Epidemiology and Pathology of T- and NK-Cell Lymphomas.

PURPOSE: This review will describe and update readers on the recent changes in the 2017 WHO classification regarding peripheral T-cell lymphomas. RECENT FINDINGS: Signficant advances in molecular studies have resulted in revisions to the classification as well as introduction to provisional entities such as breast implant-associated ALCL and nodal PTCL with T-follicular helper phenotype. SUMMARY: Major advances in molecular and gene expression profiling has expanded our knowledge of these rare and aggressive diseases.

Relative frequency and clinicopathologic characteristics of MYC-rearranged follicular lymphoma.

MYC rearrangement is a relatively rare genetic abnormality in follicular lymphoma (FL). In this study, we evaluated the relative frequency of MYC rearrangement in 522 cases of FL and studied their clinicopathologic, cytogenetic, and molecular characteristics. Fluorescence in situ hybridization studies for MYC (break-apart probe), MYC/IGH, IGH/BCL2, and BCL6 rearrangements were performed on tissue microarrays. Immunohistochemical stains for CD10, BCL2, BCL6, and MYC were performed and scored on MYC-rearranged cases. On 4 FL cases, a custom targeted panel of 356 genes was used for mutation analysis. Ten cases (1.9%) were positive for MYC rearrangement. Histologically, 6 of 10 cases were grade 1-2, and 4 cases were grade 3A. By immunohistochemistry, 9 of 9 tested cases were CD10+, all cases were BCL6+, and 9/10 cases were BCL2+. MYC protein staining was low in all cases tested. IGH/BCL2 rearrangement was detected in 5 of 9 cases, whereas BCL6 rearrangement was detected in 3 of 7 tested cases and 4 of 10 cases showed MYC/IGH rearrangement. The most commonly detected mutations in the MYC-positive cases included HLA-B, TNFRSF14, and KMT2D. MYC and/or B2M abnormalities were detected in 2 cases. In conclusion, MYC rearrangement is uncommon in FL and these cases do not appear to have specific histologic characteristics. Molecular analysis showed abnormalities in genes associated with transformation, namely MYC and B2M. Larger studies are needed to evaluate if MYC-rearrangement in FL has prognostic significance.

Quantification of Early-Stage Myeloid-Derived Suppressor Cells in Cancer Requires Excluding Basophils.

Myeloid derived suppressor cells (MDSC) are a heterogeneous group of immature cells that accumulate in the peripheral blood and tumor microenvironment and are barriers to cancer therapy. MDSCs serve as prognostic biomarkers and are targets for therapy. On the basis of surface markers, three subsets of MDSCs have been defined in humans: granulocytic, monocytic, and early stage (e-MDSC). The markers attributed to e-MDSCs overlap with those of basophils, which are rare circulating myeloid cells with unrecognized roles in cancer. Thus, we asked whether e-MDSCs in circulation and the tumor microenvironment include basophils. On average, 58% of cells with e-MDSC surface markers in blood and 36% in ascites from patients with ovarian cancer were basophils based on CD123high expression and cytology, whereas cells with immature features were rare. Circulating and ascites basophils did not suppress proliferation of stimulated T cells, a key feature of MDSCs. Increased accumulation of basophils and basogranulin, a marker of basophil degranulation, were observed in ascites compared to serum in patients with newly diagnosed ovarian cancer. Basophils recruited to the tumor microenvironment may exacerbate fluid accumulation by their release of proinflammatory granular constituents that promote vascular leakage. No significant correlation was observed between peripheral basophil counts and survival in patients with ovarian cancer. Our results suggest that studies in which e-MDSCs were defined solely by surface markers should be reevaluated to exclude basophils. Both immaturity and suppression are criteria to define e-MDSCs in future studies.

Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment.

Epithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid-derived suppressor cells are an immature population that impairs antitumor immunity. Since suppressive granulocytes in the ascites of patients with newly diagnosed EOC were morphologically mature, we hypothesized that PMN were rendered suppressive in the tumor microenvironment (TME). Circulating PMN from patients were not suppressive but acquired a suppressor phenotype (defined as ≥1 log10 reduction of anti-CD3/CD28-stimulated T cell proliferation) after ascites supernatant exposure. Ascites supernatants (20 of 31 supernatants) recapitulated the suppressor phenotype in PMN from healthy donors. T cell proliferation was restored with ascites removal and restimulation. PMN suppressors also inhibited T cell activation and cytokine production. PMN suppressors completely suppressed proliferation in naive, central memory, and effector memory T cells and in engineered tumor antigen-specific cytotoxic T lymphocytes, while antigen-specific cell lysis was unaffected. Inhibition of complement C3 activation and PMN effector functions, including CR3 signaling, protein synthesis, and vesicular trafficking, abrogated the PMN suppressor phenotype. Moreover, malignant effusions from patients with various metastatic cancers also induced the C3-dependent PMN suppressor phenotype. These results point to PMN impairing T cell expansion and activation in the TME and the potential for complement inhibition to abrogate this barrier to antitumor immunity.

Determination of fractional flow reserve (FFR) based on scaling laws: a simulation study.

Fractional flow reserve (FFR) provides an objective physiological evaluation of stenosis severity. A technique that can measure FFR using only angiographic images would be a valuable tool in the cardiac catheterization laboratory. To perform this, the diseased blood flow can be measured with a first pass distribution analysis and the theoretical normal blood flow can be estimated from the total coronary arterial volume based on scaling laws. A computer simulation of the coronary arterial network was used to gain a better understanding of how hemodynamic conditions and coronary artery disease can affect blood flow, arterial volume and FFR estimation. Changes in coronary arterial flow and volume due to coronary stenosis, aortic pressure and venous pressure were examined to evaluate the potential use of flow and volume for FFR determination. This study showed that FFR can be estimated using arterial volume and a scaling coefficient corrected for aortic pressure. However, variations in venous pressure were found to introduce some error in FFR estimation. A relative form of FFR was introduced and was found to cancel out the influence of pressure on coronary flow, arterial volume and FFR estimation. The use of coronary flow and arterial volume for FFR determination appears promising.

Estimation of regional myocardial mass at risk based on distal arterial lumen volume and length using 3D micro-CT images.

The determination of regional myocardial mass at risk distal to a coronary occlusion provides valuable prognostic information for a patient with coronary artery disease. The coronary arterial system follows a design rule which allows for the use of arterial branch length and lumen volume to estimate regional myocardial mass at risk. Image processing techniques, such as segmentation, skeletonization and arterial network tracking, are presented for extracting anatomical details of the coronary arterial system using micro-computed tomography (micro-CT). Moreover, a method of assigning tissue voxels to their corresponding arterial branches is presented to determine the dependent myocardial region. The proposed micro-CT technique was utilized to investigate the relationship between the sum of the distal coronary arterial branch lengths and volumes to the dependent regional myocardial mass using a polymer cast of a porcine heart. The correlations of the logarithm of the total distal arterial lengths (L) to the logarithm of the regional myocardial mass (M) for the left anterior descending (LAD), left circumflex (LCX) and right coronary (RCA) arteries were log(L)=0.73log(M)+0.09 (R=0.78), log(L)=0.82log(M)+0.05 (R=0.77) and log(L)=0.85log(M)+0.05 (R=0.87), respectively. The correlation of the logarithm of the total distal arterial lumen volumes (V) to the logarithm of the regional myocardial mass for the LAD, LCX and RCA were log(V)=0.93log(M)-1.65 (R=0.81), log(V)=1.02log(M)-1.79 (R=0.78) and log(V)=1.17log(M)-2.10 (R=0.82), respectively. These morphological relations did not change appreciably for diameter truncations of 600-1400microm. The results indicate that the image processing procedures successfully extracted information from a large 3D dataset of the coronary arterial tree to provide prognostic indications in the form of arterial tree parameters and anatomical area at risk.

