Influence of hypoxia on tracer accumulation in squamous-cell carcinoma: in vitro evaluation for PET imaging

Hypoxic accumulation of 2-[5,6-³H]fluoro-2-deoxy- -glucose ([³H]FDG), -[methyl-³H]methionine ([³H]MET), and -[1-³H]leucine ([³H]LEU) was evaluated in two cell lines (UT-SCC-5 and UT-SCC-20) obtained from patients with squamous-cell carcinoma of the head and neck. Both cell lines were exposed to decreasing oxygen atmosphere (20%, 1.5%, or 0% O₂) for 6 h, after which they were incubated for a further 1 h with tritiated FDG, MET, or LEU. An anoxic atmosphere resulted in a mean increase of [³H]FDG uptake of 120% and 46% over a baseline 20% oxygen atmosphere for UT-SCC-5 and UT-SCC-20A, respectively. Both total and acid-precipitable [³H]MET uptake remained unchanged at 0% versus baseline, whereas acid-precipitable [³H]LEU uptake decreased by 46% for UT-SCC-5 and by 34% for UT-SCC-20A at 0% O₂. Our findings demonstrate that [³H]FDG accumulation is increased in hypoxic UT-SCC cell lines probably through activation of the metabolic steps associated with the glycolytic pathway. The decrease in acid-precipitable [³H]LEU uptake in hypoxia may indicate a decline in protein synthesis, whereas the unchanged [³H]MET uptake probably reflects the unaffected amino acid transport and slow incorporation of radiolabeled methyl group of MET in tumor proteins and nucleic acids. FDG and LEU, but probably not MET, warrant additional study as hypoxia-avid or hypoxia-reduced tracers for assessment of treatment effects designed to modify hypoxia.     

Preparation of the hypoxia imaging PET tracer [F]FAZA: reaction parameters and automation

¹⁸F-labeling of the nitroimidazole nucleoside analogue 1-(5-fluoro-5-deoxy--D-arabinofuranosyl)-2-nitroimidazole (FAZA) was developed to use this tracer in PET for detection of hypoxia. Parameters for labeling and hydrolysis were optimized with regard to amount of precursor, temperature and time. Labeling yields reached a maximum of 62±4% at 100 °C within 5 min using 5 mg of precursor. Hydrolysis was best performed with 1 mL of 0.1 N NaOH at 20 °C for 2 min. Transfer of these conditions to an automated synthesizer resulted in an overall radiochemical yield of 20.7±3.5%. Absolute yields at EOS were 9.8±2.3 GBq of [¹⁸F]FAZA ready for injection (n=21; 50 min after EOB; irradiation parameters: 35 μA, 60 min). Thus, a convenient approach suitable for large-scale production of [¹⁸F]FAZA was developed by an automated process.     

PET recognition of pulmonary metastases on PET/CT imaging: impact of attenuation-corrected and non-attenuation-corrected PET images

Purpose The aims of this study were to assess the performance of FDG PET at PET/CT imaging for the detection of pulmonary metastases and to evaluate differences in lesion detectability on attenuation-corrected (AC) and non-attenuation corrected (NAC) PET images.Methods The institutional PET/CT database was searched for patients with pulmonary metastases of 3–60 mm in diameter. Ninety-two patients with 438 metastases to the lungs were included in the study. The primary tumours were 33 malignant melanomas, 12 carcinomas of unknown primary, 11 colorectal carcinomas, eight differentiated thyroid carcinomas, seven aggressive non-Hodgkins lymphomas, six head and neck cancers, three breast cancers, two prostate cancers and ten others. Lesion detectability was visually compared between PET and CT and between AC and NAC PET images using a five-point scale.Results Of the 438 pulmonary metastases, 174 were detected with FDG PET (39.7%), six of them on NAC images only (not significant). Visual scores were higher on NAC images in 41.4% and equal in 54.6% of lesions. The sensitivity of FDG PET increased significantly from 0.405 for metastases of 5–7 mm in diameter to 0.784 for lesions of 8–10 mm and to 0.935 for lesions measuring 11–29 mm in diameter. No metastases smaller than 5 mm in diameter were seen on PET images.Conclusion FDG PET/CT is useful for the assessment of pulmonary metastases. The frequency of lesion detection is similar for AC and NAC PET images. A reduced sensitivity of FDG PET has to be considered for lesions smaller than 11 mm in diameter.     

