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We investigated the usefulness of diffusion-weighted imaging (DWI) for detecting changes in the structure of hypoxic cells by evaluating the correlation between 18 F-fluoroazomycin arabinoside (FAZA) positron emission tomography activity and DWI parameters in head and neck carcinoma. The diffusion coefficient corresponding to the slow compartment of a two-compartment model had a significant positive correlation with FAZA activity (ρ = 0.58, P = 0.016), whereas the diffusional kurtosis from diffusion kurtosis imaging had a significant negative correlation (ρ = -0.62, P = 0.008), which suggests that those DWI parameters might be useful as indicators for changes in cell structure.

Purpose: A mobile positron emission tomography (PET) scanner called flexible PET (fxPET), designed to fit existing magnetic resonance imaging (MRI) or computed tomography (CT) system, has been developed. The purpose of this study was to evaluate the image quality, lesion detection rate, and quantitative values of fxPET compared with conventional bismuth germanium oxide (BGO)-based PET/CT without time-of-flight capability., Procedures: Fifty-nine patients underwent whole-body (WB) PET/CT scans approximately 1 h after injection of 2-deoxy-2-[ 18 F]fluoro-D-glucose, followed by the fxPET scans with detectors located above and below the patients (layout A) and with detectors closer to the patients (layout B). Two readers assessed the image quality using a 4-point grade for each layout and reached a consensus. We evaluated the differences and/or correlations between fxPET and WB PET/CT, including the lesion detection rates, the standardized uptake value (SUV), the metabolic tumor volume (MTV), the total lesion glycolysis (TLG), the tumor-to-normal liver ratio (TLR), and the background liver signal-to-noise ratio (SNR)., Results: The image quality of layout B was better than layout A (p < 0.0001). Of 184 lesions, the detection rate of layout B was significantly higher than WB PET/CT (p = 0.041), while the detection rate of layout A was comparable to WB PET/CT. The SUVmax/mean/peak were larger, and the MTVs were smaller in fxPET than WB PET/CT, especially in the lesions smaller than 2 cm (p < 0.01). The SUVmax/mean/peak, the MTVs and the TLGs of fxPET had significant positive correlations with WB PET/CT (p < 0.0001). The TLRs were significantly larger (p < 0.0001), but the background SNRs were significantly lower in fxPET than WB PET/CT (p < 0.05)., Conclusions: The fxPET system yielded reasonable image quality and quantitative accuracy. Bringing the detectors closer to the patient yielded improved results.

Objectives: In patients with advanced ovarian, fallopian and primary peritoneal carcinoma, complete interval debulking surgery (IDS) is often performed after neoadjuvant chemotherapy (NAC) to achieve long progression-free survival (PFS) and overall survival (OS). We aimed to investigate the utility of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET/CT in patients with these malignancies who underwent complete IDS., Methods: Between 2009 and 2017, twenty-two patients underwent FDG PET/CT scans before and after NAC. The highest SUVmax/peak (standardized uptake value), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) for whole lesions were defined as target SUVmax/peak, tMTV and tTLG, respectively. We also calculated these reduction rates during NAC. These parameters were compared between the groups with platinum-free interval (PFI) > 12 months (n = 10) and those with PFI ≤ 12 months (n = 12). The PFS and OS were evaluated using these quantitative parameters, and in terms of the presence of visually detectable residual lesions after NAC., Results: The target SUVmax/peak before NAC, the reduction rates in the target SUVmax, tMTV and tTLG were significantly higher in the group with PFI > 12 months than the shorter PFI group (p < 0.05). Especially in PFS, the higher reduction rates in the target SUVmax/peak, tMTV, and tTLG had an excellent prognostic stratification (p < 0.05) and the FDG visually negative group after NAC had a significantly better prognosis than the other group (p < 0.01)., Conclusions: The reduction rate of FDG PET-based quantitative values and visual analysis after NAC demonstrated prognostic potential, especially in PFS.

Purpose: Recently, the potential value of isocitrate dehydrogenase (IDH) mutation as a prognostic marker in glioblastomas has been established. Glioblastomas are classified by their IDH mutation status under the 2016 WHO classification system. However, noninvasive diagnostic methods for the mutation status in glioblastoma patients have not been established so far. The purpose of this study was to evaluate the difference of acetate metabolism between in glioblastomas with wild-type IDH and in those with IDH mutation by comparing the uptake of 14 C-acetate using genetically engineered glioblastoma cell lines in vitro and in vivo., Methods: We established glioblastoma cells (U251) expressing IDH1 R132H and examined the cell uptake of [1- 14 C]acetate. Biodistribution studies and an autoradiographic study for U251 cell tumor-bearing mice (BALB/c-nu/nu) with or without the IDH1 mutation were performed 1 h after [1- 14 C]acetate administration., Results: Significantly higher uptake of [1- 14 C]acetate was observed in U251/IDH1 R132H cells than in U251/IDH1 wild-type cells both in vitro (10.11 ± 0.94 vs. 4.26 ± 0.95%dose/mg, p = 0.0047) and in vivo (0.97 ± 0.14 vs. 0.66 ± 0.05%ID/g; p = 0.0037). Tumor-to-muscle ratios were also significantly higher in U251/IDH1 R132H tumors (3.36 ± 0.41 vs. 1.88 ± 0.59, p = 0.0030). The autoradiographic study shows the entirely higher radioactivity of the U251/IDH1 R132H tumor tissue section than that of the U251/IDH1 Wild-type tumor., Conclusions: In vitro and in vivo studies demonstrated that the uptake of radiolabeled acetate was significantly higher in IDH-mutated cells than in IDH-wild-type cells.

Objectives: To assess the potential value of preoperative 18 F-FDG PET to predict postoperative recurrence of solitary localized primary gastrointestinal stromal tumour (GIST) after radical resection., Methods: A total of 46 patients with primary GIST who received preoperative 18 F-FDG PET and underwent complete resection without neoadjuvant therapy were retrospectively studied. PET findings, including ring-shaped uptake and intense uptake, were compared with Joensuu risk grades using Fisher's exact test. The prognostic value of the preoperative clinico-imaging variables-age ≥60 years, male, ring-shaped uptake, intense uptake, tumour size >5 cm, heterogeneous CT attenuation and lower gastrointestinal origin-and Joensuu high risk for recurrence-free survival was evaluated using log-rank test and multivariate Cox regression analysis., Results: Ring-shaped uptake and intense uptake were significantly associated with Joensuu high risk. Univariate analysis showed that ring-shaped uptake, intense uptake, size >5 cm and Joensuu high risk were significantly associated with inferior recurrence-free survival. Multivariate analysis showed that ring-shaped uptake (P = 0.004) and Joensuu high risk (P = 0.021) were independent adverse prognostic factors of postoperative recurrence., Conclusions: Ring-shaped uptake on preoperative 18 F-FDG PET may be a potential predictor of postoperative tumour recurrence of localized primary GISTs., Key Points: • Clinical course of resectable solitary localized primary GISTs varies widely. • Ring-shaped uptake is an independent adverse prognostic factor of postoperative recurrence. • Preoperative 18 F-FDG PET may help predict postoperative recurrence of GISTs.

We recently succeeded in resuscitating an extracted rat heart following 24-48 hours of preservation in a high-pressure gaseous mixture of carbon monoxide (CO) and oxygen (O2). This study aimed to examine the function of rat hearts transplanted after being preserved in the high-pressure CO and O2 gas mixture. The hearts of donor rats were preserved in a chamber filled with CO and O2 under high pressure for 24 h (CO24h) or 48 h at 4 °C. For the positive control (PC) group, hearts immediately extracted from donor rats were used for transplantation. The preserved hearts were transplanted into recipient rats by heterotopic cervical heart transplantation. CO toxicity does not affect the grafts or the recipients. Light microscopy and [(18)F]-fluorodeoxyglucose positron emission tomography revealed that there were no significant differences in the size of the myocardial infarction or apoptosis of myocardial cells in post-transplant hearts between the PC and CO24h groups. Furthermore, at 100 days after the transplantation, the heart rate, weight and histological staining of the post-transplanted hearts did not differ significantly between the PC and CO24h groups. These results indicate that the function of rat hearts is well preserved after 24 hours of high-pressure preservation in a CO and O2 gas mixture. Therefore, high-pressure preservation in a gas mixture can be a useful method for organ preservation.

