Citations

AbstractSrc tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP‐sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6‐month survival. A Simon MinMax two‐stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28‐day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6‐month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker‐driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin‐like growth factor‐binding protein 2 [IGFBP2] “top scoring pairs” polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker‐positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3′ untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6‐month survival endpoint. As the frequency of biomarker‐positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6‐month survival, we demonstrate that testing pancreatic tumor samples for a biomarker‐driven, multicenter study in metastatic pancreas cancer is feasible.

Background Oral steroids are commonly used in the management of chronic rhinosinusitis (CRS) with and without nasal polyps (CRSwNP and CRSsNP, respectively). Past reports have included evaluation of the evidence for the use of oral steroids in CRS subtypes. However, a review with evidence‐based recommendations for all CRS subtypes has never been performed. The purpose of this article is to provide a comprehensive, evidence‐based approach for the utilization of oral steroids in the management of CRS. A systematic review of the literature was performed following recommendations of the Clinical Practice Guideline Manual, Conference on Guideline Standardization, and Appraisal of Guidelines and Research Evaluation. Inclusion criteria were: adult population ≥18 years old; CRS; oral steroids as the treatment group; and clearly defined primary clinical end‐point. This review identified and evaluated the literature on the use of oral steroids for CRSwNP, CRSsNP, allergic fungal sinusitis (AFS), and the use of oral steroids in the perioperative period in these patients. Recommendations based on evidence, benefit/harm assessment, and value judgments are made. Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC. Methods A systematic review of the literature was performed following recommendations of the Clinical Practice Guideline Manual, Conference on Guideline Standardization, and Appraisal of Guidelines and Research Evaluation. Inclusion criteria were: adult population ≥18 years old; CRS; oral steroids as the treatment group; and clearly defined primary clinical end‐point. This review identified and evaluated the literature on the use of oral steroids for CRSwNP, CRSsNP, allergic fungal sinusitis (AFS), and the use of oral steroids in the perioperative period in these patients. Recommendations based on evidence, benefit/harm assessment, and value judgments are made. Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC. Results This review identified and evaluated the literature on the use of oral steroids for CRSwNP, CRSsNP, allergic fungal sinusitis (AFS), and the use of oral steroids in the perioperative period in these patients. Recommendations based on evidence, benefit/harm assessment, and value judgments are made. Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC. Conclusion Oral steroids are strongly recommended for short‐term management of CRSwNP. Oral steroids are also recommended for management of AFS. Oral steroid use in CRSsNP is optional due to insufficient strong evidence. Oral steroids are also strongly recommended in the perioperative period for CRSwNP and AFS. There is no recommendation for oral steroids use in the perioperative period in patients with CRSsNP. The risks of oral steroids are rare, but significant adverse effects must be considered. © 2012 ARS–AAOA, LLC.

Abstract Background: Based upon preclinical synergy and prior phase 1 study results, the clinical efficacy of flavopiridol combined with cisplatin was assessed in patients with recurrent ovarian and primary peritoneal cancers. Methods: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) followed by flavopiridol (100 mg/m2 IV, 24 h continuous infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant ovarian/primary peritoneal cancers (defined by disease progression &gt; vs. &lt;6 months following platin-based therapy). Measurable disease (RECIST criteria) – or evaluable disease plus CA125 &gt;2X the post-treatment nadir – was required, as was ECOG performance &lt;2 and exposure to only one prior treatment regimen. Results: Forty-five patients were enrolled between April 20, 2004 and March 4, 2010 – 40 platin-resistant patients (Group 1), and 5 platin-sensitive patients (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12); 39 of the 40 eligible patients have now discontinued treatment. While only 10% of all patients incurred grade 4 toxicities, grade 3 toxicities were seen in the majority (65%). The most frequent grade 3 and 4 toxicities were neutropenia (all grade 3, 17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Sensory neuropathy, grade 1 or 2, was observed in 75% of all patients – with grade 3 and 4 neuropathy not observed primarily due to pre-specified aggressive dose reductions. Six patients (15%) in Group 1 achieved a confirmed response (1 CR, 5 PR), with a median response duration of 119 days (range 84-212). Ten additional Group 1 patients (32.5%) experienced maintained stable disease. Median Group 1 overall time to progression was 3.7 months; overall survival was 17.2 months. Pilot assessment of attained ascites flavopiridol level and sensitivity of patient ascitic tumor cells to flavopiridol confirmed that patient flavopiridol levels were consistent with observed clinical antitumor efficacy. In Group 2, although 2 of 5 patients also responded (40%; 2 PR), the cohort was closed due to poor accrual. Conclusions: The combination of flavopiridol and cisplatin has promising clinical activity in both platin-sensitive and platin-resistant ovarian and primary peritoneal cancers. Supported in part by NCI CA097129, CA15083 and CM62205; clinicaltrials.gov identifier NCT00083122 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2011-4712

Relationships between artefacts in recorded intracardiac pulses and the dynamic response and susceptibility of catheter-manometer systems to artefacts caused by motion of the catheter were investigated. Sine-wave motions of the catheter, resembling motion frequently seen when the catheter is in the pulmonary artery, produce sine-wave pressure variations with peak-to-peak amplitudes of 10 mm. Hg. Square-wave motions (impacts) produce high-frequency pressure variations, greatest (10 to 200 mm. Hg) when directed along the axis and much less when perpendicular to the axis of the catheter. High-fidelity records of pressure by conventional cardiac catheter-manometer systems are most unlikely when such catheters are threaded through the beating heart.

BACKGROUND Recent studies have reported that asymptomatic left ventricular dysfunction (ALVD) in humans is characterized by early neurohumoral activation. Specifically, atrial natriuretic factor (ANF) and norepinephrine are activated without activation of the renin-angiotensin-aldosterone system (RAAS). The current study describes hemodynamic and renal function associated with this neurohumoral profile in a canine model of early and presumably "asymptomatic" ventricular dysfunction. We hypothesized that the neurohumoral profile observed in ALVD is associated with preservation of renal function despite significant hemodynamic compromise. METHODS AND RESULTS ALVD was produced by ventricular pacing at 180 beats per minute for 10 days. Intravascular volume expansion was performed before and after producing ALVD in eight conscious dogs. The model of ALVD was characterized by decreases in ejection fraction (48 +/- 2 to 29 +/- 4%), cardiac output (4.64 +/- 0.29 to 2.89 +/- 0.17 L/min), and mean arterial pressure (119 +/- 4 to 108 +/- 4 mm Hg). Atrial pressures and systemic vascular resistance were increased. ANF (60 +/- 19 to 165 +/- 27 pg/mL) and norepinephrine (382 +/- 127 to 690 +/- 211 pg/mL) were activated, whereas the RAAS was not. Creatinine clearance and sodium excretion (UNa V) were unchanged after producing ALVD. The natriuretic response to volume expansion in ALVD was completely intact, with increases in UNa V similar to that observed with volume expansion in ALVD was completely intact, with increases in UNa V similar to that observed with volume expansion before producing ALVD. CONCLUSIONS The current study demonstrates that significant ventricular dysfunction with peripheral vasoconstriction can be associated with normal renal function and thus suggests an important functional role for the neurohumoral profile of ALVD in preserving sodium balance.

This study was undertaken to ascertain whether coarctation of the aorta produces permanent hemodynamic abnormalities that may persist despite resection and end-to-end anastomosis. The results of studies in 10 patients 4 to 7 years after operation are compared to those obtained before and immediately after operation. The most significant finding was continued decrease in residual coarctation, in addition to dramatic immediate postoperative improvement in the degree of circulatory impairment.

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.