Dual-tracer Positron Emission Research Articles

Predicting neuroendocrine neoplasm grade with dual tracer positron emission tomography/computed tomography (PET/CT) using 18F-fluorodeoxyglucose (18F-FDG) and 18F–AlF-NOTA-octreotide: a lesion-based analysis

Predicting neuroendocrine neoplasm grade with dual tracer positron emission tomography/computed tomography (PET/CT) using 18F-fluorodeoxyglucose (18F-FDG) and 18F–AlF-NOTA-octreotide: a lesion-based analysis

Metachronous Second Primary in the Form of Nasopharyngeal Carcinoma Following Treatment of Small Cell Neuroendocrine Carcinoma of the Head and Neck: Dual Tracer PET/CT Findings Highlighting SSTR2 Expression and Its Theranostic Implications

AbstractPatients of head and neck squamous cell carcinoma (HNSCC) experience increased risk of developing second primary cancer (SPC) necessitating active surveillance during their disease course. SPCs are associated with poor prognosis and are the leading cause of long-term morbidity and mortality impacting survival of patients with HNSCC. Small cell neuroendocrine carcinoma (SmNEC) is a rare but aggressive neoplasm with poor prognosis and high risk of local recurrence and distant metastasis. We report an exceedingly rare case of nasopharyngeal carcinoma (NPC) presenting as a recurrence in the form of metachronous second primary to primary SmNEC 9 years after chemotherapy. The dual tracer positron emission tomography and computed tomography (PET/CT) imaging approach ([68Ga]Ga-DOTATATE-PET/CT with 18F-FDG-PET/CT) was explored in such metachronous NPCs, and the findings are illustrated with its potential for theranostic applications. NPC is a rare malignancy with significant geographical variations in incidence rates. Somatostatin receptor 2 (SSTR2) expression in NPC is well documented and can serve as a potential theragnostic marker in advanced NPC where the successful outcome is minimal with currently available treatment modalities.

Aggressive Metastatic Insulinoma in a Patient of Diabetes Mellitus with Documentation on Dual-Tracer PET-CT ([68Ga]Ga-DOTATATE and [18F]FDG): Clinical Benefits with Combined Chemo-PRRT Approach

AbstractInsulinoma is a relatively uncommon pancreatic neuroendocrine tumor, with approximately 10% of the cases being malignant. Diabetes mellitus (DM) with concurrent insulinoma is very rare and the diagnosis of such condition is easily missed as it can be misconstrued as improved glycemic control. Therefore, persistent hypoglycemic symptoms even after stopping antidiabetic medications may be considered for insulinoma. Herein, we present a patient with DM and pancreatic insulinoma with extensive hepatic and skeletal metastases on dual-tracer positron emission tomography/computed tomography (PET/CT) ([68Ga]Ga-DOTATATE and [18F]fluorodeoxyglucose). Given the extensive disease, the patient was treated with a combination of peptide receptor radionuclide therapy (PRRT) and chemotherapy (capecitabine and temozolomide). During therapy, patient showed early clinical and imaging response for insulinoma leading to unmasking of poor glycemic control necessitating requirement of insulin administration for DM. The patient did not experience any life-threatening hypoglycemia during the chemo-PRRT treatment and showed an improvement in quality of life. Unfortunately, the disease progressed at the 4th cycle, 10 months after the initiation of PRRT. We conclude that combined chemo-PRRT may be considered an effective treatment option for patients with metastatic insulinoma and DM owing to its favorable imaging response and effective symptom control.

Dual-Tracer Positron Emission Tomography/Computed Tomography with [18F]FDG and [18F]fluorocholine in a Patient with Metastatic Parathyroid Carcinoma.

Here, we describe the case of a 43-year-old male patient with a metastatic parathyroid carcinoma who underwent dual-tracer whole-body positron emission tomography/computed tomography (PET/CT) with [18F]fluorocholine and fluorodeoxyglucose ([18F]FDG) for staging. [18F]FDG PET/CT detected multiple cervical and mediastinal lymph nodal lesions with increased tracer uptake, whereas [18F]fluorocholine PET/CT detected increased tracer uptake on cervical and mediastinal lymph nodal lesions and bone and lung lesions with a better evaluation of metastatic spread. Due to these imaging findings, the patient underwent systemic treatment with chemotherapy. This case demonstrates the added value of dual-tracer PET/CT in this rare metastatic tumor.