Objective: C-labeled 2-amino-2-methyl-butanoic acid (Iva) was previously reported to provide high tumor uptake; however, the pharmacokinetic properties of C-labeled Iva have not been characterized. In the present study, we evaluated the potential of [C]Iva as a PET probe for tumor imaging., Methods: [C]Iva was incubated in mouse serum for 60 min at 37°C and then analyzed by high-performance liquid chromatography and thin-layer chromatography. In-vitro cellular uptake of [C]Iva was determined in PBS and sodium-free buffer at 37°C using SY human small-cell lung cancer cells. The effects of inhibitors of amino acid transporters on [C]Iva uptake were also determined in PBS. In-vivo distribution and dynamic PET studies were conducted in SY tumor-bearing mice., Results: [C]Iva was stable in mouse serum in vitro for 60 min. The cellular uptake of [C]Iva was linearly increased for 20 min in both PBS and sodium-free buffer and almost completely inhibited by an inhibitor of system L amino acid transporters and another of LAT1, a transporter of system L. In-vivo distribution and dynamic PET studies showed that [C]Iva was highly accumulated in tumor, but not in normal tissues, except for the pancreas and kidneys. The [C]Iva uptake ratio of tumor to several normal tissues, such as the lung, muscle, and brain, was high., Conclusion: [C]Iva was stable in mouse serum and transported through system L amino acid transporters including LAT1, which is highly expressed in several tumors. [C]Iva is a promising PET probe for noninvasive tumor imaging.

Objective: Versatile emission computed tomography (VECTor) for small-animal imaging enables fully simultaneous SPECT/PET image acquisition based on clustered multi-pinhole collimation. The present study experimentally evaluated the detailed performance characteristics of the clustered multi-pinhole system for simultaneous (99m)Tc and (18)F imaging from the user perspective., Methods: Spatial resolution, sensitivity, count rate linearity were determined for the VECTor system (MILabs). Two hot-rod micro-resolution phantoms with 6 sectors were created to test the resolution of (99m)Tc and (18)F. Sensitivity and count rate linearity were measured by scanning (99m)Tc and (18)F point sources positioned at the center of the field of view. Furthermore, we quantified the influence of (18)F on (99m)Tc SPECT images. The ratios of SPECT counts on the (99m)Tc-only and simultaneous (18)F-(99m)Tc at various time points were evaluated as a function of the (18)F-to-(99m)Tc activity concentration ratio., Results: The 0.5-mm hot-rods can be visually distinguished in the (99m)Tc image, and 0.8-mm rods for (18)F remained clearly visible. The point-source sensitivity was 2800 cps/MBq for (99m)Tc and 2899 cps/MBq for (18)F, respectively. Count rates up to 120,000 cps for one bed position were linear for the activity. Spill-over from (18)F into (99m)Tc SPECT images was negligible when the activity concentration of the administered (18)F solution exceeded that of the (99m)Tc solution by up to a factor of 2., Conclusions: We evaluated the performance characteristics of the VECTor that lead to determination of the optimal administered doses of (99m)Tc and (18)F tracers. We found that the VECTor achieved high resolution and high sensitivity as well as good (99m)Tc and (18)F linearity. Simultaneous SPECT/PET imaging with (99m)Tc and (18)F tracers, and stand-alone (99m)Tc and (18)F imaging using clustered-pinhole collimators is feasible and practical for a wide range of research applications using small animals.

Objective: Pancreatic cancer is aggressive and its prognosis remains poor; thus, effective therapy is urgently needed. Transferrin receptor (TfR) is highly expressed in pancreatic cancer and is considered to be a good candidate for molecular-targeted therapy. We radiolabeled and evaluated fully human anti-TfR monoclonal antibodies as a new PET probe for evaluating the biodistribution of the anti-TfR antibody in pancreatic cancer., Materials and Methods: TfR expression was evaluated in four human pancreatic cancer (MIAPaCa-2, PANC-1, BxPC-3, and AsPC-1) and murine A4 cell lines. The binding of 125I-labeled anti-TfR antibodies (TSP-A01, TSP-A02, TSP-A03, and TSP-A04) to MIAPaCa-2 cells was compared. 125I-labeled, 67Ga-labeled, and 89Zr-labeled TSP-A01 were evaluated by cell binding, competitive inhibition, and internalization assays. Biodistribution studies of 125I-labeled and 89Zr-labeled TSP-A01 were conducted in mice bearing MIAPaCa-2 and A4 tumors. PET imaging with [89Zr]TSP-A01 was carried out., Results: MIAPaCa-2 cells showed the highest TfR expression in vitro and in vivo, whereas A4 cells showed no expression. Of the four antibodies, [125I]TSP-A01 showed the highest binding to MIAPaCa-2 cells, but not to A4 cells. The dissociation constant of TSP-A01 was 0.29 nmol/l. Uptake of radiolabeled TSP-A01, especially [89Zr]TSP-A01, was significantly higher in MIAPaCa-2 tumors than in A4 tumors. PET with [89Zr]TSP-A01 clearly visualized MIAPaCa-2 xenografts but not A4 xenografts., Conclusion: [89Zr]TSP-A01 is a promising PET probe for evaluating the accumulation of anti-TfR antibody in pancreatic cancer and has the potential to facilitate the selection of appropriate patients who would benefit from anti-TfR antibody therapy.

Radiation-induced thymic lymphoma (RITL) in mice is induced by fractionated whole-body X-irradiation (FX) and has served as a useful model for studying radiation carcinogenesis. In this model, the initial postirradiation cellular events in the thymus and bone marrow (BM) are critically important for tumorigenesis, and BM transplantation (BMT) prevents RITL. However, direct assessment of these events is so far restricted by the lack of noninvasive monitoring techniques. Here, we have developed positron emission tomography (PET) and magnetic resonance imaging (MRI) methods to quantify the events critical for RITL development and the effects of BMT in living animals. Apparent diffusion coefficients (ADCs) were calculated from diffusion-weighted MRI to evaluate the changes in the BM of mice receiving FX. ADC values dramatically changed in the irradiated BM, corresponding to pathological findings of the irradiated BM, returning to normal levels following BMT sooner than with spontaneous recovery. PET with 4'-[methyl-(11)C]thiothymidine, a novel tracer for cell proliferation, revealed that the irradiated thymus showed significantly higher tracer uptake than the unirradiated thymus 1 week after FX. Interestingly, its increased uptake was completely abolished by BMT, even with very few donor-derived cells in the thymus. Thereafter, the thymus receiving BMT had significantly increased tracer uptake. These findings suggest that BMT first suppresses FX-induced aberrant thymocyte proliferation and then accelerates thymic regeneration. This study demonstrates the feasibility of using PET and MRI for noninvasive monitoring of tumorigenic cellular processes in an animal model of radiation-induced cancer., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

(64)Cu-cyclam-RAFT-c(-RGDfK-)4, an αVβ3 integrin-targeting tetrameric cyclic RGD peptide probe, is a potential theranostic compound for positron emission tomography (PET) of tumor angiogenesis and for internal radiotherapy owing to the multiple decay modes of (64)Cu. Since kidneys are dose-limiting organs in internal radiotherapy, we aimed to reduce the renal accumulation of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 by co-injection with Gelofusine (GF), a succinylated gelatin solution, and/or L-lysine (Lys), and to explore, for the first time, the related mechanisms using the noninvasive and quantitative PET imaging technology. Biodistribution assays, dynamic and static PET scans, and metabolism studies with radio-thin-layer chromatography (radio-TLC) were performed in healthy or αVβ3-positive tumor-bearing mice. In the results, co-injection with GF markedly reduced the renal uptake and slightly increased the tumor uptake of (64)Cu-cyclam-RAFT-c(-RGDfK-)4. L-Lysine alone had no effect on the probe biodistribution, but the combined use of Lys and GF tended to enhance the effect of GF. Dynamic PET and metabolite analysis by radio-TLC highly revealed that GF blocks the renal reabsorption of (64)Cu-cyclam-RAFT-c(-RGDfK-)4, but does not interfere with its metabolism and excretion. In conclusion, administration of GF and Lys is a useful strategy for kidney protection in (64)Cu-cyclam-RAFT-c(-RGDfK-)4-based internal radiotherapy., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