Quantitative coronary angiography using image recovery techniques for background estimation in unsubtracted images.

Densitometry measurements have been performed previously using subtracted images. However, digital subtraction angiography (DSA) in coronary angiography is highly susceptible to misregistration artifacts due to the temporal separation of background and target images. Misregistration artifacts due to respiration and patient motion occur frequently, and organ motion is unavoidable. Quantitative densitometric techniques would be more clinically feasible if they could be implemented using unsubtracted images. The goal of this study is to evaluate image recovery techniques for densitometry measurements using unsubtracted images. A humanoid phantom and eight swine (25-35 kg) were used to evaluate the accuracy and precision of the following image recovery techniques: Local averaging (LA), morphological filtering (MF), linear interpolation (LI), and curvature-driven diffusion image inpainting (CDD). Images of iodinated vessel phantoms placed over the heart of the humanoid phantom or swine were acquired. In addition, coronary angiograms were obtained after power injections of a nonionic iodinated contrast solution in an in vivo swine study. Background signals were estimated and removed with LA, MF, LI, and CDD. Iodine masses in the vessel phantoms were quantified and compared to known amounts. Moreover, the total iodine in left anterior descending arteries was measured and compared with DSA measurements. In the humanoid phantom study, the average root mean square errors associated with quantifying iodine mass using LA and MF were approximately 6% and 9%, respectively. The corresponding average root mean square errors associated with quantifying iodine mass using LI and CDD were both approximately 3%. In the in vivo swine study, the root mean square errors associated with quantifying iodine in the vessel phantoms with LA and MF were approximately 5% and 12%, respectively. The corresponding average root mean square errors using LI and CDD were both 3%. The standard deviations in the differences between measured iodine mass in left anterior descending arteries using DSA and LA, MF, LI, or CDD were calculated. The standard deviations in the DSA-LA and DSA-MF differences (both approximately 21 mg) were approximately a factor of 3 greater than that of the DSA-LI and DSA-CDD differences (both approximately 7 mg). Local averaging and morphological filtering were considered inadequate for use in quantitative densitometry. Linear interpolation and curvature-driven diffusion image inpainting were found to be effective techniques for use with densitometry in quantifying iodine mass in vitro and in vivo. They can be used with unsubtracted images to estimate background anatomical signals and obtain accurate densitometry results. The high level of accuracy and precision in quantification associated with using LI and CDD suggests the potential of these techniques in applications where background mask images are difficult to obtain, such as lumen volume and blood flow quantification using coronary arteriography.

Regional blood flow analysis and its relationship with arterial branch lengths and lumen volume in the coronary arterial tree.

The limitations of visually assessing coronary artery disease are well known. These limitations are particularly important in intermediate coronary lesions (30-70% diameter stenosis) where it is difficult to determine whether a particular lesion is the cause of ischaemia. Therefore, a functional measure of stenosis severity is needed. The purpose of this study is to determine whether the expected maximum coronary blood flow in an arterial tree is predictable from its sum of arterial branch lengths or lumen volume. Using a computer model of a porcine coronary artery tree, an analysis of blood flow distribution was conducted through a network of millions of vessels that included the entire coronary artery tree down to the first capillary branch. The flow simulation results show that there is a linear relationship between coronary blood flow and the sum of its arterial branch lengths. This relationship holds over the entire arterial tree. The flow simulation results also indicate that there is a 3/4 power relation between coronary blood flow (Q) and the sum of its arterial lumen volume (V). Moreover, there is a linear relationship between normalized Q and normalized V raised to a power of 3/4 over the entire arterial tree. These results indicate that measured arterial branch lengths or lumen volumes can be used to predict the expected maximum blood flow in an arterial tree. This theoretical maximum blood flow, in conjunction with an angiographically measured blood flow, can potentially be used to calculate fractional flow reserve based entirely on angiographic data.

Feasibility of real time dual-energy imaging based on a flat panel detector for coronary artery calcium quantification.

