Glucose Avidity Research Articles

Warthin's Tumour as a Parotid Gland Incidentaloma Identified by PET-CT Scan in a Large Series of Cases.

Occasionally in imaging scans there are findings unrelated to the pathology for which the scan was indicated, findings that are called incidentalomas. Warthin tumors have a high glucose avidity, being one of the common incidentalomas in PET-CT scans. The aim of the present study is to analyze the frequency of occurrence of Warthin's tumor as an incidental finding in a large series of patients undergoing 18F-FDG PET-CT. Retrospective analysis of 18F-FDG PET-CT scans performed in our center during the period 2010-2021. Parotid hypermetabolic lesions were identified, as well as their SUVmax, size, smoking habit, BMI (body mass index), and otorhinolaryngology follow-up. 31,423 PET-CT-18FDG studies corresponding to 12,806 patients were analyzed. The frequency of incidentalomas at the parotid level with a diagnosis compatible with Warthin's tumor was 0.87% (n = 111). Eighty percent of the patients with incidentalomas accordant to Warthin's tumor had a history of tobacco use. The highest percentage of incidentalomas compatible with a Warthin tumor was found in patients in whom the indication for PET-CT was the study of a lung carcinoma (1.44%). Only 37% of patients with a PET-CT lesion compatible with a Warthin's tumor were referred for evaluation by the Otorhinolaryngology service. The incidence of Warthin's tumor in 18-FDG PET-CT scans in our center was 0.87%.

Elevated glucose metabolism driving pro-inflammatory response in B cells contributes to the progression of type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune system's failure to maintain self-tolerance, resulting in the autoimmune destruction of pancreatic beta cells. Although T1D has conventionally been viewed as a T-cell-dominant disease, recent research has emphasized the contribution of B cells in the onset of the disease. However, the mechanism underlying aberrant B cell responses remains unknown. B cell metabolism is a crucial prerequisite for B cell function and the development of adaptive immune responses. Here, we investigated the metabolic features of B cells, first in a cross-sectional cohort and subsequently in non-obese diabetic (NOD) mice, and revealed that there is an increased frequency of high-glucose-avidity (2-NBDGhigh) B cell population that may contribute to T1D progression. Further characterization of the metabolic, transcriptional and functional phenotype of B cells in NOD mice found that elevated glucose avidity is associated with a greater capacity for co-stimulation, proliferation and inflammatory cytokine production. Mechanistically, elevated Myc signaling orchestrated the glucose metabolism and the pro-inflammatory response of B cells in T1D. In vitro experiments demonstrated that pharmacological inhibition of glucose metabolism using metformin and 2-DG reduced pro-inflammatory cytokine production and B cell proliferation. Moreover, the combination of these inhibitors successfully delayed insulitis development, onset of diabetes, and improved high blood glucose levels in streptozotocin (STZ)-induced diabetic mice model. Taken together, our work has uncovered these high-glucose-avidity B cells as novel adjuvant diagnostic and therapeutic targets for T1D.

A case of ectopic prostatic tissue presenting as a cystic pelvic mass

A 74-year-old man initially presenting with fall had an incidental finding on CT of a heterogeneous, partly cystic lesion in the pelvis that was moderately glucose avid on FDG-PET. The pelvic mass and adherent right seminal vesicle were excised.

Enhancing Clinical Diagnosis for Patients With Persistent Pulmonary Abnormalities After COVID-19 Infection: The Potential Benefit of 68 Ga-FAPI PET/CT.

Six post COVID-19 patients suspected for pulmonary fibrosis were scheduled for dual-tracer PET/CT with 18 F-FDG and 68 Ga-fibroblast activation protein inhibitor (FAPI)-46. The uptake of 68 Ga-FAPI-46 in the involved lung was compared with a control group of 9 non-COVID-19 patients. Clinical data and PET/CT imaging were collected and analyzed. PET/CT revealed in all 6 pulmonary impaired patients the reduced glucose avidity on 18 F-FDG and clear positivity on 68 Ga-FAPI-46 PET/CT in comparison to the control group. Enhancing fibrotic repair mechanisms, 68 Ga-FAPI PET/CT may improve noninvasive clinical diagnostic performance in patients with long-term CT abnormalities after severe COVID-19. Although this study shows promising results, additional studies in larger populations are required to establish a general diagnostic guideline.

