正电子发射断层成像/CT观察健康人空腹时不同器官对~(18)F脱氧葡萄糖的摄取

背景:既往国内外研究中,主要针对肿瘤患者体内葡萄糖的摄取情况,而关于正常人在空腹状态下不同器官对葡萄糖的摄取作用研究很少。目的:正电子发射断层成像/CT观察健康人在空腹状态下不同器官对18F脱氧葡萄糖的摄取情况,分析空腹时脑、肝、肾、心脏和骨骼肌组织在糖代谢中的相关性。方法:31例健康成年人空腹抽血测肝肾功能、血糖和血脂,并行正电子发射断层成像/CT检查,测脑、心脏、肝、肾脏和骨骼肌的18F脱氧葡萄糖的平均标准摄入值以及最大标准摄入值。结果与结论:空腹时脑皮质18F脱氧葡萄糖的平均标准摄入值约是心脏和肾脏的两三倍,是肝脏的4倍左右,是骨骼肌的15倍。肝脏平均标准摄入值与肾脏和骨骼肌的平均标准摄入值呈显著正相关(r=0.406,0.391,P=0.023,0.030),但肝脏的平均标准摄入值与心和脑的平均标准摄入值无相关性。结果提示空腹状态下脑组织对葡萄糖摄取最多,骨骼肌最少,心脏、肝脏和肾脏居中;空腹状态下肝脏与肾脏和骨骼肌之间对葡萄糖的代谢存在显著相关性。     

Altered dopamine D2 receptor binding in atypical facial pain

Animal studies suggest that the dopaminergic system plays a role in central pain modulation. We have previously demonstrated with positron emission tomography (PET) that striatal dopaminergic hypofunction may be involved in the burning mouth syndrome. The aim of the present study was to evaluate the nigrostriatal dopaminergic system in patients with atypical facial pain using PET. In seven patients with atypical facial pain, striatal presynaptic dopaminergic function was assessed with [18F]FDOPA and dopamine D1 and D2 receptor availabilities with [11C]NNC 756 and [11C]raclopride, respectively. The results were compared with those of healthy controls. A quantitative region-of-interest analysis showed that the uptakes of [18F]FDOPA and [11C]NNC 756 did not differ between patients and controls. There was a tendency of increased D2 receptor availability in the left putamen (P=0.056), and the D1/D2 ratio in the putamen was decreased bilaterally by 7.7% (P=0.002) in patients when compared to controls. In a voxel-based analysis, the uptake of [11C]raclopride was increased in the left putamen (P=0.025). In conclusion, the increase in D2 receptor availability in the left putamen and the decrease in D1/D2 ratio imply that alterations in the striatal dopaminergic system as evaluated by PET may be involved in chronic orofacial pain conditions.     

[<Superscript>11</Superscript>C] Acetoacetate Utilization by Breast and Prostate Tumors: a PET and Biodistribution Study in Mice

PURPOSE: A significant positive correlation has been observed between ketone body availability and their uptake by tumor cells. Our objective was to evaluate [11C]acetoacetate as a potential tracer of ketone body utilization by breast and prostate tumors and to compare it with [11C]acetate. METHODS: Biodistribution studies were performed with [11C]acetoacetate and [11C]acetate in mice bearing breast or prostate tumors. The percentage of the injected dose accumulated per gram of tissue was determined. These results were complemented by dynamic positron emission tomography (PET) imaging of the radiotracer uptake and dosimetry calculations. RESULTS: [11C]Acetoacetate uptake was optimal between 5 and 30 min, with maximal uptake of 2.72, 2.42, 2.54, and 2.19% injected dose (%ID)/g for MC7-L1, MC4-L2, PC3, and LN-CaP tumors respectively. Tumor retention for [11C]acetoacetate tended to be higher than [11C]acetate, but this did not reach statistical significance. [11C]Acetate uptake was reached within 15 min with optimal uptake of 1.25, 2.30, and 0.96%ID/g for MC7-L1, MC4-L2, and PC-3 tumors, respectively. CONCLUSIONS: We observed a moderate uptake of [11C]acetoacetate in breast and prostate tumors with low background activity due to rapid elimination of this tracer. Further studies are warranted to determine if this tracer can detect slow-growing breast and prostate cancers in the clinical setting.     

