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signaling, and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B cell malignancies and autoimmune disorders. Here, we describe the development of a novel positron emission tomography (PET) tracer for imaging BTK expression and/or occupancy by small molecule therapeutics. METHODS: Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]BTK-1 with a 6% decay-corrected radiochemical yield, 100 ± 6 GBq/µmol molar activity, and a radiochemical purity of 99%. Following intravenous administration of [18F]BTK-1 (3.63 ± 0.59 MBq, 0.084 ± 0.05 µg), 60-min dynamic images were acquired in two xenograft models: REC-1, an efficacious mantle cell lymphoma model, and U87MG, a non-efficacious glioblastoma model. Subsequent studies included vehicle, pretreatment (10 min prior to tracer injection), and displacement (30 min post-tracer injection) studies with different reversible BTK inhibitors to examine BTK binding. Human radiation dosimetry was estimated based on PET imaging in healthy rats. RESULTS: Uptake of [18F]BTK-1 was significantly higher in BTK expressing REC-1 tumors than non-BTK expressing U87MG tumors. Administration of BTK inhibitors prior to tracer administration blocked [18F]BTK-1 binding in the REC-1 tumor model consistent with [18F]BTK-1 binding to BTK. The predicted effective dose in humans was 0.0199 ± 0.0007 mSv/MBq. CONCLUSION: [18F]BTK-1 is a promising PET tracer for imaging of BTK, which could provide valuable information for patient selection, drug dose determination, and improving our understanding of BTK biology in humans.

Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study.

BACKGROUND: Functional mitral regurgitation (FMR), a well-recognized component of left ventricular remodeling, is associated with increased morbidity and mortality in heart failure patients. Percutaneous mitral annuloplasty has the potential to serve as a therapeutic adjunct to standard medical care. METHODS AND RESULTS: Patients with dilated cardiomyopathy, moderate to severe FMR, an ejection fraction <40%, and a 6-minute walk distance between 150 and 450 m were enrolled in the CARILLON Mitral Annuloplasty Device European Union Study (AMADEUS). Percutaneous mitral annuloplasty was achieved through the coronary sinus with the CARILLON Mitral Contour System. Echocardiographic FMR grade, exercise tolerance, New York Heart Association class, and quality of life were assessed at baseline and 1 and 6 months. Of the 48 patients enrolled in the trial, 30 received the CARILLON device. Eighteen patients did not receive a device because of access issues, insufficient acute FMR reduction, or coronary artery compromise. The major adverse event rate was 13% at 30 days. At 6 months, the degree of FMR reduction among 5 different quantitative echocardiographic measures ranged from 22% to 32%. Six-minute walk distance improved from 307+/-87 m at baseline to 403+/-137 m at 6 months (P<0.001). Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, improved from 47+/-16 points at baseline to 69+/-15 points at 6 months (P<0.001). CONCLUSIONS: Percutaneous reduction in FMR with a novel coronary sinus-based mitral annuloplasty device is feasible in patients with heart failure, is associated with a low rate of major adverse events, and is associated with improvement in quality of life and exercise tolerance.

Toward Automation of the Supine Pressor Test for Preeclampsia.

Preeclampsia leads to increased risk of morbidity and mortality for both mother and fetus. Most previous studies have largely neglected mechanical compression of the left renal vein by the gravid uterus as a potential mechanism. In this study, we first used a murine model to investigate the pathophysiology of left renal vein constriction. The results indicate that prolonged renal vein stenosis after 14 days can cause renal necrosis and an increase in blood pressure (BP) of roughly 30 mmHg. The second part of this study aimed to automate a diagnostic tool, known as the supine pressor test (SPT), to enable pregnant women to assess their preeclampsia development risk. A positive SPT has been previously defined as an increase of at least 20 mmHg in diastolic BP when switching between left lateral recumbent and supine positions. The results from this study established a baseline BP increase between the two body positions in nonpregnant women and demonstrated the feasibility of an autonomous SPT in pregnant women. Our results demonstrate that there is a baseline increase in BP of roughly 10-14 mmHg and that pregnant women can autonomously perform the SPT. Overall, this work in both rodents and humans suggests that (1) stenosis of the left renal vein in mice leads to elevation in BP and acute renal failure, (2) nonpregnant women experience a baseline increase in BP when they shift from left lateral recumbent to supine position, and (3) the SPT can be automated and used autonomously.

