The First Human Application of an F-18-Labeled Tryptophan Analog for PET Imaging of Cancer.

PURPOSE: Preclinical studies showed the tryptophan analog PET radiotracer 1-(2-18F-fluoroethyl)-L-tryptophan (18F-FETrp) to accumulate in various tumors, including gliomas, and being metabolized via the immunosuppressive kynurenine pathway. In this first-in-human study, we tested the use 18F-FETrp-PET in patients with neuroendocrine and brain tumors. PROCEDURES: We applied dynamic brain imaging in patients with gliomas (n = 2) and multi-pass 3D whole-body PET scans in patients with neuroendocrine tumors (n =4). Semiquantitative analysis of organ and tumor tracer uptake was performed using standardized uptake values (SUVs). In addition, organ dosimetry was performed based on extracted time-activity curves and the OLINDA software. RESULTS: Neuroendocrine tumors showed an early peak (10-min post-injection) followed by washout. Both gliomas showed prolonged 18F-FETrp accumulation plateauing around 40 min and showing heterogeneous uptake including non-enhancing tumor regions. Biodistribution showed moderate liver uptake and fast clearance of radioactivity into the urinary bladder; the estimated effective doses were similar to other 18F-labeled radioligands. CONCLUSIONS: The study provides proof-of-principle data for the safety and potential clinical value of 18F-FETrp-PET for molecular imaging of human gliomas.

Fully Automated, Fast Motion Correction of Dynamic Whole-Body and Total-Body PET/CT Imaging Studies.

We introduce the Fast Algorithm for Motion Correction (FALCON) software, which allows correction of both rigid and nonlinear motion artifacts in dynamic whole-body (WB) images, irrespective of the PET/CT system or the tracer. Methods: Motion was corrected using affine alignment followed by a diffeomorphic approach to account for nonrigid deformations. In both steps, images were registered using multiscale image alignment. Moreover, the frames suited to successful motion correction were automatically estimated by calculating the initial normalized cross-correlation metric between the reference frame and the other moving frames. To evaluate motion correction performance, WB dynamic image sequences from 3 different PET/CT systems (Biograph mCT, Biograph Vision 600, and uEXPLORER) using 6 different tracers (18F-FDG, 18F-fluciclovine, 68Ga-PSMA, 68Ga-DOTATATE, 11C-Pittsburgh compound B, and 82Rb) were considered. Motion correction accuracy was assessed using 4 different measures: change in volume mismatch between individual WB image volumes to assess gross body motion, change in displacement of a large organ (liver dome) within the torso due to respiration, change in intensity in small tumor nodules due to motion blur, and constancy of activity concentration levels. Results: Motion correction decreased gross body motion artifacts and reduced volume mismatch across dynamic frames by about 50%. Moreover, large-organ motion correction was assessed on the basis of correction of liver dome motion, which was removed entirely in about 70% of all cases. Motion correction also improved tumor intensity, resulting in an average increase in tumor SUVs by 15%. Large deformations seen in gated cardiac 82Rb images were managed without leading to anomalous distortions or substantial intensity changes in the resulting images. Finally, the constancy of activity concentration levels was reasonably preserved (<2% change) in large organs before and after motion correction. Conclusion: FALCON allows fast and accurate correction of rigid and nonrigid WB motion artifacts while being insensitive to scanner hardware or tracer distribution, making it applicable to a wide range of PET imaging scenarios.

177Lu-DOTATATE Theranostics: Predicting Renal Dosimetry From Pretherapy 68Ga-DOTATATE PET and Clinical Biomarkers.