The purpose of this study was to develop a clinically relevant orthotopic xenotransplantation model of pancreatic cancer and to perform a preclinical evaluation of a new positron emission tomography (PET) imaging probe, ⁶⁴Cu-labeled cyclam-RAFT-c(-RGDfK-)₄ peptide (⁶⁴Cu-RAFT-RGD), using this model. Varying degrees of αvβ₃ integrin expression in several human pancreatic cancer cell lines were examined by flow cytometry and Western blotting. The cell line BxPC-3, which is stably transfected with a red fluorescence protein (RFP), was used for surgical orthotopic implantation. Orthotopic xenograft was established in the pancreas of recipient nude mice. An in vivo probe biodistribution and receptor blocking study, preclinical PET imaging coregistered with contrast-enhanced computed tomography (CECT) comparing ⁶⁴Cu-RAFT-RGD and ¹⁸F-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) accumulation in tumor, postimaging autoradiography, and histologic and immunohistochemical examinations were done. Biodistribution evaluation with a blocking study confirmed that efficient binding of probe to tumor is highly αvβ₃ integrin specific. ⁶⁴Cu-RAFT-RGD PET combined with CECT provided for precise and easy detection of cancer lesions. Autoradiography, histologic, and immunohistochemical examinations confirmed the accumulation of ⁶⁴Cu-RAFT-RGD in tumor versus nontumor tissues. In comparative PET studies, ⁶⁴Cu-RAFT-RGD accumulation provided better tumor contrast to background than ¹⁸F-FDG. Our results suggest that ⁶⁴Cu-RAFT-RGD PET imaging is potentially applicable for the diagnosis of αvβ₃ integrin-expressing pancreatic tumors.

Introduction: Pancreatic cancer is an aggressive cancer and its prognosis remains poor. Therefore, additional effective therapy is required to augment and/or complement current therapy. CD147, high expression in pancreatic cancer, is involved in the metastatic process and is considered a good candidate for targeted therapy. CD147-specfic imaging could be useful for selection of appropriate patients. Therefore, we evaluated the potential of a fully human anti-CD147 monoclonal antibody 059-053 as a new positron emission tomography (PET) probe for pancreatic cancer., Methods: CD147 expression was evaluated in four pancreatic cancer cell lines (MIA Paca-2, PANC-1, BxPC-3, and AsPC-1) and a mouse cell line A4 as a negative control. Cell binding, competitive inhibition and internalization assays were conducted with (125)I-, (67)Ga-, or (89)Zr-labeled 059-053. In vivo biodistribution of (125)I- or (89)Zr-labeled 059-053 was conducted in mice bearing MIA Paca-2 and A4 tumors. PET imaging with [(89)Zr]059-053 was conducted in subcutaneous and orthotopic tumor mouse models., Results: Among four pancreatic cancer cell lines, MIA Paca-2 cells showed the highest expression of CD147, while A4 cells had no expression. Immunohistochemical staining showed that MIA Paca-2 xenografts also highly expressed CD147 in vivo. Radiolabeled 059-053 specifically bound to MIA Paca-2 cells with high affinity, but not to A4. [(89)Zr]059-053 uptake in MIA Paca-2 tumors increased with time from 11.0±1.3% injected dose per gram (ID/g) at day 1 to 16.9±3.2% ID/g at day 6, while [(125)I]059-053 uptake was relatively low and decreased with time, suggesting that 059-053 was internalized into tumor cells in vivo and (125)I was released from the cells. PET with [(89)Zr]059-053 clearly visualized subcutaneous and orthotopic tumors., Conclusion: [(89)Zr]059-053 is a promising PET probe for imaging CD147 expression in pancreatic cancer and has the potential to select appropriate patients with CD147-expressing tumors who could gain benefit from anti-CD147 therapy.

Objective: The purpose of this prospective study was to assess the prognostic value of 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography/computed tomography (PET/CT) for the outcome of carbon ion radiotherapy (CIRT) in patients with mucosal malignant melanoma (MMM) of the head and neck., Methods: Thirteen patients (69 ± 13 years) with histologically proven MMM tumor were enrolled. CIRT was performed with a total dose of 57.6-64.0 gray equivalents per 16 fractions over a period of 4 weeks. FLT-PET/CT was performed before and again 1 month after CIRT. Tumor FLT uptake was quantitatively assessed using the maximum standardized uptake value (SUV(max)). FLT-PET parameters [pre-CIRT SUV(max), post-CIRT SUV(max), and the reduction rate (RR)] and clinical parameters [age, gender, tumor site, tumor status, gross tumor volume (GTV), and regional lymph node involvement] were evaluated in relation to survival estimates. The follow-up period was 16.1 ± 5.9 months for 9 deceased patients, and 36.7 ± 7.9 months for 4 survivors., Results: Pre-CIRT SUV(max) of ≥4.3, age of ≥80 years old, sinonasal cavity tumor site, and GTV of ≥39 mL were found to be statistically significant prognostic factors for better overall survival. Pre-CIRT SUV(max) of ≥5.0, age of ≥80 years old, sinonasal cavity tumor site, and the absence of regional lymph node involvement were statistically significant prognostic factors for better metastasis-free survival. RR of ≥35 % and GTV of <73 mL were predictive of better local control., Conclusions: The present study indicated for the first time that in patients with the head and neck MMM, FLT-PET/CT imaging was useful for predicting the therapeutic outcome of CIRT. Our results will contribute to the establishment of an effective staging system for MMM based on prognostic factors, depending on treatment choice.

64Cu-cyclam-RAFT-c(-RGDfK-)4 is a novel multimeric positron emission tomography (PET) probe for αVβ3 integrin imaging. Its uptake and αVβ3 expression in tumors showed a linear correlation. Since αVβ3 integrin is strongly expressed on activated endothelial cells during angiogenesis, we aimed to determine whether 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET can be used to image tumor angiogenesis and monitor the antiangiogenic effect of a novel multi-targeted tyrosine kinase inhibitor, TSU-68. Athymic nude mice bearing human hepatocellular carcinoma HuH-7 xenografts, which expressed negligible αVβ3 levels on the tumor cells, received intraperitoneal injections of TSU-68 or the vehicle for 14 days. Antiangiogenic effects were determined at the end of therapy in terms of 64Cu-cyclam-RAFT-c(-RGDfK-)4 uptake evaluated using PET, biodistribution assay, and autoradiography, and they were compared with microvessel density (MVD) determined by CD31 immunostaining. 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET enabled clear tumor visualization by targeting the vasculature, and the biodistribution assay indicated high tumor-to-blood and tumor-to-muscle ratios of 31.6 ± 6.3 and 6.7 ± 1.1, respectively, 3 h after probe injection. TSU-68 significantly slowed tumor growth and reduced MVD; these findings were consistent with a significant reduction in the tumor 64Cu-cyclam-RAFT-c(-RGDfK-)4 uptake. Moreover, a linear correlation was observed between tumor MVD and the corresponding standardized uptake value (SUV) (r = 0.829, P = 0.011 for SUV(mean); r = 0.776, P = 0.024 for SUV(max)) determined by quantitative PET. Autoradiography and immunostaining showed that the distribution of intratumoral radioactivity and tumor vasculature corresponded. We concluded that 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET can be used for in vivo angiogenesis imaging and monitoring of tumor response to antiangiogenic therapy.

Purpose: The usefulness of 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) in pediatric Hodgkin lymphoma (p-HL) has been well demonstrated; however, pediatric non-Hodgkin lymphoma (p-NHL) has distinct characteristics from p-HL and adult NHL. We assessed roles of FDG PET in p-NHL., Materials and Methods: Nineteen patients with p-NHL underwent 80 scans. Scans for staging (group A, n=6) and response assessment (group B, n=42) were compared with conventional imaging modalities (CIMs). Scans within group B for end-chemotherapy assessment (subgroup B+, n=11) and for post-therapeutic surveillance (group C, n=32) were analyzed for diagnostic performance., Results: In group A, PET and CIM demonstrated comparable results. In group B, PET diagnoses were concordant with CIM in 21 and discordant in 11 studies. Of the discordant cases, PET suggested remnant lesions in 5 cases, whereas CIM suggested lesions in 6 cases. PET modified therapeutic strategy in 4 cases by detecting new extranodal lesions. In subgroup B+, sensitivity, specificity, and accuracy for predicting relapse were 50%, 71%, and 64%, respectively. In group C, sensitivity, specificity, and accuracy were 100%, 87%, and 88%, respectively, but positive predictive value was 33%., Conclusions: The role of FDG PET in p-NHL may be limited, unlike with p-HL or adult NHL. Nevertheless, FDG PET may serve complementarily in detecting unexpected lesions that can emerge in p-NHL.

