Dual-time-point 18F-FDG PET imaging for diagnosis of disease type and disease activity in patients with idiopathic interstitial pneumonia

Purpose Individual clinical courses of idiopathic interstitial pneumonia (IIP) are variable and difficult to predict because the pathology and disease activity are contingent, and chest computed tomography (CT) provides little information about disease activity. In this study, we applied dual-time-point [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET), commonly used for diagnosis of malignant tumors, to the differential diagnosis and prediction of disease progression in IIP patients. Methods Fifty patients with IIP, including idiopathic pulmonary fibrosis (IPF, n=21), nonspecific interstitial pneumonia (NSIP, n=18), and cryptogenic organizing pneumonia (COP, n=11), underwent 18F-FDG PET examinations at two time points: Scan 1 at 60 min (early imaging) and Scan 2 at 180 min (delayed imaging) after 18F-FDG injection. The standardized uptake values (SUV) at the two points and the retention index (RI-SUV) calculated from them were evaluated and compared with chest CT findings, disease progression, and disease types. To evaluate short term disease progression, all patients were examined pulmonary function test every 3 months for 1 year after 18F-FDG PET scanning. Results The early SUV for COP (2.47±0.74) was significantly higher than that for IPF (0.99±0.29, P=0.0002) or NSIP (1.22±0.44, P=0.0025). When an early SUV cut-off value of 1.5 and greater was used to distinguish COP from IPF and NSIP, the sensitivity, specificity, and accuracy were 90.9%, 94.3%, and 93.5%, respectively. The RI-SUV for IPF and NSIP lesions was significantly greater in patients with deteriorated pulmonary function after 1-year of follow-up (progressive group, 13.0±8.9%) than in cases without deterioration during the 1-year observation period (stable group, -16.8±5.9%, P<0.0001). However, the early SUV for all IIP types provided no additional information of disease progression. When an RI-SUV cut-off value of 0% and greater was used to distinguish progressive IIPs from stable IIPs, the sensitivity, specificity, and accuracy were 95.5%, 100%, and 97.8%, respectively. Conclusion Early-SUV and RI-SUV obtained from dual-time point 18F-FDG PET are useful parameter for the differential diagnosis and prediction of disease progression in patients with IIP

In Vivo Simultaneous Imaging of Vascular Pool and Hypoxia with a HT-29 Tumor Model: the Application of Dual-Isotope SPECT/PET/CT