PURPOSE: Pretreatment predictions of absorbed doses can be especially valuable for patient selection and dosimetry-guided individualization of radiopharmaceutical therapy. Our goal was to build regression models using pretherapy 68Ga-DOTATATE PET uptake data and other baseline clinical factors/biomarkers to predict renal absorbed dose delivered by 177Lu-DOTATATE peptide receptor radionuclide therapy (177Lu-PRRT) for neuroendocrine tumors. We explore the combination of biomarkers and 68Ga PET uptake metrics, hypothesizing that they will improve predictive power over univariable regression. PATIENTS AND METHODS: Pretherapy 68Ga-DOTATATE PET/CTs were analyzed for 25 patients (50 kidneys) who also underwent quantitative 177Lu SPECT/CT imaging at approximately 4, 24, 96, and 168 hours after cycle 1 of 177Lu-PRRT. Kidneys were contoured on the CT of the PET/CT and SPECT/CT using validated deep learning-based tools. Dosimetry was performed by coupling the multi-time point SPECT/CT images with an in-house Monte Carlo code. Pretherapy renal PET SUV metrics, activity concentration per injected activity (Bq/mL/MBq), and other baseline clinical factors/biomarkers were investigated as predictors of the 177Lu SPECT/CT-derived mean absorbed dose per injected activity to the kidneys using univariable and bivariable models. Leave-one-out cross-validation (LOOCV) was used to estimate model performance using root mean squared error and absolute percent error in predicted renal absorbed dose including mean absolute percent error (MAPE) and associated standard deviation (SD). RESULTS: The median therapy-delivered renal dose was 0.5 Gy/GBq (range, 0.2-1.0 Gy/GBq). In LOOCV of univariable models, PET uptake (Bq/mL/MBq) performs best with MAPE of 18.0% (SD = 13.3%), and estimated glomerular filtration rate (eGFR) gives an MAPE of 28.5% (SD = 19.2%). Bivariable regression with both PET uptake and eGFR gives LOOCV MAPE of 17.3% (SD = 11.8%), indicating minimal improvement over univariable models. CONCLUSIONS: Pretherapy 68Ga-DOTATATE PET renal uptake can be used to predict post-177Lu-PRRT SPECT-derived mean absorbed dose to the kidneys with accuracy within 18%, on average. Compared with PET uptake alone, including eGFR in the same model to account for patient-specific kinetics did not improve predictive power. Following further validation of these preliminary findings in an independent cohort, predictions using renal PET uptake can be used in the clinic for patient selection and individualization of treatment before initiating the first cycle of PRRT.

Automated radiosynthesis of 1-(2-[18 F]fluoroethyl)-L-tryptophan ([18 F]FETrp) for positron emission tomography (PET) imaging of cancer in humans.

The radiotracer 1-(2-[18 F]fluoroethyl)-L-tryptophan (L-[18 F]FETrp or [18 F]FETrp) is a substrate of indoleamine 2,3-dioxygenase, the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical positron emission tomography studies, [18 F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first-in-human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging. However, efficient purification is essential for human studies in order to assure radiochemical and enantiomeric purity. In this work, we report a fully automated radiosynthesis of [18 F]FETrp on a Synthra RNPlus research module, including a one-pot two steps radiosynthesis, dual independent chiral and reverse-phase semipreparative high-performance liquid chromatography purifications, and solid-phase extraction-assisted formulation. The presented approach has led to its Investigational New Drug application and approval that allows the testing of this tracer in humans.

Fully Automated, Semantic Segmentation of Whole-Body 18F-FDG PET/CT Images Based on Data-Centric Artificial Intelligence.

We introduce multiple-organ objective segmentation (MOOSE) software that generates subject-specific, multiorgan segmentation using data-centric artificial intelligence principles to facilitate high-throughput systemic investigations of the human body via whole-body PET imaging. Methods: Image data from 2 PET/CT systems were used in training MOOSE. For noncerebral structures, 50 whole-body CT images were used, 30 of which were acquired from healthy controls (14 men and 16 women), and 20 datasets were acquired from oncology patients (14 men and 6 women). Noncerebral tissues consisted of 13 abdominal organs, 20 bone segments, subcutaneous fat, visceral fat, psoas muscle, and skeletal muscle. An expert panel manually segmented all noncerebral structures except for subcutaneous fat, visceral fat, and skeletal muscle, which were semiautomatically segmented using thresholding. A majority-voting algorithm was used to generate a reference-standard segmentation. From the 50 CT datasets, 40 were used for training and 10 for testing. For cerebral structures, 34 18F-FDG PET/MRI brain image volumes were used from 10 healthy controls (5 men and 5 women imaged twice) and 14 nonlesional epilepsy patients (7 men and 7 women). Only 18F-FDG PET images were considered for training: 24 and 10 of 34 volumes were used for training and testing, respectively. The Dice score coefficient (DSC) was used as the primary metric, and the average symmetric surface distance as a secondary metric, to evaluate the automated segmentation performance. Results: An excellent overlap between the reference labels and MOOSE-derived organ segmentations was observed: 92% of noncerebral tissues showed DSCs of more than 0.90, whereas a few organs exhibited lower DSCs (e.g., adrenal glands [0.72], pancreas [0.85], and bladder [0.86]). The median DSCs of brain subregions derived from PET images were lower. Only 29% of the brain segments had a median DSC of more than 0.90, whereas segmentation of 60% of regions yielded a median DSC of 0.80-0.89. The results of the average symmetric surface distance analysis demonstrated that the average distance between the reference standard and the automatically segmented tissue surfaces (organs, bones, and brain regions) lies within the size of image voxels (2 mm). Conclusion: The proposed segmentation pipeline allows automatic segmentation of 120 unique tissues from whole-body 18F-FDG PET/CT images with high accuracy.

Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review.

Due to its metabolism via the serotonin and kynurenine pathways, tryptophan plays a key role in multiple disease processes including cancer. Imaging tryptophan uptake and metabolism in vivo can be achieved with tryptophan derivative positron emission tomography (PET) radiotracers. While human studies with such tracers have been confined to C-11-labeled compounds, preclinical development of F-18-labeled tryptophan-based radiotracers has surged in recent years. We performed a systematic review of studies reporting on such F-18-labeled tryptophan tracers to summarize and compare their biological characteristics and their potential for tumor imaging, with a particular focus on key enzymes of the kynurenine pathway (indoleamine 2,3-dioxygenase [IDO] and tryptophan 2,3-dioxygenase [TDO]), which play an important role in tumoral immune resistance. From a PubMed search, English language articles including data on the preparation and radiochemical and/or biological characteristics of F-18-labeled tryptophan derivative radiotracers were reviewed. A total of 19 original papers included data on 15 unique radiotracers, the majority of which were synthesized with an adequate radiochemical yield. Automated synthesis was reported for 1-(2-[18F]fluoroethyl)-L-tryptophan, the most extensively evaluated tracer thus far. Biodistribution studies showed high uptake in the pancreas, while the L-type amino acid transporter was the dominant transport mechanism for most of the reviewed tracers. Tracers tested for tumor uptake showed accumulation in tumor cell lines in vitro and in xenografts in vivo, often with favorable tumor-to-background uptake ratios in comparison with clinically used F-18-labeled radiotracers. Five tracers showed promise for imaging IDO activity, including 1-(2-[18F]fluoroethyl)-L-tryptophan and a F-18-labeled analog of alpha-[11C]methyl-L-tryptophan tested clinically in previous studies. Two radiotracers were metabolized by TDO but showed defluorination in vivo. In summary, most F-18-labeled tryptophan derivative PET tracers share common transport mechanisms and biodistribution characteristics. Several reported tracers could be candidates for further testing and validation toward PET imaging applications in a variety of human diseases.

Age-dependent changes of cerebral copper metabolism in Atp7b -/- knockout mouse model of Wilson's disease by [64Cu]CuCl2-PET/CT.

Copper is a nutritional metal required for brain development and function. Wilson's disease (WD), or hepatolenticular degeneration, is an inherited human copper metabolism disorder caused by a mutation of the ATP7B gene. Many WD patients present with variable neurological and psychiatric symptoms, which may be related to neurodegeneration secondary to copper metabolism imbalance. The objective of this study was to explore the feasibility and use of copper-64 chloride ([64C]CuCl2) as a tracer for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD using an Atp7b -/- knockout mouse model of WD and positron emission tomography/computed tomography (PET/CT) imaging. Continuing from our recent study of biodistribution and radiation dosimetry of [64C]CuCl2 in Atp7b -/- knockout mice, PET quantitative analysis revealed low 64Cu radioactivity in the brains of Atp7b -/- knockout mice at 7th weeks of age, compared with 64Cu radioactivity in the brains of age- and gender-matched wild type C57BL/6 mice, at 24 h (h) post intravenous injection of [64C]CuCl2 as a tracer. Furthermore, age-dependent increase of 64Cu radioactivity was detected in the brains of Atp7b -/- knockout mice from the 13th to 21th weeks of age, based on the data derived from a longitudinal [64C]CuCl2-PET/CT study of Atp7b -/- knockout mice with orally administered [64Cu]CuCl2 as a tracer. The findings of this study support clinical use of [64Cu]CuCl2-PET/CT imaging as a tool for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD patients presenting with variable neurological and psychiatric symptoms.

