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PubMedDate not supplied

Heterogeneity analysis of Gd-DTPA uptake: improvement in breast lesion differentiation.

PURPOSE: The aim of this study was to assess whether lesion heterogeneity through pixel-by-pixel analysis of contrast-enhanced MR parameter maps would improve breast lesion differentiation. METHOD: Forty-nine female patients with primary tumors of the breast were imaged using contrast-enhanced MRI. The rate of transfer of contrast medium between the lesion and plasma was calculated via compartmental modeling over semiautomatically delineated regions of interest. The distributions of transfer rate values were subdivided into 10 segments for each lesion. The rate of change of the statistical moments of the transfer rate measured over the 10 segments allowed a quantitative measure of heterogeneity. RESULTS: In this patient group of 25 malignant and 25 benign lesions, improved differentiation was achieved by using a measure of lesion heterogeneity. The sensitivity and specificity obtained were 88 and 88%, respectively, compared with 84 and 76% when using the mean value of the transfer rate coefficient. CONCLUSION: Pixel-by-pixel analysis of contrast medium transfer rate maps allows the examination of lesion heterogeneity and offers improved lesion differentiation. The new method used to quantify lesion heterogeneity relies on the manner in which the exchange rate parameter varies when calculated over different segments of the distribution.

Adult↗
PubMed1999

Relations between cognitive and symptom profile heterogeneity in schizophrenia.

Although numerous studies have consistently revealed cognitive heterogeneity in schizophrenia, the relationships between such heterogeneity and clinical phenomenology are not clear. Clusters derived from cognitive heterogeneity studies may or may not be associated with symptom profile or severity of illness. The purpose of this study was to examine the relationship between cognitive heterogeneity and demographic and clinical phenomenological measures. We examined cognitive heterogeneity in schizophrenia by empirically deriving clusters of patients based upon WAIS-R subtest scores and then analyzed the way in which these clusters related to demographic and symptom variables and to DSM-III-R diagnostic subtypes. Four cognitive clusters were identified that were consistent with previous research. These clusters were differentiated on the basis of educational level and occupational status but not on the basis of symptom profile, severity, or DSM-III-R subtypes. Results suggest that cognitive measures are independent of severity of the disorder and phenomenological symptom presentation in these subgroups of schizophrenic patients.

Adult↗
PubMed1993

Heterogeneity of the T-cell and macrophage infiltrate in cutaneous and subcutaneous metastases of melanoma patients.

To examine the intra-individual heterogeneity of the local inflammatory infiltrate in metastases of untreated melanoma patients we analysed 42 skin and subcutaneous metastases from 11 patients. Metastases were excised on the same date (10 patients) or consecutively (six patients), and processed in a two-step immunoperoxidase technique using monoclonal antibodies directed against T-cells (CD3, CD25) and two macrophage subpopulations (RM 3/1, 27E10). The number of positively stained T-cells and macrophages were counted for each lesion in representative high power fields. The mean values were calculated. We observed limited heterogeneity among T-cells (CD3+) and activated T-cells (CD25+) in simultaneously excised metastases. Contrary to this, markedly heterogeneous CD3+ infiltrates were found in metastases taken on different dates, even if there was a time difference of only 1 day between excisions, suggesting spontaneous variations. However, activated T-cells in follow-up biopsies showed only limited heterogeneity. In spite of inter-individual variations, metastases taken simultaneously, as well as consecutively, showed little intra-individual heterogeneity with respect to macrophages. Our findings should be taken into account for comparative studies of the infiltrate in metastatic melanoma during immunotherapy.

Aged↗
PubMed2004

HER-2/neu (c-erbB-2) evaluation in primary breast carcinoma by fluorescent in situ hybridization and immunohistochemistry with special focus on intratumor heterogeneity and comparison of invasive and in situ components.

