Radiomic Analysis using Density Threshold for FDG-PET/CT-Based N-Staging in Lung Cancer Patients

Purpose

Mediastinal nodal (N)-staging done by integrated 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) in lung cancer patients is not always accurate. In order to reduce the need for invasive staging procedures, additional surrogate parameters for the detection of malignant lymph node infiltration would be helpful. The purpose of this study was to evaluate if radiomic semi-automated density profiling in mediastinal lymph nodes can improve preclinical N-staging, irrespective of the specific lung cancer entity.

Procedures

This retrospective study was approved by the institutional review board. Two hundred forty-eight histologically proven lymph nodes in 122 lung cancer patients were investigated. In malignantly infiltrated lymph nodes, the specific lung cancer entity was histologically classified; benign lymph nodes were histologically classified as benign. Non-contrast enhanced [¹⁸F]FDG-PET/CT was performed before surgery/biopsy. Lymph node analyses were performed on the basis of FDG uptake and volumetric CT histogram analysis for metric lymph node sampling.

Results

Of the 248 lymph nodes, 118 were benign, 130 malignant. Malignant lymph nodes had a significantly higher median CT density (32.4 Hounsfield units (HU) (min 5.4/max 77.5 HU)) compared to benign lymph nodes (9.3 HU (min ?49.5/max 60.4 HU, p?<?0.05), irrespective of the histological subtype. The discrimination between different malignant tumour subtypes by means of volumetric density analysis failed. Irrespective of the malignant subtype, a possible cutoff value of 20 HU may help differentiate between benign and malignant lymph nodes.

Conclusion

Density measurements in unclear mediastinal and hilar lymph nodes with equivocal FDG uptake in PET might serve as a possible surrogate parameter for N-staging in lung cancer patients, irrespective of the specific lung cancer subtype. This could also help to find possible high yield targets in cases where invasive lymph node staging is necessary.

     

Applying Amide Proton Transfer MR Imaging to Hybrid Brain PET/MR: Concordance with Gadolinium Enhancement and Added Value to [<Superscript>18</Superscript>F]FDG PET

Purpose

The purpose of this study is to evaluate the diagnostic concordance and metric correlations of amide proton transfer (APT) imaging with gadolinium-enhanced magnetic resonance imaging (MRI) and 2-deoxy-2-[¹⁸F-]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET), using hybrid brain PET/MRI.

Procedures

Twenty-one subjects underwent brain gadolinium-enhanced [¹⁸F]FDG PET/MRI prospectively. Imaging accuracy was compared between unenhanced MRI, MRI with enhancement, APT-weighted (APTW) images, and PET based on six diagnostic criteria. Among tumors, the McNemar test was further used for concordance assessment between gadolinium-enhanced imaging, APT imaging, and [¹⁸F]FDG PET. As well, the relation of metrics between APT imaging and PET was analyzed by the Pearson correlation analysis.

Results

APT imaging and gadolinium-enhanced MRI showed superior and similar diagnostic accuracy. APTW signal intensity and gadolinium enhancement were concordant in 19 tumors (100 %), while high [¹⁸F]FDG avidity was shown in only 12 (63.2 %). For the metrics from APT imaging and PET, there was significant correlation for 13 hypermetabolic tumors (P < 0.05) and no correlation for the remaining six [¹⁸F]FDG-avid tumors.

Conclusions

APT imaging can be used to increase diagnostic accuracy with no need to administer gadolinium chelates. APT imaging may provide an added value to [¹⁸F]FDG PET in the evaluation of tumor metabolic activity during brain PET/MR studies.

     

Coupled Imaging with [<Superscript>18</Superscript>F]FBB and [<Superscript>18</Superscript>F]FDG in AD Subjects Show a Selective Association Between Amyloid Burden and Cortical Dysfunction in the Brain

Purpose

The present study was aimed to investigate the relationships between dysfunction of cortical glucose metabolism as detectable by means of 2-deoxy-2-[¹⁸F]fluoro -D-glucose ([¹⁸F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) and amyloid burden as detectable by means of 4-{(E)-2-[4-(2-{2-[2-[¹⁸F]fluoroethoxy]ethoxy}ethoxy)phenyl]vinyl}-N-methylaniline (florbetaben; [¹⁸F]FBB) in a group of patients affected by Alzheimer’s disease (AD).