Effects of a Ketogenic Diet on [18F]FDG-PET Imaging in a Mouse Model of Lung Cancer

Purpose

Myocardial uptake can hamper visualization of lung tumors, atherosclerotic plaques, and inflammatory diseases in 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) studies because it leads to spillover in adjacent structures. Several preparatory pre-imaging protocols (including dietary restrictions and drugs) have been proposed to decrease physiological [¹⁸F]FDG uptake by the heart, although their effect on tumor glucose metabolism remains largely unknown. The objective of this study was to assess the effects of a ketogenic diet (as an alternative protocol to fasting) on tumor glucose metabolism assessed by [¹⁸F]FDG positron emission tomography (PET) in a mouse model of lung cancer.

Procedures

PET scans were performed 60 min after injection of 18.5 MBq of [¹⁸F]FDG. PET data were collected for 45 min, and an x-ray computed tomograph (CT) image was acquired after the PET scan. A PET/CT study was obtained for each mouse after fasting and after the ketogenic diet. Quantitative data were obtained from regions of interest in the left ventricular myocardium and lung tumor.

Results

Three days on a ketogenic diet decreased mean standard uptake value (SUVmean) in the myocardium (SUVmean 0.95?±?0.36) more than one night of fasting (SUVmean 1.64?±?0.93). Tumor uptake did not change under either dietary condition.

Conclusions

These results show that 3 days on high-fat diets prior to [¹⁸F]FDG-PET imaging does not change tumor glucose metabolism compared with one night of fasting, although high-fat diets suppress myocardial [¹⁸F]FDG uptake better than fasting.

     

Analysis of adrenal masses by 18F-FDG positron emission tomography scanning

This study aimed to analyse the characteristics of adrenal masses visible in the computerised tomography (CT) scans which have been also evaluated by 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), and to characterise the features of 18F-FDG PET scans associated with various adrenal endocrine tumours, especially benign functional tumours. 18F-FDG PET scans of 105 patients with adrenal masses on the CT scan were analysed. Positive uptakes in the 18F-FDG PET scans were seen in 60 malignant tumours (54 metastasic lesions, six primary adrenal cancers) and seven benign tumours. The positive predictive value of 18F-FDG PET imaging to characterise an adrenal mass as a malignant tumour was 90%; the corresponding negative predictive value to rule out malignancy was also 90%. Benign adrenal tumours were smaller than that of malignant lesions (p<0.05). The mean standardised uptake value max (SUVmax) of the metastatic lesions [8.4+/-6.5 (microCi/g)/microCi/kg] was significantly higher than that of the benign adrenal tumours [2.4+/-1.2 (microCi/g)/microCi/kg, p<0.001]. Examination of only the primary adrenal lesions revealed that all adrenocortical carcinomas, two of three cases of pheochromocytomas, three of five neuroblastomas and two of four cases of primary aldosteronism showed positive 18F-FDG uptake. In conclusion, for patients presenting adrenal masses with a high probability of malignancy, 18F-FDG PET can be used to differentiate malignant from benign adrenal lesions. However, the 18F-FDG PET uptake did not show an always consistent pattern for endocrine tumours, which was probably due to the variability inherent in 18F-FDG uptake. This study suggests that 18F-FDG PET scanning can offer supporting data to localise and characterise adrenal tumours.     

Comparison of an 18F labeled derivative of vasoactive intestinal peptide and 2-deoxy-2-[18F]fluoro-D-glucose in nude mice bearing breast cancer xenografts.

PURPOSE: A 18fluorine-labeled derivative of vasoactive intestinal peptide [18F- Arg,Arg VIP(18F-dVIP)] was evaluated as a potential imaging agent for breast cancer by comparison with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) using standard ex vivo determinations and small animal position emission tomography (PET) imaging. PROCEDURES: Human breast carcinomas, T-47D and MDA-MB231, tumor-bearing nude mice were injected intravenously with 18F-dVIP or FDG for imaging and/or biodistribution (ex vivo) determined by gamma counting. RESULTS: FDG had two- to three-fold greater tumor accumulation and target-to-non target contrast relative to 18F-dVIP. VIP receptors were detected in both tumor types but in low concentrations (<15,000 receptors/cell) consistent with lower uptakes. FDG was cleared rapidly from non-target tissues while 18F-dVIP cleared into the kidneys. CONCLUSIONS: 18F-dVIP uptake in mice T-47D tumors and kidneys determined by imaging correlated with values determined by ex vivo counting suggesting that tumor and other tissue uptakes can be quantified by in vivo positron projection imaging.     

Reproducibility of common semi-quantitative parameters for evaluating lung cancer glucose metabolism with positron emission tomography using 2-deoxy-2-[18F]fluoro-D-glucose.