Dual-tracer positron emission tomography/computed tomography as an imaging probe of de novo lipogenesis in preclinical models of hepatocellular carcinoma.

BackgroundDe novo lipogenesis is upregulated in many cancers, and targeting it represents a metabolic approach to cancer treatment. However, the treatment response is unpredictable because lipogenic activity varies greatly among individual tumors, thereby necessitating the assessment of lipogenic activity before treatment. Here, we proposed an imaging probe, positron emission tomography/computed tomography (PET/CT) with dual tracers combining 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG), to assess the lipogenic activity of hepatocellular carcinoma (HCC) and predict the response to lipogenesis-targeted therapy.MethodsWe investigated the association between 11C-acetate/18F-FDG uptake and de novo lipogenesis in three HCC cell lines (from well-differentiated to poorly differentiated: HepG2, Hep3B, and SkHep1) by examining the expression of lipogenic enzymes: acetyl-CoA synthetase 2 (ACSS2), fatty acid synthase (FASN), and ATP citrate lyase (ACLY). The glycolysis level was determined through glycolytic enzymes: pyruvate dehydrogenase expression (PDH). On the basis of the findings of dual-tracer PET/CT, we evaluated the treatment response to a lipase inhibitor (orlistat) in cell culture experiments and xenograft mice.ResultsDual-tracer PET/CT revealed the lipogenic activity of various HCC cells, which was positively associated with 11C-acetate uptake and negatively associated with 18F-FDG uptake. This finding represents the negative association between 11C-acetate and 18F-FDG uptake. Because these two tracers revealed the lipogenic and glycolytic activity, respectively, which implies an antagonism between lipogenic metabolism and glucose metabolism in HCC. In addition, dual-tracer PET/CT not only revealed the lipogenic activity but also predicted the treatment response to lipogenesis-targeted therapy. For example, HepG2 xenografts with high 11C-acetate but low 18F-FDG uptake exhibited high lipogenic activity and responded well to orlistat treatment, whereas SkHep1 xenografts with low 11C-acetate but high 18F-FDG uptake exhibited lower lipogenic activity and poor response to orlistat.ConclusionThe proposed non-invasive dual-tracer PET/CT imaging can reveal the lipogenesis and glycolysis status of HCC, thus providing an ideal imaging probe for predicting the therapeutic response of HCC to lipogenesis-targeted therapy.

Combined 18F-FDG and 11C-acetate positron emission tomography/computed tomography in staging and treatment decision in patients with hepatocellular carcinoma: A cost-effectiveness analysis.

e16176 Background: Dual-tracer positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose and 11C-acetate is increasingly used in the management of hepatocellular carcinoma (HCC). However, considering the high cost of dual-tracer PET/CT, there is a need to assess its value by considering both the efficacy and cost. Methods: In this retrospective cohort study, 223 dual-tracer PET/CT scans were performed in 206 patients between 2014 and 2020 for tumor staging for radiologically or histologically confirmed HCC. New lesion detection rate, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and changes in treatment allocation based on dual-tracer PET/CT were evaluated. Validation was performed on a cohort of staging patients from another institution (n = 48). A cost-benefit analysis model was built for the incurred costs and the impact of dual-tracer PET/CT findings on treatment strategy over conventional imaging was studied. Results: Of the 223 patients that underwent dual-tracer PET/CT for staging, new lesions were detected in 33 (14.8%) patients, resulting in BCLC upstaging in 26 (11.6%) and treatment modification in 16 (7.2%) cases. The external staging cohort showed similar findings where dual-tracer PET/CT resulted in 12.5% (6/48) BCLC upstaging and 10.4% (5/48) treatment modifications (concordance-index: 0.85; 95% CI: 0.82-0.88). In subgroup analysis of 200 patients performed for pre-treatment metastatic screening, dual-tracer PET/CT detected extra-hepatic metastasis in 11, 10, and 16 patients, respectively, and led to treatment modifications in all of these patients. Sixteen locoregional therapies (8%) were avoided (8 resections, 3 transplantations, and 5 TACEs), with an estimated cost saving of US$161,665 (US$808 / patient) from the use of dual-tracer PET/CT. Sensitivity analyses suggested that dual-tracer PET/CT is consistently more cost-saving than conventional imaging, irrespective of the changes in the cost of imaging, procedures, and the duration of hospital stay (range: US$112,945-210,385). The cost of PET/CT had the greatest influence on the cost savings. Conclusions: Comparing to conventional imaging, dual-tracer PET/CT improves tumor staging, alters treatment allocation and is cost-saving in patients undergoing pre-treatment metastatic screening. Our results demonstrated that the use of dual-tracer PET/CT provides additional value and improves patient care.

High-grade esophageal neuroendocrine neoplasm with waxing and waning disease course and differential response to chemotherapy: Dual tracer positron emission tomography-computed tomography (18F-flurodeoxyglucose and 68Ga-DOTATATE) features and disease monitoring with functional molecular imaging

Esophageal neuroendocrine neoplasms (NENs) are uncommon type of esophageal malignancies. We describe the clinical course and molecular imaging features of the relatively rare esophageal malignancy (an aggressive poorly differentiated NEN) that was widely metastatic at the initial presentation. The patient underwent multiple cycles of chemotherapeutic regimens, employing cisplatin-etoposide and nanopaclitaxel-carboplatin and later on rechallenge with cisplatin-etoposide. There was observation of fluctuating disease course and differential characteristics of tumor lesions in terms of treatment response and recurrences with multiple cycles of chemotherapy. In view of the histopathology of high Mib-1 labeling index and dual tracer positron emission tomography-computed tomography (PET-CT) (flurodeoxyglucose [FDG] and 68Ga-DOTATATE) features, the patient was not a suitable candidate for 177Lu-DOTATATE PRRT and FDG PET-CT was the preferred imaging modality for both treatment response assessment and disease monitoring in this patient. The varying response among metastatic lesions in the same individual (with one lesion showing partial response and the other one demonstrating disease progression) was an additional noteworthy feature of the case.

Metastatic large cell neuroendocrine carcinoma of larynx: Individualizing tumor biology by dual tracer positron emission tomography/computed tomography (68Ga-DOTATATE and 18F-fluorodeoxyglucose) molecular imaging and disease stabilization following 177Lu-DOTATATE peptide receptor radionuclide therapy after initial progression on chemoradiotherapy

Metastatic large cell neuroendocrine carcinoma of larynx: Individualizing tumor biology by dual tracer positron emission tomography/computed tomography (⁶⁸Ga-DOTATATE and ¹⁸F-fluorodeoxyglucose) molecular imaging and disease stabilization following ¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy after initial progression on chemoradiotherapy

Glucose consumption of inflammatory cells masks metabolic deficits in the brain

Inflammatory cells such as microglia need energy to exert their functions and to maintain their cellular integrity and membrane potential. Subsequent to cerebral ischemia, inflammatory cells infiltrate tissue with limited blood flow where neurons and astrocytes died due to insufficient supply with oxygen and glucose. Using dual tracer positron emission tomography (PET), we found that concomitant with the presence of inflammatory cells, transport and consumption of glucose increased up to normal levels but returned to pathological levels as soon as inflammatory cells disappeared. Thus, inflammatory cells established sufficient glucose supply to satisfy their energy demands even in regions with insufficient supply for neurons and astrocytes to survive. Our data suggest that neurons and astrocytes died from oxygen deficiency and inflammatory cells metabolized glucose non-oxidatively in regions with residual availability. As a consequence, glucose metabolism of inflammatory cells can mask metabolic deficits in neurodegenerative diseases. We further found that the PET tracer did not bind to inflammatory cells in severely hypoperfused regions and thus only a part of the inflammation was detected. We conclude that glucose consumption of inflammatory cells should be taken into account when analyzing disease-related alterations of local cerebral metabolism.

Exploring spatial overlap of high-uptake regions derived from dual tracer positron emission tomography-computer tomography imaging using 18F-fluorodeoxyglucose and 18F-fluorodeoxythymidine in nonsmall cell lung cancer patients: a prospective pilot study.