Objective: This study was a controlled multicenter clinical study on patients with peripheral lung nodules to verify the improvement in the diagnostic ability of FDG-PET when used in combination with thin-section CT (TS-CT)., Methods: Patients with peripheral lung nodules (long maximal diameter: 10-30 mm) detected using CT were examined using TS-CT and FDG-PET for the differential diagnosis of benign or malignant lesions. The primary endpoint was the specificity of the results using a combination of TS-CT and FDG-PET, compared with the results for TS-CT alone. Images were interpreted by investigators at each institution. Blind readings were also performed by an independent image interpretation committee. The gold standard was a pathological diagnosis determined using a surgical or biopsy specimen obtained after PET; and the patients in whom a pathological diagnosis could not be obtained were diagnosed based on a follow-up TS-CT performed more than 6 months later. Adverse reactions to FDG were also evaluated., Results: The blind reading results for 82 lesions in 81 subjects eligible for analysis among the 90 subjects included in the study showed a specificity of 91.2% (31/34) (95% CI: 76.3-98.1) for TS-CT + PET, compared with a specificity of 67.6% (23/34) (95% CI: 49.5-82.6) for TS-CT alone. The specificity was significantly improved by the addition of the PET findings (p < 0.05). The sensitivity improved from 89.6% (43/48) for TS-CT to 91.7% (44/48) for TS-CT + PET; the addition of PET increased the level of confidence in the diagnosis, but the difference was not significant. The results reported by the institutional investigators were not significantly different. No serious adverse reactions occurred, although two of the 90 subjects exhibited mild adverse reactions., Conclusions: The addition of FDG-PET to TS-CT for the differential diagnosis of benign or malignant peripheral lung nodules resulted in a significant improvement in specificity. Although a definitive diagnosis of lung nodules requires a histopathological or cytological examination, when combined with TS-CT, FDG-PET can provide additional diagnostic information and improve the specificity.

Objective: This study was a controlled multicenter clinical study to verify the diagnostic effects of additional FDG-PET to contrast-enhanced CT for mediastinal lymph node metastasis in patients with operable non-small cell lung cancer (NSCLC)., Methods: NSCLC patients with enlarged mediastinal lymph nodes (short diameter, 7-20 mm), confirmed using contrast-enhanced CT, were examined using FDG-PET to detect metastases prior to surgery. The primary endpoint was the accuracy for concomitantly used CT and FDG-PET showing the additional effects of FDG, compared with CT alone. The secondary endpoints were the clinical impact of FDG-PET on therapeutic decisions and adverse reaction from FDG administration. The images were interpreted by investigators at each institution. Moreover, blinded readings were performed by an image interpretation committee independent of the institutions. The gold standard was the pathological diagnosis determined by surgery or biopsy after PET, and patients in whom a pathological diagnosis was not obtained were excluded from the analysis., Results: Among 99 subjects, the results for 81 subjects eligible for analysis showed that the accuracy improved from 69.1% (56/81) for CT alone to 75.3% (61/81) for CT + PET (p = 0.404). These findings contributed to treatment decisions in 63.0% (51/81) of the cases, mainly with regard to the selection of the operative procedure. The results of the image interpretation committee showed that the accuracy improved from 64.2% (52/81) (95% CI 52.8-74.6) for CT to 75.3% (61/81) (95% CI 64.5-84.2) for CT + PET. The accuracy for 106 mediastinal lymph nodes improved significantly from 62.3% (66/106) (95% CI 52.3-71.5) for CT to 79.2% (84/106) (95% CI 70.3-86.5) for CT + PET (p < 0.05). We found that no serious adverse drug reactions appeared in any of the 99 patients who received FDG, except for transient mild outliers in the laboratory data for two patients., Conclusions: The addition of FDG-PET to contrast-enhanced CT imaging for the staging of NSCLC improved the diagnostic accuracy for mediastinal lymph node metastasis. FDG-PET improved the precision of the staging of NSCLC and contributed to the surgical decisions.

Unlabelled: Recently, we developed [methyl-(11)C]4'-thiothymidine ((11)C-4DST) as an in vivo cell proliferation marker. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain tumor imaging of (11)C-4DST in humans., Methods: Multiorgan biodistribution and radiation dosimetry of (11)C-4DST were assessed in 3 healthy humans, who underwent 2-h whole-body PET scanning. Radiation dosimetry was estimated from the residence times of source organs using the OLINDA program. Six brain tumor patients underwent dynamic (11)C-4DST scans with arterial blood sampling. These patients were also evaluated with (11)C-methionine PET on the same day (n = 4) as, or 3 wk before (n = 2), (11)C-4DST PET studies. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. Breakdown of the blood-brain barrier in tumor tissue was confirmed by gadolinium-enhanced T1-weighted MRI., Results: There were no serious adverse events in any subjects at any time during the study period. (11)C-4DST PET demonstrated selective uptake in the bone marrow, which has a high rate of proliferation. In addition, high-level uptake was also seen in the liver. The highest absorbed organ dose was in the urinary bladder wall (17.6 μGy/MBq). The estimated effective dose for (11)C-4DST was 4.2 μSv/MBq. (11)C-4DST showed little uptake in normal brain tissues, resulting in low background activity for imaging of brain tumors. In contrast, (11)C-4DST PET demonstrated rapid uptake in aggressive tumor masses, whereas no signal of (11)C-4DST was seen in clinically stable disease in which (11)C-methionine uptake was high. The distribution pattern of (11)C-methionine in tumor regions was not always identical to that of (11)C-4DST. Analysis of plasma samples by high-performance liquid chromatography indicated that more than 60% of the radioactivity was present as unchanged (11)C-4DST at 20 min., Conclusion: The initial findings of the present study in a small group of patients indicated that (11)C-4DST PET is feasible for imaging of brain tumors. Dosimetry and pharmacologic safety were acceptable at the dose required for adequate PET images.

Purpose: The clinical value of positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) for follow-up or suspected recurrence of renal cell carcinoma (RCC) has not been fully evaluated. The purpose of this study was to assess the diagnostic performance of FDG-PET for postoperative assessment in patients with RCC., Methods: We reviewed 28 scans in 23 patients who had undergone FDG-PET scans after surgery for RCC. Diagnostic accuracy of visually interpreted PET was evaluated based on final diagnoses obtained histologically or by clinical follow-up at least 6 months. Also, additional information over CT, influence on treatment decisions, and the accuracy of FDG uptake as a predictor of survival were assessed., Results: Recurrence of renal carcinoma was histologically (n=15) or clinically (n=6) confirmed in 21 of 28 cases. Overall, the sensitivity, specificity, and diagnostic accuracy using FDG-PET were 81%, 71%, and 79%, respectively. In papillary RCC, the sensitivity was 100%; however, that was 75% in clear cell RCC in patient-basis. PET correctly detected local recurrence and metastases in all cases in the peritoneum, bone, muscle and adrenal gland. Additional information was obtained from scans in 6 cases (21%), which influenced therapeutic management in 3 cases (11%). Cumulative survival rates over 5 years in the PET-positive vs. the PET-negative group were 46% vs. 83%, respectively (p=0.17)., Conclusions: FDG-PET would be useful for postoperative surveillance in patients with RCC, although its impact on treatment decisions may be limited. Further investigations are necessary to conclude whether PET has a prognostic value., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The α(V)β(3) integrin is a well-known transmembrane receptor involved in tumor invasion, angiogenesis and metastasis. Our aim was to evaluate a novel positron emission tomography (PET) probe, (64)Cu-cyclam-RAFT-c(-RGDfK-)(4), for noninvasive visualization and quantification of α(V)β(3) integrin expression., Methods: RAFT-c(-RGDfK-)(4), a tetrameric cyclic Arg-Gly-Asp (RGD)-based peptide, was conjugated with a bifunctional chelator, 1,4,8,11-tetraazacyclotetradecane (cyclam), radiolabeled with the positron emitter (64)Cu and evaluated in vitro by cell binding and competitive inhibition assays and in vivo by biodistribution and receptor blocking studies, and PET imaging. The following cell lines, human embryonic kidney HEK293(β(1)) [α(V)β(3)-negative] and HEK293(β(3)) [α(V)β(3)-overexpressing] and human glioblastoma U87MG [naturally expressing α(V)β(3)], together with their subcutaneous xenografts in athymic nude mice, were used for the present study. The expression levels of α(V)β(3) on these cell lines and tumor xenografts were analyzed by flow cytometry and sodium dodecyl sulfate-polyacrylamide gel electrophoresis/autoradiography, respectively., Results: (64)Cu-cyclam-RAFT-c(-RGDfK-)(4) demonstrated the in vitro and in vivo specificity for the α(V)β(3) integrin and displayed rapid blood clearance, predominantly renal excretion and low uptake in nontumor tissues. Tumor uptake of (64)Cu-cyclam-RAFT-c(-RGDfK-)(4) (3 h postinjection) in HEK293(β(3)) (high levels of α(V)β(3)), U87MG (moderate levels of α(V)β(3)) and HEK293(β(1)) (undetectable levels of α(V)β(3)) tumors was 9.35%±1.19%, 3.46%±0.45% and 1.18%±0.30% injected dose per gram, respectively, with a strong and positive correlation with the tumor α(V)β(3) expression levels (correlation coefficient=0.967; P<.0001). Positron emission tomographic images showed that α(V)β(3)-positive tumors were clearly visualized with high tumor-to-background contrast, and agreed well with the biodistribution results., Conclusion: (64)Cu-cyclam-RAFT-c(-RGDfK-)(4) exhibits potential for noninvasively quantifying α(V)β(3) expression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Whole body positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) has been widely used in various malignancies, but the clinical value of FDG-PET for endometrial cancer has not been fully investigated. The purpose of this study was to evaluate the usefulness of FDG-PET for preoperative evaluation of endometrial cancer., Methods: Forty female patients suspected of having endometrial cancer were included in this study. All patients underwent an FDG-PET or PET/CT scan, and images were interpreted visually. The diagnostic performance in detecting the primary tumor, regional nodal status, and distant metastasis was determined. In addition, the usefulness of PET was assessed in terms of additional information and clinical impact for therapeutic management., Results: Of 40 patients, 30 were histologically confirmed to have endometrial cancer. The patient-based sensitivity and specificity of FDG-PET for primary tumors were 83 and 100%, respectively, and 100 and 100%, respectively, for nodal metastases. There were 12 distant metastases in 6 patients and two second primary cancers in two patients, which were all accurately diagnosed by PET on a patient-basis. PET yielded 12 additional findings in 10 patients, and had a bearing on the therapeutic management of four patients, including one patient with recurrent breast cancer., Conclusions: FDG-PET had a reasonably high diagnostic accuracy in endometrial cancer. Although the number of cases with clinical impact was limited, additional information by PET was obtained in one-third of the cases.