PURPOSE: Positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been used for various cancers, but reproducibility of common utilized semi-quantitative parameters, such as the maximal single pixel standardized uptake value (SUV) and effective glycolytic volume (EGV), remains unknown. Knowledge of precision is essential for applying these parameters to treatment monitoring. The purpose of this investigation was to assess the precision of PET results obtained by repeated examinations of patients with untreated lung cancer. PATIENTS AND METHODS: Ten patients with lung cancer underwent two PET examinations within a week with no intervening treatment. The reproducibility of three parameters:((1) maximal SUV of 1 x 1 pixel anywhere in the tumor, calculated on the basis of predicted lean body mass [SULmax]; (2) highest average SUV at 4 x 4 pixels in the tumor adjusted by predicted lean body mass [SULmean]; and (3) EGV calculated by multiplying SUL by tumor volume), using PET images obtained at 50-60 min post-injection, were examined. Plasma glucose, insulin and free fatty acid levels were also monitored. RESULTS: The SULmax, SULmean, and EGV were measured with a mean +/- S.D. difference of 11.3% +/- 8.0, 10.1% +/- 8.2, and 10.1% +/- 8.0%, respectively. By multiplying SUL by plasma glucose concentration, the mean differences were slightly reduced to 7.2% +/- 5.8, 6.7% +/- 6.2, and 9.5% +/- 8.2, respectively. CONCLUSION: These data indicate that commonly used semi-quantitative indices of glucose metabolism on PET show high reproducibly. This supports their use in sequential quantitative analysis in PET, such as in treatment response monitoring.     

Investigating the Existence of Quantum Metabolic Values in Non-Hodgkin’s Lymphoma by 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography

Objectives To investigate the existence of quantum metabolic values in various subtypes of non-Hodgkin’s lymphoma (NHL). Methods Fifty-eight patients with newly diagnosed NHL and positron emission tomography (PET) performed within three months of biopsy were included. The standardized uptake value (SUV) from PET over the area of biopsy and serum glucose [Glc] were recorded. The group glucose sensitivity(G) for indolent and aggressive NHL was obtained by linear regression with ln(SUV) = G·ln[Glc] + C, where C is a constant for the group. Finally, the individual’s glucose sensitivity (g) was obtained by g = {ln(SUV)-C}/ln[Glc], along with their means in various subtypes of NHL. To further investigate the influence of extreme [Glc] conditions, the SUVs corrected by the individually calculated g at various glucose levels, [Glc′] using SUV′ =SUV·{[Glc′]/[Glc]} ^g , were compared to the original SUVs for both indolent and aggressive NHL. Results The averaged g (=G) for aggressive was significant different from that for indolent NHL (−0.94 ± 0.51 vs. +0.13 ± 0.10, respectively, p < 0.00005). There were significant differences in SUV for [Glc] < 80 or >110 mg/dl for both types of NHL. Unlike overlap among SUVs between NHL subtypes, the g value clearly categorized them into two distinct groups with positive (near-zero) and negative g values (around −1) for the indolent and aggressive NHLs, respectively. Conclusions Distinct quantum metabolic values of −1 and 0 were noted in NHL. Aggressive NHL has a more negative value (or higher glucose sensitivity) than that of indolent and, thus, is more susceptible to extreme glucose variation.     

Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration

OBJECTIVE: An elevated C3 concentration has been reported in people with obesity, type 2 diabetes, hypertension, and dyslipidemia, and has been proposed to play a role in the development of atherosclerosis. We hypothesized that an elevated C3 concentration might be linked to insulin resistance and/or hyperinsulinemia, abnormalities commonly observed in association with the above conditions. RESEARCH DESIGN AND METHODS: Fasting concentrations of C3 and acylation stimulating protein (ASP, C3adesarg), a cleavage product of C3 recently found to stimulate glucose uptake in vitro, were measured in 33 healthy nondiabetic Pima Indians (14 women and 19 men; age 27 +/- 1 and body fat 33 +/- 1%, means +/- SEM). Subjects were characterized for body composition dual-energy X-ray absorptiometry, insulin action (insulin-stimulated glucose disposal [M], hyperinsulinemic glucose clamp), and glucose tolerance (75-g oral glucose tolerance test). RESULTS: Fasting C3 and ASP concentrations were positively correlated (r = 0.43, P < 0.05). Fasting C3 concentration was closely related to percent body fat (r = 0.77), M (r = -0.75), and fasting insulin concentration (r = 0.72) (all P < 0.0001). Fasting C3 concentrations remained significantly related to M and fasting insulin after adjusting for percent body fat (partial r = -0.53 and 0.33, both P < 0.05). In subjects with impaired glucose tolerance, fasting C3 concentrations were higher than in those with normal glucose tolerance--a difference that remained after adjustment for percent body fat and M. We found that fasting ASP concentrations were significantly related to percent body fat (r = 0.37, P < 0.05), but not to M or fasting insulin. CONCLUSIONS: In Pima Indians, fasting C3 concentration is closely related to adiposity, insulin action, and fasting insulin levels and may thus be a mediator for the postulated link between obesity, insulin resistance, hyperinsulinemia, and possibly atherosclerosis.     

