Mechanisms of progression and regression of coronary artery disease by PET related to treatment intensity and clinical events at long-term follow-up.

Changes in regional myocardial perfusion throughout the entire coronary vascular tree, as opposed to changes in the worst regional perfusion defect, have not been described during long-term regression or progression of coronary artery disease (CAD) or related to clinical outcomes. METHODS: Four-hundred nine patients with CAD undergoing dipyridamole PET at baseline and after 2.6 +/- 1.4 y were followed over 5 more years for coronary events. PET images were objectively quantified by automated software for changes in severity of the (i) baseline worst quadrant, indicating the worst flow-limiting stenosis at baseline PET; (ii) follow-up worst quadrant, indicating the worst stenosis on follow-up PET; and (iii) maximal change quadrant, indicating the largest change of any same quadrant pair from baseline-to-follow-up images. RESULTS: At follow-up PET, new regional perfusion defects were seen in 40% of patients. In 77% of patients, the greatest change was in a quadrant different from the worst baseline defect. The maximal change quadrant improved in 70% of patients on intense lifestyle and pharmacologic lipid treatment, in 48% on moderate treatment, and in 39% on poor treatment (P < 0.0001). Combined quadrant changes integrated throughout the heart independently predicted cardiovascular events at long-term follow-up. In contrast, changes of any single baseline-to-follow-up quadrant pair did not. CONCLUSION: By PET, 77% of patients with CAD had the greatest perfusion changes in areas different from the baseline worst perfusion defect and 40% had new perfusion defects. Changes in perfusion defects throughout the entire coronary vascular tree predicted coronary events, whereas changes in the worst flow-limiting stenosis at baseline or in any one segment of myocardium did not. To our knowledge, these data provide the first direct evidence on mechanisms for disproportionately greater reduction in cardiac events than changes in single stenosis severity with lipid treatment.     

Frequent diagnostic errors in cardiac PET/CT due to misregistration of CT attenuation and emission PET images: a definitive analysis of causes, consequences, and corrections.

Cardiac PET combined with CT is rapidly expanding despite artifactual defects and false-positive results due to misregistration of PET and CT attenuation correction data-the frequency, cause, and correction of which remain undetermined. METHODS: Two hundred fifty-nine consecutive patients underwent diagnostic rest-dipyridamole myocardial perfusion PET/CT using (82)Rb, a 16-slice PET/CT scanner, helical CT attenuation correction with breathing and also at end-expiratory breath-hold, and averaged cine CT data during breathing. Misregistration on superimposed PET/CT fusion images was objectively measured in millimeters and correlated with associated quantitative size and severity of PET defects. Misregistration artifacts were defined as PET defects with corresponding misregistration on helical CT-PET fusion images that resolved after correct coregistration using a repeat CT scan, cine CT averaged attenuation during normal breathing, or shifted cine CT data that coregistered with PET data. RESULTS: Misregistration of standard helical CT PET images caused artifactual PET defects in 103 of 259 (40%) patients that were moderate to severe in 59 (23%) (P = 0.0000) and quantitatively normalized on cine or shifted cine CT PET (P = 0.0000). Quantitative misregistration was a powerful predictor of artifact size and severity (P = 0.0000), particularly for transaxial misregistration >6 mm occurring in anterior or lateral areas in 76%, in inferior areas in 16%, and at the apex in 8% of 103 artifactual defects. CONCLUSION: Misregistration of helical CT attenuation and PET emission images causes artifactual defects with false-positive results in 40% of patients that normalize on cine CT PET using averaged CT attenuation data during normal breathing comparable to normal breathing during PET emission scanning and shifting cine CT images to coregister visually with PET.     

Evaluation of myocardial function in patients with end-stage heart failure during support with the Jarvik 2000 left ventricular assist device.

In 2 patients with the Jarvik 2000 left ventricular assist device (LVAD), we assessed left ventricular systolic function through pressure-volume loops and E(max) at the beginning and end of the support period to potentially predict the possibility of pump removal without transplantation. Immediately before LVAD implantation and explantation, pressure and volume measurements were made with catheters and echocardiography, respectively, the E(max) being calculated from the slope of the pressure-volume loops, and the left ventricular ejection fraction (LVEF) being estimated by echocardiography. Transplantation was performed after 14 and 62 days, respectively, during which the LVEF increased by 75% (from 12% to 21%) in Patient 1 and remained unchanged (from 16% to 18%) in Patient 2, whereas the E(max) increased from 0.63 and 0.42 mm Hg/ml, respectively, to 1.31 and 1.07 mm Hg/ml, reflecting a 107% and 155% improvement. In these 2 cases, the E(max) was a more reliable indicator of intrinsic myocardial contractility than was the LVEF.     

Regulation of Abortion by γλ T Cells

PROBLEM: T cells are present at the feto-maternal interface, but their function during pregnancy has not been fully elucidated. T cells bearing γλ T-cell receptor (TCR) may be particularly important, as some subsets can react to trophoblast cells by producing cytokines, such as interleukin-2 (IL-2). METHOD: We depleted T cells bearing the γλ receptor by injecting monoclonal antibodies (mAB) into females of the abortion-prone animal model CBA x DBA/2. We investigated the percentage and number of γλ T-cell receptor positive (TCR)⁺ cells in decidua and spleen during pregnancy in control and γλ-depleted female mice. Pregnant females were also exposed to ultrasonic sound stress to boost the abortion rate. RESULTS: Stress failed to increase the abortion rate in the γλ TCR-depleted mice. FACScan analysis show that the ratio of cells bearing the γλ TCR dramatically decreased after injection of mAB to the γλ TCR in spleen and decidua, these cells recovered six days after depletion, showing a change in cytokine pattern. Levels of TNF-α in decidual γλ T cells decreased; similar effects of decreasing Th₁ cytokines could be observed in splenic γλ T cells. We further identified increased levels of intracellular TNF-α in the Vλ4 subset in the decidua, compared to spleen. CONCLUSIONS: Trophoblast recognition by the Vλ4 T-cell subset in the decidua may cause the release of abortogenic cytokines such as TNF-α. Depletion of such γλ TCR T cells during early pregnancy may promote successful pregnancy outcome in normal pregnancy and prevent stress-induced abortions.     