Interest is growing in radiotherapy to nonuniformly boost radioresistant regions within nonsmall cell lung cancer (NSCLC) using molecular imaging techniques. The complexity of tumor behavior is beyond the ability of any single radiotracer to reveal. We hold dual tracer positron emission tomography–computer tomography (PET/CT) imaging with fluorodeoxyglucose (FDG) and fluorodeoxythymidine (FLT) for NSCLC patients to offer an integrated overlook of tumor biological behaviors quantitatively and localizationally, which may help biological target volume delineation and subvolume boost.Pathological confirmed that NSCLC patients were eligible. FDG and FLT PET/CT were performed for each patient before anticancer treatment and coregistrated for analysis. Maximum and mean standardized uptake values (SUVmax and SUVmean) were calculated automatically. Metabolic volumes (MVs) were delineated by a fixed 50% of SUVmax in FDG PET/CT and proliferative volumes (PVs) were delineated by 50% to 90% of SUVmax with 10% interval in FLT PET/CT. Overlap ratio (OR) were determined as overlapped volume between MV and PV divided PV. Conventional contrast-enhanced CT-based intensity-modulated radiotherapy (IMRT) plans with and without additional PET/CT-guided subtarget boost were made for each of the 5 typical NSCLC patients. Dosimetric parameters derived from dose–volume histogram, tumor control probability (TCP), and normal tissue complication probability (NTCP) of lung, esophagus, heart, and spinal cord were calculated and compared.Thirty-one patients were prospectively included and 23 were selected for analysis. Totally, 23 primary diseases, 41 metastatic lymph nodes, and 15 metastatic lesions were positive in dual PET/CTs and included for analysis. Median ORs increased from 58.61% to 93.12% under thresholds of 50% of SUVmax in FDG PET/CT and increased thresholds from 50% to 90% of SUVmax in FLT PET/CT. Based on conventional IMRT, additional boost to union of high FDG (determined by 50% SUVmax) and FLT (determined by 80% SUVmax) uptake subtargets exhibited higher TCP without significant elevated NTCP of lung, esophagus, spinal cord, and heart.Dual tracer PET/CT of FDG and FLT is suggested for NSCLC patients to guide tumor target delineation in clinical practice. FDG PET/CT is necessary whereas FLT PET/CT may be optional when guiding tumor target delineation clinically. Additional information from randomized trials is required to validate.

Bone metastases in hepatocellular carcinoma: an emerging issue

The nature and the characteristics of bone metastases (BMs) in hepatocellular carcinoma (HCC) have not been fully explored in literature, presumably because HCC skeletal involvement was rarely diagnosed until a few years ago. Recently, the prognosis and the management of HCC clinical progression have been improved thanks to novel imaging techniques and multidisciplinary treatment approaches. As in other osteotropic cancers, both angiogenesis and the epithelial-to-mesenchymal transition play a crucial role in skeletal colonization, with the cooperation of additional factors including vascular endothelial growth factor, transforming growth factor beta, platelet-derived growth factor, insulin-like growth factors I and II, bone morphogenetic proteins, secretory protein clusterin, and others. BMs from HCC are often characterized by soft-tissue expansion with an abundant vascular component and elevated tumor burden. As the majority of metastatic bone lesions from HCC are osteolytic, they are detectable by computerized tomography only at a late stage and not usually visualized by traditional bone scintigraphy. For this reason, new imaging tools are currently being investigated, such as dual tracer positron emission computerized tomography. HCC is frequently complicated by liver failure, resulting in a lower tolerance to opioids used for pain control, but radiotherapy and other local-regional treatments are useful in the treatment of BMs from HCC.

Brain glucose and acetoacetate metabolism: a comparison of young and older adults

The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brain's major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min−1) of glucose (Kg) and acetoacetate (Ka) were significantly lower (−11 ± 6%; [p = 0.005], and −19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.

Preoperative characterization of indeterminate large adrenal masses with dual tracer PET-CT using fluorine-18 fluorodeoxyglucose and gallium-68-DOTANOC: initial results

