Citations

BackgroundBiomarkers that have been developed largely for the study of patients with clinically diagnosed Alzheimer's disease (AD) can also be used in the study of cognitively normal individuals who may harbor underlying AD pathology.MethodsA meeting of invited experts on AD biomarkers was held on November 11 and 12, 2004 to review currently available data and to discuss unmet needs for biomarker research in presymptomatic AD.ResultsNeuroimaging biomarkers have been studied to some extent in subjects at risk for AD. These imaging techniques include volumetric magnetic resonance imaging and positron emission tomography using either fluorodeoxyglucose or newer ligands that bind directly to amyloid plaque. Similarly, biochemical measures from cerebrospinal fluid or other physiologic fluids are emerging as potentially useful tools. Such biomarkers may be used either as diagnostic tools or as indicators of disease severity when followed longitudinally. A clinical diagnosis of asymptomatic individuals using biomarkers and studies involving asymptomatic subjects may raise logistical and ethical concerns.ConclusionsThe technical development of biomarkers that are used for presymptomatic AD diagnosis and for longitudinally measuring disease severity is evolving rapidly. Ethical and privacy considerations must be made before such biomarkers can be applied routinely to asymptomatic populations.

Purpose To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors. Patients and Methods Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3. Results Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 μmol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2). Conclusion The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

Background— Restenosis after implantation of coronary artery stents remains a significant clinical problem. We undertook a randomized, double-blind, placebo-controlled trial to determine whether cilostazol, a drug that suppresses intimal proliferation, would reduce renarrowing in patients after stent implantation in native coronary arteries. Methods and Results— We assigned 705 patients who had successful coronary stent implantation to receive, in addition to aspirin, cilostazol 100 mg BID or placebo for 6 months; clopidogrel 75 mg daily was administered to all patients for 30 days. Restenosis was determined by quantitative coronary angiography at 6 months. The minimal luminal diameter at 6 months for cilostazol-treated patients was 1.77 mm for the analysis segment (stent plus 5-mm borders) compared with 1.62 mm in the placebo group ( P =0.01). Restenosis, defined as ≥50% narrowing, occurred in 22.0% of patients in the cilostazol group and in 34.5% of the placebo group ( P =0.002), a 36% relative risk reduction. Restenosis was significantly lower in cilostazol-treated diabetics (17.7% versus 37.7%, P =0.01) and in those with small vessels (23.6% versus 35.2%, P =0.02), long lesions (29.9% versus 46.6%, P =0.04), and left anterior descending coronary artery site (19.3% versus 39.8%, P =0.001). There was no difference in bleeding, rehospitalization, target-vessel revascularization, myocardial infarction, or death. Conclusions— Treatment with the drug cilostazol resulted in a significantly larger minimal luminal diameter and a significantly lower binary restenosis rate compared with placebo-treated patients. These favorable effects were apparent in patients at high risk for restenosis.

Purpose Surgical resection of liver-only metastases from colorectal cancer has undergone extensive evaluation and review. The use of neoadjuvant chemotherapy to improve the likelihood of resection in disease that is not optimally resectable has not been as well studied. Patients and Methods Patients with liver-only metastases from colorectal cancer deemed not optimally resectable by a surgeon with expertise in liver surgery received fluorouracil, leucovorin, and oxaliplatin (FOLFOX4). Patients were periodically reassessed for resectability. Surgical response was classified as completely resectable (S-CR), partially resectable (S-PR), or unresectable (S-UR). Study design specified the accrual of 39 patients, with two or more S-CRs considered evidence of promising activity with respect to increasing the S-CR rate. Results Forty-two of 44 patients were assessable for this analysis. Twenty-five patients (60%) had tumor reduction by serial imaging. Seventeen patients (40%) underwent surgery (S-CR, n = 14; S-PR, n = 1; and S-UR, n = 2) after a median of 6 months of chemotherapy. With a median postsurgical follow-up of 22 months (range, 13 to 32 months), 11 recurrences have occurred in the 15 S-CR and S-PR patients. Median survival time was 26 months. Conclusion Our data suggest that FOLFOX4 has a high response rate (complete response, partial response, or reduction) in patients with liver-only metastases from colorectal cancer, allowing for successful resection of disease in a portion of patients initially not judged to be optimally resectable. However, a high recurrence rate after surgery was observed, which, in 73% of patients, involved the liver. Further trials are indicated based on the promising results observed in this trial.