Objective: The aim of this study was to investigate the clinical value of 3'-deoxy-3'-[F]fluorothymidine-positron emission tomography/computed tomography (FLT-PET/CT) for lung cancer patients receiving carbon-ion radiotherapy., Methods: Twenty consecutive patients with lung cancer underwent FLT-PET/CT before and after carbon-ion radiotherapy. Fifty minutes after intravenous injection of approximately 300 MBq of FLT, PET/CT data were acquired. Maximal standardized uptake value of the tumor was measured, from which the reduction rate of tumor FLT uptake was calculated. After treatment, the patients were followed (17-42 months for survivors) for the development of recurrence and survival., Results: Primary responses to carbon-ion radiotherapy were partial in 13 patients, stable disease in six patients, and nonevaluable in one patient. Although tumor FLT uptake significantly decreased after treatment (P < 0.001), the presence of radiation pneumonitis hampered its precise evaluation. During the follow-up period, nine patients developed recurrence, and seven patients died including two deaths from other causes. Pretreatment FLT uptake of patients who developed recurrence and who died of lung cancer were significantly higher than that of patients who did not (P = 0.008 and 0.007, respectively). Kaplan-Meier analysis using a cut-off value also supported the prognostic value of pre-carbon-ion radiotherapy FLT-PET/CT., Conclusion: This investigation suggests that FLT-PET/CT is feasible in evaluating lung cancer patients undergoing carbon-ion radiotherapy. The presence of radiation pneumonitis can influence tumor FLT uptake and needs special attention. Pre-carbon-ion radiotherapy FLT-PET/CT seems to have a prognostic value and may contribute to decision-making on the treatment strategy.

Introduction: C-kit is an important diagnostic and therapeutic target molecule for several malignancies, and c-kit-targeted drugs have been used clinically. Because abundant c-kit expression in tumors is a prerequisite for successful c-kit-targeted therapy, imaging of c-kit expression is expected to play a pivotal role in the therapeutic decision for each patient. We evaluated (64)Cu-labeled Fab of anti-c-kit antibody 12A8 as a positron emission tomography (PET) imaging probe., Methods: (111)In- or (125)I-Labeled 12A8 Fab was evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays, and in vivo by biodistribution in mice bearing c-kit-expressing and -non-expressing tumors. Next, Fab fragment was labeled with the positron emitter (64)Cu and evaluated by PET., Results: Radiolabeled 12A8 Fab showed specific binding to c-kit-expressing cells with high affinity and internalized into cells after binding to c-kit on cell surface. Although tumor accumulation of [(111)In]Fab was lower than that of [(111)In]IgG, the faster blood clearance of [(111)In]Fab provided higher tumor-to-blood ratio at 6 h postinjection onwards. Blood clearance of (64)Cu-labeled 12A8 Fab was slower than that of [(111)In]Fab, but PET using [(64)Cu]Fab clearly visualized the tumor at 6 h postinjection onwards., Conclusion: The (64)Cu-labeled 12A8 Fab could be used for c-kit-specific PET imaging and might help in selecting appropriate patients for c-kit-targeted treatments., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Purpose: The purpose was to characterize (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) findings after stereotactic body radiation therapy (SBRT) for lung cancer., Materials and Methods: This was a retrospective review of 32 FDG-PET scans from 23 patients who underwent SBRT for lung cancer and who showed no evidence of local recurrence. The FDG uptake by lesions was assessed visually using a 3-point scale (0, none or faint; 1, mild; or 2, moderate to intense), and the demarcation (ill- or well-defined) was evaluated. For semi-quantitative analysis, the maximum standardized uptake value (SUVmax) was calculated., Results: Grade 2 intensity was observed in 70%, 33%, 30%, and 0% of PET scans performed <6, 6-12, 12-24, and >24 months, respectively, after SBRT; well-defined demarcation was observed in 80%, 33%, 40%, and 17%, respectively, and the respective means of the SUVmax were 4.9, 2.6, 3.0, and 2.3. The SUVmax was significantly higher for scans performed at <6 months than at 6-12 or >24 months., Conclusions: FDG uptake tended to be intense and well-defined at early times after SBRT, especially within 6 months, and was faint and ill-defined at later periods. Moderate to intense FDG uptake observed soon after SBRT does not always indicate a residual tumour., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Retained textiles with foreign body granulomatous reaction can form mass-mimicking soft tissue tumors, which may cause diagnostic, clinical, and medicolegal problems. In this study, we present 3 cases of foreign body granuloma by retained textiles, and demonstrate FDG PET findings with detailed pathologic correlation. We also provide a review of previous literatures., Materials and Methods: Three patients (all females; age range, 48-61 years) with histopathologic diagnosis of mass-forming foreign body granuloma caused by retained textiles were retrospectively studied. They underwent an FDG PET scan in our institute. The mass was located in the abdominopelvic cavity in all cases. The time interval between the prior surgery and the PET acquisition was 11 months, 15 or 19 years, and 26 years, respectively., Results: Intense FDG uptake with a ring-shaped pattern was observed in 2 cases, while no uptake in 1 case. Microscopically, 2 with ring-shaped FDG uptake showed a cellular foreign body reaction peripherally, and artificial textile fibers and acellular eosinophilic amorphous materials in the central portion. In the one without FDG uptake, the mass was composed of mainly necrotic debris surrounding by a thick layer of well-formed collagen fibers. In previous case reports describing the accumulation of FDG in foreign body granulomas, 9 of 10 cases showed intense FDG uptake with a ring-shaped pattern., Conclusions: The ring-shaped pattern of FDG uptake seems to well characterize pseudotumor with foreign body granulomas. However, the pattern of FDG accumulation in retained textile with foreign body granulomas may vary due to histologic features.