新诊断2型糖尿病患者血糖波动与胰岛细胞功能的关系

目的：探讨新诊断2型糖尿病患者血糖波动与胰岛细胞功能的关系。方法分析51例新诊断2型糖尿病患者的临床资料,血糖波动采用OGTT 1 h与OGTT 0 h差值（GLU1）、OGTT 2 h与OGTT 0 h差值（GLU2）表示。胰岛细胞功能采用空腹血清胰岛素、空腹血清C肽、稳态模式评估法的胰岛素分泌指数（HOMA-β）及胰岛素抵抗指数（HOMA-IR）表示。分析患者血糖波动情况,即GLU1、GLU2与空腹血清胰岛素、空腹血清C肽、HOMA-β、HOMA-IR的相关性。结果该组患者的GLU1为（7.84±2.31）mmol/L,GLU2为（7.4±2.7）mmol/L,空腹血清胰岛素为（13.8±6.0）mU/L,空腹血清C肽为（0.85±0.26）nmol/L,HOMA-β的对数值为4.10±0.64,HOMA-IR的对数值为1.43±0.54。GLU1、GLU2与空腹血清胰岛素、空腹血清C肽、HOMA-IR的对数无相关性（P均＞0.05）,但与HOMA-β的对数值呈负相关（r值分别为-0.344、-0.498,P均＜0.05）。结论新诊断2型糖尿病患者血糖波动可能与胰岛素分泌缺陷密切相关。     

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 “A” allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.     

The Effects of Anesthetic Agent and Carrier Gas on Blood Glucose and Tissue Uptake in Mice Undergoing Dynamic FDG-PET Imaging: Sevoflurane and Isoflurane Compared in Air and in Oxygen

PURPOSE: We sought to identify an anesthetic regime that, unlike isoflurane in air, would maintain glucose homeostasis in mice undergoing Positron emission tomography (PET) imaging with 2-deoxy-2-[18F]fluoro-D: -glucose (FDG). MATERIALS AND METHODS: FDG uptake was also measured in normal and tumor tissues. Athymic and Balb/c nude mice were studied. Blood glucose levels were measured before and after 30 min of FDG PET imaging under isoflurane or sevoflurane carried in air or oxygen. FDG uptake was quantified as a percentage of the injected dose and using Patlak analysis yielding Ki values. RESULTS: Blood glucose levels were more stable under sevoflurane than under isoflurane, especially in the athymic nude mice. Under isoflurane, FDG uptake into myocardium was higher than under sevoflurane and was strongly correlated with the intrascan change in blood glucose. CONCLUSION: Sevoflurane should be preferred for physiologic imaging in mice, minimizing changes in glucose and, for FDG PET, reducing signal spillover from the myocardium.     

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [<Superscript>18</Superscript>F]FDG PET and acidoCEST MRI

Purpose

We sought to determine if the synergy between evaluations of glucose uptake in tumors and extracellular tumor acidosis measured with simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) can improve longitudinal evaluations of the response to metformin treatment.

Procedures

A standard 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) PET protocol that evaluates glucose uptake in tumors, and a standard acidoCEST MRI protocol that measures extracellular pH (pHe) in tumors, were simultaneously performed to assess eight vehicle-treated (control) mice and eight metformin-treated mice 1 day before treatment, 1 day after initiating daily treatment with metformin, and 7 days after initiating treatment. Longitudinal changes in SUV_max and extracellular pH (pHe) were evaluated for each treatment group, and differences in SUV_max and pHe between metformin-treated and control groups were also evaluated.

