Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone).

Cu-Diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate (64)Cu-ATSM as a hypoxia PET marker by comparing autoradiographic distributions of (64)Cu-ATSM with a well-established hypoxia marker drug, EF5. METHODS: R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochemical analysis. (64)Cu-ATSM microPET and autoradiography were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images-microPET, autoradiography, EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-and-eosin histology-were superimposed, evaluated, and compared. RESULTS: A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation analysis between (64)Cu-ATSM autoradiography and EF5 immunostained images varied between the 3 tumor types. There was close correlation of (64)Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated (64)Cu-ATSM uptake was observed in well-perfused areas in FSA, indicating a correlation between (64)Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was observed with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of (64)Cu-ATSM. These results indicate that some other (64)Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor. CONCLUSION: To our knowledge, this study is the first comparison between (64)Cu-ATSM uptake and immunohistochemistry in these 3 tumors. Although we have shown that (64)Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type-dependent hypoxia selectivity of (64)Cu-ATSM challenges the use of (64)Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.     

Evaluation of62Cu labeled diacetyl-bis(N 4-methylthiosemicarbazone) as a hypoxic tissue tracer in patients with lung cancer

62Cu labeled diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM) has been proposed as a generator-produced, positron-emitting tracer for hypoxic tissue imaging. From basic studies, the retention mechanism of 62Cu-ATSM is considered to be closely related to cytosolic/microsomal bioreduction, a possible system for hypoxic bioreductive drug activation. In order to evaluate the characteristics of 62Cu-ATSM, PET studies were performed in 4 normal subjects and 6 patients with lung cancer. 62Cu-ATSM cleared rapidly from the blood with little lung uptake (0.43+/-0.09, uptake ratio; divided by the arterial input function) in normal subjects. Intense tumor uptake of 62Cu-ATSM was observed in all patients with lung cancer (3.00+/-1.50). A negative correlation was observed between blood flow and flow-normalized 62Cu-ATSM uptake in three of four patients. In contrast, 62Cu-ATSM uptake was not related to that of 18F-fluorodeoxyglucose. The negative correlation between blood flow and flow normalized 62Cu-ATSM uptake suggests an enhancement of retention of 62Cu-ATSM by low flow. 62Cu-ATSM is a promising PET tracer for tumor imaging, which might bring new information for chemotherapeutic treatment as well as radiotherapy of hypoxic tumors.     

Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone)

Tumor hypoxia indicates a poor prognosis. This study was undertaken to confirm our prior pilot results showing that pretreatment tumor hypoxia demonstrated by PET with (60)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) is a biomarker of poor prognosis in patients with cervical cancer. Thirty-eight women with biopsy-proved cervical cancer underwent (60)Cu-ATSM PET before the initiation of radiotherapy and chemotherapy. (60)Cu-ATSM uptake was evaluated semiquantitatively as the tumor-to-muscle activity ratio (T/M). A log-rank test was used to determine the cutoff uptake value that was strongly predictive of prognosis. All patients also underwent clinical PET with (18)F-FDG before the institution of therapy. The PET results were correlated with clinical follow-up. Tumor (60)Cu-ATSM uptake was inversely related to progression-free survival and cause-specific survival (P = 0.006 and P = 0.04, respectively, as determined by the log-rank test). We found that a T/M threshold of 3.5 best discriminated patients likely to develop a recurrence from those unlikely to develop a recurrence; the 3-y progression-free survival of patients with normoxic tumors (as defined by T/M of < or = 3.5) was 71%, and that of patients with hypoxic tumors (T/M of > 3.5) was 28% (P = 0.01). Tumor (18)F-FDG uptake did not correlate with (60)Cu-ATSM uptake, and there was no significant difference in tumor (18)F-FDG uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.9). Pretherapy (60)Cu-ATSM PET provides clinically relevant information about tumor oxygenation that is predictive of outcome in patients with cervical cancer.     