Development of a Lensless Radiomicroscope for Cellular-Resolution Radionuclide Imaging.

The action of radiopharmaceuticals takes place at the level of cells. However, existing radionuclide assays can only measure uptake in bulk or in small populations of single cells. This potentially hinders the development of effective radiopharmaceuticals for disease detection, staging, and treatment. Methods: We have developed a new imaging modality, the lensless radiomicroscope (LRM), for invitro, cellular-resolution imaging of β- and α-emitting radionuclides. The palm-sized instrument is constructed from off-the-shelf parts for a total cost of less than $100, about 500 times less than the radioluminescence microscope, its closest equivalent. The instrument images radiopharmaceuticals by direct detection of ionizing charged particles via a consumer-grade complementary metal-oxide semiconductor detector. Results: The LRM can simultaneously image more than 5,000 cells within its 1 cm2 field of view, a 100-times increase over state-of-the-art technology. It has spatial resolution of 5 μm for brightfield imaging and 30 μm for 18F positron imaging. We used the LRM to quantify 18F-FDG uptake in MDA-MB-231 breast cancer cells 72 h after radiation treatment. Cells receiving 3 Gy were 3 times larger (mean = 3,116 μm2) than their untreated counterparts (mean = 940 μm2) but had 2 times less 18F-FDG per area (mean = 217 Bq/mm2), a finding in agreement with the clinical use of this tracer to monitor response. Additionally, the LRM was used to dynamically image the uptake of 18F-FDG by live cancer cells, and thus measure their avidity for glucose. Conclusion: The LRM is a high-resolution, large-field-of-view, and cost-effective approach to image radiotracer uptake with single-cell resolution invitro.

Dietary experience with glucose and fructose fosters heightened avidity for glucose-containing sugars independent of TRPM5 taste transduction in mice

ABSTRACT Objective Experience with metabolically distinct sugars, glucose and fructose, enhances attraction to the orosensory properties of glucose over fructose. To gain insight into which sensory signals are affected, we investigated how this nutritive learning reshapes behavioral responding to various sugars in brief access taste tests in C57BL6/J (B6) mice and assessed whether sugar-exposed mice lacking the TRPM5 channel involved in G-protein coupled taste transduction could acquire these types of preferences for glucose-containing sugars. Methods B6, TRPM5 knockout (KO), and TRPM5 heterozygous (Het) mice were given extensive access to water (sugar naïve) or 0.316, 0.56, and 1.1 M glucose and fructose (sugar-exposed) and then tested, whilst food deprived, for their relative avidities for glucose, fructose, sucrose, maltose, and/or a non-metabolizable glucose analog in a series of taste tests. Results Sugar-exposed B6 mice licked relatively more for glucose than fructose, driven by an increased avidity for glucose, not an avoidance of fructose, and licked more for maltose, compared to their sugar-naïve counterparts. Sugar-exposed B6 mice did not lick with such avidity for a non-metabolizable glucose analog. TRPM5 KO mice took longer to acquire the sugar discrimination than the Het controls, but both groups ultimately licked significantly more for glucose than fructose. Het mice displayed clear preferential licking for sucrose over fructose, while licking comparably high for glucose, sucrose, and maltose. KO mice licked significantly more for maltose than sucrose. Conclusions Collectively, the findings suggest that ingestive experience with glucose and fructose primarily reprograms behavioral responding to a TRPM5-independent orosensory signal generated by glucose-containing sugars.