Identification of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors.

Tumor angiogenesis is mediated by KDR and other VEGFR and PDGFR kinases. Their inhibition presents an attractive approach for developing anticancer therapeutics. Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors. A number of compounds have been identified to be orally bioavailable and efficacious in the mouse edema model.

Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate.

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795-805. ©2018 AACR.

Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor.

In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.

Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor.

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.

Image quality of Zr-89 PET imaging in the Siemens microPET Focus 220 preclinical scanner.

PURPOSE: Zr-89 positron emission tomography (PET) is a valuable tool for understanding the biodistribution and pharmacokinetics of antibody-based therapeutics. We compared the image quality of Zr-89 PET and F-18 PET in the Siemens microPET Focus 220 preclinical scanner using different reconstruction methods. PROCEDURES: Image quality metrics were measured in various Zr-89 and F-18 PET phantoms, including the NEMA NU 4-2008 image quality phantom. Images were reconstructed using various algorithms. RESULTS: Zr-89 PET had greater image noise, inferior spatial resolution, and greater spillover than F-18 PET, but comparable recovery coefficients for cylinders of various diameters. Of the reconstruction methods, OSEM3D resulted in the lowest noise, highest recovery coefficients, best spatial resolution, but also the greatest spillover. Scatter correction results were found to be sensitive to varying object sizes. CONCLUSIONS: Zr-89 PET image quality was inferior to that of F-18, and no single reconstruction method was superior in all aspects of image quality.

Coronary sinus-based percutaneous annuloplasty as treatment for functional mitral regurgitation: the TITAN II trial.

OBJECTIVE: Functional (or secondary) mitral regurgitation (FMR) is associated with greater morbidity and worse outcomes in patients with congestive heart failure (CHF) and cardiomyopathy. The Carillon® Mitral Contour System® is a coronary sinus-based percutaneous therapy to reduce FMR. We evaluated the safety and efficacy of a modified version of the Carillon device in the treatment of patients with cardiomyopathy and FMR. METHODS: 36 patients with CHF, depressed left ventricular function (ejection fraction <40%) and at least moderate FMR underwent the Carillon device implant. RESULTS: There was 1 major adverse event within 30 days-a death (not device related)-occurring 17 days after the implant. Reductions in FMR and improvements in functional class and 6 min walk tests were seen, similar to prior studies. Device fractures in the high strain region of the proximal anchor (seen in prior studies) were not seen in this study. CONCLUSIONS: The modified Carillon device was associated with improvements in clinical and echocardiographic parameters in treating patients with FMR, while successfully addressing the issue of anchor fracture. This version of the Carillon device will be used in a blinded randomised trial of symptomatic patients with FMR.

Can preeclampsia be considered a renal compartment syndrome? A hypothesis and analysis of the literature.

The morbidity and mortality associated with preeclampsia is staggering. The physiology of the Page kidney, a condition in which increased intrarenal pressure causes hypertension, appears to provide a unifying framework to explain the complex pathophysiology. Page kidney hypertension is renin-mediated acutely and ischemia-mediated chronically. Renal venous outflow obstruction also causes a Page kidney phenomenon, providing a hypothesis for the increased vulnerability of a subset of women who have what we are hypothesizing is a "renal compartment syndrome" due to inadequate ipsilateral collateral renal venous circulation consistent with well-known variation in normal venous anatomy. Dynamic changes in renal venous anatomy and physiology in pregnancy appear to correlate with disease onset, severity, and recurrence. Since maternal recumbent position is well known to affect renal perfusion and since chronic outflow obstruction makes women vulnerable to the ischemic/inflammatory sequelae, heightened awareness of renal compartment syndrome physiology is critical. The anatomic and physiologic insights provide immediate strategies to predict and prevent preeclampsia with straightforward, low-cost interventions that make renewed global advocacy for pregnant women a realistic goal.