Procedures

We examined 38 patients newly diagnosed with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a PET/CT scan using both [¹⁸F]FDG and [¹⁸F]FBB with an average interval of 1 month. We used statistical parametric mapping (SPM8) implemented in Matlab R2012b and WFU pickatlas for the definition of a region of interest (ROI) mask including the whole cortex. These data were then normalized on the counts of the cerebellum and then used for a regression analysis on [¹⁸F]FDG scans in SPM. Furthermore, 58 control subjects were used as control group for [¹⁸F]FDG PET/CT scans.

Results

SPM analysis in AD patients showed a significant negative correlation between [¹⁸F] FBB and [¹⁸F] FDG uptake in temporal and parietal lobes bilaterally. Of note, these areas in AD patients displayed a marked glucose hypometabolism compared to control group.

Conclusions

Combined imaging with [¹⁸F]FBB and [¹⁸FFDG shows that amyloid burden in the brain is related to cortical dysfunction of temporal and parietal lobes in AD.

     

Repeatability of Radiomic Features in Non-Small-Cell Lung Cancer [<Superscript>18</Superscript>F]FDG-PET/CT Studies: Impact of Reconstruction and Delineation

Purpose

To assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomorgraphy/computed tomography (PET/CT) studies.

Procedures

Eleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (n?=?19) were delineated twice, once on PET and once on CT images.

Results

Sixty-three features showed an intraclass correlation coefficient?≥?0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively).

Conclusions

The majority of features in NSCLC [¹⁸F]FDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.

     

Multimodal <Emphasis Type="Italic">In Vivo</Emphasis> Imaging of Tumorigenesis and Response to Chemotherapy in a Transgenic Mouse Model of Mammary Cancer

Purpose

Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy.

Procedures

Positron emission tomography (PET) with 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) and 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT), single photon emission tomography (SPECT) with [^99mTc]TcO₄ ([^99mTc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [¹⁸F]FDG and [^99mTc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel-treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed.

Results

All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [^99mTc]TEC and [¹⁸F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [¹⁸F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [¹⁸F]FDG and [^99mTc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week^?1 in untreated, doxorubicin, and docetaxel groups, respectively.

Conclusions

Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [¹⁸F]FDG-PET and [^99mTc]TEC SPECT monitor tumor response to chemotherapy.

     

Role of CT Density in PET/CT-Based Assessment of Lymphoma

Purpose

In patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL), primary staging, as well as intermediate and late response assessment, is often performed by integrated 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography/X-ray computed tomography (PET/CT). The purpose of this analysis was to evaluate if findings in patients with histopathologically proven HL or NHL might correlate with semi-automated density measurements of target lesions (TLs) in the CT component of the integrated PET/CT examination.

Procedures

After approval by the institutional review board, 176 lymph nodes (LN) in 90 PET/CT examinations of 90 patients were retrospectively analyzed (HL, 108 TLs out of 55 patients; NHL, 68 TLs out of 35 patients). PET/CT was performed for reasons of primary staging, response evaluation as interim PET, or as final examination after therapy, according to the clinical schedule. Analyses of TLs were performed on the basis of tracer uptake (SUV) 60 min after tracer injection and volumetric CT histogram analysis in non-contrast-enhanced CT.

Results

All patients were diagnosed with HL or NHL in a pretreatment biopsy. Prior to therapy induction, staging of all patients was performed using contrast-enhanced CT of the neck to the pelvis, or by [¹⁸F]FDG PET/CT. Of the 176 TLs, 119 were classified as malignant, and 57 were benign. Malignant TLs had significantly higher CT density values compared to benign (p?<?0.01).

Conclusion

Density measurements of TLs in patients with HL and NHL correlate with the dignity of TLs and might therefore serve as a complementary surrogate parameter for the differentiation between malignant and benign TLs. A possible density threshold in clinical routine might be a 20-Hounsfield units (HU) cutoff value to rule out benignancy in TLs that are above the 20-HU threshold.