We have studied the intratumor HER-2/neu heterogeneity in 78 consecutive and population-based primary invasive breast carcinomas. Within the invasive component, heterogeneity was detected in only 1 of 78 tumors. In 48 tumors (62%), we found both in situ and invasive components in analyzed tissue sections. Twelve of these 48 tumors had a difference of at least 2 arbitrary units in the in situ compared with the invasive part of the tumor with regard to the HER-2/neu status analyzed by HercepTest (immunohistochemistry). Eight of these 12 tumors were reanalyzed with fluorescent in situ hybridization and immunohistochemistry with and without a new Automated Cellular Imaging System. In this limited material, immunohistochemistry in combination with the Automated Cellular Imaging System seemed to have a better correlation with fluorescent in situ hybridization than immunostaining analyzed manually. In conclusion, HER-2/neu expression is not seldom heterogeneous in invasive compared with in situ components within a tumor. This finding should be considered in the choice of evaluation method. To avoid heterogeneity as a confounding factor in HER-2/neu analyses, detection methods such as immunohistochemistry and fluorescent in situ hybridization, which can provide evaluation in a preserved tissue architecture, should be used. Perhaps the intratumor HER-2/neu heterogeneity can explain some of the unexpected failures of trastuzumab therapy.

Breast Neoplasms↗
PubMed2006

Suppression of calcium-induced repolarization heterogeneity as a mechanism of nitroglycerin's antiarrhythmic action.

This study examined whether the antifibrillatory action of nitroglycerin (NTG) is attributable to reduction in calcium-induced heterogeneity of repolarization independent of autonomic and coronary vasodilatory influences. The effects of intrapericardial (IPC) NTG on coronary blood flow, contractility, repolarization, and arrhythmia susceptibility were measured in anesthetized pigs (N = 43). Autonomic influences were minimized by vagotomy and beta-adrenergic blockade (metoprolol, 1.25 mg/kg, intravenous). Electrophysiological parameters were tested at 30 min, a time when coronary hemodynamics had returned to baseline. Intracoronary calcium chloride (CaCl2, 50-mg bolus) injection augmented contractility (dP/dt(max), 1760 +/- 144 to 2769 +/- 274 mmHg/s, and following NTG, 1531 +/- 384 to 2138 +/- 242 mmHg/s, P < 0.0002), reflecting increased myocardial intracellular calcium. Calcium increased repolarization heterogeneity (interlead precordial T-wave heterogeneity, 95 +/- 15 to 264 +/- 33 microV, P < 0.006; T(peak)-T(end), an index of transmural dispersion of repolarization, 37 +/- 3 to 76 +/- 6 ms, P < 0.05) and lowered repetitive extrasystole threshold (RET; 24 +/- 2 to 13 +/- 1 mA, and following NTG, 32 +/- 4 to 18 +/- 1 mA, P < 0.0001). IPC NTG raised the RET from baseline by 33% and blunted calcium-induced contractility (dP/dt(max) by 23%, P < 0.05), repolarization changes (T-wave heterogeneity by 24%, P < 0.006; T(peak)-T(end) by 18%, P = 0.04), and arrhythmia vulnerability (RET by 39%, P < 0.003). Thus, the capacity of NTG to suppress calcium-induced repolarization heterogeneity is an important mechanism of its antiarrhythmic action, which is independent of autonomic and vasodilatory actions.

Animals↗
PubMed2006

Cerebral perfusion heterogeneity and complexity in patients with acute subarachnoid haemorrhage.

BACKGROUND: The pathophysiological mechanisms of impaired perfusion during acute subarachnoid haemorrhage (SAH) are incompletely understood. Cerebral perfusion at the micro vascular level can be assessed by single photon emission computed tomography (SPECT). We used a SPECT approach with 99mTc-ECD to measure the cerebral perfusion heterogeneity and complexity in patients with acute aneurysmal SAH or perimesencephalic non-aneurysmal SAH (PNSAH). METHODS: The perfusion SPECT data of 61 patients with aneurysmal SAH, 18 patients with PNSAH, and 20 healthy control subjects were analysed by dividing the brain into 384 regions of interest. The magnitude of spatial perfusion heterogeneity was assessed by calculating the relative dispersion (RD=coefficient of variation). The fractal dimension (FD) was used to describe the overall complexity of global cerebral perfusion. RESULTS: Patients with aneurysmal SAH (RD=11.30+/-2.17, P<0.001) and PNSAH (10.38+/-2.27, P=0.023) had a higher perfusion heterogeneity than control subjects (8.69+/-0.80). Patients with aneurysmal SAH tended to have a higher perfusion heterogeneity than patients with PNSAH (P=0.061). Also the overall complexity of cerebral perfusion was decreased in aneurysmal SAH (FD=1.11+/-0.06, P<0.001) and PNSAH (1.11+/-0.06, P=0.004) as compared with control subjects (1.17+/-0.06). Acute SAH causes increased regional cerebral perfusion heterogeneity and decreased overall complexity of global cerebral perfusion. CONCLUSION: Non-invasive assessment of cerebral perfusion characteristics is feasible with SPECT and fractal analysis in patients with acute SAH and may help evaluating micro vascular function in SAH.