Delayed hypersensitivity to the Comirnaty coronavirus disease 2019 vaccine presenting with pneumonitis and rash

Delayed hypersensitivity to the Comirnaty coronavirus disease 2019 vaccine presenting with pneumonitis and rash

The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage

Cancer cells are metabolically similar to their corresponding normal tissues. Differences between cancers and normal tissues may reflect reprogramming during transformation or maintenance of the metabolism of the specific normal cell type that originated the cancer. Here, we compare glucose metabolism in hematopoiesis and leukemia. Thymus Tcell progenitors were glucose avid and oxidized more glucose in the tricarboxylic acid cycle through pyruvate dehydrogenase (PDH) as compared with other hematopoietic cells. PDH deletion decreased double-positive Tcell progenitor cells but had no effect on hematopoietic stem cells, myeloid progenitors, or other hematopoietic cells. PDH deletion blocked the development of Pten-deficient Tcell leukemia, but not the development of a Pten-deficient myeloid neoplasm. Therefore, the requirement for PDH in leukemia reflected the metabolism of the normal cell of origin independently of the driver genetic lesion. PDH was required to prevent pyruvate accumulation and maintain glutathione levels and redox homeostasis.

Including the mitochondrial metabolism of L-lactate in cancer metabolic reprogramming.

Glucose avidity, high glycolysis and L-lactate production, regardless of oxygen availability, are the main traits of cancer metabolic reprogramming. The idea that mitochondria are dysfunctional in cancer, thus causing a glycolysis increase for ATP production and L-lactate accumulation as a dead-end product of glucose catabolism, has oriented cancer research for many years. However, it was shown that mitochondrial metabolism is essential for cancer cell proliferation and tumorigenesis and that L-lactate is a fundamental energy substrate with tumor growth-promoting and signaling capabilities. Nevertheless, the known ability of mitochondria to take up and oxidize L-lactate has remained ignored by cancer research. Beginning with a brief overview of the metabolic changes occurring in cancer, we review the present knowledge of L-lactate formation, transport, and intracellular oxidation and underline the possible role of L-lactate metabolism as energetic, signaling and anabolic support for cancer cell proliferation. These unexplored aspects of cancer biochemistry might be exploited for therapeutic benefit.

Changes in glucose metabolism during and after radiotherapy in non-small cell lung cancer

Evaluation of the metabolic response to radiotherapy in nonsmall cell lung cancer patients is commonly performed about three months after the end of radiotherapy. The aim of the present study was to assess with positron emission tomography/computed tomography (PET/CT) and [18F]fluorodeoxyglucose changes in glucose metabolism during and after radiotherapy in non-small cell lung cancer patients. In 6 patients, PET/CT scans with [18F]fluorodeoxyglucose were performed before (PET0), during (PET1; at a median of 14 days before the end of radiotherapy) and after the end of radiotherapy (PET2 and PET3, at a median of 28 and 93 days, respectively). The metabolic response was scored according to visual and semiquantitative criteria. Standardize maximum uptake at PET1 (7.9 +/- 4.8), PET2 (5.1 +/- 4.1) and PET3 (2.7 +/- 3.1) were all significantly (P < 0.05; ANOVA repeated measures) lower than at PET0 (16.1 +/- 10.1). Standardized maximum uptake at PET1 was significantly higher than at both PET2 and PET3. There were no significant differences in SUV(max) between PET2 and PET3. PET3 identified 4 complete and 2 partial metabolic responses, whereas PET1 identified 6 partial metabolic responses. Radiotherapy-induced increased [l8F]fluorodeoxyglucose uptake could be visually distinguished from tumor uptake based on PET/CT integration and was less frequent at PET1 (n = 2) than at PET3 (n = 6). In non-small cell lung cancer, radiotherapy induces a progressive decrease in glucose metabolism that is greater 3 months after the end of treatment but can be detected during the treatment itself. Glucose avid, radiotherapy-induced inflammation is more evident after the end of radiotherapy than during radiotherapy and does not preclude the interpretation of [18F]fluorodeoxyglucose images, particularly when using PET/CT.