Results

MRI acquisition protocols had little effect on the PET count rate, and the PET instrumentation had little effect on image contrast during acidoCEST MRI, verifying that [¹⁸F]FDG PET and acidoCEST MRI can be performed simultaneously. The average SUV_max of the tumor model had a significant decrease after 7 days of treatment with metformin, as expected. The average tumor pHe decreased after 7 days of metformin treatment, which reflected the inhibition of the consumption of cytosolic lactic acid caused by metformin. However, the average SUV_max of the tumor model was not significantly different between the metformin-treated and control groups after 7 days of treatment, and average pHe was also not significantly different between these groups. For comparison, the combination of average SUV_max and pHe measurements significantly differed between the treatment group and control group on Day 7.

Conclusions

[¹⁸F]FDG PET and acidoCEST MRI studies can be performed simultaneously. The synergistic combination of assessing glucose uptake and tumor acidosis can improve differentiation of a drug-treated group from a control group during drug treatment of a tumor model.

     

Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c)

OBJECTIVE: The exact contributions of postprandial and fasting glucose increments to overall hyperglycemia remain controversial. The discrepancies between the data published previously might be caused by the interference of several factors. To test the effect of overall glycemic control itself, we analyzed the diurnal glycemic profiles of type 2 diabetic patients investigated at different levels of HbA(1c). RESEARCH DESIGN AND METHODS: In 290 non-insulin- and non-acarbose-using patients with type 2 diabetes, plasma glucose (PG) concentrations were determined at fasting (8:00 A.M.) and during postprandial and postabsorptive periods (at 11:00 A.M., 2:00 P.M., and 5:00 P.M.). The areas under the curve above fasting PG concentrations (AUC(1)) and >6.1 mmol/l (AUC(2)) were calculated for further evaluation of the relative contributions of postprandial (AUC(1)/AUC(2), %) and fasting [(AUC(2) - AUC(1))/AUC(2), %] PG increments to the overall diurnal hyperglycemia. The data were compared over quintiles of HbA(1c). RESULTS: The relative contribution of postprandial glucose decreased progressively from the lowest (69.7%) to the highest quintile of HbA(1c) (30.5%, P < 0.001), whereas the relative contribution of fasting glucose increased gradually with increasing levels of HbA(1c): 30.3% in the lowest vs. 69.5% in the highest quintile (P < 0.001). CONCLUSIONS: The relative contribution of postprandial glucose excursions is predominant in fairly controlled patients, whereas the contribution of fasting hyperglycemia increases gradually with diabetes worsening. These results could therefore provide a unifying explanation for the discrepancies as observed in previous studies.     

Alcohol intake and incidence of type 2 diabetes in men

OBJECTIVE: To evaluate the relation between alcohol intake and incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS: This prospective study included 8,663 men with fasting plasma glucose measurements from at least two medical examinations. Alcohol intake was classified into five groups: nondrinkers and four quartiles (Qs) of drinkers according to the amount of alcohol intake. Type 2 diabetes was diagnosed by 1997 American Diabetes Association criteria. RESULTS: There were 149 incident cases of type 2 diabetes during 52,588 person-years of follow-up. There was a U-shaped association between alcohol intake and diabetes, with the lowest incidence of diabetes at Q2 (61.9-122.7 g/week). As compared with Q2, men in Q3 and Q4 had a 2.2- (95% CI 1.2-3.9, P = 0.01) and 2.4-fold (1.4-4.4, P<0.01) risk of developing diabetes, while nondrinkers and men in Q1 had 1.8- (1.0-3.3, P<0.05) and 1.4-fold (0.7-2.6, P = 0.34) higher risk of diabetes, respectively. These associations persisted after adjustment for age, fasting plasma glucose, smoking, BMI, blood pressure, serum triglyceride concentration, cardiorespiratory fitness, HDL cholesterol, waist circumference, and parental diabetes. CONCLUSIONS: We observed an elevated risk of developing type 2 diabetes in nondrinkers and men with high alcohol intakes, when compared with men who reported moderate alcohol intake. Men with a high alcohol intake may be able to reduce their risk of developing type 2 diabetes if they drink less.     

[<Superscript>18</Superscript>F]Fluorocholine PET/CT Imaging of Liver Cancer: Radiopathologic Correlation with Tissue Phospholipid Profiling

Purpose

[¹⁸F]fluorocholine PET/CT can detect hepatocellular carcinoma (HCC) based on imaging the initial steps of phosphatidylcholine synthesis. To relate the diagnostic performance of [¹⁸F]fluorocholine positron emission tomography (PET)/x-ray computed tomography (CT) to the phospholipid composition of liver tumors, radiopathologic correspondence was performed in patients with early-stage liver cancer who had undergone [¹⁸F]fluorocholine PET/CT before tumor resection.