Adolescent↗
PubMed2006

How do pathogen evolution and host heterogeneity interact in disease emergence?

Heterogeneity in the parameters governing the spread of infectious diseases is a common feature of real-world epidemics. It has been suggested that for pathogens with basic reproductive number R(0)>1, increasing heterogeneity makes extinction of disease more likely during the early rounds of transmission. The basic reproductive number R(0) of the introduced pathogen may, however, be less than 1 after the introduction, and evolutionary changes are then required for R(0) to increase to above 1 and the pathogen to emerge. In this paper, we consider how host heterogeneity influences the emergence of both non-evolving pathogens and those that must undergo adaptive changes to spread in the host population. In contrast to previous results, we find that heterogeneity does not always make extinction more likely and that if adaptation is required for emergence, the effect of host heterogeneity is relatively small. We discuss the application of these ideas to vaccination strategies.

Adaptation, Biological↗
PubMed1984

Murine leukaemia virus p30 heterogeneity as revealed by two-dimensional gel electrophoresis is not an artefact of the technique.

We have utilized two-dimensional (2D) gel electrophoresis [the first dimension being a linear pH gradient (5 to 8) and the second and 8 to 15% acrylamide gradient] to characterize the virion protein, p30, from several strains of purified murine leukaemia virus (MuLV). In all cases, we found that there was a predominant (70 to 90%) Coomassie Brilliant Blue-staining p30 spot, as well as several other species which differed in pI. The major p30 spot differed in pI among different MuLV strains and the minor spots varied depending on the host cell used to grow the virus. Specifically, (i) Moloney (M)-MuLV/NIH-3T3 showed two spots, a major one at pI 6.3 and a more acidic one, (ii) AKR/NIH-3T3, AKR/mouse embryo, and Gross/NIH-3T3 showed four spots, with the two basic, minor spots of AKR/NIH-3T3 appearing relatively decreased in intensity, and (iii) Rauscher (R)-MuLV/JLS-V9 (BALB/c) showed two spots, a major one with greater than 90% of the estimated Coomassie Brilliant Blue stain at a pI of 6.5 and a minor, acidic one. The major spots of AKR and M-MuLV viruses also differed in pI. The major spot of the AKR and Gross N-tropic viruses had a pI of 6.7 while that of NB-tropic virus M-MuLV had a pI of 6.3. The possibility that the heterogeneity observed in p30 was an artefact of the 2D gel technique had to be considered since urea was used to denature proteins in the first dimension of the gel. This possibility was made unlikely by our finding that another technique, chromatofocusing, gave the same results. Specifically, M-MuLV/JLS-V9 p30, when separated on chromatofocusing columns under non-denaturing conditions yielded three peaks, each of which directly corresponded to the three spots (pI: 6.1, 6.3, 6.6) observed on 2D gels. Furthermore, tryptic peptide maps of the major (pI 6.3) and one of the minor (pI 6.6) M-MuLV spots, although very similar in peptide composition, showed about five clearly defined differences. These results indicate (i) that the p30s of several N- and NB-tropic viruses are heterogeneous in pI, and (ii) for one particular MuLV, the p30 heterogeneity can be explained by a difference in amino acid composition. These findings of p30 charge heterogeneity may reflect either the presence of several different p30s in each virus particle and/or a heterogeneity in the virus population.

AKR murine leukemia virus↗
PubMed1987

Differences in the pI heterogeneity of virion and intracellular Moloney murine leukaemia virus p30s.

