Dynamic contrast agent -enhanced magnetic resonance imaging assessment of tumor microvasculature

Dynamic contrast agent-enhanced magnetic resonance imaging (DCE MRI) data, when analyzed with the appropriate pharmacokinetic models, have been shown to provide quantitative estimates of microvascular parameters important in characterizing the angiogenic activity of malignant tissue. These parameters consist of the whole blood volume per unit volume of tissue, v b, transport constant from the plasma to the extravascular, extracellular space (EES), k1 and the transport constant from the EES to the plasma, k2. Parameters vb and k1 are expected to correlate with microvascular density (MVD) and vascular permeability, respectively, which have been suggested to serve as surrogate markers for angiogenesis. In addition to being a marker for angiogenesis, vascular permeability is also useful in estimating tumor penetration potential of chemotherapeutic agents. ^ Histological measurements of the intratumoral microvascular environment are limited by their invasiveness and susceptibility to sampling errors. Also, MVD and vascular permeability, while useful for characterizing tumors at a single time point, have shown less utility in longitudinal studies, particularly when used to monitor the efficacy of antiangiogenic and traditional chemotherapeutic agents. These limitations led to a search for a non-invasive means of characterizing the microvascular environment of an entire tumor. ^ The overall goal of this project was to determine the utility of DCE MRI for monitoring the effect of antiangiogenic agents. Further applications of a validated DCE MRI technique include in vivo measurements of tumor microvascular characteristics to aid in determining prognosis at presentation and in estimating drug penetration. DCE MRI data were generated using single- and dual-tracer pharmacokinetic models with different molecular-weight contrast agents. The resulting pharmacokinetic parameters were compared to immunohistochemical measurements. The model and contrast agent combination yielding the best correlation between the pharmacokinetic parameters and histological measures was further evaluated in a longitudinal study to evaluate the efficacy of DCE MRI in monitoring the intratumoral microvascular environment following antiangiogenic treatment. ^

Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. OBJECTIVE: Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. DESIGN/METHODS: A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. RESULTS: Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. CONCLUSIONS: Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

THE RELATIONSHIP BETWEEN DEGREE OF BLOOD PRESSURE REDUCTION AND MORTALITY AMONG HYPERTENSIVES IN THE HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM

The relationship between degree of diastolic blood pressure (DBP) reduction and mortality was examined among hypertensives, ages 30-69, in the Hypertension Detection and Follow-up Program (HDFP). The HDFP was a multi-center community-based trial, which followed 10,940 hypertensive participants for five years. One-year survival was required for inclusion in this investigation since the one-year annual visit was the first occasion where change in blood pressure could be measured on all participants. During the subsequent four years of follow-up on 10,052 participants, 568 deaths occurred. For levels of change in DBP and for categories of variables related to mortality, the crude mortality rate was calculated. Time-dependent life tables were also calculated so as to utilize available blood pressure data over time. In addition, the Cox life table regression model, extended to take into account both time-constant and time-dependent covariates, was used to examine the relationship change in blood pressure over time and mortality.^ The results of the time-dependent life table and time-dependent Cox life table regression analyses supported the existence of a quadratic function which modeled the relationship between DBP reduction and mortality, even after adjusting for other risk factors. The minimum mortality hazard ratio, based on a particular model, occurred at a DBP reduction of 22.6 mm Hg (standard error = 10.6) in the whole population and 8.5 mm Hg (standard error = 4.6) in the baseline DBP stratum 90-104. After this reduction, there was a small increase in the risk of death. There was not evidence of the quadratic function after fitting the same model using systolic blood pressure. Methodologic issues involved in studying a particular degree of blood pressure reduction were considered. The confidence interval around the change corresponding to the minimum hazard ratio was wide and the obtained blood pressure level should not be interpreted as a goal for treatment. Blood pressure reduction was attributed, not only to pharmacologic therapy, but also to regression to the mean, and to other unknown factors unrelated to treatment. Therefore, the surprising results of this study do not provide direct implications for treatment, but strongly suggest replication in other populations. ^