The orotic acid dietary “liver lipid” model has successfully been used to study ultrasonic properties in excessively fatty rat livers [O'Brien et al., J. Acoust. Soc. Am. 83, 1159–1166 (1988)]. The model was used again in order to evaluate more fully ultrasound properties within a more condensed (2%–10%) lipid concentration range. The fatty livers were first evaluated in the intact animal (in situ) with an ultrasonic imaging system (≅ 5 MHz) and then the excised (in vitro) livers were evaluated over the 1- to 100-MHz frequency range. Water, lipid, total protein, and collagen were evaluated for each liver. Significant (p < 0.001) correlations of ultrasonic properties (absorption, all attenuation, speed, and Markovian entropy) against tissue properties (water and lipid) were obtained, thus suggesting that the independent measure of texture may relate to basic ultrasonic propagation properties. [Work supported by NIH Grant CS36O29.]

In this paper, an experimental test of a theoretical model published previously is presented that describes the behavior of an acoustoelectric transducer with a nonuniform distribution of the piezoelectric coefficient within its bulk. Results of this theoretical model are first reviewed. Uniform and nonuniform piezoelectric transducers were fabricated, following a procedure described herein. The receive transfer functions of the transducers were recorded experimentally, and a comparison is made with the theoretical transfer functions predicted by the model, which shows good agreement. The transmit transfer functions of the uniform and nonuniform transducers were also measured and are reported. Numerical calculations of the different transfer functions given by the theoretical model for a uniform transducer associated with different backing materials are also presented, and the results are shown to be equivalent to the results following from the Mason equivalent circuit. Comparisons with experimental results and with Mason’s equivalent circuit verified the new theoretical model.

Research suggests that negative affect is an important mediator in the relationship between body dissatisfaction and bulimic symptoms. This study examines the mediational role of specific emotion regulation processes (i.e., negative emotionality, poor awareness of emotion, nonconstructive coping with negative emotion) in bulimic symptoms. In addition to these emotion regulation variables, body dissatisfaction and bulimic symptoms were assessed in 234 girls in Grades 6 to 8 (mean age = 12 years, 11 months). The results indicated that negative affect, poor awareness of emotion, and nonconstructive coping with negative emotion partially mediated the relationship between body dissatisfaction and bulimic behaviors. The findings are discussed in light of previous research that suggests emotion regulation needs to be viewed as a multidimensional construct.

Background— The goal of this study was to determine whether the expression of vascular endothelial growth factor (VEGF) is critical for coronary collateral growth. Previous studies have provided an association between coronary collateral growth and VEGF, but none have allowed determination of a causal role. Methods and Results— We measured coronary collateral growth in rats subjected to repetitive episodes of myocardial ischemia (RI; one 40-second occlusion every 20 minutes for 2 hours 40 minutes, followed by 5 hours 20 minutes of rest, with this 8-hour cycle repeated 3 times per day for 10 days). Collateral growth was measured from blood flow (radioactive microspheres), visualization of arterial-arterial anastomoses (x-ray micro-CT), and maintenance of function during complete coronary occlusion in 3 groups of animals: sham (received instrumentation but no RI), experimental (subjected to RI), and anti–vascular endothelial growth factor (RI+anti-VEGF 0.6 mg/100 g per day) to block the endogenous actions of VEGF. In the 3 groups, native collateral flow (measurement for RI or sham protocol) averaged 0.2 to 0.3 mL · min −1 · g −1 of tissue. In the sham group, collateral flow did not increase during the protocol. Collateral flow in the control RI group increased by ≈6-fold to 1.63 mL · min −1 · g −1 tissue, but in the anti-VEGF group, collateral flow did not increase after the RI protocol (0.22 mL · min −1 · g −1 ). In acute experiments, collateral flow was unchanged during vasodilation with dipyridamole, indicating the increases in collateral flow are due to collateral growth and not vasodilation. X-ray micro-CT analysis revealed a 3-fold increase (versus sham group) in the number of arterial-arterial anastomoses per heart after RI, which was prevented by treatment with anti-VEGF. The growth of the collateral circulation was functional in the RI group because complete coronary occlusion did not induce any untoward effects on hemodynamics or arrhythmias. In the sham or anti-VEGF groups, coronary occlusion at the end of the protocol induced many arrhythmias and deterioration of function. Conclusions— From these results, we conclude that the expression of VEGF is critical to the growth of coronary collaterals.

Purpose Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients. Patients and Methods One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology. Results BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS. Conclusion BPT results in a significant decrease in 5-year OS in patients who are treated for HL. Age ≥ 40 years seems to add substantially to the risk. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin.