[Show abstract][Hide abstract] ABSTRACT: Study Objective: To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA). Design, Setting, and Participants: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures. Intervention: Active or sham CPAP Measurements: Three neurocognitive variables, each representing a neurocognitive domain: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F]) Results: The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test. Conclusions: CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.
[Show abstract][Hide abstract] ABSTRACT: To determine associations between obstructive sleep apnea (OSA) and neurocognitive performance in a large cohort of adults.
Cross-sectional analyses of polysomnographic and neurocognitive data from 1204 adult participants with a clinical diagnosis of obstructive sleep apnea (OSA) in the Apnea Positive Pressure Long-term Efficacy Study (APPLES), assessed at baseline before randomization to either continuous positive airway pressure (CPAP) or sham CPAP.
Sleep and respiratory indices obtained by laboratory polysomnography and several measures of neurocognitive performance.
Weak correlations were found for both the apnea hypopnea index (AHI) and several indices of oxygen desaturation and neurocognitive performance in unadjusted analyses. After adjustment for level of education, ethnicity, and gender, there was no association between the AHI and neurocognitive performance. However, severity of oxygen desaturation was weakly associated with worse neurocognitive performance on some measures of intelligence, attention, and processing speed.
The impact of OSA on neurocognitive performance is small for many individuals with this condition and is most related to the severity of hypoxemia.
[Show abstract][Hide abstract] ABSTRACT: To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control).
Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3.
In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected.
It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.
[Show abstract][Hide abstract] ABSTRACT: This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC).
PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued.
Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively.
Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.
Cancer Chemotherapy and Pharmacology 05/2010; 67(3):503-9. DOI:10.1007/s00280-010-1343-8 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with reduced risk of breast cancer. Sulindac, a nonselective NSAID with both cyclooxygenase-2-dependent and -independent activities, is a candidate for breast chemoprevention. We conducted a phase Ib trial in 30 women at increased risk for breast cancer to evaluate the breast tissue distribution of sulindac at two dose levels (150 mg daily and 150 mg twice daily for 6 weeks), using nipple aspirate fluid (NAF) as a surrogate of breast tissue drug exposure. We also explored the effect of sulindac on drug-induced biomarkers in NAF. We show that sulindac and its metabolites partition to human breast as measured by NAF levels. Sulindac intervention did not decrease 13,14-dihydro-15-keto prostaglandin A(2), a stable derivative of prostaglandin E(2), in NAF, but exposure was associated with a significant trend towards higher levels of growth differentiation factor 15 in NAF in women receiving 150 mg twice daily (P = 0.038). These results are the first to show partitioning of sulindac and metabolites to human breast tissue and the first evidence for a potential dose-dependent effect of sulindac on growth differentiation factor 15 levels in NAF.
Cancer Prevention Research 01/2010; 3(1):101-7. DOI:10.1158/1940-6207.CAPR-09-0120 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cycloxygenase-2 (COX-2) is overexpressed in pancreatic tumors where it may be involved in inflammation, carcinogenesis, and the regulation of neoangiogenesis. The purpose of this trial was to evaluate the combination of intravenous gemcitabine with selective COX-2 inhibitor, celecoxib for effect on survival, disease progression, and tolerability in patients with advanced pancreatic cancer. In addition, limited pharmacokinetic and pharmacodynamic analyses were preformed.
Eligible patients included those with locally advanced or metastatic pancreatic cancer with no prior chemotherapy and ECOG performance status 0-2. The treatment consisted of intravenous gemcitabine 1000 mg/m weekly x 7 weeks and concurrent daily oral celecoxib 400 mg orally twice a day. Daily oral low-dose aspirin 81 mg was administered throughout the study as a precaution for increased risk of thrombotic events. Those with stable or responsive disease were continued on intravenous gemcitabine 1000 mg/m weekly x 3 weeks and concurrent oral celecoxib.
Twenty five patients have been enrolled at 3 centers. Five patients had locally advanced cancer; 20 had metastatic disease. The most common grade 3/4 hematological toxicities were neutropenia (32%) and anemia (20%). Four patients (17%) had partial response and 7 (35%) demonstrated stable disease. The estimated 12-month survival rate was 15%, which did not reach the predetermined efficacy end point. There was a trend suggestive of correlation between a decrease in serum vascular endothelial growth factor and patient survival.
The addition of celecoxib to gemcitabine therapy did not demonstrate significant improvement in measured clinical outcomes, in patients with advanced pancreatic cancer. Higher doses of celecoxib may be needed to observe significant antitumor activity.
American journal of clinical oncology 05/2008; 31(2):157-62. DOI:10.1097/COC.0b013e31815878c9 · 3.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant bowel obstruction (MBO) is a commonly encountered palliative care problem. There have been very few comparative trials in this area, and consequently there is very little clinical evidence upon which therapy can be rationally based. The purpose of this paper is to highlight the discussion and decision-making process that was undertaken by the Clinical Protocol Subcommittee during the development of a proposed clinical trial of best medical care versus surgical or endoscopic treatment for MBO. The development of the proposed clinical trials followed an orderly process. The first step taken was a discussion of a specific definition for MBO. Once agreed upon, this definition helped identify inclusion and exclusion criteria for the proposed trial. This was followed by an extensive literature review, which helped define both surgical and endoscopic approaches to MBO as well as what constituted best medical care. An extensive discussion was then undertaken concerning the best outcome measure of success for medical, surgical, and endoscopic interventions. All of the above steps culminated in two proposed protocols, one for MBO of the small intestine distal to the ligament of Treitz and a second for colonic obstructions. The small intestinal trial is designed to compare surgical intervention versus best medical care, whereas the colonic trial seeks to compare surgery with endoscopically-placed intraluminal stents coupled with best medical care.
Journal of Pain and Symptom Management 08/2007; 34(1 Suppl):S49-59. DOI:10.1016/j.jpainsymman.2007.04.011 · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]. This review examines the clinical experience from the MDS-001 and MDS-003 clinical trials that led to this approval, the results of biological correlates supporting the targets of drug action, and the results from a non-del(5q) multicenter study (MDS-002). Lenalidomide treatment resulted in both erythroid and cytogenetic responses in the majority of patients with del(5q), accompanied by reductions in inflammatory cytokine generation and marrow microvessel density and improvement in primitive hematopoietic progenitor recovery. Central pathology review showed that resolution of cytologic dysplasia was common in patients with del(5q) but was infrequent in erythroid-responding patients without the chromosome 5 deletion. These findings indicate that lenalidomide promotes erythropoiesis in lower-risk MDS, with two apparently distinct mechanisms of action: suppression of the ineffective del(5q) clone and promotion of effective erythropoiesis in non-del(5q) MDS progenitors. These studies identified lenalidomide as a highly active erythropoietic- and cytogenetic-remitting agent in lower-risk MDS patients who otherwise would not be expected to benefit from recombinant erythropoietin therapy. The most common adverse reactions include dose-dependent neutropenia and thrombocytopenia that are more pronounced in patients with del(5q) in whom early suppression of the clone is expected.
Cancer control: journal of the Moffitt Cancer Center 01/2007; 13 Suppl(supplement 4–11):4-11. · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the size, time course, and durability of the effects of long-term continuous positive airway pressure (CPAP) therapy on neurocognitive function, mood, sleepiness, and quality of life in patients with obstructive sleep apnea.
Randomized, double-blinded, 2-arm, sham-controlled, multicenter, long-term, intention-to-treat trial of CPAP therapy.
Sleep clinics and laboratories at 5 university medical centers and community-based hospitals. Patients or Participants: Target enrollment is 1100 randomly assigned subjects across 5 clinical centers.
Active versus sham (subtherapeutic) CPAP. Measurements and Results: A battery of conventional and novel tests designed to evaluate neurocognitive function, mood, sleepiness, and quality of life.
The Apnea Positive Pressure Long-term Efficacy Study (APPLES) is designed to study obstructive sleep apnea and test the effects of CPAP through a comprehensive, controlled, and long-term trial in a large sample of subjects with obstructive sleep apnea.
Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 08/2006; 2(3):288-300. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over-expression of Aurora-A (Aurora 2 kinase, STK-15), a protein found in centrosomes thought to be associated with genetic instability, has been previously documented in prostate cancer [Pihan et al.: Cancer Res 61(5):2212-2219, 2001]. It is unknown if this protein is also over-expressed in high-grade prostatic intraepithelial neoplasia (PIN) lesions.
PIN lesions were examined for increased Aurora-A using immunohistochemical staining on archival paraffin embedded prostatectomy tissue. Aurora-A expression was scored using size, number, and staining intensity. Protein expression was examined and compared between stromal cells, normal glands, high-grade PIN lesions, and invasive cancer.
Immunohistochemistry shows an increased expression of Aurora-A in 96% of high-grade PIN cases, and 98% in cancer lesions. Twenty-nine percent of cases of normal glands from cancerous prostates also showed increased Aurora-A expression.
Over-expression of Aurora-A is present in some normal and the majority of high-grade PIN lesions indicating that this may be an early event that leads to the genetic instability seen in prostate carcinogenesis.
The Prostate 09/2005; 64(4):341-6. DOI:10.1002/pros.20247 · 3.57 Impact Factor