Dosimetry of 60/61/62/64Cu-ATSM: a hypoxia imaging agent for PET

Purpose Cu-diacetyl-bis(N⁴-methylthiosemicarbazone (Cu-ATSM) is an effective marker for the delineation of hypoxic tissue. Dosimetry calculations by the established Medical Internal Radionuclide Dose (MIRD) approach were performed with both animal and patient data.Methods Human absorbed dose estimates extrapolated from rat data were based on the biodistribution of ⁶¹Cu-ATSM in adult rats. Eighteen tissues were harvested and time–activity curves generated. The measured residence times and the MIRD S-values for ⁶⁰Cu-ATSM were used to estimate human absorbed doses. The biodistribution of the tracer was directly measured in five patients injected with approximately 480 MBq of ⁶⁰Cu-ATSM and imaged by positron emission tomography (PET) with a whole-body protocol. The combined data from all patients were used to derive organ residence times, and organ doses were calculated by MIRD methodology for ⁶⁰Cu-ATSM, ⁶¹Cu-ATSM, ⁶²Cu-ATSM, and ⁶⁴Cu-ATSM.Results Human absorbed dose estimates extrapolated from rat biodistribution data indicated that the kidneys appeared to be the dose-limiting organ (0.083 mGy/MBq) with a whole-body dose of 0.009 mGy/MBq. Based on the human PET imaging data, the liver appeared as the dose-limiting organ, with an average radiation dose of 0.064 mGy/MBq. The whole-body dose was 0.009 mGy/MBq and the effective dose was 0.011 mSv/MBq.Conclusion These relatively small absorbed doses to normal organs allow for the safe injection of 500–800 MBq of ⁶⁰Cu-ATSM, which is sufficient for PET imaging in clinical trials.     

Differential mechanism of retention of Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) by brain and tumor: A novel radiopharmaceutical for positron emission tomography imaging

The reductive retention of⁶²Cu-PTSM was comparatively studied in the brain and Ehrlich ascites tumor cells by electron spin resonance spectrometry and nonradioactive Cu-PTSM. In the brain, only the mitochondrial fraction showed the ability to reduce Cu-PTSM, and the other subcellular fractions did not. In contrast, the cytosolic fraction of Ehrlich ascites tumor cells was the specific site of Cu-PTSM reduction. It was therefore considered that the retention of Cu-PTSM in the brain is closely related to mitochondrial reduction, most probably involving the mitochondrial electron transport system.     

Delineation of hypoxia in canine myocardium using PET and copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone).

Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (copper-ATSM) is a hypoxia-avid tracer for the selective identification of hypoxic tissue. Using canine models of hypoxic myocardium, we report our findings on *Cu-ATSM PET (*Cu is defined as either (60)Cu, (61)Cu, or (64)Cu) for the delineation of ischemic and hypoxic myocardium. METHODS: In protocol I, myocardial hypoxia was induced by global hypoxia (n = 3). In protocol II, myocardial ischemia was generated by occlusion of the left anterior descending coronary artery (n = 9). In protocol III, coronary artery stenosis was induced by a stenosis in the left anterior descending coronary artery (n = 4). PET dynamic data were acquired immediately after tracer injection. Tracer retention kinetics were analyzed using either monoexponential analysis (1/k(mono)) or a simple 2-compartment model (1/k(4)). RESULTS: In protocol I, tracer retention in hypoxic myocardium was 2-fold greater than in normal myocardium, despite a 7-fold increase in blood flow (normal, 0.70 +/- 0.42 mL.min(-1).g(-1); hypoxic, 4.94 +/- 3.00 mL.min(-1).g(-1) [P < 0.005]). In protocol II, approximately 3 h after occlusion, retention of *Cu-ATSM within 20 min was greater in ischemic regions (myocardial blood flow, 0.28 +/- 0.26 mL.min(-1).g(-1)) than in normal tissue (myocardial blood flow, 0.52 +/- 0.19 mL.min(-1).g(-1)) (1/k(mono), 40.72 +/- 39.0 min vs. 26.69 +/- 22.29 min [P < 0.05]; 1/k(4), 6.85 +/- 4.90 min vs. 3.51 +/- 1.97 min [P < 0.05]). In selected dogs, tracer retention decreased at 24 h, suggesting the development of necrosis with no subsequent retention of *Cu-ATSM. In protocol III, dobutamine infusion after stenosis placement resulted in increased tracer retention consistent with hypoxia in the damaged regions. CONCLUSION: *Cu-ATSM PET has shown quantitative selective uptake in hypoxic myocardium within 20 min of tracer administration in 3 canine models of hypoxia.     