     

Investigation of Image Reconstruction Parameters of the Mediso nanoScan PC Small-Animal PET/CT Scanner for Two Different Positron Emitters Under NEMA NU 4-2008 Standards

Purpose

The Tera-Tomo 3D image reconstruction algorithm (a version of OSEM), provided with the Mediso nanoScan® PC (PET8/2) small-animal positron emission tomograph (PET)/x-ray computed tomography (CT) scanner, has various parameter options such as total level of regularization, subsets, and iterations. Also, the acquisition time in PET plays an important role. This study aims to assess the performance of this new small-animal PET/CT scanner for different acquisition times and reconstruction parameters, for 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) and Ga-68, under the NEMA NU 4-2008 standards.

Procedures

Various image quality metrics were calculated for different realizations of [¹⁸F]FDG and Ga-68 filled image quality (IQ) phantoms.

Results

[¹⁸F]FDG imaging produced improved images over Ga-68. The best compromise for the optimization of all image quality factors is achieved for at least 30 min acquisition and image reconstruction with 52 iteration updates combined with a high regularization level.

Conclusion

A high regularization level at 52 iteration updates and 30 min acquisition time were found to optimize most of the figures of merit investigated.

     

Contrast-enhanced ultrasound for needle biopsy of central lung cancer with atelectasis

Purpose

Contrast-enhanced ultrasound (CEUS) can distinguish between central lung cancer and atelectatic lung tissue. The aim of this study was to explore the clinical value of CEUS for biopsy in patients with central lung cancer with obstructive atelectasis.

Methods

One hundred and twelve patients were selected and CEUS was performed to display central lung cancer and atelectatic lung tissue. The front edge of central lung cancer was punctured with a needle, avoiding the necrotic area, under the guidance of CEUS.

Results

All of the 112 lesions were diagnosed with a clear central lung cancer mass and atelectatic lung tissue. In 104 cases, the central lung cancer mass presented with a “slow-in and fast-out” pattern compared to atelectatic lung tissue. In eight cases, the central lung cancer mass presented with a “fast-in and fast-out” pattern compared to atelectatic lung tissue. The mean number of punctures was 2.6, and the success rate of puncture biopsy was 98%. Of the 112 patients, six cases had hemoptysis during the procedure and 10 patients had bloody sputum in the postoperative period. No complications were found in the other cases.

Conclusion

CEUS has important clinical value for needle biopsy of central lung cancer with atelectasis.

     

A Comparison of microCT and microPET for Evaluating Lymph Node Metastasis in a Rat Model

Purpose

The demand to optimize multidisciplinary treatment strategies in patients with benign and malignant diseases of the lung and other organs has led to the increased need of mechanistic proof-of-concept studies in preclinical small animal models using new non-invasive imaging methods. Therefore, we evaluated the role of microPET and microCT for mediastinal lymph node staging in an orthotopic lung cancer model in rats.

Procedures

Human lung cancer cells (NCI-H460) were injected transthoracically in nude rats (NIH-RNU). After 2 weeks of tumour growth, animals underwent multiphase contrast-enhanced microCT using ExiTron nano 12000 as a contrast agent and dynamic microPET using the tracer 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG). Thereafter, animals were sacrificed for histological analysis.

Results

Late phase micro X-ray computed tomography (microCT) revealed the best delineation of lymph node metastases, as compared to earlier scans. In terms of an increased [¹⁸F]FDG uptake over time, dynamic micro positron emission tomography (microPET) delineated lymph node metastases and enabled metabolic examinations of the induced lung cancer metastases.

Conclusion

The combination of contrast-enhanced microCT and dynamic microPET is feasible in rats for the visualization of mediastinal lymph node metastases.

     

Preclinical Evaluation of 4-[<Superscript>18</Superscript>F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer

Purpose

Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated as a promising lung cancer biomarker. (2S,4R)-4-[¹⁸F]Fluoroglutamine (4-[¹⁸F]fluoro-Gln) positron emission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer as a quantitative, non-invasive measure of ASCT2 expression.

Procedures

In vivo microPET studies of 4-[¹⁸F]fluoro-Gln uptake were undertaken in human cell line xenograft tumor-bearing mice of varying ASCT2 levels, followed by a genetically engineered mouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer. The relationship between a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC and immunoblotting.

Result

4-[¹⁸F]Fluoro-Gln uptake, but not 2-deoxy-2-[¹⁸F]fluoro-D-glucose, correlated with relative ASCT2 levels in xenograft tumors. In genetically engineered mice, 4-[¹⁸F]fluoro-Gln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues.

