Takamitsu Hara

Simultaneous cardiac imaging to detect inflammation and scar tissue with (18)F-fluorodeoxyglucose PET/MRI in cardiac sarcoidosis.

A 50-year-old female was referred to our hospital for complete right bundle branch block, which was detected by annual health check-up. Although she had no symptoms, echocardiography demonstrated left ventricular wall thinning and aneurysm at basal inter-ventricular septum and apex of the left ventricle (Figure 1, arrows). Thus, we suspected cardiac sarcoidosis and performed F-fluorodeoxyglucose (FDG) PET/MRI. After low carbohydrate diet for 24 hour before imaging and fasting for more than 18 hour, the patient was administered heparin 50 IU/kg intravenously to suppress physiological FDG uptake on the myocardium. Image acquisition was initiated 60 minutes after FDG administration.Maximum intensity projection revealed FDG uptake on bilateral hilar lymph nodes and mediastinal lymph nodes (Figure 2, arrows). Intense FDG uptake and late gadolinium enhancement (LGE) were observed in the left ventricle and in the right ventricle (Figure 3). T2-weighted images (T2WI) also showed high signal intensity indicating myocardial edema (Figure 3, arrows). Fusion images showed concordance of myocardial FDG uptake and LGE in most regions, but it should be noted that there was a discrepancy among the areas of FDG uptake, LGE, and high-intensity region on T2WI. This discrepancy revealed by simultaneous PET/MRI reminds us differential aspects of myocardial FDG uptake (active inflammation), LGE (fibrotic scar), and high-intensity region on T2WI (myocardial edema). PET/MRI is a useful imaging technology to provide helpful diagnostic information and guide a therapeutic strategy of cardiac sarcoidosis.

Accelerator mass spectrometry analysis of background 14C-concentrations in human blood: aiming at reference data for further microdosing studies

ObjectivePhase 0 clinical studies, which are known as microdose trials, are expected to promote drug development and reduce development costs. The accelerator mass spectrometry (AMS) system is expected to play an important role in the microdosing tests, as it is a highly sensitive measurement system that can be used to determine the drug concentrations in these tests. Using the AMS system, we measured the background 14C-concentration in human blood and evaluated the data for use as a reference in microdose studies that administer 14C-labeled compounds in humans.MethodsBlood samples of five healthy Japanese volunteers (three men, two women, median age 40.4 ± 9.8 years) were collected around the same time and just prior to when the subjects ate a meal (between 12:00 noon and 2:00 pm). Centrifugal separations of blood that was allowed to clot and the plasma were performed at 503 g for 2 min at 4°C. Background 14C-concentration for each of the samples was measured using the AMS system. The Institute of Accelerator Analysis, which is the first contract research organization in Japan that is capable of providing AMS analysis services for carbon dating and bioanalysis work, performed the AMS analysis.ResultsThe mean 14C-concentration in blood was 1.613 ± 0.125 dpm/ml (men 1.668 ± 0.114 dpm/ml, women 1.514 ± 0.076 dpm/ml), in clots 2.373 ± 0.087 dpm/ml (men 2.381 ± 0.101 dpm/ml, women 2.357 ± 0.060 dpm/ ml), and in plasma 0.648 ± 0.049 dpm/ml (men 0.647 ± 0.059 dpm/ml, women 0.649 ± 0.032 dpm/ml). The coefficient variation (CV) for blood was 7.8% (men 6.9%, women 5.0%), for clots 3.7% (men 4.3%, women 2.5%), and for plasma 7.6% (men 9.1%, women 4.9%). The 14C-concentrations of the clot and blood were higher than those of plasma. The 14C-concentrations in the blood and plasma were slightly different between individuals when compared with the values for the clot, although the differences were quite small, with a CV value less than 7.8%.ConclusionsEven though the 14C-concentration differed only slightly between individuals, 14C-concentrations of the clot and blood were higher than those of the plasma. Therefore, the variation and difference of the background data for blood and plasma might be of use as a reference for microdosing test evaluations.