The Specificity of a Diagnostic FDG-PET Study Is a Function of the Patient and the Location

The present paper is based on the observations that 1) there is reported variation in the specificities according to the type of tumor targeted (target) by FDG PET and 2) that while one can posit that the sensitivity of the tracer depends on the avidity for glucose and the plasma supply of the target, even so that the targeting cannot influence the avidity of unrelated tissues or lesions. The hypothesis to be tested is twofold: 1) patients imaged for different types of lesions could have a different prevalence of FDG avid tissues or lesions different from the target and 2) that the target lesions could be generally located in body location (sites) more likely to contain unrelated foci of increased uptake. Variance analysis shows that the sensitivity varies according to the target (p = 0.022), but not according to the location (p = 0.34); the specificity varies with the location (p = 0.0012) and the target (p = 0.05). Specificities are significantly different in different primary targets and target locations. The former is assumed to be due to different comorbidities in patients with different targets, the latter to the different locations of unrelated glucose avid organs or structures. Conclusion: When specificities are recorded or defined, the patient population characteristics and the organ or pathology of the false positives should also be described.

Linker structure-activity relationships in fluorodeoxyglucose chlorambucil conjugates for tumor-targeted chemotherapy

Nitrogen mustards, such as chlorambucil (CLB), can cause adverse side-effects due to ubiquitous distribution in non-target organs. To minimize this toxicity, strategies of tumor-targeting drug delivery have been developed, where a cytotoxic warhead is linked to a tumor-cell-specific small ligand. Malignant cells exhibit marked glucose avidity and an accelerated metabolism by aerobic glycolysis, known as the Warburg effect, and recognized as a hallmark of cancer. A targeting approach exploiting the Warburg effect by conjugation of CLB to 2-fluoro-2-deoxyglucose (FDG) was previously reported and identified two peracetylated glucoconjugates 2 and 3 with promising antitumor activities in vivo. These results prompted us to investigate the importance of the spacer in this tumor-targeting glucose-based conjugates. Here we report the chemical synthesis and an in vitro cytotoxicity evaluation, using a 5-member panel of human tumor cell lines and human fibroblasts, of 16 new CLB glucoconjugates in which the alkylating drug is attached to the C-1 position of FDG via different linkages. We studied the structure-activity relationships in the linker, and evidenced the positive impact of an aromatic linker on in vitro cytotoxicity: compound 51 proved to be the most active FDG-CLB glucoside, characterized by a bis-aromatic spacer tethered to CLB through an amide function.

A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI.

To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med 78:1922-1932, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Glucose Promotes a Pro-Oxidant and Pro-Inflammatory Stromal Microenvironment Which Favors Motile Properties in Breast Tumor Cells.

Chronic inflammation and metabolic reprogramming have been proposed as hallmarks of cancer development. Currently, many of the functional clues between these two phenomena are studied under the integrative view of functional stroma-epithelia interaction. It has been proposed that stromal cells, due to their abundance and avidity for glucose, are able to modify the metabolic behavior of an entire solid tumor. In the present study, using a mammary stromal cell line derived from healthy tissue subjected to long-term culture in low (5 mM) or high (25 mM) glucose, we found that the hyperglycemic condition favors the establishment of a pro-inflammatory and pro-oxidant environment characterized by the induction of the COX-2/PGE2 axis. In this condition, epithelial migration was stimulated. Moreover, we also found that stromal-derived PGE2, acting as a stimulator of IL-1 epithelial expression was one of the factors that promote the acquisition of motile properties by epithelial cells and the maintenance of a COX-2/PGE2-dependent inflammatory condition. Overall, our work provides experimental evidence that glucose stimulates a tumor inflammatory environment that, as a result of a functional cross-talk between stroma and epithelia, may be responsible for tumor progression. J. Cell. Biochem. 118: 994-1002, 2017. © 2016 Wiley Periodicals, Inc.

Voxelwise analysis of simultaneously acquired and spatially correlated 18 F-fluorodeoxyglucose (FDG)-PET and intravoxel incoherent motion metrics in breast cancer.