Conclusions

4-[¹⁸F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2 expression. Given the potential of ASCT2 as a lung cancer biomarker, this and other tracers reflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting.

     

Baseline [<Superscript>18</Superscript>F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model

Purpose

The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC).

Procedures

Therapy response to 5-FU?±?PX-12 was assessed with baseline [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) and longitudinal 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n?=?36) during breathing of a hypoxic (10 % O₂) or normoxic (21 % O₂) atmosphere. Ex vivo, immunohistochemistry was performed.

Results

Baseline [¹⁸F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU?+?PX-12 administration correlated significantly (p?≤?0.01). Under hypoxic breathing conditions, [¹⁸F]FDG uptake (?53.1?±?8.4 %) and Ki67 expression (?16 %) decreased and RTV stagnated in the 5-FU?+?PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [¹⁸F]FDG uptake (?23.5?±?15.2 % and ?72.8?±?7.1 %) and Ki67 expression (?5 % and ?19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively.

Conclusion

Baseline [¹⁸F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.

     

[<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.

     

CD80 Is Upregulated in a Mouse Model with Shear Stress-Induced Atherosclerosis and Allows for Evaluating CD80-Targeting PET Tracers

Purpose

A shear stress-induced atherosclerosis mouse model was characterized for its expression of inflammation markers with focus on CD80. With this model, we evaluated two positron emission tomography (PET) radiotracers targeting CD80 as well as 2-deoxy-2-[¹⁸F]fluoro-d-mannose ([¹⁸F]FDM) in comparison with 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG).

Procedure

A flow constrictive cuff implanted around the common carotid artery in apolipoprotein E knockout mice resulted in plaque formation. CD80 expression levels and plaque histopathology were evaluated. Serial PET/X-ray computed tomography scans were performed to follow inflammation.

Results

Plaque formation with increased levels of CD80 was observed. Histologically, plaques presented macrophage-rich and large necrotic areas covered by a thin fibrous cap. Of the CD80-specific tracers, one displayed an increased uptake in plaques by PET. Both [¹⁸F]FDG and [¹⁸F]FDM accumulated in atherosclerotic plaques.

Conclusion

This mouse model presented, similar to humans, an increased expression of CD80 which renders it suitable for non-invasively targeting CD80-positive immune cells and evaluating CD80-specific radiotracers.

     

Radionuclide Imaging of Infective Endocarditis: State of Art and Future Perspective

Purpose of Review

Infectious endocarditis is a serious disease requiring rapid diagnosis and accurate risk stratification to offer the best therapeutic strategy. Infection of prosthetic valve (PV) and cardiovascular implantable electronic device (CIED) is increasing due to the ageing of the population and the growing number of implants. Foreign material infection remains clinically challenging given the limitation of ultrasound techniques in this context whereas the diagnosis must be precocious.

Recent Findings

¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography ([¹⁸F]FDG PET/CT) and radiolabelled leukocytes single-photon emission computed tomography/computed tomography (SPECT/CT) are commonly used for this purpose.

Summary

In the present article, we summarized the available evidence for the use of nuclear imaging for the evaluation of infectious endocarditis.

     

Al[<Superscript>18</Superscript>F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression

Purpose

Chemokine receptor CXCR4 plays an important role in tumor aggressiveness, invasiveness, and metastasis formation. Quantification of CXCR4 expression by tumors may have an impact on prediction and evaluation of tumor response to therapies. In this study, we developed a robust and straightforward F-18 labeling route of T140, a CXCR4 peptide-based antagonist.

Procedures

T140 derivative was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and labeled with Al[¹⁸F]. Al[¹⁸F]NOTA-T140 was evaluated in vitro in cell-based assay and stability in mouse serum and in vivo using CXCR4 positive and negative tumor xenograft models.

Results

Labeling of Al[¹⁸F]NOTA-T140 was completed within 30 min with a radiochemical yield of 58?±?5.3 % at the end of synthesis, based on fluoride-18 activity. Al[¹⁸F]NOTA-T140 accumulated in CHO-CXCR4 positive but not negative tumors. Al[¹⁸F]NOTA-T140 uptake in the tumors correlated with CXCR4 protein expression. Moreover, Al[¹⁸F]NOTA-T140 had high accumulation in CXCR4-positive metastatic tumors.

