Diffuse Heterogeneity Research Articles

Brain Perfusion in Adult Patients with Acute Myeloblastic Leukemia before and after Cytosine Arabinoside

High-dose (HD) cytosine arabinoside (ara-C) is a major treatment in acute myeloblastic leukemia (AML) that can lead to cerebellar complications, although electroencephalogram, computed tomography, and magnetic resonance imaging remain normal. We conducted a prospective study to evaluate brain perfusion with single-photon emission computed tomography (SPECT) in adult patients before and after receiving ara-C. Forty-three patients were pre-included, and 20 reached a complete remission. These 20 patients were definitively included and underwent three technetium-99m hexamethyl-propylene-amine oxime (HMPAO) SPECT acquisitions with a double-head camera: SPECT1 at AML diagnosis, SPECT2 after induction (conventional ara-C dose), and SPECT3 during HD ara-C treatment. All the included patients underwent six series of neurological and cognitive examinations: N1, N2, and N3 at the time of SPECT1, SPECT2, and SPECT3, respectively; N4 during HD ara-C treatment; N5 (at 10 days); and N6 during follow-up (at 6 months). Statistical parametric mapping (SPM2) was used to test perfusion changes. A specific method based on random walk (RW) was used to analyze diffuse brain perfusion heterogeneity. No neurological adverse effect was observed, and all neurological and cognitive examinations remained normal. Between SPECT1 and SPECT2, SPM2 analysis showed a decrease in cerebral blood flow, i.e., in the cerebellum, in the occipitoparietal cortex, and in the thalamus. No significant difference was observed between SPECT2 and SPECT3 or between SPECT1 and SPECT3. RW analysis showed no significant difference in perfusion heterogeneity between the three SPECTs. HMPAO SPECT demonstrated a decrease in thalamus, cerebellar, and parieto-occipital perfusion after conventional doses of ara-C in AML patients, although the neurological examinations were normal and the patients had no neurological adverse effects.

Brain perfusion heterogeneity measurement based on Random Walk algorithm: Choice and influence of inner parameters

A Random Walk (RW) algorithm was designed to quantify the level of diffuse heterogeneous perfusion in brain SPECT images in patients suffering from systemic brain disease or from drug-induced therapy. The goal of the present paper is to understand the behavior of the RW method on different kinds of images (extrinsic parameters) and also to understand how to choose the right parameters of the RW (intrinsic parameters) depending on the image characteristics (i.e. SPECT images). “Extrinsic parameters” are related to the image characteristics (level/size of defect and diffuse heterogeneity) and “intrinsic” parameters are related to the parameters of the method (number ( N rw ) and length of walk ( L rw ), temperature ( T) and slowing parameter ( S)). Two successive studies were conducted to test the influence of these parameters on the RW result. In the first study, calibrated checkerboard images are used to test the influence of “extrinsic parameters” (i.e. image characteristics) on the RW result ( R-value). The R-value was tested as a function of (i) the size of black & white (B&W) squares simulating the size of a cortical defect, (ii) the intensity level gaps between the B&W squares simulating the intensity of the cortical defect and (iii) intensity (=variance) of noise, simulating the diffuse heterogeneity. The second study was constructed with simulated representative brain SPECT images, to test the “intrinsic” parameters. The R-value was tested regarding the influence of four parameters: S, T, N rw and L rw . The third study is constructed so as to see if the classification by diffuse heterogeneity of real brain SPECT images is the same if it's made by senior clinicians or by RW algorithm. Results Study 1: the RW was strongly influenced by all the characteristics of the images. Moreover, these characteristics interact with each other. The RW is influenced most by diffuse heterogeneity, then by intensity and finally by the size of a defect. Study 2: N rw and L rw values of 1000 give an optimal reproducibility of the measurement (mean standard deviation < 0.1), a fast computation time (time < 0.5 s/image) and have a maximum difference in terms of R-value between the two extreme images corresponding to the range of the population studied. The best S and T values for SPECT images are 3 and 15, respectively. Study 3: A significant correlation was found between RW ranking and the physicians’ consensus ( ρ = 0.789; p < 0.0001). Conclusion This study confirms that the RW method is able to measure the heterogeneity of brain SPECT images even in the presence of a large defect. However, the result of the method is strongly influenced by the “intrinsic” parameters, so the program should be calibrated for each different type of image.