The feasibility of a real-time dual-energy imaging technique with dynamic filtration using a flat panel detector for quantifying coronary arterial calcium was evaluated. In this technique, the x-ray beam was switched at 15 Hz between 60 kVp and 120 kVp with the 120 kVp beam having an additional 0.8 mm silver filter. The performance of the dynamic filtration technique was compared with a static filtration technique (4 mm Al+0.2 mm Cu for both beams). The ability to quantify calcium mass was evaluated using calcified arterial vessel phantoms with 20-230 mg of hydroxylapatite. The vessel phantoms were imaged over a Lucite phantom and then an anthropomorphic chest phantom. The total thickness of Lucite phantom ranges from 13.5-26.5 cm to simulate patient thickness of 16-32 cm. The calcium mass was measured using a densitometric technique. The effective dose to patient was estimated from the measured entrance exposure. The effects of patient thickness on contrast-to-noise ratio (CNR), effective dose, and the precision of calcium mass quantification (i.e., the frame to frame variability) were studied. The effects of misregistration artifacts were also measured by shifting the vessel phantoms manually between low- and high-energy images. The results show that, with the same detector signal level, the dynamic filtration technique produced 70% higher calcium contrast-to-noise ratio with only 4% increase in patient dose as compared to the static filtration technique. At the same time, x-ray tube loading increased by 30% with dynamic filtration. The minimum detectability of calcium with anatomical background was measured to be 34 mg of hydroxyapatite. The precision in calcium mass measurement, determined from 16 repeated dual-energy images, ranges from 13 mg to 41 mg when the patient thickness increased from 16 to 32 cm. The CNR was found to decrease with the patient thickness linearly at a rate of (-7%/cm). The anatomic background produced measurement root-mean-square (RMS) errors of 13 mg and 18 mg when the vessel phantoms were imaged over a uniform (over the rib) and nonuniform (across the edge of rib) bone background, respectively. Misregistration artifacts due to motions of up to 1.0 mm between the low- and high-energy images introduce RMS error of less than 4.3 mg, which is much smaller than the frame to frame variability and the measurement error due to anatomic background. The effective dose ranged from 1.1 to 6.6 microSv for each dual-energy image, depending on patient thickness. The study shows that real-time dual-energy imaging can potentially be used as a low dose technique for quantifying coronary arterial calcium.

Real-time tumor tracking using implanted positron emission markers: concept and simulation study.

The delivery accuracy of radiation therapy for pulmonary and abdominal tumors suffers from tumor motion due to respiration. Respiratory gating should be applied to avoid the use of a large target volume margin that results in a substantial dose to the surrounding normal tissue. Precise respiratory gating requires the exact spatial position of the tumor to be determined in real time during treatment. Usually, fiducial markers are implanted inside or next to the tumor to provide both accurate patient setup and real-time tumor tracking. However, current tumor tracking systems require either substantial x-ray exposure to the patient or large fiducial markers that limit the value of their application for pulmonary tumors. We propose a real-time tumor tracking system using implanted positron emission markers (PeTrack). Each marker will be labeled with low activity positron emitting isotopes, such as 124I, 74As, or 84Rb. These isotopes have half-lives comparable to the duration of radiation therapy (from a few days to a few weeks). The size of the proposed PeTrack marker will be 0.5-0.8 mm, which is approximately one-half the size of markers currently employed in other techniques. By detecting annihilation gammas using position-sensitive detectors, multiple positron emission markers can be tracked in real time. A multimarker localization algorithm was developed using an Expectation-Maximization clustering technique. A Monte Carlo simulation model was developed for the PeTrack system. Patient dose, detector sensitivity, and scatter fraction were evaluated. Depending on the isotope, the lifetime dose from a 3.7 MBq PeTrack marker was determined to be 0.7-5.0 Gy at 10 mm from the marker. At the center of the field of view (FOV), the sensitivity of the PeTrack system was 240-320 counts/s per 1 MBq marker activity within a 30 cm thick patient. The sensitivity was reduced by 45% when the marker was near the edge of the FOV. The scatter fraction ranged from 12% (124I, 74As) to 16% (84Rb). In addition, four markers (labeled with 124I) inside a 30 cm diameter water phantom were simulated to evaluate the feasibility of the multimarker localization algorithm. Localization was considered successful if a marker was localized to within 2 mm from its true location. The success rate of marker localization was found to depend on the number of annihilation events used and the error in the initial estimate of the marker position. By detecting 250 positron annihilation events from 4 markers (average of 62 events per marker), the marker success rates for initial errors of +/-5, +/-10, and +/-15 mm were 99.9%, 99.6%, and 92.4%, respectively. Moreover, the average localization error was 0.55 (+/-0.27) mm, which was independent of initial error. The computing time for localizing four markers was less than 20 ms (Pentium 4, 2.8 GHz processor, 512 MB memory). In conclusion, preliminary results demonstrate that the PeTrack technique can potentially provide real-time tumor tracking with low doses associated with the marker's activity. Furthermore, the small size of PeTrack markers is expected to facilitate implantation and reduce patient risk.