Percutaneous mitral annular reduction provides continued benefit in an ovine model of dilated cardiomyopathy.

BACKGROUND: Functional mitral valve regurgitation plays a key role in the symptomatic severity and progression of heart failure. In an ovine model of dilated cardiomyopathy, we examined the chronic functional consequences of mitral regurgitation reduction using a recently developed novel percutaneous mitral annular reduction (PMAR) device. METHODS AND RESULTS: Fourteen adult sheep were paced right ventricularly at 180 to 190 bpm for 5 weeks, leading to the development of moderate mitral valve regurgitation. After echocardiographic, hemodynamic, and neurohormonal analysis, 9 animals underwent PMAR. All animals were subsequently paced for another 28 days, and a final echocardiographic and hemodynamic study was conducted. Animals that had undergone PMAR showed significantly increased negative and positive dP/dt, whereas pulmonary capillary wedge pressure and mitral valve regurgitation were significantly reduced compared with those at device implant despite continued pacing. In conjunction, significant improvements in plasma norepinephrine and brain natriuretic peptide were apparent. CONCLUSIONS: The application of PMAR in animals with pacing-induced dilated cardiomyopathy and functional mitral valve regurgitation resulted in continued improvements in hemodynamic and neurohormonal parameters.

Acute and chronic reduction of functional mitral regurgitation in experimental heart failure by percutaneous mitral annuloplasty.

OBJECTIVES: We sought to determine acute and chronic efficacy of a percutaneous mitral annuloplasty (PMA) device in experimental heart failure (HF). Further, we evaluated the potential for adverse effects on left ventricular (LV) function and coronary perfusion. BACKGROUND: Reduction of mitral annular dimension with a PMA device in the coronary sinus may reduce functional mitral regurgitation (MR) in advanced HF. METHODS: Study 1: a PMA device was placed acutely in anesthetized open-chest dogs with rapid pacing-induced HF (n = 6) instrumented for pressure volume analysis. Study 2: in 12 anesthetized dogs with HF, fluoroscopic-guided PMA was performed, and dogs were followed for four weeks with continuing rapid pacing. RESULTS: Study 1: percutaneous mitral annuloplasty reduced annular dimension and severity of MR at baseline and with phenylephrine infusion to increase afterload (MR jet/left atrial [LA] area 26 +/- 1% to 7 +/- 2%, p < 0.05). Pressure volume analysis demonstrated no acute impairment of LV function. Study 2: no device was placed in two dogs because of prototype size limitations. Attempted PMA impaired coronary flow in three dogs. Percutaneous mitral annuloplasty (n = 7) acutely reduced MR (MR jet/LA area 43 +/- 4% to 8 +/- 5%, p < 0.0001), regurgitant volume (14.7 +/- 2.1 ml to 3.1 +/- 0.5 ml, p < 0.05), effective regurgitant orifice area (0.130 +/- 0.010 cm(2) to 0.040 +/- 0.003 cm(2), p < 0.05), and angiographic MR grade (2.8 +/- 0.3 device to 1.0 +/- 0.3 device, p < 0.001). In the conscious state, MR was reduced at four weeks after PMA (MR jet/LA area 33 +/- 3% HF baseline vs. 11 +/- 4% four weeks after device, p < 0.05) CONCLUSIONS: Percutaneous mitral annuloplasty results in acute and chronic reduction of functional MR in experimental HF.

Common emergent pediatric neurologic problems.