Cytosolic/microsomal redox pathway: a reductive retention mechanism of a PET-oncology tracer, Cu-pyruvaldehyde-bis(N 4-methylthiosemicarbazone) (Cu-PTSM)

OBJECTIVE: To clarify the retention mechanism of a PET imaging agent Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-62-PTSM) in tumor cells, reductive metabolism of non-radioactive Cu-PTSM in five cultured tumor cell lines, a tumor specimen and non-tumor tissues in vitro was evaluated by electron spin resonance spectrometry (ESR). RESULTS: In the brain, mitochondrial electron transport enzyme reduced Cu-PTSM specifically. On the other hand, Cu-PTSM was not reduced in tumor mitochondria. The mitochondrial electron transport enzyme in tumor cells was not damaged, but NADH was considered to be depleted. In compensation for that, the tumor cells acquired complementary reduction activity in the microsome/cytosol. The reduction was enzymatic and NADH-dependent, possibly similar to the activation mechanism of bioreductive anticancer drugs. CONCLUSION: Cu-PTSM and its derivatives are considered to be used as a marker for microsome/cytosol redox ability in PET oncology, although the physiological role of the redox enzyme system in tumor cells has not been clarified. The change in electron (NADH) flow in tumor cells might be a mechanism supporting aerobic glycolysis in tumor cells.     

Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning

Tumor hypoxia, present in many human cancers, can lead to resistance to radiation and chemotherapy, is associated with a more aggressive tumor phenotype and is an independent prognostic factor of clinical outcome. It is therefore important to identify and localize tumor hypoxia in cancer patients. In the current study, serial microPET imaging was used to evaluate iodine-124-labeled iodo-azomycin-galactoside (¹²⁴I-IAZG) (4.2-day physical half-life) as a hypoxia imaging agent in 17 MCa breast tumors and six FSaII fibrosarcomas implanted in mice. For comparison, another promising hypoxic-cell PET radiotracer, fluorine-18-labeled fluoro-misonidazole (¹⁸F-FMISO), was also imaged in the same tumor-bearing animals. Twelve animals were also imaged with ¹⁸F-labeled fluoro-deoxyglucose (¹⁸F-FDG). In addition, histological examination was performed, and direct measurement of tumor oxygenation status carried out with the Oxylite probe system. Two size groups were used, relatively well-oxygenated tumors in the range of 80–180 mg were designated as small, and those >300 mg and highly hypoxic, as large. Based on the data from 11 MCa and six FSaII tumors, both ¹²⁴I-IAZG and ¹⁸F-FMISO images showed high tracer uptake in the large tumors. In ¹⁸F-FMISO images at 1, 3–4, and 6–8 h post-injection (p.i.), there was considerable whole-body background activity. In contrast, ¹²⁴I-IAZG imaging was optimal when performed at 24–48 h p.i., when the whole-body background had dissipated considerably. As a result, the ¹²⁴I-IAZG images at 24–48 h p.i. had higher tumor to whole-body activity contrast than the ¹⁸F-FMISO images at 3–6 h p.i. Region-of-interest analysis was performed as a function of time p.i. and indicated a tumor uptake of 5–10% (of total-body activity) for FMISO at 3–6 h p.i., and of ~17% for IAZG at 48 h p.i. This was corroborated by biodistribution data in that the tumor-to-normal tissue (T/N, normal tissues of blood, heart, lung, liver, spleen, kidney, intestine, and muscle) activity ratios of IAZG at 24 h p.i. was 1.5–2 times higher than those of FMISO at 3 h p.i., with the exception of stomach. Statistical analysis indicated that these differences in T/N ratios were significant. The small tumors were visualized in the ¹⁸F-FDG images, but not in the ¹²⁴I-IAZG or ¹⁸F-FMISO images. This was perhaps due to the combined effect of a smaller tumor volume and a lower hypoxic fraction. Oxylite probe measurement indicated a lesser proportion of regions with pO₂<2.5 mmHg in the small tumors (e.g., pO₂ was <2.5 mmHg in 28% and 67% of the data in small and large FSaII tumors, respectively), and the biodistribution data showed lower uptake of the tracers in the small tumors than in the large tumors. In the first study of its kind, using serial microPET imaging in conjunction with biodistribution analysis and direct probe measurements of local pO₂ to evaluate tumor hypoxia markers, we have provided data showing the potential of ¹²⁴I-IAZG for hypoxia imaging.     

Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation.