Dosimetry of transmission measurements in nuclear medicine: a study using anthropomorphic phantoms and thermoluminescent dosimeters

Quantification in positron emission tomography (PET) and single photon emission tomographic (SPET) relies on attenuation correction which is generally obtained with an additional transmission measurement. Therefore, the evaluation of the radiation doses received by patients needs to include the contribution of transmission procedures in SPET (SPET-TM) and PET (PET-TM). In this work we have measured these doses for both PET-TM and SPET-TM. PET-TM was performed on an ECAT EXACT HR+ (CTI/Siemens) equipped with three rod sources of germanium-68 (380 MBq total) and extended septa. SPET-TM was performed on a DST (SMV) equipped with two collimated line sources of gadolinium-153 (4 GBq total). Two anthropomorphic phantoms representing a human head and a human torso, were used to estimate the doses absorbed in typical cardiac and brain transmission studies. Measurements were made with thermoluminescent dosimeters (TLDs, consisting of lithium fluoride) having characteristics suitable for dosimetry investigations in nuclear medicine. Sets of TLDs were placed inside small plastic bags and then attached to different organs of the phantoms (at least two TLDs were assigned to a given organ). Before and after irradiation the TLDs were placed in a 2.5-cm-thick lead container to prevent exposure from occasional sources. Ambient radiation was monitored and taken into account in calculations. Transmission scans were performed for more than 12 h in each case to decrease statistical noise fluctuations. The doses absorbed by each organ were calculated by averaging the values obtained for each corresponding TLD. These values were used to evaluate the effective dose (ED) following guidelines described in ICRP report number 60. The estimated ED values for cardiac acquisitions were 7.7×10^–4±0.4×10^–4 mSv/MBq · h and 1.9×10^–6±0.4×10^–6 ███/MBq · h for PET-TM and SPET-TM. respectively. For brain scans, the values of ED were calculated as 2.7×10^–4±0.2×10^–4 mSv/MBq · h for PET-TM and 5.2×10^–7±2.3×10^–7 mSv/MBq · h for SPET-TM. In our institution, PET-TM is usually performed for 15 min prior to emission. SPET-TM is performed simultaneously with emission and usually lasts 30 and 15 min for brain and cardiac acquisitions respectively. Under these conditions ED values, estimated for typical source activities at delivery time (22000 MBq in SPET and 555 MBq for PET), were 1.1×10^–1± 0.1×10^–1 mSv and 1.1×10^–2±0.2×10^–2 mSv for cardiac PET-TM and SPET-TM respectively. For brain acquisitions, the ED values obtained under the same conditions were 3.7×10^–2±0.3×10^–2 mSv and 5.8×10^–3±2.6×10^–3███ for PET-TM and SPET-TM respectively. These measurements show that the dose received by a patient during a transmission scan adds little to the typical dose received in a routine nuclear medicine procedure. Radiation dose, therefore, does not represent a limit to the generalised use of transmission measurements in clinical SPET or PET. Received 12 May and in revised form 1 July 1998     

Exploring new frontiers in molecular imaging: Emergence of Ga PET/CT

Since US Food and Drug Administration approval of 18-fluorodeoxyglucose as a positron tracer, and the development of hybrid positron emission tomography/computed tomography machines, there has been a great increase in clinical application and progress in the field of nuclear molecular imaging. However, not underestimating the value of (18)F, there are known limitations in the use of this cyclotron-produced positron tracer. We hence turn our focus to an emerging positron tracer, (68)Ga, and examine the advantages, current clinical uses and potential future applications of this radioisotope.     