Positron emission tomo graphy imaging in the differentiatial diagnosis of cardio megaly of ischemic and noncoronarogenic origin

Objective. The study addresses differentiation of ischemic and non-ischemic cardiomegaly by positron emission tomography (PET). Design and methods. Based on echocardiography data 50 patients with cardiomegaly and reduced systolic function were included in the study: 32 patients with coronary heart disease (CHD) and 18 patients with normal coronary arteries according to angiography results (6 of them had alcohol abuse). All patients underwent PET with [13N]-ammonia and [18F]-FDG for myocardial perfusion and metabolism evaluation. A semiquantitative analysis of the images was performed. Results. All patients with CHD showed large hypoperfusion areas (more than 3 segments) matching the coronary artery flow. Perfusion/metabolism match was revealed in all (100 %) patients with CHD and perfusion/metabolism mismatch was observed in 25 (79 %) patients of the same group. The patients with noncoronarogenic cardiomegaly (NCM) had diffuse heterogeneity of myocardial perfusion, 5 of them showed small and mild perfusion defects with non-segmental distribution. The areas of abnormal perfusion were significantly larger in cases of CHD. Perfusion/metabolism match was noted in 2 (11 %) patients with NCM and none of the patients with NCM showed perfusion/metabolism mismatch. Conclusion. Diffuse heterogeneity of myocardial perfusion, non-segmental distribution of perfusion defects and lack of perfusion/metabolism mismatch are the most important features of noncoronarogenic cardiomegaly as compared to ischemic cardiomegaly.

Chromosome 3 Intratumor Heterogeneity in Uveal Melanoma

To investigate the presence of focal or diffuse heterogeneity of monosomy 3 in uveal melanoma, by using fluorescence in situ hybridization (FISH). Direct interphase FISH in a series of 151 uveal melanomas revealed 82 tumors with loss of chromosome 3. Tumors with monosomy 3 were suspected to be heterogeneous if there were low percentages of monosomy 3, triploid clones, inconsistencies between FISH on centromere 3 and the long arm of chromosome 3, or discrepancies between fine-needle-aspiration biopsies (FNABs) and the main tumor. These tumors (n=16), all choroidal melanomas, were selected and analyzed for intratumor heterogeneity by using FISH on paraffin-embedded tissue sections. Different sections of each tumor were evaluated with FISH: 6 tumors showed monosomy 3 in the same percentage throughout the tumor, and 10 showed multiple clones with different percentages of monosomy 3. However, these tumors did not show focal heterogeneity with respect to chromosome 3 status, and differences in monosomy 3 distribution between the base and apex of the tumor could not be identified. Although a small number of uveal melanomas show heterogeneity for chromosome 3, it does not affect survival. In the presence of triploid clones, the loss of chromosome 3 is more difficult to interpret. In general, tumor biopsies in uveal melanoma provide an accurate prediction of the patient's prognosis.

Development and Validation of the Random Walk Algorithm

Heterogeneity analysis has been studied for radiological imaging, but few methods have been developed for functional images. Diffuse heterogeneous perfusion frequently appears in brain single photon emission computed tomography (SPECT) images, but objective quantification is lacking. An automatic method, based on random walk (RW) theory, has been developed to quantify perfusion heterogeneity. We assess the robustness of our algorithm in differentiating levels of diffuse heterogeneity even when focal defects are present. Heterogeneity is quantified by counting R (percentage), the mean rate of visited pixels in a fixed number of steps of the stochastic RW process. The algorithm has been tested on the numerical anthropomorphic Zubal head phantom. Seven diffuse cortical heterogeneity levels were simulated with an adjustable Gaussian function and 6 temporoparietal focal defects simulating Alzheimer Disease, leading to 42 phantoms. Data were projected and smoothed (full width at half maximum, 5.5 mm), and Poisson noise was added to the 64 projections. The SPECT data were reconstructed using filtered backprojection (Hamming filter, 0.5 c/p). R values for different levels of perfusion defect and diffuse heterogeneity were evaluated on 3 parameters: the number of slices studied (20 vs 40), the use of Talairach normalization versus original space, and the use of a cortical mask within the Talairach space. For each parameter, regression lines for heterogeneity and temporoparietal defect quantification were analyzed by covariance statistics. R values were also evaluated on SPECT images performed on 25 subjects with suspected focal dementia and on 15 normal controls. Scans were blindly ranked by 2 experienced nuclear physicians according to the degree of diffuse heterogeneity. Variability of R was smaller than 0.17% for repeated measurements. R was more particularly influenced by diffuse heterogeneity compared with focal perfusion defect. The Talairach normalization had a significant influence on the heterogeneity quantification. The number of slices visited by the RW and the cortical masking have a weak influence on the heterogeneity quantification but only for very low heterogeneity levels. The Spearman coefficient between physicians' consensus and RW automatic ranking is 0.85, in the same order of magnitude as the Spearman coefficient between the rankings of the 2 senior physicians (0.86). Random walk is an original and objective method and is able to quantify heterogeneous brain perfusion, even in presence of cortical defects. This method is repeatable, robust, and mainly influenced by spatial normalization.