Cyclam and DOTA-containing positron emission tomography radiotracers were prepared by using a modular chemical strategy based on peptide synthesis and chemoselective ligations. These molecules encompass two functional domains, one a tumour 'homing' domain and the other a chelating ligand for copper allowing nuclear imaging of tumours., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

The use of tumor-suppressor gene p53 as an anticancer therapeutic has been vigorously investigated. However, progress has met with limited success to date. Some major drawbacks are the difficulty in achieving controllable and efficient gene transfer as well as in analyzing the transferred gene expression in real time and the treatment response in a timely manner. Thus, development of novel gene transfer vector with a regulative gene expression system coupled with the reporter gene, by which transgene can be monitored simultaneously, is critical. Moreover, noninvasive imaging-based assessment of the therapeutic response to exogenous wild-type p53 gene transfer is crucial for refining treatment protocols. In this study, as a simple preclinical model, we constructed a doxycycline-regulated bidirectional vector harboring a reporter gene encoding red fluorescence protein and p53. Then, we determined the controllable and simultaneously coordinated expression of both proteins and the p53-mediated anticancer effects in vitro and in vivo. Next, we observed that cells or tumors with induced p53 overexpression exhibited decreased uptake of [(14)C]FDG in cellular assay and [(18)F]FDG in positron emission tomography (PET) imaging. Thus, by coupling with bidirectional vector, controllable p53 transfer was achieved and the capability of fluoro-2-deoxy-D-glucose (FDG)-PET to assess the therapeutic response to p53 gene therapy was evidently confirmed, which may have an impact on the improvement of p53 gene therapy.

Objective: The purpose of this study was to evaluate the prevalence of positive findings of positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) in patients with high serum CEA levels., Methods: A total of 303 patients who had undergone an FDG-PET scan in our institution with high serum CEA levels were analyzed. The prevalence of positive PET findings was evaluated with regard to a previous history of malignancy, absolute value of CEA levels, and the time course of CEA levels (an increasing or decreasing pattern, a change divided by time (DeltaCEA) and doubling time of CEA)., Results: Of 303 patients, 232 were confirmed to have malignancy, and the patient-based sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET were 87, 86, 95, 66, and 86%, respectively. There was no statistically significant difference in positive rates according to the history of previous malignancy. The prevalence of PET-positive cases was higher with an increase in absolute CEA levels, and more than 90% of the patients were positive when CEA levels were more than 20 ng/ml. The DeltaCEA was significantly higher and the doubling time was significantly shorter in patients with positive results than those with negative results., Conclusions: A high value of serum CEA levels was correlated with a higher prevalence of positive PET findings. FDG-PET scans would be justified in patients with high serum CEA levels, regardless of whether there was or was not a previous history of malignancy.

Objective: Standardized uptake value (SUV) is affected by many factors. In that respect, the brain reference index (BRI: regions of interest of tumor/regions of interest of cerebellum) is one of the quantitative approaches to eliminate the variety of factors that affect SUV. MRI pulse sequence findings can also provide information about tissue cellularity. This information is useful for evaluating the malignancy of lesions. We evaluated the role of glucose metabolism and cellularity for the diagnosis of pancreatic tumor malignancy., Method: We performed a radionuclide 2-(18)F-fluoro-2-deoxyglucose ((18)F-FDG) uptake analysis and a signal intensity analysis using MRI on 16 presurgery patients with either proven or suspected pancreatic cancer. The tumor glucose metabolism was evaluated with SUV and BRI in an FDG-PET study. Tumor cellularity was determined with the MRI factors, apparent diffusion coefficient (ADC), T2 value and tumor to nontumor ratio of proton density. We compared these results with the pathological findings., Results: SUV (= 0.855), BRI ( =0.875), and ADC ( =0.830) showed a larger the area under the curve than T2 value (= 0.582) and tumor to nontumor ratio of proton density ( = 0.786) according to the receiver operating characteristics analysis, and we therefore considered that these three factors were better indexes for the diagnosis of tumor malignancy. SUV and BRI had a high specificity. In contrast, ADC had a high sensitivity., Conclusion: The glucose metabolism with PET/CT and cellularity with MRI are different indexes for the diagnosis of tumor malignancy. Both provide necessary information for making an accurate diagnosis. Using both types of information may therefore help in obtaining a highly accurate diagnosis.

Background: Malignant mesothelioma is a highly aggressive form of cancer. Curative surgery is the only effective therapy for mesothelioma, and therefore early diagnosis is important. However, early diagnosis is difficult using current diagnostic imaging techniques, and a new imaging method for early diagnosis is urgently required. We evaluated the affinity of radiolabeled monoclonal antibodies to the C-terminal fragment of ERC/mesothelin for this purpose., Methods: In-labeled or I-labeled IgG against C-terminal fragment of ERC and its Fab fragment were evaluated in vitro by cell binding, competitive inhibition, and cellular internalization assays, and in vivo by biodistribution in mice bearing ERC-expressing tumors. Next, the Fab fragment was labeled with the positron emitter Cu and evaluated by positron emission tomography (PET)., Results: Radiolabeled IgG and Fab showed specific binding to ERC-expressing mesothelioma cells with high affinity. Both radiolabeled IgG and Fab internalized into cells after binding to ERC on the cell surface. In-labeled IgG accumulated in ERC-expressing tumors and resulted in a moderate tumor-to-blood ratio at 4 days after injection. Furthermore, PET using Cu-labeled Fab visualized the tumor at 6 h after injection., Conclusion: Cu-labeled Fab can be useful for ERC-specific PET imaging, and can thus facilitate improved diagnosis of patients with early-stage mesothelioma.

Unlabelled: Acute allograft rejection remains a major complication after liver transplantation. We report a semiquantitative imaging method of detecting acute allograft rejection with (18)F-FDG PET., Methods: Syngeneic and allogeneic transplanted rats, with or without immunosuppressive treatment, were subjected to serial PET. Autoradiography of the liver was conducted in both the syngeneic and the allogeneic rats., Results: A significant increment of (18)F-FDG accumulation in liver allografts was observed by PET on day 2. The (18)F-FDG signal was concentrated in the area where inflammatory cells around the vessels were detected by autoradiography. Allotransplanted rats treated with an immunosuppressive agent displayed a marked decrease in hepatic (18)F-FDG uptake, compared with allotransplanted rats that were not treated., Conclusion: (18)F-FDG PET may be a valid method for facilitating the development of protocols to diagnose graft rejection and to monitor the efficacy of immunosuppressive therapy.

Introduction: Malignant mesothelioma is a highly aggressive tumor originating in the pleura, peritoneum and pericardium, and the prognosis of patients undergoing current treatment remains poor. To develop new therapies, it is important to have a noninvasive imaging system for evaluating the efficacy of such prospective treatments. We have established clinically relevant mouse models and evaluated conventional and novel positron emission tomography (PET) tracers., Methods: Epithelioid and sarcomatoid mesothelioma cells were inoculated subcutaneously and intrapleurally into nude mice. Biodistribution and PET imaging studies were conducted by injecting [(18)F]fluoro-2-deoxy-D-glucose (FDG), 3'-[(18)F]fluoro-3'-doxythymidine (FLT) or 4'-methyl-[(11)C]thiothymidine (S-dThd) into the mouse models. In vitro cellular uptake of [(14)C]FDG and [(3)H]FLT and thymidine kinase 1 (TK(1)) activity in both cell lines were measured. Expression of glucose transporter 1 (GLUT-1) and Ki-67 in xenografted tumors was evaluated by immunohistochemical staining., Results: In epithelioid mesothelioma models, biodistribution experiments showed that tumor uptake of [(11)C]S-dThd was significantly higher than that of [(18)F]FDG. On the other hand, in sarcomatoid models, [(18)F]FDG showed significantly higher accumulation than the other two tracers. These differential uptakes of the three tracers were confirmed by PET imaging. The cellular uptake of [(14)C]FDG and [(3)H]FLT and TK(1) activity in sarcomatoid cells were higher than those of epithelioid cells. GLUT-1 protein was strongly expressed in sarcomatoid but not in epithelioid tumor. We observed a high percentage of Ki-67-positive cells in both epithelioid and sarcomatoid tumors., Conclusions: We established nude mouse models of epithelioid and sarcomatoid subtypes of mesothelioma. PET tracers applicable for the evaluation of epithelioid and sarcomatoid mesothelioma would vary: [(18)F]FLT and [(11)C]S-dThd seemed suitable for the epithelioid subtype and [(18)F]FDG seemed suitable for the sarcomatoid subtype in our mouse models. Our results indicated that cellular uptake and TK(1) activity in vitro are not always consistent with tracer uptake of [(18)F]FLT and [(11)C]S-dThd in vivo. These mouse models and PET imaging might be useful tools for evaluating new and effective treatments in mesothelioma.