Procedures

Tumor and adjacent liver were profiled by liquid chromatography mass spectrometry, quantifying phosphatidylcholine species by mass-to-charge ratio. For clinical-radiopathologic correlation, HCC profiles were reduced to two orthogonal principal component factors (PCF1 and PCF2) accounting for 80 % of total profile variation.

Results

Tissues from 31 HCC patients and 4 intrahepatic cholangiocarcinoma (ICC) patients were analyzed, revealing significantly higher levels of phosphocholine, CDP-choline, and highly saturated phosphatidylcholine species in HCC tumors relative to adjacent liver and ICC tumors. Significant loading values for PCF1 corresponded to phosphatidylcholines containing poly-unsaturated fatty acids while PCF2 corresponded only to highly saturated phosphatidylcholines. Only PCF2 correlated significantly with HCC tumor-to-liver [¹⁸F]fluorocholine uptake ratio (ρ = 0.59, p < 0.0005). Sensitivity for all tumors based on an abnormal [¹⁸F]fluorocholine uptake ratio was 93 % while sensitivity for HCC based on increased tumor [¹⁸F]fluorocholine uptake was 84 %, with lower levels of highly saturated phosphatidylcholines in tumors showing low [¹⁸F]fluorocholine uptake.

Conclusion

Most HCC tumors contain high levels of saturated phosphatidylcholines, supporting their dependence on de novo fatty acid metabolism for phospholipid membrane synthesis. While [¹⁸F]fluorocholine PET/CT can serve to identify these lipogenic tumors, its imperfect diagnostic sensitivity implies metabolic heterogeneity across HCC and a weaker lipogenic phenotype in some tumors.

     

不同胎龄和缺氧缺血性脑病新生儿脑18F-FDG PET 显像的临床研究

目的 对不同胎龄新生儿及新生儿缺氧缺血性脑病(HIE)患儿应用18 F-FDG PET 测定脑葡萄糖代谢,探讨PET 测定脑葡萄糖代谢在不同胎龄新生儿中的变化及HIE 中的临床应用价值.方法 研究对象包括不同胎龄新生儿及HIE 患儿,共计67 例,其中7 例因各种原因导致PET 数据采集失败未纳入统计,其余60 例新生儿纳入统计.其中,不同胎龄新生儿36 例,包括≤32 周4 例,33 ～34 周5 例,35 ～36 周12 例,≥37 周15 例;HIE 患儿24 例,包括轻度13 例,中度7 例,重度4 例.以RDSⅢ型回旋加速器获得18 F 后,通过自动化学合成装置制备18 F-FDG 溶液,在注射0.1 mCi/kg 18 F-FDG 后应用PET 成像仪采集数据,并通过测定新生儿脑不同部位的标准摄取值(standardized uptakevalues,SUV)进行脑葡萄糖代谢半定量分析.结果 比较不同胎龄新生儿18 F-FDG PET 脑显像,可见随着胎龄的成熟,新生儿脑葡萄糖活性呈现逐步增高的趋势,结构也变得较为清晰,尤其以胎龄达到足月新生儿标准(≥37 周)后更为显著.不同胎龄新生儿脑18 F-FDG PET 显像的结果显示:其葡萄糖代谢活性在大脑皮层普遍较低,在丘脑则较高,其次为小脑、感觉运动皮质、基底节.胎龄≥37 周的足月新生儿,其不同部位的葡萄糖代谢活性较胎龄＜32 周的早产儿显著增高(P ＜0.01).与胎龄≥37 周的足月新生儿相比,HIE 患儿18 F-FDG PET 脑显像在所有测定的脑组织均呈现低代谢状况(P ＜0.05),而且,病情越重越为明显,重度HIE 患儿脑葡萄糖代谢较轻、中度HIE 患儿显著降低(P ＜0.05).结论 随着胎龄的成熟,新生儿脑葡萄糖活性呈现逐步增高的趋势,结构也变得较为清晰,尤其以胎龄达到足月新生儿标准(≥37 周)后更为显著.HIE 患儿PET 脑显像存在明显18 F-FDG 代谢异常,且与病情严重程度相关.应用18 F-FDG PET 测定脑葡萄糖代谢为研究新生儿脑发育和损伤提供了新的方法,其临床意义值得进一步研究.     