We aimed to evaluate the usefulness of dual tracer positron emission tomography-computed tomography (PET-CT) with flourine-18 fluorodeoxyglucose (18F-FDG) and gallium-68 [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-octreotide (68Ga-DOTANOC) in preoperative characterization of large indeterminate adrenal masses. Ten patients (four males, six females; median age, 35 years) with indeterminate, large (≥4 cm) adrenal masses were included in this prospective study. All patients underwent both 18F-FDG PET-CT and 68Ga-DOTANOC PET-CT within one week. Images were evaluated both visually and semi-quantitatively, with standardized uptake value (SUVmax) and SUVratio (SUVmax) of tumor/SUVmax) of mediastinum). Based on differential uptake pattern on 18F-FDG and 68Ga-DOTANOC, lesions were classified as cortical (18F-FDG>68Ga-DOTANOC), medullary (68Ga-DOTANOC>18F-FDG), or indeterminate (18F-FDG=68Ga-DOTANOC). Histopathology was taken as reference standard. Receiver operating characteristic (ROC) analysis was performed to find a cut-off of SUVmax) and SUVratio to differentiate cortical and medullary lesions. On histopathology, eight lesions were adrenocortical carcinomas, one was benign pheochromocytoma, and one was malignant pheochromocytoma. Visually, 18F-FDG PET-CT was positive in all ten lesions, while 68Ga-DOTANOC PET-CT was positive in two, both of which were pheochromocytomas. On SUVmax) based analysis, nine lesions were cortical and one was medullary. On ROC analysis, a SUVmax) cut-off of > 2.3 was obtained for 18F-FDG PET-CT and 3.6 for 68Ga-DOTANOC PET-CT for differentiating adrenal cortical and medullary lesions. The cut-off for SUVratio was 4.5 on 18F-FDG PET-CT and 11.1 on 68Ga-DOTANOC PET-CT. These preliminary results demonstrate that dual tracer PET-CT using 18F-FDG and 68Ga-DOTANOC could be informative in the preoperative characterization of large indeterminate adrenal masses.

The ketogenic diet increases brain glucose and ketone uptake in aged rats: A dual tracer PET and volumetric MRI study

Despite decades of study, it is still unclear whether regional brain glucose uptake is lower in the cognitively healthy elderly. Whether regional brain uptake of ketones (β-hydroxybutyrate and acetoacetate [AcAc]), the main alternative brain fuel to glucose, changes with age is unknown. We used a sequential, dual tracer positron emission tomography (PET) protocol to quantify brain (18)F-fluorodeoxyglucose ((18)F-FDG) and (11)C-AcAc uptake in two studies with healthy, male Sprague-Dawley rats: (i) Aged (21 months; 21M) versus young (4 months; 4M) rats, and (ii) The effect of a 14 day high-fat ketogenic diet (KD) on brain (18)F-FDG and (11)C-AcAc uptake in 24 month old rats (24M). Similar whole brain volumes assessed by magnetic resonance imaging, were observed in aged 21M versus 4M rats, but the lateral ventricles were 30% larger in the 21M rats (p=0.001). Whole brain cerebral metabolic rates of AcAc (CMR(AcAc)) and glucose (CMR(glc)) did not differ between 21M and 4M rats, but were 28% and 44% higher, respectively, in 24M-KD compared to 24M rats. The region-to-whole brain ratio of CMR(glc) was 37-41% lower in the cortex and 40-45% lower in the cerebellum compared to CMR(AcAc) in 4M and 21M rats. We conclude that a quantitative measure of uptake of the brain's two principal exogenous fuels was generally similar in healthy aged and young rats, that the % of distribution across brain regions differed between ketones and glucose, and that brain uptake of both fuels was stimulated by mild, experimental ketonemia.

PET Measurement of rCBF in the presence of a neurochemical tracer

Functional neurochemical imaging can indicate neurotransmitter release by detecting changes in receptor occupancy. A dual tracer positron emission tomography (PET) technique is presented here to extend such studies by simultaneously measuring changes in regional cerebral blood flow (rCBF). This would permit correlations of task or drug induced changes in rCBF and neurochemical function. In this proposed method, the rapidly varying signal from a blood flow tracer is distinguished from the slowly changing signal due to a long-lived neurochemical tracer. As a proof of principle, baseline studies were carried out in rhesus monkeys. Two monkeys were anesthetized with isoflurane, and [ 18 F ]fallypride ( t 1/2=110 min), a dopamine D2 receptor antagonist, was injected. Starting 99–137 min after injection, PET images were acquired every 10 s while the blood flow tracer [ 17 F ]fluoromethane ( t 1/2=65 s) was administered by inhalation in a repeating pattern of 45 s on/45 s off. The observed time–activity curves for 2 ml brain regions were fit with a three compartment lung–body–brain model of fluoromethane kinetics with whole brain perfusion fixed. Comparing consecutive 6 min scans, reproducibility of relative rCBF and striatal [ 18 F ]fallypride concentration were 9 and 8%, respectively.