At least three different p30 forms which vary in isoelectric point (pI) were previously shown by two-dimensional (2D) gel electrophoresis to be present in purified virions obtained from several strains of murine leukaemia virus (MLV). This heterogeneity which had been identified by Coomassie Brilliant Blue staining has been further characterized by immunological techniques. Using as substrates two Moloney (M) MLV chronically infected cell lines (MJD-54 and clone 2 cells), we found that (i) all p30s had the antigenicity of M-MLV p30, when analysed by immunoblotting of virion proteins with anti-p30 sera, and (ii) when cells were labelled with [35S]methionine, a 14C-amino acid mixture, or [14C]serine and lysates of purified virions were immunoprecipitated with goat anti-p30 sera, four p30 spots (pI 6.0, 6.1, 6.3 and 6.6) could be clearly identified. These results strongly support the viral origin of the heterogeneous p30 spots. We next examined infected cell lysates in an attempt to pinpoint the molecular basis of this heterogeneity. When we immunoprecipitated p30s from labelled cell lysates utilizing goat anti-p30 sera it was observed that in contrast to the four virion p30s, there were only three intracellular p30s (pI 6.0, 6.3 and 6.6), there was a threefold greater amount of the intracellular compared to the virion form of p30 with pI 6.0, tryptic peptide maps of both virion and intracellular p30s labelled either with [35S]methionine or 125I showed basically similar patterns with only slight differences in intensity among certain peptides for the p30s with pI 6.1, 6.3 and 6.6, and the intracellular p30 with pI 6.0 had a peptide that was not present in any of the other p30s. These results suggest that due to some as yet uncharacterized modification(s) of p30 and/or some structural differences between different p30s, a heterogeneity in pI exists. This may be important for assembly of the virion capsid. However, it is also possible that the p30 heterogeneity reflects the presence of multiple M-MLV proviruses within each of the infected cell clones.

Antibodies, Viral↗
PubMed2006

Enterococcus faecalis strains show culture heterogeneity in cell surface charge.

Adhesion of micro-organisms to biotic and abiotic surfaces is an important virulence factor and involves different types of interactions. Enterococcus faecalis, a human commensal and an important opportunistic pathogen, has the ability to adhere to surfaces. Biliary stents frequently become clogged with bacterial biofilms, with E. faecalis as one of the predominant species. Six E. faecalis strains isolated from clogged biliary stents were investigated for the presence of specific biochemical factors involved in their adhesion: aggregation substances (Aggs) and the enterococcal surface protein (encoded by the esp gene). In addition, physico-chemical factors involved in adhesion (zeta potential and cell surface hydrophobicity) were determined, as well as the influence of ox bile on these properties. Two-thirds of the biliary stent isolates displayed culture heterogeneity in the pH dependence of their zeta potentials. Moreover, 24 out of 46 clinical isolates of E. faecalis, including 11 laboratory strains, also displayed such heterogeneity. The culture heterogeneity was demonstrated to be a stable trait, not caused by quorum sensing, not plasmid mediated, and independent of the presence of esp and Agg. Data presented show that culture heterogeneity in zeta potential enhances adhesion to an abiotic surface. A higher prevalence of culture heterogeneity in zeta potential in pathogenic as compared to non-pathogenic isolates could indicate that this phenomenon might play a role in virulence and putatively in pathogenesis.

Animals↗
PubMed2025

H3K27me3 chromatin heterogeneity reveals variable cell responses to estrogen and endocrine treatment.

Gene expression heterogeneity generates subpopulations of tumor cells that can evade therapeutic pressure. This heterogeneity has been observed in both primary Estrogen Receptor alpha positivebreast tumors and cell lines. Therefore, understanding the mechanisms regulating expression heterogeneity is critical towards developing effective therapies. A key contributor to gene expression variability is the stochastic nature of transcription. Transcription occurs in a probabilistic, burst-like manner, in which gene activation occurs intermittently, producing RNA in pulses and interspersed with transcriptional off-periods. The estrogen-responsive gene TFF1 is expressed in the majority ofbreast tumors and exemplifies such heterogeneity, with transcriptional inactivity ranging from minutes to several days. Here, we identify the molecular mechanism underlying the wide range in TFF1 expression by analyzing cells sorted based on their TFF1 activity levels. We observed that TFF1 inactive (TFF1low) cells exhibit a repressive chromatin state marked by H3K27me3 at the TFF1 promoter and enhancer. Despite global similarity inbinding, occupancy at the TFF1 regulatory elements was selectively reduced in TFF1low cells, resulting in fewer active alleles and diminished transcriptional bursting frequency. Conversely, TFF1high cells exhibited more active TFF1 alleles and hyperbursting. These cells also retained sensitivity to endocrine therapy, while TFF1low cells displayed reduced drug responsiveness. Genome-wide, differentially enriched H3K27me3 regions correlated with variable expression of estrogen-responsive genes, highlighting a broader regulatory mechanism that links chromatin state to expression variability. Together, our findings establish how repressive chromatin dynamics contribute to gene expression heterogeneity and endocrine resistance inbreast cancer.