2型糖尿病患者血糖水平及血糖变异性与糖化血红蛋白水平的相关性研究

目的探讨2型糖尿病患者血糖水平及血糖变异性与糖化血红蛋白(HbA1_c)的相关性。 方法选取2019年3月至2020年4月在克拉玛依市人民医院内分泌科就诊的240例2型糖尿病患者，根据HbA1_c水平，分为Q1组(5.5%～6.8%)(n＝60)、Q2组(6.9%～7.9%)(n＝55)、Q3组(8.0%～9.0%)(n＝62)和Q4组(9.1%～14.0%)(n＝63)；采用动态持续血糖监测系统(CGMS)进行连续72 h动态血糖监测，以HbA1_c为因变量，以与HbA1_c具有相关性的参数为自变量，采用多元线性回归方法进行回归分析。 结果Q1、Q2、Q3和Q4组的空腹及餐后2 h血糖分别为5.92(4.81，6.64)mmol/L和10.27(8.79，12.34)mmol/L，6.37(5.49，8.49)mmol/L和12.02(9.98，15.27)mmol/L，8.45(6.78，9.97)mmol/L和14.45(11.51，18.12)mmol/L，10.16(8.09，11.52)mmol/L和16.08(12.47，19.27)mmol/L，4组患者72 h动态血糖平均值分别为7.41(6.71，8.14)mmol/L，8.20(7.40，9.30)mmol/L，8.91(7.93，10.35)mmol/L和10.36(9.12，11.79)mmol/L，4组间的平均空腹血糖、餐后2 h血糖随HbA1_c的增高而增高，组间比较均差异有统计学意义(H＝81.35，37.26，均P<0.05)；空腹及餐后2 h血糖、72 h动态血糖平均值、血糖>10.0 mmol/L时间百分率、血糖>7.8 mmol/L时间百分率以及血糖平均标准差(SDBG)与HbA1_c具有相关性(r＝0.68，0.46，0.63，0.59，0.42，0.36，均P<0.05)；多元线性回归分析结果显示72 h动态血糖平均值和空腹血糖为HbA1_c的独立影响因素(B＝0.23，0.53；均P<0.05)。 结论血糖变异对HbA1_c无影响，空腹血糖和平均血糖为影响HbA1_c的主要因素。     

18F-FDG肿瘤显像中心肌显影的研究

目的:观察~(18)F-FDG肿瘤显像患者中心肌显影的现象及心肌摄取与血糖水平的关系。方法:行~(18)F-FDG肿瘤显像的患者110例,年龄30～87岁,平均64.12±11.53岁。所有患者均空腹显像,胸部采集数据经默认条件处理后观察心脏显影程度。按照心肌显影程度分为4级:1级心肌完全不显影,2级心影高于纵隔影仅少部分清晰,3级心影高于纵隔影少于1/2心室,4级心肌完整显影。结果:72例男性中,心肌完全不显影26例,部分显影17例,完全显影29例,分别占36%,24%,40%,女性38例中,心肌完全不显影23例,部分显影8例,完全显影7例,分别占61%,21%,18%。各组心肌显影程度与空腹血糖(P值均>0.05)无明显关系。结论:肿瘤患者葡萄糖代谢显像心肌显影的程度各不相同,提示肿瘤惠者心肌葡萄糖代谢的复杂性。     

Tyrosine Kinase Inhibitors Reduce Glucose Uptake by Binding to an Exofacial Site on hGLUT‐1: Influence on 18F‐FDG PET Uptake

Positron emission tomography (PET) using 2‐deoxy‐2‐[¹⁸F]fluoro‐d‐glucose ([¹⁸F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter‐1 (hGLUT‐1) in FaDu and GIST‐1 cells by measuring [³H]2‐deoxy‐d‐glucose ([³H]2‐DG) and [³H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [³H]2‐DG uptake. In GIST‐1 cells, [³H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H‐pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT‐1. We hypothesize that inhibition of hGLUT‐1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [¹⁸F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT‐1 inhibition by TKIs may have implications for routine [¹⁸F]FDG‐PET monitoring of tumor response in patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Human glucose transporter‐1 transports glucose and 18‐flurodexoyglucose (FDG) into cells where it gets phosphorylated and trapped. A retrospective study of blood glucose concentrations in diabetic and nondiabetic patients with cancer treated with dasatinib, imatinib, sorafenib, or sunitinib showed a statistically significant decrease in blood glucose levels.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Inhibition of glucose uptake was examined and tyrosine kinase inhibitors (TKIs) inhibited [³H]2‐DG and [³H]FDG uptake to varying extents and competitively. Molecular modeling studies confirmed TKI interaction with amino acid residues at glucose binding sites.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ We hypothesized that TKI inhibition of glucose uptake might lead to changes in tissue and blood glucose levels and might explain the hypo/hyperglycemia and fatigue observed in TKI‐treated patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Because FDG uptake is increasingly used as a marker of tumor response, these results indicate careful evaluation of [¹⁸F]FDG‐positron emission tomography tumor response monitoring during TKI treatment, and in clinical trials validating new TKI effectiveness.