Lateral Epicondylitis of the Elbow: US Findings

To determine the sensitivity and specificity of ultrasonography (US) in the detection of lateral epicondylitis and identify the US findings that are most strongly associated with symptoms. Internal review board approval was obtained for retrospective review of the patient images, and the need for informed consent was waived. Internal review board approval was also obtained for scanning the 10 volunteers, all of whom gave informed consent. The study was compliant with the Health Insurance Portability and Accountability Act. US of the common extensor tendon was performed in 20 elbows in 10 asymptomatic volunteers (six men, four women; age range, 22-38 years; mean age, 29.6 years) and 37 elbows in 22 patients with symptoms of lateral epicondylitis (10 men, 12 women; age range, 30-59 years; mean age, 46 years). Fifty-seven representative images, one from each elbow, were randomly assorted and interpreted by three independent readers who rated each common extensor tendon as normal or abnormal. Abnormal images were further classified as demonstrating one or more of eight US findings. Readers interpreted each image at two separate sessions to determine intrareader variability. The authors calculated the sensitivity and specificity of US in the diagnosis of lateral epicondylitis and the odds ratio for each US finding. Odds ratios were considered statistically significant at P < .05 when 95% confidence intervals did not include one. Sensitivities of US in the detection of symptomatic lateral epicondylitis ranged from 72% to 88% and specificities from 36% to 48.5%. Odds ratios for the following findings were statistically significant (P < .05) for both reading sessions: calcification of common extensor tendon, tendon thickening, adjacent bone irregularity, focal hypoechoic regions, and diffuse heterogeneity. Odds ratios for lateral epicondyle enthesophytes were statistically significant (P < .05) for the first reading session only. Odds ratios for linear intrasubstance tears and peritendinous fluid were not statistically significant. US of the common extensor tendon had high sensitivity but low specificity in the detection of symptomatic lateral epicondylitis. The relationship between symptoms and intratendinous calcification, tendon thickening, adjacent bone irregularity, focal hypoechoic regions, and diffuse heterogeneity was statistically significant.

Hepatobiliary sonography in cystic fibrosis.

Real-time abdominal sonograms of 27 pediatric patients with cystic fibrosis were reviewed to determine the frequency of hepatobiliary abnormalities and their variation with patient age. Attention was paid to hepatic echotexture and gallbladder size and contents. Seventeen patients (63%) had abnormal livers appearing as diffuse hyperechogenicity with loss of visualization of periportal echoes in 5 of 17 patients (29%), periportal hyperechogenicity in 9 of 17 (53%) and heterogeneity in 3 of 17 (17%). Gallbladder abnormalities, including a small gallbladder and sludge, were found in 9 patients (33%). Our findings show that altered hepatic echotexture is quite common in children with cystic fibrosis. Younger children tend to have diffusely hyperechoic livers, while older children often demonstrate periportal hyperechogeneity or diffuse hepatic heterogeneity.

FACS analysis of a hyperthermia-induced alteration in Hoechst 33342 permeability and direct measurement of its relationship to cell survival.

Heat-induced alterations in CHO-10B cell Hoechst 33342 (Ho342) permeability in vitro were analyzed by flow cytometry. Immediately after 45.5 degrees C heating, uptake was decreased in a dose-dependent manner with cytotoxicity. Kinetic analysis indicated that a treatment that reduced cell survival to approximately 10%, reduced the maximal velocity, Vmax, to 53% of control and increased the dissociation constant, Km, to 156% of control. Also, little change in Ho342 efflux was found to occur from control up to 90 min after heating. Upon incubation at 37 degrees C after the heat treatment from 1 to 24 hr (depending on the severity of the dose) diffuse heterogeneity of Ho342 staining developed which was not evident immediately after heating. The altered staining was not due to the presence of trypan blue staining cells. Membrane permeabilization and nuclei isolation studies indicated that the lesion responsible was most likely a plasma membrane event. Induction of the heterogenous staining was not inhibited by either actinomycin D or hydroxyurea but was inhibited by incubation at 4 degrees C. An inverse correlation existed between Ho342 permeability and clonogenicity, with nearly a 10-fold difference in survival between the high and low fluorescence intensity sorted cells. Also, larger fractions of heat-sensitive S and G2M-phase cells were found in the highly fluorescent sorted fractions. These results are discussed in terms of the putative molecular events that may be involved in hyperthermic modulation of Ho342 permeability.