Automated technique for angiographic determination of coronary blood flow and lumen volume.

RATIONALE AND OBJECTIVES: Visual interpretation of angiographic images has been shown to be inadequate for assessing the severity of intermediate coronary stenoses. An approach for evaluating both the anatomic and functional impact of a stenosis is needed. An automated technique for determining both coronary blood flow and lumen volume based on a first-pass analysis (FPA) of coronary angiograms and a template matching algorithm was evaluated. MATERIALS AND METHODS: Coronary angiograms of a swine animal model were obtained during power injections of contrast material into the left coronary ostium. Background anatomy was subtracted with an automated phase matching program. A template matching algorithm and first-pass analysis were then used to quantify coronary blood flow and lumen volume. Coronary blood flow and lumen volume measurements were validated with a transit-time ultrasound flow probe and a polymer cast of the coronary arteries, respectively. RESULTS: In 14 independent comparisons, the mean coronary blood flow measured with FPA showed strong correlation with the mean flow measured with the ultrasound flow probe (Q(FPA) = 0.88Q(probe) - 1.99; r = 0.977; standard error of estimate = 3.23 mL/minute). The lumen volumes determined with FPA and cast measurements demonstrated excellent correlation and can be related to each other by V(FPA) = 0.95V(C) - 0.01 (r = 0.997; standard error of estimate = 0.01 mL). CONCLUSIONS: The proposed automated method for accurate determination of coronary blood flow and lumen volume can supplement visual evaluation of coronary anatomy with quantitative physiologic data. This automated technique potentially offers a clinically feasible method of quantifying coronary blood flow and lumen volume in conjunction with routine cardiac catheterization.

Estimation of coronary artery hyperemic blood flow based on arterial lumen volume using angiographic images.

The purpose of this study is to develop a method to estimate the hyperemic blood flow in a coronary artery using the sum of the distal lumen volumes in a swine animal model. The limitations of visually assessing coronary artery disease are well known. These limitations are particularly important in intermediate coronary lesions where it is difficult to determine whether a particular lesion is the cause of ischemia. Therefore, a functional measure of stenosis severity is needed using angiographic image data. Coronary arteriography was performed in 10 swine (Yorkshire, 25-35 kg) after power injection of contrast material into the left main coronary artery. A densitometry technique was used to quantify regional flow and lumen volume in vivo after inducing hyperemia. Additionally, 3 swine hearts were casted and imaged post-mortem using cone-beam CT to obtain the lumen volume and the arterial length of corresponding coronary arteries. Using densitometry, the results showed that the stem hyperemic flow (Q) and the associated crown lumen volume (V) were related by Q = 159.08 V(3/4) (r = 0.98, SEE = 10.59 ml/min). The stem hyperemic flow and the associated crown length (L) using cone-beam CT were related by Q = 2.89 L (r = 0.99, SEE = 8.72 ml/min). These results indicate that measured arterial branch lengths or lumen volumes can potentially be used to predict the expected hyperemic flow in an arterial tree. This, in conjunction with measured hyperemic flow in the presence of a stenosis, could be used to predict fractional flow reserve based entirely on angiographic data.