Journal Article↗
PubMed2003

Dynamic heterogeneities in the out-of-equilibrium dynamics of simple spherical spin models.

The response of spherical two-spin interaction models, the spherical ferromagnet (s-FM) and the spherical Sherrington-Kirkpatrick (s-SK) model, is calculated for the protocol of the so-called nonresonant hole burning (NHB) experiment for temperatures below the respective critical temperatures. It is shown that it is possible to select dynamic features in the out-of-equilibrium dynamics of both models, one of the hallmarks of dynamic heterogeneities. The behavior of the s-SK model and the s-FM model in three dimensions is very similar, showing dynamic heterogeneities in the long-time behavior, i.e., in the aging regime. The appearance of dynamic heterogeneities in the s-SK model explicitly demonstrates that these are not necessarily related to spatial heterogeneities. For the s-FM model, it is shown that the nature of the dynamic heterogeneities changes as a function of dimensionality. With the increasing dimension, the frequency selectivity of the NHB diminishes and the dynamics in the mean-field limit of the s-FM model becomes homogeneous.

Journal Article↗
PubMed2003

Effective dispersion in temporally fluctuating flow through a heterogeneous medium.

In this paper we investigate the effective transport of a passive solute in temporally fluctuating flow through a spatially heterogeneous medium. The Darcy equation for an incompressible fluid in the heterogeneous medium is solved with temporally fluctuating boundary conditions using perturbation theory. We distinguish between a spatial random process reflecting the medium heterogeneities and a temporal random process which models the fluctuations of the boundary conditions. By appropriately averaging over the corresponding random fields, we evaluate the second-order perturbation approximation to the time evolution of the "effective" and "ensemble" dispersion coefficients. Both quantities consist of three terms reflecting: (1) local dispersion; (2) dispersion caused by spatial heterogeneities (identical to the corresponding dispersion in steady random flow); (3) dispersion linked to the enhanced solute spreading caused by the interactions between temporal fluctuations, local dispersion, and spatial heterogeneity. The behavior of this latter contribution is complex due to the interplay of three different time scales (set by fluctuating boundary conditions, local dispersion, and advection). Temporal fluctuations of the velocity field lead to effective transverse dispersion coefficients that evolve in time to macroscopic values (i.e., independent of the local dispersion), which is consistent with observations in the field but was not predicted by theories based on steady flow. Due to their perturbative nature, the derived results are intrinsically limited to moderately fluctuating random velocity fields. However, numerical transport simulations indicate a wide range of applicability. The reported results support remediation techniques that attempt to enhance the mixing of injected reactants with contaminated ground water by temporal variations of injection and pumping rates.

Journal Article↗
PubMed2006

Structure and dynamics of colloidal depletion gels: coincidence of transitions and heterogeneity.

Transitions in structural heterogeneity of colloidal depletion gels formed through short-range attractive interactions are correlated with their dynamical arrest. The system is a density and refractive index matched suspension of 0.20 volume fraction poly(methyl methacyrlate) colloids with the nonadsorbing depletant polystyrene added at a size ratio of depletant to colloid of 0.043. As the strength of the short-range attractive interaction is increased, clusters become increasingly structurally heterogeneous, as characterized by number-density fluctuations, and dynamically immobilized, as characterized by the single-particle mean-squared displacement. The number of free colloids in the suspension also progressively declines. As an immobile cluster to gel transition is traversed, structural heterogeneity abruptly decreases. Simultaneously, the mean single-particle dynamics saturates at a localization length on the order of the short-range attractive potential range. Both immobile cluster and gel regimes show dynamical heterogeneity. Non-Gaussian distributions of single particle displacements reveal enhanced populations of dynamical trajectories localized on two different length scales. Similar dependencies of number density fluctuations, free particle number, and dynamical length scales on the order of the range of short-range attraction suggests a collective structural origin of dynamic heterogeneity in colloidal gels.

Journal Article↗
PubMed2006

Relation between rotational and translational dynamic heterogeneities in water.