Although there are a variety of neurologic disease processes that the emergency physician should be aware of the most common of these include seizures, closed head injury, headache, and syncope. When one is evaluating a patient who has had a seizure, differentiating between febrile seizures, afebrile seizures, and SE helps to determine the extent of the work-up. Febrile seizures are typically benign, although a diagnosis of meningitis must not be missed. Educating parents regarding the likelihood of future seizures, and precautions to be taken should a subsequent seizure be witnessed, is important. The etiology of a first-time afebrile seizure varies with the patient's age at presentation, and this age-specific differential drives the diagnostic work-up. A follow-up EEG is often indicated, and imaging studies can appropriate on a nonurgent basis. Appropriate management of SE requires a paradigm of escalating pharmacologic therapy, and early consideration of transport for pediatric intensive care services if the seizure cannot be controlled with conventional three-tiered therapy. Closed head injury frequently is seen in the pediatric emergency care setting. The absence of specific clinical criteria to guide the need for imaging makes management of these children more difficult. A thorough history and physical examination is important to uncover risk factors that prompt emergent imaging. Headaches are best approached by assessing the temporal course, associated symptoms, and the presence of persistent neurologic signs. Most patients ultimately are diagnosed with either a tension or migraine headache; however, in those patients with a chronic progressive headache course, an intracranial process must be addressed and pursued with appropriate imaging. Syncope has multiple causes but can generally be categorized as autonomic, cardiac, or noncardiac. Although vasovagal syncope is the most common cause of syncope, vigilance is required to identify those patients with a potentially fatal arrhythmia or with heart disease that predisposes to hypoperfusion. As such, all patients who present with syncope should have an ECG. Additional work-up studies are guided by the results of individual history and physical examination.

FDG-PET as a pharmacodynamic biomarker for early assessment of treatment response to linifanib (ABT-869) in a non-small cell lung cancer xenograft model.

Linifanib (ABT-869) is a multitargeted receptor tyrosine kinase inhibitor. This work aims to evaluate F-fluorodeoxyglucose-positron emission tomography (FDG-PET) as a pharmacodynamic (PD) biomarker for linifanib treatment utilizing the Calu-6 model of human non-small cell lung (NSCLC) cancer in SCID-beige mice. Animals received either vehicle or 12.5 mg/kg linifanib orally twice a day for the duration of the study. Imaging was performed at -1, 1, 3, and 7 days after beginning treatment (n = 12-14 per group). Linifanib inhibited tumor growth and suppressed tumor metabolic activity. Changes in tumor FDG uptake were observed as early as 1 day after beginning linifanib treatment and were sustained for the duration of the study. This study confirms that linifanib is efficacious in this xenograft model of human NSCLC and confirms FDG-PET is a potential PD biomarker strategy for linifanib therapy.

A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model.

Tyrosine kinase inhibitors represent a class of targeted therapy that has proven to be successful for cancer treatment. Linifanib is a novel, orally active multi-targeted receptor tyrosine kinase (RTK) inhibitor that exhibits potent antitumor and antiangiogenic activities against a broad spectrum of experimental tumors and malignancies in patients. The compound is currently being evaluated in phase 2 and 3 clinical trials. To investigate the effectiveness of linifinib against gliomas and the mechanism of drug action, we characterized treatment-induced antitumor and antiangiogenic responses to linifanib in an orthotopic rat glioma model. The effect of linifanib treatment on tumor growth was determined by tumor volume assessment using anatomical magnetic resonance imaging (MRI). Changes in tumor microvessel function were evaluated with dynamic contrast-enhanced MRI (DCE-MRI). Immunohistochemistry (IHC) was applied to excised tumor samples to examine underlying changes in vascular structures and target receptor expression. Linifanib (10 mg/kg) given twice daily inhibited tumor growth following treatment for 7 days with tumor volumes being 149 ± 30 and 66 ± 7 mm(3) for vehicle-and linifanib-treated groups, respectively. A significant reduction of 37 ± 13% in tumor perfusion and microvessel permeability (measured by K (trans)) was observed as early as 2 h after administration compared with vehicle treatment. Continuous linifanib administration further reduced K (trans) at later time points until the end of the study (7 days post-treatment). At day 7, K (trans) was reduced by 75 ± 32% for linifanib treatment compared with vehicle treatment. Significant reduction in total blood vessel density and improved vessel wall integrity were observed, and staining for target receptor expression confirmed inhibition of phospho VEGFR-2 and PDGFR-ß by linifanib treatment. These results demonstrate significant antitumor and antiangiogenic activity against gliomas by linifanib, a property that may result from the inhibition of VEGFR-2 and PDGFR-ß-mediated vascular changes. DCE-MRI measured K (trans) changes at early treatment stages may be a useful pharmacodynamic marker for linifanib activity in clinical trials, and basal K (trans) may provide predictive value for tumor progression.