The present status of cancer molecular imaging (MI) with nuclear medicine techniques is reviewed, highlighting the Japanese activities in this field. With the progress in MI research, including significant contributions from Japanese studies, it has become possible to noninvasively evaluate various important characters of cancer in clinical patients, such as metabolism, cellular proliferation, tumor hypoxia, and receptor expression. Tumor metabolic information is used for tumor characterization, treatment response evaluation, and prognosis prediction. Hypoxia imaging is used for treatment planning and predicting treatment response. Receptor imaging can be used for the selection of the candidate for receptor-targeted treatment. Various novel probes that can target cancer-associated antigens, various cellular growth factor receptors, tumor angiogenesis, and so on, are under development, aiming for clinical evaluation. Application of radiolabeled ligands for treatment (targeted internal radiation therapy) is another important field in which MI technique can play a critical role. MI, which can deliver the outcome of basic oncological research to the bedside, is essential translational research for improved individualized patient management, and further advances in MI studies are eagerly awaited.

Purpose: This study aimed to evaluate the clinical value of image fusion from magnetic resonance (MR) combined with positron emission tomography (PET) imaging, using 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) in head and neck cancer., Methods: Sixty-five consecutive patients underwent MR and FDG-PET scans before or after the treatment of known or suspected head and neck cancer. T1-weighted and T2-weighted images were first assessed by MR interpretation, and then, the fused images of T2-weighted images from MR and PET were evaluated in a blind manner. Diagnostic performance was compared., Procedures: For initial staging, in 48 patients, malignant tumors were histologically confirmed in 45 patients. The interpretation sensitivities of MR alone and fused images for primary tumors were 98% and 100%, respectively. For lymph node metastasis, the sensitivity and specificity of both methods were 85% and 92%, respectively. Of 15 patients with suspected recurrence, ten patients had recurrent tumors, three patients developed second malignant tumors, and two patients had no recurrence. For these patients, the overall sensitivity of MR alone was 67%, whereas that of the fused images was 92%. Eight additional lesions were accurately diagnosed by image fusion only. In two patients with lymph node metastasis from unknown origin, the primary site was not detected in one patient, while tonsilar cancer was identified only by image fusion interpretation., Conclusion: Image fusion from MR with PET might be useful in evaluating head and neck cancer, especially in suspected recurrent cases rather than in fresh cases.

Introduction: Various techniques are available for in vivo imaging, and precise understanding of their characteristics is essential for effective use of the imaging results. We established human mesothelioma cell lines expressing red fluorescent protein (RFP) and examined their fluorescence intensity and uptake of positron emission tomography (PET) tracer analogs to compare their characteristics and assess their usefulness in the evaluation of therapeutics., Method: A human mesothelioma cell line was stably transfected to express RFP. Fluorescence, cell number and protein amount were measured during cell growth and treatment with cytotoxic reagents. In in vivo experiments, RFP-expressing cells were injected subcutaneously or into the pleural cavity of nude mice, and fluorescence images were taken with or without pemetrexed treatment. The uptake of [(3)H]3'-deoxy-3'-fluorothymidine ([(3)H]FLT) and [(14)C]2-fluoro-2-deoxy-d-glucose ([(14)C]FDG) under treatment with the above reagents in vitro and in vivo were examined., Results: Strong correlation was observed between fluorescence intensity and total cell number with or without cytotoxic treatment. The uptake of [(3)H]FLT and [(14)C]FDG decreased rapidly after the initiation of treatment with actinomycin D or cycloheximide. When treated with pemetrexed, the uptake of [(3)H]FLT temporarily increased. The cells formed subcutaneous and orthotopic tumors, with fluorescence intensity correlating with tumor volume. The correlation was sustained under pemetrexed treatment. The uptake of [(3)H]FLT in vivo increased significantly early after pemetrexed treatment., Conclusion: Fluorescence imaging could be used to semiquantitatively monitor tumor size, whereas PET could be used to monitor tumor response to therapeutic treatments, and especially, FLT might be a good marker of the response to anti-folate chemotherapeutics.

Purpose: Progress of the novel carbon ion radiotherapy (CIRT) in the treatment of cancers has created the need for a method to accurately evaluate the response. We investigated whether L-[11C]methyl-methionine (11C-methionine) uptake at pre- and post-CIRT could be an early response predictor in patients with pelvic recurrence of rectal cancer., Procedures: 11C-Methionine-positron emission tomography (PET) was performed prospectively in 53 patients with pelvic recurrence of rectal cancer before CIRT, and 48 patients were performed 11C-methionine PET at 1 month after CIRT. 11C-Methionine tumor uptake was measured by the tumor to muscle ratio (T/M ratio). The T/M ratios were evaluated in relation to clinical outcomes such as local re-recurrence, distant metastasis, and survival. The response to CIRT was also judged by computed tomography (CT) and magnetic resonance imaging (MRI). 11C-Methionine PET judgment was compared with CT/MRI judgment regarding the relevance to clinical outcome., Results: Baseline T/M ratio was 5.27+/-1.90 (mean+/-SD) in patients without developing local re-recurrence and 7.66+/-3.17 in patients with local re-recurrence (p=0.023, Mann-Whitney U test). Post-CIRT T/M ratios were 3.10+/-1.28 in patients without local re-recurrence and 6.15+/-2.98 in patients with local re-recurrence (p=0.006, Mann-Whitney U test). By Kaplan-Meier analysis with log-rank test, patients with a baseline T/M ratio of

F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) can play an important role in evaluating patients who have locally advanced diseases and in recurrence detection and restaging in patients who have gastrointestinal tract malignancies. Introduction of an integrated PET/CT system enabled the precise co-evaluation of function and morphology and improved the diagnostic ability of FDG-PET. Application of FDG-PET for treatment response evaluation and prognosis prediction is becoming important. Development of novel PET probes is expected to improve the characterization of individual cancer and to contribute to individualized patient management.

Purpose: The purpose of this study was to compare the diagnostic performance of the manual fusion of positron emission tomography (PET) and computed tomography (CT) images with that of CT alone and that of side-by-side PET and CT (PET/CT) in patients with suspected recurrent lung cancer., Procedures: Fifty-three patients who had previously had surgery for lung cancer underwent a whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET scan, followed by a diagnostic CT scan. The PET and CT images were fused on a workstation. CT alone, PET/CT, and fused images were evaluated separately using a five-point grading scale (0=definitely negative, 1=probably negative, 2=equivocal, 3=probably positive, and 4=definitely positive). Lesions of grade 3 or 4 were considered positive, and diagnostic accuracy and certainty were evaluated., Results: Overall, 67 lesions in 33 patients were considered true positive pathologically or clinically. Of these 67 lesions, the evaluation of CT, PET/CT, and fused images detected 46, 55, and 66 lesions, respectively, with the number of grade 4 lesions detected being 38, 50, and 63, respectively. The diagnostic accuracy of CT, PET/CT, and fused images according to patients was 75%, 79%, and 87%, respectively., Conclusion: These results suggest that interpreting fused images increased diagnostic certainty for detecting recurrence and provided more accurate diagnoses.

Positron emission tomography (PET) is a functional imaging modality that can non-invasively visualize the distribution and dynamic movement of injected PET probes. In this article, the basic principle of PET technique is briefly explained followed by the introduction of various positron-emitters and PET probes used in clinical and research settings. With the coincidence detection of a pair of annihilation radiation emitted from positron emitters and the attenuation correction technique, PET can afford highly sensitive and quantitative data for analysis. However, spatial resolution of PET is limited and not suitable for detecting small lesions. In addition, PET image lacks anatomical information, and correct anatomical localization of the detected uptake is sometimes difficult. Most positron emitters are produced by cyclotrons and have very short half-lives. Therefore, PET institution should be equipped with an in-house cyclotron to produce positron emitters as well as the facility to prepare PET probes. Using positron emitters such as C-11, N-13 and O-15, functional/physiological molecules such as water, oxygen gas, carbon dioxide gas and ammonia, can be radiolabeled without modifying the structure or behavior, which makes these molecules suitable for the precise evaluation of physiological function and its deviation under pathological conditions. Although 18F-fluorodeoxyglucose (FDG), a marker of glucose metabolism, is the most commonly used PET probe especially in the field of oncology, many PET probes are available to evaluate various important characteristics such as blood flow, metabolism, tumor hypoxia, and neurotransmitter and receptor conditions, and are applied in the fields of oncology, neurology/psychiatry and cardiology.