We showed previously that, in vitro, copper-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concentration (pO2). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO2 dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO2. METHODS: Experiments were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO2. Using PET and electronic autoradiography, Cu-ATSM uptake was measured in tumor tissue under various pO2 levels. The oxygen concentration within implanted tumors was manipulated by chemical means or by altering the inhaled oxygen content. RESULTS: A good correlation between low pO2 and high Cu-ATSM accumulation was observed. Hydralazine administration in animals caused a decrease in the average tumor pO2 from 28.61 +/- 8.74 mm Hg to 20.81 +/- 7.54 mm Hg in untreated control animals breathing atmospheric oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the average tumor pO2 increased to 45.88 +/-15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time-activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues. CONCLUSION: These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO2, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.     

Copper-64-diacetyl-bis (N4-methylthiosemicarbazone) accumulates in rich regions of CD133+ highly tumorigenic cells in mouse colon carcinoma

Introduction⁶⁴Cu-diacetyl-bis (N⁴-methylthiosemicarbazone) (⁶⁴Cu-ATSM) is a potential imaging agent of hypoxic tumor for use with PET. Recent literature demonstrated that cancer cells expressing CD133, which is a frequently used marker for so-called cancer stem cells or cancer stem cell-like cells (collectively referred to here as CSCs), contribute to tumor's therapeutic resistance and metastasis ability. Culturing under hypoxia is also reported to enlarge the proportion of CD133⁺ cells, which would indicate survival advantage of CD133⁺ cells under hypoxia. Here, we investigated the relationships between ⁶⁴Cu-ATSM accumulation and existence of CD133⁺ cells using mouse colon carcinoma (colon-26) tumor.MethodsIntratumor distribution of ⁶⁴Cu-ATSM and ¹⁸F-fluorodeoxyglucose (¹⁸FDG) was compared with immunohistochemical staining for CD133 with a colon-26 model. In vitro characterization of CD133⁺ colon-26 cells was also performed.ResultsIn colon-26 tumors, ⁶⁴Cu-ATSM localized preferentially in regions with a high density of CD133⁺ cells. The percentage of CD133⁺ cells was 11-fold higher in ⁶⁴Cu-ATSM high-uptake regions compared with ¹⁸FDG high- (but ⁶⁴Cu-ATSM low-) uptake regions. CD133⁺ colon-26 cells showed characteristics previously linked with CSCs in other cancer cell lines, such as high colony-forming ability, high tumor-initiating ability and enrichment under hypoxic cultivation. The proportion of CD133⁺ cells was enlarged by culturing under glucose starvation as well as hypoxia, and ⁶⁴Cu-ATSM uptake was increased under such conditions.ConclusionsOur findings showed that, in colon-26 tumors, ⁶⁴Cu-ATSM accumulates in rich regions of CD133⁺ cells with characteristics of CSCs. Therefore ⁶⁴Cu-ATSM could be a potential imaging agent for rich regions of CD133⁺ cells, associated with CSCs, within tumors.     

Uptake of FDG (2-fluoro-2-deoxy-D-glucose) as a tumor imaging agent into erythrocytes and accumulation of FDG in tumor cells

Fluorine-18-2-fluoro-2-deoxy-D-glucose (18F-FDG) injectable was developed as a tumor imaging agent reflecting glucose metabolism. In membrane transportation studies, the uptake of 14C-FDG into erythrocytes decreased with an increase in glucose concentration, and Cytochalasin B, inhibitor of glucose transporter (GLUT), blocked the uptake about 75%. The results means FDG is transported into tumor cells mainly by GLUT as glucose analogues. 18F-FDG is recognized to be phosphorylated to 18F-FDG-6-phosphate with hexokinase. We found that FDG-6-phosphate was further isomerized to 18F-FDM-6-phosphate by phosphoglucose isomerase (PGI) in vitro. About 27% 18F-FDM-6-phosphate was generated at the reaction with 70 U PGI for 90 min. These results show that the 18F-FDG injectable manufactured by the commercial supply system has equivalent properties; membrane transportation characteristic and enzyme affinity, to FDG synthesized at each PET institution.     

Investigating temporal fluctuations in tumor vasculature with combined carbogen and ultrasmall superparamagnetic iron oxide particle (CUSPIO) imaging

A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R₂* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ΔR₂*_carbogen followed by positive ΔR₂*_USPIO with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ΔR₂*_carbogen but no significant ΔR₂*_USPIO were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining ΔR₂*_carbogen and ΔR₂*_USPIO with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture. Magn Reson Med 66:227–234, 2011. © 2011 Wiley‐Liss, Inc.     