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts.

Abnormal tryptophan metabolism via the kynurenine pathway is involved in the pathophysiology of a variety of human diseases including cancers. α-11C-methyl-l-tryptophan (11C-AMT) PET imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of 11C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-18F-fluoroethyl)-l-tryptophan (18F-FETrp) may be useful to assess tryptophan metabolism via the kynurenine pathway. In this study, we tested in vivo organ and tumor uptake and kinetics of 18F-FETrp in patient-derived xenograft mouse models and compared them with 11C-AMT uptake. METHODS: Xenograft mouse models of glioblastoma and metastatic brain tumors (from lung and breast cancer) were developed by subcutaneous implantation of patient tumor fragments. Dynamic PET scans with 18F-FETrp and 11C-AMT were obtained for mice bearing human brain tumors 1-7 d apart. The biodistribution and tumoral SUVs for both tracers were compared. RESULTS: 18F-FETrp showed prominent uptake in the pancreas and no bone uptake, whereas 11C-AMT showed higher uptake in the kidneys. Both tracers showed uptake in the xenograft tumors, with a plateau of approximately 30 min after injection; however, 18F-FETrp showed higher tumoral SUV than 11C-AMT in all 3 tumor types tested. The radiation dosimetry for 18F-FETrp determined from the mouse data compared favorably with the clinical 18F-FDG PET tracer. CONCLUSION: 18F-FETrp tumoral uptake, biodistribution, and radiation dosimetry data provide strong preclinical evidence that this new radiotracer warrants further studies that may lead to a broadly applicable molecular imaging tool to examine abnormal tryptophan metabolism in human tumors.

Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.

Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM.

Flow perfusion culture of MC3T3-E1 osteogenic cells on gradient calcium polyphosphate scaffolds with different pore sizes.

Calcium polyphosphate is a biodegradable bone substitute. It remains a challenge to prepare porous calcium polyphosphate with desired gradient porous structures. In this study, a modified one-step gravity sintering method was used to prepare calcium polyphosphate scaffolds with desired-gradient-pore-size distribution. The differences of porous structure, mechanical strength, and degradation rate between gradient and homogenous calcium polyphosphate scaffolds were evaluated by micro-computed tomography, scanning electron microscopy, and mechanical testing. Preosteoblastic MC3T3-E1 cells were seeded onto gradient and homogenous calcium polyphosphate scaffolds and cultured in a flow perfusion bioreactor. The distribution, proliferation, and differentiation of the MC3T3-E1 cells were compared to that of homogenous calcium polyphosphate scaffolds. Though no significant difference of cell proliferation was found between the gradient and the homogenous calcium polyphosphate scaffolds, a much higher cell differentiation and mineralization were observed in the gradient calcium polyphosphate scaffolds than that of the homogenous calcium polyphosphate scaffolds, as manifested by increased alkaline phosphatase activity (p < 0.05). The improved distribution and differentiation of cultured cells within gradient scaffolds were further supported by both (18)F-fluorine micro-positron emission tomography scanning and in vitro tetracycline labeling. We conclude that the calcium polyphosphate scaffold with gradient pore sizes enhances osteogenic cell differentiation as well as mineralization. The in vivo performance of gradient calcium polyphosphate scaffolds warrants further investigation in animal bone defect models.

Assessment of Traumatic Brain Injury by Increased 64Cu Uptake on 64CuCl2 PET/CT.

UNLABELLED: Copper is a nutritional trace element required for cell proliferation and wound repair. METHODS: To explore increased copper uptake as a biomarker for noninvasive assessment of traumatic brain injury (TBI), experimental TBI in C57BL/6 mice was induced by controlled cortical impact, and (64)Cu uptake in the injured cortex was assessed with (64)CuCl2 PET/CT. RESULTS: At 24 h after intravenous injection of the tracer, uptake was significantly higher in the injured cortex of TBI mice (1.15 ± 0.53 percentage injected dose per gram of tissue [%ID/g]) than in the uninjured cortex of mice without TBI (0.53 ± 0.07 %ID/g, P = 0.027) or the cortex of mice that received an intracortical injection of zymosan A (0.62 ± 0.22 %ID/g, P = 0.025). Furthermore, uptake in the traumatized cortex of untreated TBI mice (1.15 ± 0.53 %ID/g) did not significantly differ from that in minocycline-treated TBI mice (0.93 ± 0.30 %ID/g, P = 0.33). CONCLUSION: Overall, the data suggest that increased (64)Cu uptake in traumatized brain tissues holds potential as a new biomarker for noninvasive assessment of TBI with (64)CuCl2 PET/CT.

Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas.

BACKGROUND: Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas. However, details of tryptophan metabolism in meningiomas have not been elucidated. In this study, we evaluated in vivo tryptophan metabolism in meningiomas and compared it with gliomas using α-[(11)C]-methyl-L-tryptophan (AMT)-PET. We also explored expression patterns of KP enzymes in resected meningiomas. METHODS: Forty-seven patients with MRI-detected meningioma (n = 16) and glioma (n = 31) underwent presurgical AMT-PET scanning. Tumoral AMT uptake and tracer kinetic parameters (including K and k3' evaluating unidirectional uptake and trapping, respectively) were measured, correlated with meningioma grade, and compared between meningiomas and gliomas. Patterns of KP enzyme expression were assessed by immunohistochemistry in all meningiomas. RESULTS: Meningioma grade showed a positive correlation with AMT k3' tumor/cortex ratio (r = 0.75, P = .003), and this PET parameter distinguished grade I from grade II/III meningiomas with 92% accuracy. Kinetic AMT parameters could differentiate meningiomas from both low-grade gliomas (97% accuracy by k3' ratios) and high-grade gliomas (83% accuracy by K ratios). Among 3 initial KP enzymes (indoleamine 2,3-dioxygenase 1/2, and tryptophan 2,3-dioxygenase 2 [TDO2]), TDO2 showed the strongest immunostaining, particularly in grade I meningiomas. TDO2 also showed a strong negative correlation with AMT k3' ratios (P = .001). CONCLUSIONS: PET imaging of tryptophan metabolism can provide quantitative imaging markers for differentiating grade I from grade II/III meningiomas. TDO2 may be an important driver of in vivo tryptophan metabolism in these tumors. These results can have implications for pharmacological targeting of the KP in meningiomas.

Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma.

UNLABELLED: α-(11)C-methyl-L-tryptophan (AMT) PET allows evaluation of brain serotonin synthesis and can also track upregulation of the immunosuppressive kynurenine pathway in tumor tissue. Increased AMT uptake is a hallmark of World Health Organization grade III-IV gliomas. Our recent study also suggested decreased frontal cortical AMT uptake in glioma patients contralateral to the tumor. The clinical significance of extratumoral tryptophan metabolism has not been established. In the present study, we investigated clinical correlates of tryptophan metabolic abnormalities in the nontumoral hemisphere of glioma patients. METHODS: Standardized AMT uptake values (SUVs) and the uptake rate constant of AMT (K [mL/g/min], a measure proportional to serotonin synthesis in nontumoral gray matter) were quantified in the frontal and temporal cortex and thalamus in the nontumoral hemisphere in 77 AMT PET scans of 66 patients (41 men, 25 women; mean age ± SD, 55 ± 15 y) with grade III-IV gliomas. These AMT values were determined before treatment in 35 and after treatment in 42 patients and were correlated with clinical variables and survival. RESULTS: AMT uptake in the thalamus showed a moderate age-related increase before treatment (SUV, r = 0.39, P = 0.02) but decrease after treatment (K, r = -0.33, P = 0.057). Women had higher thalamic SUVs before treatment (P = 0.037) and higher thalamic (P = 0.013) and frontal cortical K values (P = 0.023) after treatment. In the posttreatment glioma group, high thalamic SUVs and high thalamocortical SUV ratios were associated with short survival in Cox regression analysis. The thalamocortical ratio remained strongly prognostic (P < 0.01) when clinical predictors, including age, glioma grade, and time since radiotherapy, were entered in the regression model. Long interval between radiotherapy and posttreatment AMT PET as well as high radiation dose affecting the thalamus were associated with lower contralateral thalamic or cortical AMT uptake values. CONCLUSION: These observations provide evidence for altered tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system. Low thalamic tryptophan uptake appears to be a strong, independent predictor of long survival in patients with previous glioma treatment.