放射性核素标记的胆碱在PET/CT肿瘤显像中的应用

18F-FDG PET/CT可明显提高恶性肿瘤诊断的准确性,指导恶性肿瘤的分期与再分期,对患者治疗方案的选择产生了重要影响。其在全身许多肿瘤中的应用价值已获得认可,但还存在一些不足。随着正电子标记药物的不断研发,放射性核素标记的胆碱逐渐应用于临床。胆碱是细胞膜的重要组成成分,恶性肿瘤的胆碱代谢增高。近年来的研究表明,胆碱PET/CT在胶质瘤、头颈部肿瘤、肺癌、肝细胞肝癌、前列腺癌、膀胱肿瘤等的诊断、分期及复发检测等方面具有很好的应用价值,特别是对颅内病变的观察、高分化肝细胞肝癌的诊断、生物靶区勾画、复发病灶的定位等,在一定程度上弥补了18F-FDG PET/CT的不足。笔者回顾了放射性核素标记的胆碱（11C-胆碱和18F-胆碱）在肿瘤显像中的应用。     

Design of hypoxia-targeting radiopharmaceuticals: selective uptake of copper-64 complexes in hypoxic cells in vitro

The well-known perfusion tracer CuPTSM, labelled with ⁶²Cu or ⁶⁴Cu, is believed to be trapped in cells non-selectively by a bioreductive mechanism. It is proposed that by modifying the ligand to increase its electron donor strength (for example by adding alkyl functionality or replacing sulphur ligands with oxygen ligands), the copper complexes will become less easily reduced and tracers with selectivity for hypoxic tissues could thus be developed. The aim of this work was to prepare ⁶⁴Cu-labelled complexes of two series of ligands, based on the bis(thiosemicarbazone) (13 ligands) and bis(salicylaldimine) (3 ligands) skeletons, and to evaluate the hypoxia dependence of their uptake in cells. The complexes were incubated with Chinese hamster ovary cells under normoxic and hypoxic conditions, and the cells isolated by centrifugation to determine radioactivity uptake at various time points up to 90 min. Several members of both series demonstrated significant (P<0.05) or highly significant (P<0.01) hypoxia selectivity, indicating that both series of complexes offer a basis for development of hypoxia-targeting radiopharmaceuticals for positron emission tomography (⁶⁰Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu) and targeted radiotherapy (⁶⁴Cu, ⁶⁷Cu). Received 30 March 1998     

PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator

OBJECTIVE: Copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) and copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) are being studied as potential markers of hypoxia and perfusion, respectively. The use of short-lived radionuclides (e.g., 62Cu) has advantages for clinical PET, including a lower radiation dose than long-lived radionuclides and serial imaging capability. A 62Zn/62Cu microgenerator and rapid synthesis kits now provide a practical means of producing 62Cu-PTSM and 62Cu-ATSM on-site. Tumors can be characterized with 62Cu-PTSM, 62Cu-ATSM, and 18F-FDG PET scans during one session. We present the initial clinical data in two patients with lung neoplasms. CONCLUSION: Hypoxia and perfusion are important parameters in tumor physiology and can have major implications in diagnosis, prognosis, treatment planning, and response to therapy. We have shown the feasibility of performing 62Cu-ATSM and 62Cu-PTSM PET together with FDG PET/CT during a single imaging session to provide information on both perfusion and hypoxia and tumor anatomy and metabolism.     

18F-FDG PET/CT and PET/MRI fusion imaging for neuroendocrine carcinoma of the tongue: A case report

Neuroendocrine carcinoma (NEC) involving the tongue is a rare and aggressive disease that is more common in middle-aged and elderly males. We report a case of a 56-year-old male who presented to our hospital with sore throat and was found to have a mass in the left root of the tongue. ¹⁸F-FDG PET/CT revealed intense FDG uptake in the mass of the tongue base, as well as different uptake of FDG in the mid-posterior mediastinal mass, right adrenal gland, and enlarged lymph nodes in the neck and mediastinum. Gadolinium-enhanced MRI clearly showed the extent of the tongue lesion, additionally suggesting the presence of brain metastases. ¹⁸F-FDG PET/MRI fusion images of the neck were obtained on the workstation, which may have a higher diagnostic value for tongue NEC. The patient underwent a biopsy of the mass in the left root of the tongue and was pathologically diagnosed with NEC. Whole-body ¹⁸F-FDG PET/CT and regional PET/MRI fusion images have complementary roles in the diagnosis of tongue NEC, and the former is mainly applied to determine the clinical stage of the disease and to guide treatment.     