Feasibility studies of 4'-[methyl-(11)C]thiothymidine as a tumor proliferation imaging agent in mice

This study reports on the radiosynthesis and feasibility studies of 4'-[methyl-(11)C]thiothymidine ([methyl-(11)C]S-dThd) as a tumor proliferation imaging agent. [Methyl-(11)C]S-dThd was synthesized by rapid methylation of corresponding 5-trimethylstannyl- or 5-tributylstannyl-precursor via a palladium-promoted Stille cross-coupling reaction with [(11)C]methyl iodide. The decay-corrected radiochemical yields of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor based on [(11)C]CO(2) were 18.9% and 14.5%, respectively. The radiochemical purity of [methyl-(11)C]S-dThd was always greater than 99%. The specific activities of [methyl-(11)C]S-dThd synthesized by the corresponding 5-trimethylstannyl-precursor and 5-tributylstannyl-precursor were 47 GBq/mumol and 121 GBq/mumol, respectively, at the end of the synthesis. The total synthesis time was 30 min after the end of bombardment. The comparison between in vivo distribution of [methyl-(14)C]S-dThd and that of [methyl-(3)H]FLT showed that tracer uptake was comparable in nonproliferating tissues. In contrast, [methyl-(14)C]S-dThd showed significantly higher uptake in proliferating tissues than did [methyl-(3)H]FLT. [Methyl-(11)C]S-dThd uptake levels in five different tumor tissues were well correlated with the DNA synthesis levels determined by [2-(14)C]thymidine DNA incorporation. At 30 min after injection, plasma analysis found 95% of the activity in unmetabolized form. The microPET imaging of the C6 glioma xenograft showed significantly high uptake in the tumor and urinary bladder, followed by the intestine and marrow. Our results demonstrated that the tumor uptake of [methyl-(11)C]S-dThd was higher than that of [methyl-(3)H]FLT and was well correlated with the DNA synthesis level. Consequently, 4'-[methyl-(11)C]thiothymidine has promise for the imaging of tumor cell proliferation by positron emission tomography.     

Tumor hypoxia and microscopic diffusion capacity in brain tumors: A comparison of 62Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) PET/CT and diffusion-weighted MR imaging

Objectives

The aim of this study was to clarify the relationship between tumor hypoxia and microscopic diffusion capacity in primary brain tumors using ⁶²Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) (⁶²Cu-ATSM) PET/CT and diffusion-weighted MR imaging (DWI).

Methods

This study was approved by the institutional human research committee and was HIPAA compliant, and informed consent was obtained from all patients. ⁶²Cu-ATSM PET/CT and DWI were performed in a total of 40 primary brain tumors of 34 patients with low grade glioma (LGG, n?=?13), glioblastoma (GBM, n?=?20), and primary central nervous system lymphoma (PCNSL, n?=?7). ⁶²Cu-ATSM PET/CT parameters and apparent diffusion coefficient (ADC) obtained by DWI were compared.

Results

High intensity signals by ⁶²Cu-ATSM PET/CT and DWI in patients with GBM and PCNSL, and low intensity signals in LGG patients were observed. An inverse correlation was found between maximum SUV (SUV_max) and minimum ADC (ADC_min) (r?=??0.583, p?<?0.0001), and between tumor/brain ratio (T/B_ratio) and ADC_min for all tumors (r?=??0.532, p?<?0.0001). Both SUV_max and T/B_ratio in GBM were higher than LGG (p?<?0.0001 and p?<?0.0001), and those in PCNSL were also higher than GBM (p?=?0.033 and p?=?0.044). The ADC_min was lower in GBM (p?=?0.011) and PCNSL (p?=?0.01) than in LGG, while no significant difference was found between GBM and PCNSL (p?=?0.90).

Conclusion

Tumor hypoxia assessed by ⁶²Cu-ATSM PET/CT correlated with microscopic diffusion capacity obtained by DWI in brain tumors. Both ⁶²Cu-ATSM PET/CT and DWI were considered feasible imaging methods for grading glioma. However, ⁶²Cu-ATSM PET/CT provided additional diagnostic information to differentiate between GBM and PCNSL.     