A Framework for Analysis of Abortive Colony Size Distributions Using a Model of Branching Processes in Irradiated Normal Human Fibroblasts

Background Clonogenicity gives important information about the cellular reproductive potential following ionizing irradiation, but an abortive colony that fails to continue to grow remains poorly characterized. It was recently reported that the fraction of abortive colonies increases with increasing dose. Thus, we set out to investigate the production kinetics of abortive colonies using a model of branching processes. Methodology/Principal Findings We firstly plotted the experimentally determined colony size distribution of abortive colonies in irradiated normal human fibroblasts, and found the linear relationship on the log-linear or log-log plot. By applying the simple model of branching processes to the linear relationship, we found the persistent reproductive cell death (RCD) over several generations following irradiation. To verify the estimated probability of RCD, abortive colony size distribution (≤15 cells) and the surviving fraction were simulated by the Monte Carlo computational approach for colony expansion. Parameters estimated from the log-log fit demonstrated the good performance in both simulations than those from the log-linear fit. Radiation-induced RCD, i.e. excess probability, lasted over 16 generations and mainly consisted of two components in the early (<3 generations) and late phases. Intriguingly, the survival curve was sensitive to the excess probability over 5 generations, whereas abortive colony size distribution was robust against it. These results suggest that, whereas short-term RCD is critical to the abortive colony size distribution, long-lasting RCD is important for the dose response of the surviving fraction. Conclusions/Significance Our present model provides a single framework for understanding the behavior of primary cell colonies in culture following irradiation.

Vulnerable plaque on the common iliac artery detected by 18F-FDG PET/MRI

A 69-year-old man with suspected peripheral arterial disease underwent F-FDG PET/MRI to evaluate arterial stenosis and the characteristics of plaques in the arteries. After fasting for more than 6 h, 185 MBq of F-FDG was administered 60 min before image acquisition. MR angiography without contrast enhancement showed stenosis of the common iliac arteries bilaterally (a). The left common iliac artery showed marked FDG uptake (b, d, red arrows) that corresponded to a stenosis with high signal intensity on T1-weighted images (c, red arrow) that suggested that the lesion was a vulnerable plaque [1, 2]. No FDG uptake was observed in the right common iliac artery, although there was a significant stenosis. Arterial angiography and intravascular ultrasonography revealed a hypoechoic but ruptured plaque in the left common iliac artery and a hypoechoic plaque in the right common iliac artery (e, red arrowheads). Increased uptake of F-FDG in an atherosclerotic plaque is associated with plaque vulnerability [1, 3]. MRI has also been used to characterize the tissue of atherosclerotic plaques [2]. Combined PET/MRI plays an important role in evaluating vulnerable plaque from the point of view of functional and structural information. Furthermore, combined PET/MRI is able to acquire images simultaneously and provides precise fusion images. We report here the first case of the effective evaluation of a vulnerable plaque in the common iliac artery by F-FDG PET/MRI.

A branching process model for the analysis of abortive colony size distributions in carbon ion-irradiated normal human fibroblasts.

A single cell can form a colony, and ionizing irradiation has long been known to reduce such a cellular clonogenic potential. Analysis of abortive colonies unable to continue to grow should provide important information on the reproductive cell death (RCD) following irradiation. Our previous analysis with a branching process model showed that the RCD in normal human fibroblasts can persist over 16 generations following irradiation with low linear energy transfer (LET) γ-rays. Here we further set out to evaluate the RCD persistency in abortive colonies arising from normal human fibroblasts exposed to high-LET carbon ions (18.3 MeV/u, 108 keV/µm). We found that the abortive colony size distribution determined by biological experiments follows a linear relationship on the log–log plot, and that the Monte Carlo simulation using the RCD probability estimated from such a linear relationship well simulates the experimentally determined surviving fraction and the relative biological effectiveness (RBE). We identified the short-term phase and long-term phase for the persistent RCD following carbon-ion irradiation, which were similar to those previously identified following γ-irradiation. Taken together, our results suggest that subsequent secondary or tertiary colony formation would be invaluable for understanding the long-lasting RCD. All together, our framework for analysis with a branching process model and a colony formation assay is applicable to determination of cellular responses to low- and high-LET radiation, and suggests that the long-lasting RCD is a pivotal determinant of the surviving fraction and the RBE.

Optimized workflow and imaging protocols for whole-body oncologic PET/MRI

Although PET/MRI has the advantages of a simultaneous acquisition of PET and MRI, high soft-tissue contrast of the MRI images, and reduction of radiation exposure, its low profitability and long acquisition time are significant problems in clinical settings. Thus, MRI protocols that meet oncological purposes need to be used in order to reduce examination time while securing detectability. Currently, half-Fourier acquisition single-shot turbo spin echo and 3D-T1 volumetric interpolated breath-hold examination may be the most commonly used sequences for whole-body imaging due to their shorter acquisition time and higher diagnostic accuracy. Although there have been several reports that adding diffusion weighted image (DWI) to PET/MRI protocol has had no effect on tumor detection to date, in cases of liver, kidney, bladder, and prostate cancer, the use of DWI may be beneficial in detecting lesions. Another possible option is to scan each region with different MRI sequences instead of scanning the whole body using one sequence continuously. We herein report a workflow and imaging protocols for whole-body oncologic PET/MRI using an integrated system in the clinical routine, designed for the detection, for example by cancer screening, of metastatic lesions, in order to help future users optimize their workflow and imaging protocols.