Reduced 64Cu uptake and tumor growth inhibition by knockdown of human copper transporter 1 in xenograft mouse model of prostate cancer.

UNLABELLED: Copper is an element required for cell proliferation and angiogenesis. Human prostate cancer xenografts with increased (64)Cu radioactivity were visualized previously by PET using (64)CuCl2 as a radiotracer ((64)CuCl2 PET). This study aimed to determine whether the increased tumor (64)Cu radioactivity was due to increased cellular uptake of (64)Cu mediated by human copper transporter 1 (hCtr1) or simply due to nonspecific binding of ionic (64)CuCl2 to tumor tissue. In addition, the functional role of hCtr1 in proliferation of prostate cancer cells and tumor growth was also assessed. METHODS: A lentiviral vector encoding short-hairpin RNA specific for hCtr1 (Lenti-hCtr1-shRNA) was constructed for RNA interference-mediated knockdown of hCtr1 expression in prostate cancer cells. The degree of hCtr1 knockdown was determined by Western blot, and the effect of hCtr1 knockdown on copper uptake and proliferation were examined in vitro by cellular (64)Cu uptake and cell proliferation assays. The effects of hCtr1 knockdown on tumor uptake of (64)Cu were determined by PET quantification and tissue radioactivity assay. The effects of hCtr1 knockdown on tumor growth were assessed by PET/CT and tumor size measurement with a caliper. RESULTS: RNA interference-mediated knockdown of hCtr1 was associated with the reduced cellular uptake of (64)Cu and the suppression of prostate cancer cell proliferation in vitro. At 24 h after intravenous injection of the tracer (64)CuCl2, the (64)Cu uptake by the tumors with knockdown of hCtr1 (4.02 ± 0.31 percentage injected dose per gram [%ID/g] in Lenti-hCtr1-shRNA-PC-3 and 2.30 ± 0.59 %ID/g in Lenti-hCtr1-shRNA-DU-145) was significantly lower than the (64)Cu uptake by the control tumors without knockdown of hCtr1 (7.21 ± 1.48 %ID/g in Lenti-SCR-shRNA-PC-3 and 5.57 ± 1.20 %ID/g in Lenti-SCR-shRNA-DU-145, P < 0.001) by PET quantification. Moreover, the volumes of prostate cancer xenograft tumors with knockdown of hCtr1 (179 ± 111 mm(3) for Lenti-hCtr1-shRNA-PC-3 or 39 ± 22 mm(3) for Lenti-hCtr1-shRNA-DU-145) were significantly smaller than those without knockdown of hCtr1 (536 ± 191 mm(3) for Lenti- SCR-shRNA-PC-3 or 208 ± 104 mm(3) for Lenti-SCR-shRNA-DU-145, P < 0.01). CONCLUSION: Overall, data indicated that hCtr1 is a promising theranostic target, which can be further developed for metabolic imaging of prostate cancer using (64)CuCl2 PET/CT and personalized cancer therapy targeting copper metabolism.

Increased tryptophan uptake on PET has strong independent prognostic value in patients with a previously treated high-grade glioma.

BACKGROUND: Previously, we demonstrated the high accuracy of alpha-[(11)C]methyl-L-tryptophan (AMT) PET for differentiating recurrent gliomas from radiation injury. The present study evaluated the prognostic value of increased AMT uptake in patients with previously treated high-grade glioma. METHODS: AMT-PET was performed in 39 patients with suspected recurrence of World Health Organization grades III-IV glioma following surgical resection, radiation, and chemotherapy. Mean and maximum standardized uptake values (SUVs) and unidirectional AMT uptake (K) were measured in brain regions suspicious for tumor and compared with the contralateral cortex (ie, background). Optimal cutoff thresholds for 1-year survival prediction were determined for each AMT parameter and used for calculating the prognostic value of high (above threshold) versus low (below threshold) values for post-PET overall survival (OS). RESULTS: In univariate analyses, 1-year survival was strongly associated with 3 AMT parameters (SUVmax, SUVmean, and tumor-to-background K-ratio; odds ratios: 21.3-25.6; P ≤ .001) and with recent change in MRI contrast enhancement (odds ratio: 14.7; P = .02). Median OS was 876 days in the low- versus 177 days in the high-AMT groups (log-rank P < .001). In multivariate analyses, all 3 AMT parameters remained strong predictors of survival: high AMT values were associated with unfavorable 1-year survival (binary regression P ≤ .003) and shorter overall survival in the whole group (Cox regression hazard ratios: 5.3-10.0) and in patients with recent enhancement change on MRI as well (hazard ratios: 7.0-9.3; P ≤ .001). CONCLUSION: Increased AMT uptake on PET is highly prognostic for 1-year and overall survival, independent of MRI contrast enhancement and other prognostic factors in patients with a previously treated high-grade glioma.