Conclusions

The simplicity of Al[¹⁸F]NOTA-T140 labeling along with its properties to specifically image CXCR4 expression by tumors warrant further clinical application for the diagnosis of CXCR4 clinically.

     

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.

     

Glucose Metabolism as a Pre-clinical Biomarker for the Golden Retriever Model of Duchenne Muscular Dystrophy

Purpose

Metabolic dysfunction in Duchenne muscular dystrophy (DMD) is characterized by reduced glycolytic and oxidative enzymes, decreased and abnormal mitochondria, decreased ATP, and increased oxidative stress. We analyzed glucose metabolism as a potential disease biomarker in the genetically homologous golden retriever muscular dystrophy (GRMD) dog with molecular, biochemical, and in vivo imaging.

Procedures

Pelvic limb skeletal muscle and left ventricle tissue from the heart were analyzed by mRNA profiling, qPCR, western blotting, and immunofluorescence microscopy for the primary glucose transporter (GLUT4). Physiologic glucose handling was measured by fasting glucose tolerance test (GTT), insulin levels, and skeletal and cardiac positron emission tomography/X-ray computed tomography (PET/CT) using the glucose analog 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG).

Results

MRNA profiles showed decreased GLUT4 in the cranial sartorius (CS), vastus lateralis (VL), and long digital extensor (LDE) of GRMD vs. normal dogs. QPCR confirmed GLUT4 downregulation but increased hexokinase-1. GLUT4 protein levels were not different in the CS, VL, or left ventricle but increased in the LDE of GRMD vs. normal. Microscopy revealed diffuse membrane expression of GLUT4 in GRMD skeletal but not cardiac muscle. GTT showed higher basal glucose and insulin in GRMD but rapid tissue glucose uptake at 5 min post-dextrose injection in GRMD vs. normal/carrier dogs. PET/ CT with [¹⁸F]FDG and simultaneous insulin stimulation showed a significant increase (p?=?0.03) in mean standard uptake values (SUV) in GRMD skeletal muscle but not pelvic fat at 5 min post-[¹⁸F]FDG /insulin injection. Conversely, mean cardiac SUV was lower in GRMD than carrier/normal (p?<?0.01).

Conclusions

Altered glucose metabolism in skeletal and cardiac muscle of GRMD dogs can be monitored with molecular, biochemical, and in vivo imaging studies and potentially utilized as a biomarker for disease progression and therapeutic response.

     

[<Superscript>18</Superscript>F]FDG PET Neuroimaging Predicts Pentylenetetrazole (PTZ) Kindling Outcome in Rats

Purpose

Epileptogenesis, i.e., development of epilepsy, involves a number of processes that alter the brain function in the way that triggers spontaneous seizures. Kindling is one of the most used animal models of temporal lobe epilepsy (TLE) and epileptogenesis, although chemical kindling suffers from high inter-assay success unpredictability. This study was aimed to analyze the eventual regional brain metabolic changes during epileptogenesis in the pentylenetetrazole (PTZ) kindling model in order to obtain a predictive kindling outcome parameter.

Procedures

In vivo longitudinal positron emission tomography (PET) scans with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) along the PTZ kindling protocol (35 mg/kg intraperitoneally (i.p.), 18 sessions) in adult male rats were performed in order to evaluate the regional brain metabolism.

Results

The half of the PTZ-injected rats reached the kindled state. In addition, a significant decrease of [¹⁸F]FDG uptake at the end of the protocol in most of the brain structures of kindled animals was found, reflecting the characteristic epilepsy-associated hypometabolism. However, PTZ-injected animals but not reaching the kindled state did not show this widespread brain hypometabolism. Retrospective analysis of the data revealed that hippocampal [¹⁸F]FDG uptake normalized to pons turned out to be a predictive index of the kindling outcome. Thus, a 19.06 % reduction (p?=?0.008) of the above parameter was found in positively kindled rats compared to non-kindled ones just after the fifth PTZ session.

Conclusion

Non-invasive PET neuroimaging was a useful tool for discerning epileptogenesis progression in this animal model. Particularly, the [¹⁸F]FDG uptake of the hippocampus proved to be an early predictive parameter to differentiate resistant and non-resistant animals to the PTZ kindling.