Investigation of vascularity and hypoxia in tumors is important in understanding cancer biology to developthe therapeutic strategies in cancer treatment. ------------------------------------------------------------------------ *Corresponding author . Recently, an imaging technology with the VECTor SPECT/PET/CT small-animal scanner (MILabs) has been developed to obtain simultaneous images usingtwodifferent tracers labeled with SPECT and PET nuclides, respectively. In this study, we developed amethod to simultaneously visualize vascularity and hypoxia witha human colon carcinoma HT-29tumor-bearing mouse model with 99mTc-labeled human serum albumin (99mTc-HSA) to detect blood pool, and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) to detect the over-reduced conditionsunder hypoxia, by applying this SPECT/PET/CT technology.Prior to the in vivo experiments, a phantom study was conducted to confirmquantitativity of the 99mTc/64Cu dual-isotope imaging with the SPECT/PET/CT system,by comparing radioactivities detected by SPECT/PET/CT system and those of standards under the conditions of wide range of radioactivities and various content ratios, in our settings. An in vivoimaging study was conducted with HT-29 tumor-bearing mice. Both 64Cu-ATSM (37 MBq) and 99mTc-HSA (18.5 MBq) were intravenously injected into a mouse (n = 4) at 1 h and 10 min, respectively, before scanning for 20 min; the 99mTc/64Cu dual-isotope SPECT/PET/CT images were then obtained.The phantom study demonstrated that this system has high quantitativity, even when 2 isotopes co-existed and the content ratio was changed over a wide range, indicating the feasibility for in vivo experiments. In vivoSPECT/PET/CT imaging with 64Cu-ATSM and 99mTc-HSA visualized the distribution of each probe and showed that 64Cu-ATSM high-uptake regions barely overlapped with 99mTc-HSA high-uptake regions within HT-29 tumors.We developed a method to simultaneously visualize vascularity and hypoxia within HT-29tumors using in vivodual-isotope SPECT/PET/CT imaging. This methodology would be useful for studies oncancer biology with mouse tumor models anddevelopment of the treatment strategies against cancer. Examination of vascularity and hypoxia within in vivotumors is important in understanding the biology of cancer anddevelopmentof the therapeutic strategies in cancer treatment. For hypervascular tumors, antiangiogenic therapy and antivascular therapy are promising approaches. For antiangiogenic therapy, the anti-vascular endothelial growth factor antibody bevacizumab is now clinically used worldwide [1-4], and for antivascular therapy, a clinical trial withcombrestatin A4 phosphate is conducted[5]. For hypovascular tumor, which is usually associated with hypoxia, intensive treatment is necessary, since tumor hypoxia is reportedly resistant to chemotherapy and radiotherapy [6-8]. In recent years, several therapeutic methods have been proposedto damage to hypoxic regions within tumors, such as intensity modulated radiation therapy with hypoxia positron emission tomography (PET) imaging [9, 10], and carbon-ion radiotherapy, which is able to damage tumor cells even in the absence of oxygen by high linear energy transfer beam [11, 12]. However, considering the difficulty of cancer radical cure at the present moment, more effective drugs and treatment methods for antiangiogenic, antivascular, and antihypoxia therapies need to be developed. In addition, combinations of these therapies would be effective approaches, since they can attacktumor vascularity and hypoxia closely linked each other.However, it is still difficult to observe tumor vascularity and hypoxia both coincidently and concisely in in vivo tumor-bearing mouse model. Recently, a technology of single-photon emission computed tomography/positron emission tomography/computed tomography(SPECT/PET/CT) imaging with the VECTor small-animal scanner, launched from MILabs (Utrecht, Netherlands), has been reportedto obtain truly simultaneous images with twotracers labeled with SPECT and PET nuclides, respectively. Conventionally, dual-isotope imaging studies with SPECT and PET have been performed by obtaining each image independently with 2 separate systems [13, 14]. In contrast, the VECTor system is equipped with a clustered pinhole collimator, which dramatically reduces pinhole-edge penetration of high-energy annihilation ?-photons from PET nuclides and enables it to detect high-energy ?-photons derived from PET nuclides, in a manner similar to SPECT nuclides, and to obtain high-resolution images from positron emitters and single-photon emitters at the same time by separating the images based on the photon energy [15, 16]. Thus, this system has a novel concept to make images of PET nuclides, compared to the typical PET system, which measures the coincidence of annihilation ?-photons. Goorden et al. have reported that this system shows high spatial resolution, with 0.8 mm for PET nuclides and 0.5 mm for SPECT nuclides [15]. Miwa et al. also confirmed its performance in simultaneous detection of 99mTc and 18F using this system [17]. In this study, we developed a methodology to easily observe intratumoralvascularity and hypoxia in a simultaneous manner,by applyingthis SPECT/PET/CT technology. We used 99mTc-labeled human serum albumin (99mTc-HSA) labeled with a SPECT nuclide 99mTc (half-life = 6.0 h; 140 keV ?-ray: 89%) to visualize tumor vascularity by detecting blood pool [18]. The 99mTc-HSAhas been reported to detect tumor blood pool in many types of cancer, including colon cancer, renal cell carcinoma, and liver tumor in both preclinical and clinical studies [19-21]. We also used 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), labeled with a PET nuclide 64Cu (half-life = 12.7 h; ?+-decay: 17.4%; ??-decay: 38.5%; and electron capture: 43%) [22], to detect tumor hypoxia. The Cu-ATSM, labeled with Cu radioisotopes, such as 60Cu, 62Cu, and 64Cu, has been developed as an imaging agent targeting hypoxic regions in tumors for use with PET [23-26].Many studies have demonstrated that Cu-ATSM accumulation is associated with hypoxic conditions of tumor in vitro and in vivo[26-29]. The mechanism of radiolabeled Cu-ATSM accumulation has been studied: Cu-ATSM has small molecular sizeand high membrane permeability, and thus rapidly diffuses into cells and is reduced and trapped within cells under highly reduced intracellular conditions such as hypoxia [24, 29-31]. A clinical study with 62Cu-ATSM demonstrated that high levels of hypoxia-inducible factor-1? (HIF-1?) expression were found in Cu-ATSM uptake regions in the tumors of patients with glioma [32]. In this study, we performed simultaneous in vivo imaging using a SPECT/PET/CT with 99mTc-HSA and 64Cu-ATSM for detecting tumor vascularity and hypoxia with a HT-29 tumor-bearing mouse model

Diagnosis of complex renal cystic masses and solid renal lesions using PET imaging: comparison of 11C-acetate and 18F-FDG PET imaging.

The study aims to assess the usefulness of PET with C-acetate and F-FDG to differentiate renal cell carcinoma (RCC) from complicated renal cysts

Functional oestrogen receptor a imaging in endometrial carcinoma using 16a-[18F]fluoro-17b-oestradiol PET

Purpose To investigate the correlation between uptake of 16a-[18F]fluoro-17b-oestradiol (FES) and expression of oestrogen receptors as well as other related immunohistochemistry markers, positron emission tomography (PET) was performed in patients with endometrial carcinoma before surgery. Methods Nineteen patients with endometrioid adenocarcinoma underwent preoperative PET studies with FES and 2-[18F]fluoro-2-deoxy-D-glucose (FDG). Standardized uptake values (SUVs) for each tracer and the regional FDG to FES SUV ratio were calculated using images after coregistration. PET values were compared with postoperative stage, differentiation grade and immunohistochemical scores including oestrogen receptor subtypes (ERa, ERb), progesterone receptor B (PR-B), Ki-67 and glucose transporter 1 (GLUT1). Results FES uptake showed a significantly positive correlation with expression of ERa. The FDG to FES ratio showed a significantly negative correlation with expression of ERa and PR-B. The FES uptake and FDG to FES ratio did not correlate with expression of ERb, Ki-67 or GLUT1. FDG uptake was not correlated with any of the immunohistochemical scores. The PR-B score was strongly correlated with the ERa score. Well-differentiated carcinoma (grade 1) showed a significantly higher FES uptake and significantly lower FDG to FES ratio than moderately or poorly differentiated carcinoma (grade 2&#8211;3). None of the PET parameters were significantly different between advanced-stage carcinoma (&#8805; stage IB) and early-stage carcinoma (IA) based on the F&eacute;deration International de Gyn&eacute;cologie et d\u27Obst&eacute;trique (FIGO) staging classification. Differentiation grade was the most closely correlated parameter to FES uptake and FDG to FES ratio by multivariate analyses. Conclusion FES PET combined with FDG would be useful for non-invasive evaluation of ERa distribution, as well as ERa function, which reflects differentiation grade in endometrial carcinoma