P-gp功能的PET显像剂的研究进展

肿瘤对化疗药物产生耐药性是肿瘤治疗失败的主要原因,引起肿瘤对化疗药物耐药的重要机制是ATP结合盒（ABC）转运蛋白的过度表达.P-糖蛋白（P-gp）是ABC转运蛋白超家族中研究最广、最深入的一类转运蛋白,目前检测P-gp主要依赖于组织活检或术后病理组织在体外进行定性、定量分析,这些检测方法受取材技术、肿瘤标本差异等因素的限制,因此,寻找一种无创性、可以动态检测肿瘤多药耐药的方法就显得尤为重要.目前许多^18F、^11C标记的P-gp底物及抑制剂的正电子显像剂已经进行基础研究,部分进入了临床试验阶段.该文对P-gp的PET显像剂现状进行综述.     

PET/SPECT imaging: From carotid vulnerability to brain viability

Background

Current key issues in ischemic stroke are related to carotid plaque vulnerability, brain viability, and timing of intervention. The treatment of ischemic stroke has evolved into urgent active interventions, as ‘time is brain’. Functional imaging such as positron emission tomography (PET)/single photon emission computed tomography (SPECT) could improve selection of patients with a vulnerable plaque and evaluation of brain viability in ischemic stroke.

Objective

To describe the current applications of PET and SPECT as a diagnostic tool in relation to ischemic stroke.

Methods

A literature search using PubMed identified articles. Manual cross-referencing was also performed.

Results

Several papers, all observational studies, identified PET/SPECT to be used as a tool to monitor systemic atheroma modifying treatment and to select high-risk patients for surgery regardless of the degree of luminal stenosis in carotid lesions. Furthermore, PET/SPECT is able to quantify the penumbra region during ischemic stroke and in this way may identify those patients who may benefit from timely intervention.

Discussion

Functional imaging modalities such as PET/SPECT may become important tools for risk-assessment and evaluation of treatment strategies in carotid plaque vulnerability and brain viability. Prospective clinical studies are needed to evaluate the diagnostic accuracy of PET/SPECT.     

Evaluation of Dixon Sequence on Hybrid PET/MR Compared with Contrast-Enhanced PET/CT for PET-Positive Lesions

Purpose

Hybrid positron emission tomography and magnetic resonance (PET/MR) imaging performs a two-point Dixon MR sequence for attenuation correction. However, MR data in hybrid PET/MR should provide anatomic and morphologic information as well as an attenuation map. We evaluated the Dixon sequence of hybrid PET/MR for anatomic correlation of PET-positive lesions compared with contrast-enhanced PET/computed tomography (CT) in patients with oncologic diseases.

Methods

Twelve patients underwent a single injection, dual imaging protocol. PET/CT was performed with an intravenous contrast agent (85 ± 13 min after ¹⁸F-FDG injection of 403 ± 45 MBq) and then (125 ± 19 min after injection) PET/MR was performed. Attenuation correction and anatomic allocation of PET were performed using contrast-enhanced CT for PET/CT and Dixon MR sequence for hybrid PET/MR. The Dixon MR sequence and contrast-enhanced CT were compared for anatomic correlation of PET-positive lesions (scoring scale ranging from 0 to 3 for visual ratings). Additionally, standardized uptake values (SUVs) for the detected lesions were assessed for quantitative comparison.

Results

Both hybrid PET/MR and contrast-enhanced PET/CT identified 55 lesions with increased FDG uptake in ten patients. In total, 28 lymph nodes, 11 bone lesions, 3 dermal nodules, 3 pleural thickening lesions, 2 thyroid nodules, 1 pancreas, 1 liver, 1 ovary, 1 uterus, 1 breast, 1 soft tissue and 2 lung lesions were present. The best performance was observed for anatomic correlation of PET findings by the contrast-enhanced CT scans (contrast-enhanced CT, 2.64 ± 0.70; in-phase, 1.29 ± 1.01; opposed-phase, 1.29 ± 1.15; water-weighted, 1.71 ± 1.07; fat weighted, 0.56 ± 1.03). A significant difference was observed between the scores obtained from the contrast-enhanced CT and all four coregistered Dixon MR images. Quantitative evaluation revealed a high correlation between the SUVs measured with hybrid PET/MR (SUVmean, 2.63 ± 1.62; SUVmax, 4.30 ± 2.88) and contrast-enhanced PET/CT (SUVmean, 3.88 ± 2.30; SUVmax, 6.53 ± 4.04) in PET-positive lesions (SUVmean, ρ = 0.93; SUVmax, ρ = 0.95), although hybrid PET/MR presented a decrease of SUVs compared with contrast-enhanced PET/CT (mean reduction; SUVmean, 32.44 ± 15.64 %; SUVmax, 35.16 ± 12.59 %).