We use molecular dynamics simulations to probe the rotational dynamics of the extended simple point charge model of water for a range of temperatures down to 200 K, 6 K above the mode coupling temperature. We find that rotational dynamics is spatially heterogeneous; i.e., there are clusters of molecules that rotate significantly more than the average for a given time interval, and we study the size and the temporal behavior of these clusters. We find that the position of a rotational heterogeneity is strongly correlated with the position of a translational heterogeneity, and that the fraction of molecules belonging to both kinds of heterogeneities increases with decreasing temperature. We further find that although the two types of heterogeneities are not identical, they are related to the same physical picture.

Computer Simulation↗
PubMed2006

A comparison of 1-D models of cardiac pacemaker heterogeneity.

In this paper, we investigate the role of sinoatrial node (SAN) cellular heterogeneity in two key aspects of normal cardiac pacemaker function: frequency entrainment of the SAN, and propagation of excitation into the atrial tissue. Using detailed ionic models of electrical activity in SAN and atrial myocytes, we have formulated a number of one-dimensional models of SAN heterogeneity based on discrete-region (in which central and peripheral SAN type cell are separated into discrete regions), gradient and mosaic models of SAN organization. Each of the different models were assessed on their ability to achieve frequency entrainment of the SAN and activation of the adjoining atrial tissue in the presence of both uniform and linearly increasing conductivity profiles. Simulation results suggest that the gradient model of SAN heterogeneity, in which cells display a smooth variation in membrane properties from the center to the periphery of the SAN, produces action potential waveshapes and a site of earliest activation consistent with experimental observations in the intact SAN. The gradient model also achieves frequency entrainment of the SAN more easily than other models of SAN heterogeneity. Based on these results, we conclude that the gradient model of SAN heterogeneity, in the presence of a uniform conductivity profile, is the most likely model of SAN organization.

Action Potentials↗
PubMed1979

Comparison of heterogeneities of antitrinitrophenyl antibodies in strains of mice immunized by various methods.

Heterogeneity of antibodies directed against the trinitrophenyl (TNP) determinant in immunized mice was analyzed by investigating the band groups of antibodies formed by thin layer isoelectric focusing of serum. The degree of heterogeneity in C57BL/6 mice was markedly higher than that in CBA mice under the following conditions of immunization: immunization with TNP conjugated with bovine gamma-globulin or ovalbumin, interchange of these carrier proteins at the first and second injections, change of epitope density of the antigens, replacement of the hapten by dinitrophenyl group on the antigen for the secondary stimulation, and change of intervals of these injections from 15 days to five months. The degree of heterogeneity within a strain also varied with these immunizing conditions. Furthermore, the heterogeneity in C57BL/6 mice of any immunization group was greater than that in CBA mice in any group. This was also true when the heterogeneity was examined with the immune sera diluted to the same titer. These results indicate that the number of predominant clones of cells producing anti-TNP antibody after immunization is larger in C57BL/6 than in CBA mice.

Animals↗
PubMed1998

Mutational analyses of multiple target genes in histologically heterogeneous gastric cancer with microsatellite instability.

It has been recognized that gastric cancer often shows histological heterogeneity in a single tumor. Although microsatellite instability (MSI) has been reported in gastric cancer, the significance of genomic instability in gastric cancers with histological heterogeneity within a single tumor has never been addressed. We investigated MSI at 8 microsatellite loci in 40 normal/tumor DNA pairs from 20 gastric cancers with histological heterogeneity. Six of 20 patients (10 DNAs of 40 tumor DNAs) had severe MSI in more than 3 loci. Four of the MSI-positive cases had frameshift mutations in the poly(A)10 tract of the TGF beta RII gene. This mutation was found only in the MSI-positive component in the 2 cases (cases 4 and 5) in which only 1 component exhibited MSI. The other 4 cases demonstrated homozygous or heteroclonal mutations (1 and 2 base deletions) in the poly(A)8 tract of the hMSH3 gene; no mutation was detected in the poly(C)8 tract of the hMSH6 gene in any of the MSI-positive cases. The profile of alterations in multiple targets was different between the 2 components in most of the cases (5/6). These findings suggest that mismatch repair deficiency in MSI-positive tumors causes multiple gene inactivations through frameshift mutations in short repetitive sequences in a heterogeneous way within a histologically heterogeneous tumor.

Aged↗