Acetate production: a possible tumor specific metabolic pathway to survive hypoxia

Tumor cells are known to exhibit high levels of glycolysis and low levels of mitochondrial oxidative phosphorylation, even in the presence of oxygen. The high levels of glycolysis lead to increased lactate production under hypoxia but it is not always the case under normoxia. This phenomenon prompted us to speculate that tumor cells might possess tumor-specific pathways to break down pyruvate, the final product of glycolysis. While investigating tumor specific metabolites, we found that tumor cells excreted acetate under normoxia and the quantity increased under hypoxia. The acetate production followed the expression pattern of cytosolic acetyl-CoA synthetase (Acss2), an enzyme fixing acetate into acetyl-CoA using ATP. Knockdown of Acss2 by RNA interference (RNAi) led to a corresponding reduction in acetate production in tumor cells, indicating that Acss2 is conducting the reverse reaction converting acetyl-CoA into acetate with ATP synthesis. In Acss2-RNAi tumor cells, the cellular ATP levels tended to be lower than the control-RNAi tumor cells. These results suggest that Acss2 might be controlling both anabolism and catabolism of acetate coordinately to maintain the metabolic balance in tumor cells. Furthermore, Acss2 knockdown decreased cell survival under long-term hypoxia in vitro and slowed tumor growth in vivo, indicating that Acss2 plays a significant role in tumor survival under hypoxia.Kashiwa Symposium on Cancer Biology 200

Intratumoral Distribution of Cu-ATSM and FDG: Immunohistochemical characterization of the region with high Cu-ATSM or FDG accumulation

Intratumoral distribution of [Cu-64]Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) and fluorine-18 2-fluoro-2-deoxyglucose (18FDG) in mice bearing tumors of four different origins, LLC1(Lewis lung carcinoma), Meth-A (sarcoma), B16(melanoma) and colon26(adenocarcinoma), were compared to the immunohistochemical staining for proliferating cells (Ki67), blood vessels (CD34 or von Willebrand Factor(vWF)) and apoptotic cells (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method). With all the cell lines, 64Cu-ATSM and 18FDG were distributed to different regions of the tumor mass. The immunohistochemical study demonstrated that the high 64Cu-ASTM uptake regions were hypovascular and consisted of tumor cells arrested in cell cycle, while the high 18FGD uptake regions were hypervascular and consisted of proliferating cells. Through our study, it was revealed that one tumor mass contains two regions of different characteristics, which can be distinguished by 64Cu-ATSM and 18FDG. Since hypoxia and cell cycle arrest are critical factors to reduce the sensitivity of tumor to radiation and conventional chemotherapy, regions with such characteristics in tumor should be treated intensively as one of the primary targets. 64Cu-ATSM which can delineate hypoxic and cell cycle arrested regions in tumors can provide valuable information for cancer treatment as well as the possibility to treat such regions directly as an internal radiotherapy reagent.第６回放射線生物学および画像医学に関する日仏ワークショップ

Cu-ATSM Accumulation Level and Proliferation Capacity of the Tumor Cells in Solid Tumor mass

Cu-ATSM, a hypoxia imaging agent, effectively detects tumors due to the presence of hypoxia in solid tumor mass. We have reported that the intratumoral distribution of Cu-ATSM in mouse solid tumor model is quite heterogeneous and different from that of FDG. Immunohistochemical analysis of CD34 (vessel formation) and Ki-67 (cell proliferation) expression was compared with intratumoral accumulation of Cu-ATSM. The region showing high Cu-ATSM accumulation had little vessel formation and negligible proliferating cells, which suggest that the tumor cells in these regions can be resistant to conventional chemo- and radio-therapies. To further verify this inference, the proliferation capacity of the cells from various regions of mouse solid tumor mass was examined by colony formation assay, and was compared to the regional accumulation level of Cu-ATSM. The cells in the region of high Cu-ATSM accumulation showed higher clonogenicity than the region of low or moderate Cu-ATSM accumulation. Our results indicated that the tumor cells in the region of high Cu-ATSM accumulation retain high potential for proliferation though they look temporally arrested in cell cycle, and the region of high Cu-ATSM accumulation may be one of the primary targets of tumor treatment.The Fifth Annual Meeting The Society for Molecular Imagin