Conclusions

Despite different attenuation correction approaches, the SUV of PET-positive lesions correlated well between hybrid PET/MR and contrast-enhanced PET/CT. However Dixon MR images acquired for attenuation correction were insufficient to provide anatomic information of PET images because of low spatial resolution. Thus, additional MR sequence with fast and higher resolution may be necessary for anatomic information.     

Absorbed fractions for dose calculations of neuroreceptor PET studies

A simple Monte Carlo program was constructed for the purpose of calculating absorbed fractions of relevance to neurologic positron-emission-tomography studies. The caudate, putamen, and cerebellum regions of the brain were mathematically modeled to serve as source regions for the absorbed-fraction calculations for positron-annihilation photons. The target organs were the caudate, putamen, cerebellum, brain, spine portion in the head, skull, and head. Absorbed fractions were also calculated for a uniform ring source which encircled the head phantom.     

PET乏氧显像在预测肿瘤乏氧及指导临床治疗中的应用进展

放射性核素标记的乏氧显像是评估肿瘤乏氧程度的重要方法, 乏氧显像剂可以选择性地滞留于乏氧组织内, 直观反映乏氧的部位和乏氧的程度, 对肿瘤诊断、分期、疗效监测及预后评估等有指导意义, 同时也为临床选择及调整肿瘤治疗方案提供了客观依据。笔者主要对肿瘤乏氧PET显像近年来在临床研究中的进展及与肿瘤乏氧相关的治疗进展进行综述。     

PET/MRI: Multiparametric imaging of brain tumors

A combination of morphological imaging of the brain with microstructural and functional imaging provides a comprehensive overview of the properties of individual tissues. While diffusion weighted imaging provides information about tissue cellularity, spectroscopic imaging allows us to evaluate the integrity of neurons and possible anaerobic glycolysis during tumor hypoxia, in addition to the presence of accelerated synthesis or degradation of cellular membranes; on the other hand, PET metabolic imaging is used to evaluate major metabolic pathways, determining the overall extent of the tumor (¹⁸F-FET, ¹⁸F-FDOPA, ¹⁸F-FCH) or the degree of differentiation (¹⁸F-FDG, ¹⁸F-FLT, ¹⁸F-FDOPA and ¹⁸F-FET). Multi-parameter analysis of tissue characteristics and determination of the phenotype of the tumor tissue is a natural advantage of PET/MRI scanning. The disadvantages are higher cost and limited availability in all centers with neuro-oncology surgery. PET/MRI scanning of brain tumors is one of the most promising indications since the earliest experiments with integrated PET/MRI imaging systems, and along with hybrid imaging of neurodegenerative diseases, represent a new direction in the development of neuroradiology on the path towards comprehensive imaging at the molecular level.     

Quantification accuracy of neuro-oncology PET data as a function of emission scan duration in PET/MR compared to PET/CT

ObjectivesTo evaluate and compare the effect of reduced acquisition time, as a surrogate of injected activity, on the PET quantification accuracy in PET/CT and PET/MR imaging.MethodsTwenty min ¹⁸F-FDG phantom measurements and 10 min ¹⁸F-FET brain scans were acquired in a Biograph-True-Point-True-View PET/CT (n = 8) and a Biograph mMR PET/MR (n = 16). Listmode data were repeatedly split into frames of 1 min to 10 min length and reconstructed using two different reconstruction settings of a 3D-OSEM algorithm: with post-filtering (“OSEM”), and without post-filtering but with resolution recovery (“PSF”). Recovery coefficients (RC_max, RC_A50) and standard uptake values (SUV_max, SUV_A50) were evaluated.ResultsRC_max (phantom) and SUV_max (patients) increased significantly when reducing the frame duration. Significantly lower deviations were observed for RC_A50 and SUV_A50, respectively, making them more appropriate to compare PET studies at different number of counts. No statistical significant differences were observed when using post-filtering and reducing the frame time to 4 min (RC_A50, reference 20 min, phantom) and to 3 min (SUV_A50, reference 10 min, patients).ConclusionsFor hybrid aminoacid brain imaging, frame duration (or injected activity) can potentially be reduced to 30% of the standard used in clinical routine without significant changes on the quantification accuracy of the PET images if adequate reconstruction settings and quantitative measures are used. Frame times below 4 min in the NEMA phantom are not advisable to obtain quantitative and reproducible measures.     