Diffusion-weighted imaging (DWI) and 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET) independently correlate with malignancy in breast cancer, but the relationship between their structural and metabolic metrics is not completely understood. This study spatially correlates diffusion, perfusion, and glucose avidity in breast cancer with simultaneous PET/MR imaging and compares correlations with clinical prognostics. In this Health Insurance Portability and Accountability Act-compliant prospective study, with written informed consent and approval of the institutional review board and using simultaneously acquired FDG-PET and DWI, tissue diffusion (Dt ), and perfusion fraction (fp ) from intravoxel incoherent motion (IVIM) analysis were registered to FDG-PET within 14 locally advanced breast cancers. Lesions were analyzed using 2D histograms and correlation coefficients between Dt , fp , and standardized uptake value (SUV). Correlations were compared with prognostics from biopsy, metastatic burden from whole-body PET, and treatment history. SUV||Dt correlation coefficient significantly distinguished treated (0.11 ± 0.24) from nontreated (-0.33 ± 0.26) patients (P = 0.005). SUV||fp correlations were on average negative for the whole cohort (-0.17 ± 0.13). Simultaneously acquired and registered FDG-PET/DWI allowed quantifiable descriptions of breast cancer microenvironments that may provide a framework for monitoring and predicting response to treatment. Magn Reson Med 78:1147-1156, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression.

Clear cell renal cell carcinoma (ccRCC) has recently been redefined as a highly heterogeneous disease. In addition to genetic heterogeneity, the tumor displays risk variability for developing metastatic disease, therefore underscoring the urgent need for tissue-based prognostic strategies applicable to the clinical setting. We have recently employed the novel PET/magnetic resonance (MR) image modality to enrich our understanding of how tumor heterogeneity can relate to gene expression and tumor biology to assist in defining individualized treatment plans. ccRCC patients underwent PET/MR imaging, and these images subsequently used to identify areas of varied intensity for sampling. Samples from 8 patients were subjected to histologic, immunohistochemical, and microarray analysis. Tumor subsamples displayed a range of heterogeneity for common features of hypoxia-inducible factor expression and microvessel density, as well as for features closely linked to metabolic processes, such as GLUT1 and FBP1. In addition, gene signatures linked with disease risk (ccA and ccB) also demonstrated variable heterogeneity, with most tumors displaying a dominant panel of features across the sampled regions. Intriguingly, the ccA- and ccB-classified samples corresponded with metabolic features and functional imaging levels. These correlations further linked a variety of metabolic pathways (i.e., the pentose phosphate and mTOR pathways) with the more aggressive, and glucose avid ccB subtype. Higher tumor dependency on exogenous glucose accompanies the development of features associated with the poor risk ccB subgroup. Linking these panels of features may provide the opportunity to create functional maps to enable enhanced visualization of the heterogeneous biologic processes of an individual's disease. Clin Cancer Res; 22(12); 2950-9. ©2016 AACR.

Use of Nuclear Medicine Technology for Clinical Molecular Imaging: a Message from the Associate Editor.

Molecular imaging is defined as the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms; this can be achieved by various imaging technologies such as nuclear imaging, optical imaging, magnetic resonance imaging (MRI), ultrasound imaging, and computed tomography (CT) [1]. Although these modalities are actively used for sensing molecular and cellular processes in preclinical studies, the majority of imaging techniques remain unapplied in the clinical field due to various unresolved issues, such as safety, poor tissue penetration of the imaging signal, and limited sensitivity. So far, nuclear or fusion imaging modalities with the nuclear medicine component are the actively used molecular imaging modalities in the clinical field [1–3]. Nuclear imaging has many fundamental principles as molecular imaging. Nuclear medicine imaging has provided molecular information since the early years of imaging technology. In 1951, Dr. Benedict Cassen successfully imaged the thyroid gland with his rectilinear scanner; his imaging principle is still widely used in daily clinical practices to elucidate iodine avidity of benign and malignant thyroid follicular cells. F-18 FDG PET imaging is probably the most well-known clinical molecular imaging technique that can be used to visualize activity of glucose metabolism. The imaging technique is widely used in the oncologic arena as the majority of tumors utilize glucose more actively than normal tissues. High avidity of radioiodine in thyroid follicular cells functions as the tracer for thyroid diseases, while high glucose avidity of tumor functions as F-18 FDG for oncologic disorders. The elucidation of pathophysiology of certain diseases lead to the development of new diagnostic tracers, which in turn shed more light on the disease pathophysiology. This virtuous cycle would aid in uncovering diseases at an early phase and might increase the chance of complete cure by identifying appropriate molecular signatures of diseases. Nuclear molecular imaging was and still is the leading molecular imaging technology. Although nuclear molecular imaging has distinct advantages over other imaging modalities, it has its own limitations, such as low spatial/temporal resolution and high background signal. Multimodal fusion imaging might be a good strategy to overcome the disadvantages of molecular imaging modalities; PET/CT or PET/MRI is already widely installed and actively used in clinics to provide the best molecular imaging service [4]. In fact, clinical molecular imaging already plays indispensable roles in optimal patient care, and its diagnostic and theranostic potentials are increasingly recognized through better understanding of disease pathophysiology in combination with rapid advancements of electronic and biologic technologies. Constant contributions of nuclear medicine physicians and nuclear/biological scientists will retain nuclear molecular imaging as the leading clinical imaging technology to visualize hidden molecular events in human studies and link successful ideas from basic preclinical environment to clinical translation [5]. Nuclear Medicine and Molecular Imaging would be the platform for the advancement of nuclear molecular imaging and provide cutting edge * Byeong-Cheol Ahn abc2000@knu.ac.kr