Objective: The purpose of this study was to compare the diagnostic performance of positron emission tomography (PET) alone, computed tomography (CT) alone, side-by-side reading, and fused images for restaging or follow-up of patients with malignant lymphoma., Methods: Fifty patients with histologically confirmed non-Hodgkin lymphoma underwent an (18)fluoro-2-deoxyglucose (FDG)-PET scan, followed by a CT scan. CT alone, PET alone, side-by-side reading, and fused images were interpreted separately and visually using a five-point grading scale for the following eight regions: cervical, supraclavicular, axillary, mediastinal, para-aortic to iliac, mesenteric, inguinal, and extra-nodal. Diagnostic accuracy was compared on the basis of the final diagnoses determined by histological confirmation and/or clinical course., Results: For all regions combined, the interpretation of PET alone (sensitivity = 86.1%, specificity = 99.4%, accuracy = 91.0%), side-by-side reading (96.0%, 99.4%, 98.9%), and fused images (98.0%, 99.4%, 99.2%) yielded significantly higher diagnostic performance than that of CT alone (59.4%, 96.1%, 91.0%; P < 0.001). The cervical, supraclavicular, and extra-nodal regions were more accurately diagnosed with PET (P < 0.05), whereas the para-aortic to iliac regions were diagnosed more accurately with side-by-side reading and fused images than with CT alone or PET alone (P < 0.05)., Conclusions: Although fused images are clinically valuable, side-by-side reading showed equivalent performance, whereas the interpretation of PET alone yielded reasonably high diagnostic performance for restaging or follow-up of patients with malignant lymphoma.

Objective: The purpose of this study was to compare the diagnostic performance of manually fused PET images obtained using 18F-FDG and CT images with that of CT alone, PET alone, and conventional side-by-side review of PET images and CT images (hereafter referred to as "PET + CT") in patients with suspected recurrent colorectal cancer., Materials and Methods: Ethics committee approval and informed consent were obtained. Sixty-three patients with suspected recurrent colorectal cancer underwent whole-body 18F-FDG PET followed by diagnostic CT. The acquired PET and CT images were merged on a workstation on a pixel-to-pixel basis. CT, PET, PET + CT, and fused images were evaluated separately in terms of the presence or absence of recurrence, new metastases, or both using a 5-point grading scale (0 = definitely negative, 1 = probably negative, 2 = equivocal, 3 = probably positive, and 4 = definitely positive). Lesions determined to be grade 3 or 4 were considered positive, and diagnostic accuracy and certainty were evaluated with statistical analysis using the chi-square test for independence., Results: Of 119 pathologically or clinically confirmed lesions in 36 patients, evaluation of CT, PET, PET + CT, and fused images resulted in the detection of 75 (63%), 84 (71%), 91 (76%), and 111 (93%) lesions, respectively (p < 0.01) with the number of grade 4 lesions detected being 59 (50%), 72 (61%), 84 (71%), and 108 (91%), respectively (p < 0.01). Overall, the diagnostic accuracy of CT, PET, PET + CT, and fused images according to patient were 78%, 79%, 84%, and 92%, respectively (p = 0.13)., Conclusion: Interpreting fused images provided more accurate diagnoses than interpreting CT, PET, or PET + CT images. This method of manually fusing separately obtained PET and CT images increased the diagnostic certainty for detecting colorectal cancer recurrence and decreased the number of equivocal cases.

Unlabelled: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become widely available and an important oncological technique. To evaluate the influence of PET on detection of bone metastasis, we compared the diagnostic accuracy of PET and conventional bone scintigraphy (BS) in a variety of cancer patients., Methods: Consecutive ninety-five patients with various cancers, who received both PET and BS within one month, were retrospectively analyzed. A whole-body PET (from face to upper thigh) and a standard whole body BS were performed and these images were interpreted by two experienced nuclear medicine physicians with and without patient information using monitor diagnosis. Each image interpretation was performed according to 8 separate areas (skull, vertebra, upper limbs, sternum and clavicles, scapula, ribs, pelvis, and lower limbs) using a 5-point-scale (0: definitely negative, 1: probably negative, 2: equivocal, 3: probably positive, 4: definitely positive for bone metastasis)., Results: Twenty-one of 95 patients (22.1%) with 43 of 760 areas (5.7%) of bone metastases were finally confirmed. In untreated patients, 12 of 14 bone metastasis positive patients were detected by PET, while 9 of 14 were detected by BS. Three cases showed true positive in PET and false negative in BS due to osteolytic type bone metastases. In untreated cases, PET with and without clinical information showed better sensitivity than BS in patient-based diagnosis. For the purpose of treatment effect evaluation, PET showed better results because of its ability in the evaluation of rapid response of tumor cells to chemotherapy. Out of 10 cases of multiple-area metastases, 9 cases included vertebrae. There was only one solitary lesion located outside of FOV of PET scan in the femur, but with clinical information that was no problem for PET diagnosis., Conclusion: Diagnostic accuracy of bone metastasis was comparable in PET and BS in the present study. In a usual clinical condition, limited FOV (from face to upper thigh) of PET scan may not be a major drawback in the detection of bone metastases because of the relatively low risk of solitary bone metastasis in skull bone and lower limbs.

Positron emission tomography (PET) using fluorine-18-fluoro-2-deoxy-d-glucose (FDG), which originated as a research tool to evaluate glucose metabolism in cancer tissues, has now become an essential imaging modality for determining the appropriate therapeutic management of various cancer patients. The clinical role of FDG-PET for gynecologic tumors has not been established yet, but FDG-PET has come to be considered one of the important imaging modalities for evaluating patients with gynecological cancers. The objective was to review the literature regarding the utility of FDG-PET in the clinical setting of gynecological malignancies. Many articles reported that FDG-PET could be used for staging and restaging in patients with uterine cervical cancer. Although there is limited data about the feasibility of FDG-PET for endometrial cancer, preliminary results for detecting recurrence were promising. Furthermore, FDG-PET has been reported as a useful imaging modality, especially for restaging, in ovarian cancer, although the prognostic value needs to be fully investigated. Currently, a combined PET/computed tomography scanner is available, and its clinical application has begun. It is expected that this modality will contribute to the management of gynecological cancers, as has been reported recently for other malignancies.

This study was performed to investigate the feasibility of FDG- and L-[methyl-11C]methionine (Met)-PET for the follow up of lung cancer after stereotactic radiotherapy (SRT). Nine patients (pt) with solitary lung cancer underwent SRT. Met- and FDG-PET studies were performed one week before SRT and from one week to 8 months after SRT. Responses to SRT were complete in 2 pt and partial in 7 pt. Met- and FDG-PET scan showed high tracer uptake in all tumors before SRT. After SRT, standardized uptake values (SUV) of FDG and Met changed concordantly. Both decreased with time in 5 pt but did not decrease steadily in 4 pt, where 2 pt showed an increase at 1 to 2 weeks after SRT and 2 pt showed an increase at more than 3 months after SRT. The former appears to reflect the acute reaction to SRT and the latter radiation-induced pneumonitis. Although the addition of Met-PET did not provide additional information over FDG-PET, FDG- and Met-PET could be used to evaluate the treatment effect of SRT.

Purpose: To evaluate the appropriate post-injection timing for hand-held-gamma-ray-detecting probe (GDP) scanning for the intraoperative detection of malignancy after preoperative F-18 FDG (FDG) injection., Methods: Patient study with superficially located cancer was performed on three patients before operation by dual-phase whole-body PET at 2 and 6-7 hr post-injection of FDG (370 MBq), and by probe scanning from the skin at several points at 1, 3, 5, and 7 hr after FDG injection. TNRa (tumor-adjacent-normal ratio) and TNRc (tumor-contralateral-normal ratio) were calculated. Phantom study was also performed to determine basic GDP function., Results: The patient study revealed that tumors showed constant TNRa (0.9-1.3) and TNRc (1.1-3.0) by GDP count rate, and that there was no tendency of an increase in TNRa with time. The standard deviations of GDP count rate were lower at 1-3 hr post-injection compared with those of delayed scans. While delayed PET showed an increase or no change in the tumor FDG uptake, the decrease of normal tissue FDG uptake was not adequate to create higher TNRs. The phantom study revealed that LN model showed TNRa of 1.7 or greater by GDP count rate (cps) when background contained no FDG, but that they showed TNRa of 1.3 or less when the background contained 4% of the LN FDG activity per ml., Conclusion: The present study suggests that higher FDG count rate of tumors at 1-3 hr postinjection would be more suitable for the gamma-probe detection compared with lower count rate at 6-7 hr delayed scans with wide standard deviations.