FDG–PET imaging findings of a pulmonary sclerosing hemangioma

Pulmonary sclerosing hemangiomas are generally regarded as benign lung lesions arising from type II pneumocytes and bronchial epithelium. In some cases malignant features may be present. There are several case reports describing the radiographic, computed tomography (CT), and magnetic resonance imaging (MRI) characteristics of pulmonary sclerosing hemangiomas. Given the potential for low-grade malignancy 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging may be useful in the diagnostic work up and therapeutic planning in these patients, however the FDG–PET imaging features of pulmonary sclerosing hemangiomas are not well defined. We report a case of histopathologically diagnosed sclerosing hemangioma of the lung which demonstrated intermediate uptake of FDG on the preoperative PET/CT evaluation.     

18F-choline PET/CT imaging of RECIST measurable lesions in hormone refractory prostate cancer

Purpose  Apply measurability criteria based on the response evaluation criteria in solid tumors (RECIST) to lesions found on ¹⁸F-choline positron emission tomography (PET)/computerized tomography (CT) in patients with hormone refractory prostate cancer. Methods  Whole-body PET followed by CT or in-line PET/CT using 3.3–4 MBq/kg of ¹⁸F-choline was performed prospectively on 30 patients with prostate cancer, castrate testosterone levels, and rising post-treatment prostate specific antigen (PSA) levels. Lesions demonstrating increased ¹⁸F-choline uptake were classified as measurable or non-measureable based on RECIST. Results  Three patients were known previously to have RECIST measurable lesions, 10 patients had metastatic findings on radionuclide bone scan, and 17 patients had elevated serum PSA level as the only evidence of disease. Lesions demonstrating increased ¹⁸F-choline uptake were found in 28 (93%) patients. Thirty-eight PET/CT lesions from 14 patients were measurable by RECIST. Lymph node maximum standardized uptake value (SUV_max) correlated with lymph node diameter (Pearson r = 0.44, p < 0. 001). RECIST measurable lymph node SUV_max was significantly higher than that of non-measurable nodes (8.1 vs. 3.7, p < 0.0001). Detection of skeletal, prostatic, or RECIST-compatible lesions was more likely with a PSA level greater than 4.0 ng/ml (Fisher exact p = 0.0005). Conclusion  Lesions detected with ¹⁸F-choline PET/CT are frequently measurable by RECIST at baseline. Therefore, it may be feasible to include comparisons to RECIST in evaluations of ¹⁸F-choline as a therapeutic response marker for hormone refractory prostate cancer. The findings and conclusions expressed in this study do not necessarily represent the views of The Queen’s Medical Center.     

FDG PET在胰腺癌中的应用

胰腺癌的影像诊断手段较多 ,如CT、MRI、超声等 ,由于特异性及其敏感性的限制 ,难以早期作出诊断 ,延误患者早期的治疗。因此如何早期提高胰腺癌的诊断为早期治疗提供理论上的依据 ,仍是影像医学和临床医学的研究热点。正电子发射计算机断层(PET)是利用正电子放射性药物在体内的分布来反映人体组织的生理生化代谢功能 ,其中FDGPET利用肿瘤组织的葡萄糖代谢增加来鉴别恶性病变与良性病变。本文就PET的显像基本原理及其在胰腺癌诊断和分期中的应用价值作一简要介绍 ,可以看到FDGPET在胰腺肿块的良恶性鉴别的灵敏度和特异性均较高 ,对临床分析有很好的应用价值 ,在胰腺癌的分期 ,尤其是确定有否肝脏转移方面极具价值。并对FDGPET临床应用的优点和局限性做出分析。