The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth

BackgroundMetronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer.MethodsTwo primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments.ResultsTumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors’ avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor’s vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia.ConclusionThe aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-016-9503-z) contains supplementary material, which is available to authorized users.

Utility of Routine PET Imaging to Predict Response and Survival After Induction Therapy for Non-Small Cell Lung Cancer

Data from clinical trials suggest that changes in the glucose avidity of the primary site of lung cancer during induction therapy, measured by changes in (18)F-fluorodeoxyglucose positron emission tomography, correlate with tumor response. Little information about the utility of changes in positron emission tomography imaging of involved lymph nodes during induction chemotherapy is available. The utility of positron emission tomography imaging of either the primary site or nodal metastases, obtained during routine clinical care outside of a clinical trial setting, to predict response has also not been examined. A retrospective review of all surgical patients with non-small cell lung cancer at a single institution imaged between 2000 and 2006 with (18)F-fluorodeoxyglucose positron emission tomography before or after induction therapy was performed. An increase in standardized uptake value in the primary site of disease during induction therapy was associated with reduced overall survival after resection. Neither pretreatment standardized uptake value nor percentage change in the primary site was associated with overall survival after resection. A decrease in standardized uptake value of greater than 60% in the involved N2 mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary site of disease. An increase in glucose avidity of non-small cell lung cancers during induction therapy was associated with a worse prognosis compared with stable or any decrease in standardized uptake value. Changes in the glucose avidity of mediastinal nodal metastases may be a stronger predictor of survival than changes in the primary site of disease.

Caged [(18)F]FDG Glycosylamines for Imaging Acidic Tumor Microenvironments Using Positron Emission Tomography.

Solid tumors are hypoxic with altered metabolism, resulting in secretion of acids into the extracellular matrix and lower relative pH, a feature associated with local invasion and metastasis. Therapeutic and diagnostic agents responsive to this microenvironment may improve tumor-specific delivery. Therefore, we pursued a general strategy whereby caged small-molecule drugs or imaging agents liberate their parent compounds in regions of low interstitial pH. In this manuscript, we present a new acid-labile prodrug method based on the glycosylamine linkage, and its application to a class of positron emission tomography (PET) imaging tracers, termed [(18)F]FDG amines. [(18)F]FDG amines operate via a proposed two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[(18)F]fluoro-d-glucose, which is subsequently accumulated by glucose avid cells. The rate of decomposition of [(18)F]FDG amines is tunable in a systematic fashion, tracking the pKa of the parent amine. In vivo, a 4-phenylbenzylamine [(18)F]FDG amine congener showed greater relative accumulation in tumors over benign tissue, which could be attenuated upon tumor alkalinization using previously validated models, including sodium bicarbonate treatment, or overexpression of carbonic anhydrase. This new class of PET tracer represents a viable approach for imaging acidic interstitial pH with potential for clinical translation.