Pharmacokinetics of high-dose methotrexate in adult osteogenic sarcoma

The pharmacokinetics of 222 infusions of high-dose methotrexate (MTX) with leucovorin rescue were studied in 22 adults with osteosarcoma. To reduce the variability of plasma concentration, we individualized dose regimens using a Bayesian method to reach a concentration of 10^–3 M MTX at the end of an 8-h infusion. The mean concentration observed at the end of the infusion was 1016±143 mol/l. The mean dose delivered was 13.2±2 g/m². The clearance was 49.1±11.7 ml min^–1 m^–2. The decay of the plasma concentration of MTX after completion of the infusion followed a two-compartment model with at _1/2 of 2.66±0.82 h and at _1/2 of 15.69±8.63 h. The volume of distribution was 0.32±0.08 l/kg. As compared with previously published data, the interindividual and intraindividual variations in the concentration at the end of the infusion were reduced, with values of 14% and 5.9%–21%, respectively, being obtained. Severe toxicities were avoided, and there were only 3 hematologic and 8 digestive grade 3 side effects and no grade 4 complication. Thet _1/2 and the MTX plasma concentrations at 23 and 47 h were correlated with renal toxicity (P<0.001). However, no correlation was found between the pharmacokinetic parameters and other signs of toxicity. There was no significant difference in pharmacokinetics between the toxic and nontoxic groups. In the same manner, the parameters of the group of patients sensitive to MTX were not statistically significantly different from those of the group of nonsensitive patients.     

Role of T lymphocytes in secretory response to an enteric nematode parasite

Athymic (nude) rats have been used to assess the role of thymus-dependent T cells in the control of the intestinal response following infection with the enteric parasite,Nippostrongylus brasiliensis. Tissues from infected rats were excised on days 4, 7, 10, and 21 postinfection (p-i) for physiological and morphological studies; uninfected (day 0) rats served as controls. In response to the worm burden, jejunal tissues displayed a secretory response, indicated by an elevated baseline short-circuit current (I _sc ) on days 7 and 10 p-i, and were more responsive to histamine than control tissues. Despite this enhanced secretory response, 35% of the worm burden was still present on day 21 p-i (compared with expulsion of >95% by day 14 p-i in normal rats). Mast cell activation and hyperplasia, increased goblet cell (implying increased mucus synthesis) and intraepithelial leukocyte numbers, and abnormalities inI _sc responses after electrical stimulation of enteric nerves were identified following infection. These events in nude rats were attenuated or delayed in onset as compared with conventional immunocompetent rats. Our results support the postulate that thymus-dependent T cells regulate the timing and/or nature of the mucosal response to enteric parasitic infections. However, ion secretion was not altered in the absence of T cells and, therefore, is more likely to be a consequence of mast cell activation.This work was conducted with financial support from The Canadian Medical Research Council and the National Institutes of Health (NS 29536).     

A Bayesian dosing method for carboplatin given by continuous infusion for 120 h

Carboplatin (CBDCA), an analogue of cisplatin, exhibits reduced toxicity but wide interpatient variability of its pharmacokinetic parameters. Individualization of the CBDCA dose is therefore necessary. Although various formulas have been developed for this purpose, major side effects have been reported on CBDCA administration by short-term infusion (0.5 or 1h). We therefore propose a new schedule of CBDCA administration. Instead of a dosing method based on the estimation of renal function when a classic administration schedule is used, we propose a pharmacokinetic dosing method (Bayesian method), whereby CBDCA is given by continuous infusion for 120 h. First, CBDCA was given to 21 patients to determine the population pharmacokinetic parameters of carboplatin. Then, on the basis of total platinum plasma concentration measurements and Bayesian estimation of pharmacokinetic parameters, it was possible to individualize the CBDCA dose within the first 24 h of the infusion. This new protocol for CBDCA administration was evaluated in 36 new patients (60 courses). Three theoretical end points at the end of the infusion were considered. For a given theoretical end point, 20 courses were taken into account. The theoretical end points (i.e., 1, 1.5, and 1.8 mg/l) were compared with the concentrations measured at the end of the infusion, which were 0.99 ± 0.10, 1.41 ± 0.13, and 1.72 ± 0.20 mg/l, respectively. This Bayesian dosing method can easily be used in clinical practice, and the determination of predictive performances has shown that the method is precise and unbiased. With no more toxicity or practical difficulties than those produced by other methods, and with acceptable tolerance, it was possible to reach a median dose that was 20% higher than the usual dose (484 ± 190 mg/m² as compared with 400 mg/m²). In conclusion, this new schedule of CBDCA administration appears to be interesting in terms of tolerance. However, new studies are required to confirm that this new scheme leads to equal or better efficacy than the classic protocol. Received: 10 December 1995 / Accepted: 15 December 1996