Quantification of fractional flow reserve based on angiographic image data.

Coronary angiography provides excellent visualization of coronary arteries, but has limitations in assessing the clinical significance of a coronary stenosis. Fractional flow reserve (FFR) has been shown to be reliable in discerning stenoses responsible for inducible ischemia. The purpose of this study is to validate a technique for FFR quantification using angiographic image data. The study was carried out on 10 anesthetized, closed-chest swine using angioplasty balloon catheters to produce partial occlusion. Angiography based FFR was calculated from an angiographically measured ratio of coronary blood flow to arterial lumen volume. Pressure-based FFR was measured from a ratio of distal coronary pressure to aortic pressure. Pressure-wire measurements of FFR (FFR( P )) correlated linearly with angiographic volume-derived measurements of FFR (FFR( V )) according to the equation: FFR( P ) = 0.41 FFR( V ) + 0.52 (P-value < 0.001). The correlation coefficient and standard error of estimate were 0.85 and 0.07, respectively. This is the first study to provide an angiographic method to quantify FFR in swine. Angiographic FFR can potentially provide an assessment of the physiological severity of a coronary stenosis during routine diagnostic cardiac catheterization without a need to cross a stenosis with a pressure-wire.

Dynamic dual-energy chest radiography: a potential tool for lung tissue motion monitoring and kinetic study.

Dual-energy chest radiography has the potential to provide better diagnosis of lung disease by removing the bone signal from the image. Dynamic dual-energy radiography is now possible with the introduction of digital flat-panel detectors. The purpose of this study is to evaluate the feasibility of using dynamic dual-energy chest radiography for functional lung imaging and tumor motion assessment. The dual-energy system used in this study can acquire up to 15 frames of dual-energy images per second. A swine animal model was mechanically ventilated and imaged using the dual-energy system. Sequences of soft-tissue images were obtained using dual-energy subtraction. Time subtracted soft-tissue images were shown to be able to provide information on regional ventilation. Motion tracking of a lung anatomic feature (a branch of pulmonary artery) was performed based on an image cross-correlation algorithm. The tracking precision was found to be better than 1 mm. An adaptive correlation model was established between the above tracked motion and an external surrogate signal (temperature within the tracheal tube). This model is used to predict lung feature motion using the continuous surrogate signal and low frame rate dual-energy images (0.1-3.0 frames per second). The average RMS error of the prediction was (1.1 ± 0.3) mm. The dynamic dual energy was shown to be potentially useful for lung functional imaging such as regional ventilation and kinetic studies. It can also be used for lung tumor motion assessment and prediction during radiation therapy.

Allometric scaling in the coronary arterial system.

Biological variables such as basal metabolic rate scale with body mass through a power law relationship. The coronary arterial system also exhibits power law relations between morphological parameters such as total distal arterial length and lumen volume. The current study validated this power law and extended the relations to include the regional myocardial mass. The coronary arteries of 10 swine hearts were casted with a radio-opaque polymer solution and were imaged with cone-beam computed tomography. The CT images were analyzed by segmenting the vessels and myocardium. The vessels were tracked in 3D and the branch diameter, length, and lumen volume were computed. Regional myocardial mass were then computed for each branch. The perfusion beds of the three main coronary arterial trees were also colored differently to validate the measured mass and CT computed mass. The power laws for the morphological characteristics were then analyzed and the exponents were found to be 3/4 for the length-mass and length-volume relationships, and 1.0 for the volume-mass relationship. The CT computed myocardial mass (MCT) and the actual measured mass (MA) were related by MCT = 1.002 MA + 2.033 g. The relationship of the morphological parameters of the coronary arterial tree can potentially be used for quantification of diffuse coronary artery disease and anatomic area at risk.