Prognostic implications of <Superscript>62</Superscript>Cu-diacetyl-bis (<Emphasis Type="Italic">N</Emphasis><Superscript>4</Superscript>-methylthiosemicarbazone) PET/CT in patients with glioma

Objective

The potential of positron emission tomography/computed tomography using ⁶²Cu-diacetyl-bis (N⁴-methylthiosemicarbazone) (⁶²Cu-ATSM PET/CT), which was originally developed as a hypoxic tracer, to predict therapeutic resistance and prognosis has been reported in various cancers. Our purpose was to investigate prognostic value of ⁶²Cu-ATSM PET/CT in patients with glioma, compared to PET/CT using 2-deoxy-2-[¹⁸F]fluoro-d-glucose (¹⁸F-FDG).

Method

56 patients with glioma of World Health Organization grade 2–4 were enrolled. All participants had undergone both ⁶²Cu-ATSM PET/CT and ¹⁸F-FDG PET/CT within mean 33.5 days prior to treatment. Maximum standardized uptake value and tumor/background ratio were calculated within areas of increased radiotracer uptake. The prognostic significance for progression-free survival and overall survival were assessed by log-rank test and Cox’s proportional hazards model.

Results

Disease progression and death were confirmed in 37 and 27 patients in follow-up periods, respectively. In univariate analysis, there was significant difference of both progression-free survival and overall survival in age, tumor grade, history of chemoradiotherapy, maximum standardized uptake value and tumor/background ratio calculated using ⁶²Cu-ATSM PET/CT. Multivariate analysis revealed that maximum standardized uptake value calculated using ⁶²Cu-ATSM PET/CT was an independent predictor of both progression-free survival and overall survival (p?<?0.05). In a subgroup analysis including patients of grade 4 glioma, only the maximum standardized uptake values calculated using ⁶²Cu-ATSM PET/CT showed significant difference of progression-free survival (p?<?0.05).

Conclusions

⁶²Cu-ATSM PET/CT is a more promising imaging method to predict prognosis of patients with glioma compared to ¹⁸F-FDG PET/CT.

     

~(99)Tc~m-BPHA的肾排泄机制研究及肾功能显像

目的　探讨99Tcm 二胺乙基丙二胺六乙酸 (BPHA)的肾排泄机制及临床应用的可能性。方法　用丙磺舒抑制实验确定99Tcm BPHA的肾排泄机制 ;用γ射线测量装置测量一定时间内99Tcm BPHA在动物体内的残存率 ;用γ相机对家兔和正常人进行肾动态显像 ;同时进行99Tcm BPHA和99Tcm DTPA的对比研究。结果　99Tcm BPHA和99Tcm DTPA生物学性能相似 ,为肾小球滤过型显像剂。2 4h后99Tcm BPHA体内残留极少。对家兔和人的显像表明 ,肾显影清晰 ,排泄迅速。结论　自行研制的99Tcm BPHA为一种可满足临床要求的肾小球滤过型显像剂 ,可望替代99Tcm DTPA。     

放射性药物99mTc-HL91在实验性小鼠G422移植性脑胶质瘤模型的研究

目的 利用实验性小鼠G422移植性脑胶质瘤模型, 进行^99mTc- HL91体内分布和乏氧显像研究, 以探讨其在脑肿瘤诊断中应用的可能性。方法 6只模型小鼠分别于注射^99mTc- HL91后即刻、1、2、3、4、6、7、8小时行全身静态后位平面显像。于注射后4、8小时各处死3只。取血, 并剥离脏器及肿瘤组织, 称重, 测量放射性计数, 计算不同时相肿瘤与血液和各脏器的单位重量放射性比值。在全身静态平面显像图上, 利用感兴趣区技术, 分别计算不同时相肿瘤与头部(T/H)、对侧相应部位(T/A)、胸部(T/C)放射性比值。结果 注射^99mTc- HL91后自1小时起, 肿瘤部位放射性增高, 显影清晰;2小时更为明显, 3小时后较2小时变化不大。2小时T/H、T/A、T/C放射性比值分别是2.93±0.51、4.86±0.79、2.00±0.35, 与即刻及1小时比较差异均有显着性(P<0.05～P<0.01).体外测量肿瘤/血液、肌肉、脑及胸部脏器单位重量放射性比值较高, 肿瘤/腹部脏器单位重量放射性比值较低。结论 ^99mTc- HL91在移植性小鼠脑胶质瘤瘤组织中滞留增加, 清除延缓。进行乏氧显像以注射后2小时为宜。且仅适用于头颈部、胸部、骨骼及软组织肿瘤,而不能用于腹部肿瘤。