Pilocarpine Hydrochloride Improves Baseline Image of Magnetic Resonance Cholangiopancreatography.

To the Editor: Recently, secretin-stimulated magnetic resonance cholangiopancreatography (MRCP) has been focused on as a noninvasive imaging modality owing to its clinical usefulness in the diagnosis of acute, acute recurrent, and chronic pancreatitis, as well as other causes of the pancreatic duct stricture ( 1–3 ). Because the clinical use of swine secretin is restricted worldwide owing to its risk of causing bovine spongiform encephalopathy, human recombinant or synthesized secretin has been used instead in some countries. Recombinant or synthesized secretin is eff ective for improving the quality of baseline MRCP images, but has limitations including cost and intravenous route of administration. If a feasible alternative to recombinant secretin is found, improving baseline MRCP images will become easier. Pilocarpine, a parasympathomimetic alka loid, is known to increase the amount much lower than was assumed when it was recommended on the basis of incomplete data, with enormous fi nancial implications. We clearly do not have reasonable estimates of the value of chromoendoscopy in infl ammatory bowel disease (IBD). When societal (or third-party payer) decisions must be made about what should be paid for, value becomes a critical component of informed decision making. Without critical evaluation of value, enormous sums can be spent on lowvalue procedures and follow-up, stealing resources from high-value health care ( 1 ). Th e absolute risk of colorectal cancer in IBD is low, and studies suggest that this risk is falling over time ( 2,3 ). Th is may be due to improved anti-infl ammatory therapies, which may provide higher value than chasing a diminishing number of colorectal cancers with increasingly sensitive tools. We have recently learned aft er years of improving the sensitivity of mammograms (and aft er spending millions of dollars on health care) that treating ductal carcinoma in situ (25% of all positive mammogram fi ndings) in the breast does not change mortality ( 4 ). It is not clear that the improved sensitivity of chromoendoscopy will lead to a measurable clinical benefi t when applied to all IBD patients. In the absence of data on value, it seems reasonable to limit our spending of time and dollars on chromoendoscopy to the highest-risk patients until we have some prospective evidence of its actual clinical benefi t and reasonable cost-eff ectiveness. In the meantime, spending health-care dollars on delivering eff ective anti-infl ammatory therapy to all IBD patients will likely provide better value than chromoendoscopy.

Abstract 438: Establishment of MDA-MB231-derived breast cancer cell lines possessing a higher metastatic activity and a resistance to radiation.

Background and purpose: Metastatic cancer tissues might have characteristics different from their original primary regions, which could affect strategies for radiotherapy. To investigate properties of metastatic cancers and their radiosensitivities, we established MDA-MB231-derived breast cancer cell lines, which were prone to cause metastasis when transplanted into mouse. Methods: A breast cancer cell line, MDA-MB231 expressing pGL4.5/luciferase were injected into nude mice via left ventricle or mammary gland tissue to form metastatic lesions. The metastatic cells in lymph nodes, bone, and lung were detected by a bioluminescence imaging technique, which were excised, cultured, and transplanted into the next mice in the same way. Such transplantation procedures were repeated 3 times to establish organ-oriented metastasis-prone cell lines. The different characteristics of these cells were examined by morphological analysis, and proliferation, invasion, and migration assays, as well as radiation sensitivity test. Result: There was no significant difference among cell lines in morphology and proliferative ability. All three metastasis-prone cell lines showed increased activity in migration and invasion compared to the parental cell line. Moreover, they showed lower sensitivities to radiation than the parental cell line, while no difference was found among the metastasis-prone cell lines. Conclusion: We have established new cell lines that could be used for the study of metastatic breast cancers in relation to the radiotherapy. Citation Format: Takamitsu Hara, Manabu Iwadate, Shuichi Shiratori, Kenji Gonda, Tatsuo Shimura, Yoshihiro Nakagami, Masahiko Shibata, Satoshi Waguri, Seiichi Takenoshita. Establishment of MDA-MB231-derived breast cancer cell lines possessing a higher metastatic activity and a resistance to radiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 438. doi:10.1158/1538-7445.AM2013-438