Clinical decision making involves cancer treatment response monitoring to prevent ineffective therapy and resulting side effects. Positron emission tomography (PET) is used for monitoring treatment effectiveness. PET tracers 2‐deoxy‐2‐[¹⁸F]fluoro‐d‐glucose ([¹⁸F]FDG) and 3′‐deoxy‐3′‐[¹⁸F]fluorothymidine have been used for noninvasive detection of tumor energy metabolism and cell proliferation, respectively. The glucose analog [¹⁸F]‐FDG is the most widely used PET tracer for tumor staging and diagnosis, treatment response, and routine treatment monitoring. ¹ Human glucose transporter‐1 (hGLUT‐1) transports FDG, like glucose, into cells where it subsequently gets phosphorylated and trapped. ² Many small molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib and vandetanib, and lapatinib, targeted against epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and EGFR, and EGFR and Her‐2, respectively, have been developed. Multitargeted TKIs include sorafenib, axitinib, pazopanib, and sunitinib. TKIs targeting intracellular BCR‐ABL kinase of chronic myeloid leukemia include bosutinib, dasatinib, imatinib, nilotinib, and ponatinib. Multiple TKIs are used successfully for treatment of renal cell carcinoma, leukemia, gastrointestinal tumors, lung cancer, and several other malignancies. A retrospective study of blood glucose concentrations in diabetic and nondiabetic patients with cancer treated with dasatinib, imatinib, sorafenib, or sunitinib showed statistically significant decrease in blood glucose levels. ³ Many preclinical studies have investigated use of [¹⁸F]FDG PET imaging for TKI treatment monitoring, and some studies showed early changes in [¹⁸F]FDG levels while others did not. ⁴ Depending on the TKI used, accumulating evidence show either increased or decreased glucose levels in patients during TKI therapy, although dasatinib, erlotinib, sunitinib, and sorafenib were shown to lower glucose levels and improve glycemic control. ⁵ PET tracer uptake is complex and depends on tumor type, targeted kinase, and tracer uptake by tumors. In general, higher standardized uptake values have been correlated with poorer outcomes. ⁶ Solute carrier (SLC) transporters for sugars include SLC2 and SLC5 families, which regulate cellular concentrations of sugars. ⁷ , ⁸ hGLUT‐1, a widely distributed member of the facilitative SLC2 family, transports glucose down its concentration gradient. ⁹ XylE, a structurally characterized xylose transporter of E. coli, shows 65% sequence identity and 88% sequence similarity with hGLUT‐1. ¹⁰ Residues important for binding of d‐glucose (DG) in the crystal structure of XylE (although XylE does not transport dg) are conserved in hGLUT‐1 with the exception of Gln415, which is Asn411 in hGLUT‐1. Gln‐282 contributes to sugar binding in all conformations of hGLUT‐1 via hydrogen bonding. ¹¹ The sugar‐binding site is located at the interface of N‐terminal and C‐terminal domains. An earlier study showed competitive inhibition of glucose transport activity of hGLUT‐1 by flavones and isoflavones. ¹² WZB117, a polyphenol compound, inhibits erythrocyte 3‐O‐methylglucose uptake competitively by binding at the exofacial binding site. ¹³ We examined whether hGLUT‐1 activity is inhibited by TKIs targeted against EGFR, VEGFR, Her‐2, BCR‐ABL, MTK, MEK, and mTOR using [³H]2‐deoxy‐d‐glucose ([³H]2‐DG) and [³H]FDG uptake inhibition experiments in cultured FaDu and GIST‐1 cells to understand underlying mechanisms of TKI‐induced changes in glucose levels of TKI‐treated patients. TKI inhibition of hGLUT‐1 was tested further in competition experiments using one representative TKI from BCR‐ABL, EGFR, MTK, and mTOR TKIs. Reversibility of TKI inhibition of [³H]FDG uptake after removing TKIs was examined in GIST‐1 cells. Further evidence for TKI interactions with hGLUT‐1 glucose binding site was obtained by molecular modeling using three models of outward‐facing partly occluded conformation (models 1–3), one model of inward‐open conformation (model 4), and one model of fully open outward‐facing conformation (model 5).