Evaluating signal-correlated noise as a control task with language-related gamma activity on electrocorticography.

OBJECTIVE: Our recent electrocorticography (ECoG) study suggested reverse speech, a widely used control task, to be a poor control for non-language-related auditory activity. We hypothesized that this may be due to retained perception as a human voice. We report a follow-up ECoG study in which we contrast forward and reverse speech with a signal-correlated noise (SCN) control task that cannot be perceived as a human voice. METHODS: Ten patients were presented 90 audible stimuli, including 30 each of corresponding forward speech, reverse speech, and SCN trials, during ECoG recording with evaluation of gamma activity between 50 and 150 Hz. RESULTS: Sites of the lateral temporal gyri activated throughout speech stimuli were generally less activated by SCN, while some temporal sites seemed to process both human and non-human sounds. Reverse speech trials were associated with activities across the temporal lobe similar to those associated with forward speech. CONCLUSIONS: Findings herein externally validate functional neuroimaging studies utilizing SCN as a control for non-language-specific auditory function. Our findings are consistent with the notion that stimuli perceived as originating from a human voice are poor controls for non-language auditory function. SIGNIFICANCE: Our findings have implications in functional neuroimaging research as well as improved clinical mapping of auditory functions.

Differentiation of glioblastomas from metastatic brain tumors by tryptophan uptake and kinetic analysis: a positron emission tomographic study with magnetic resonance imaging comparison.

Differentiating high-grade gliomas from solitary brain metastases is often difficult by conventional magnetic resonance imaging (MRI); molecular imaging may facilitate such discrimination. We tested the accuracy of α[11C]methyl-l-tryptophan (AMT)-positron emission tomography (PET) to differentiate newly diagnosed glioblastomas from brain metastases. AMT-PET was performed in 36 adults with suspected brain malignancy. Tumoral AMT accumulation was measured by standardized uptake values (SUVs). Tracer kinetic analysis was also performed to separate tumoral net tryptophan transport (by AMT volume of distribution [VD]) from unidirectional uptake rates using dynamic PET and blood input function. Differentiating the accuracy of these PET variables was evaluated and compared to conventional MRI. For glioblastoma/metastasis differentiation, tumoral AMT SUV showed the highest accuracy (74%) and the tumor/cortex VD ratio had the highest positive predictive value (82%). The combined accuracy of MRI (size of contrast-enhancing lesion) and AMT-PET reached up to 93%. For ring-enhancing lesions, tumor/cortex SUV ratios were higher in glioblastomas than in metastatic tumors and could differentiate these two tumor types with > 90% accuracy. These results demonstrate that evaluation of tryptophan accumulation by PET can enhance pretreatment differentiation of glioblastomas and metastatic brain tumors. This approach may be particularly useful in patients with a newly diagnosed solitary ring-enhancing mass.

Tryptophan PET in pretreatment delineation of newly-diagnosed gliomas: MRI and histopathologic correlates.

Pretreatment delineation of infiltrating glioma volume remains suboptimal with current neuroimaging techniques. Gadolinium-enhanced T1-weighted (T1-Gad) MR images often underestimate the true extent of the tumor, while T2-weighted images preferentially highlight peritumoral edema. Accumulation of α-[(11)C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) has been shown in gliomas. To determine whether increased uptake on AMT-PET would detect tumor-infiltrated brain tissue outside the contrast-enhancing region and differentiate it from peritumoral vasogenic edema, volumes and spatial concordance of T1-Gad and T2 MRI abnormalities as well as AMT-PET abnormalities were analyzed in 28 patients with newly-diagnosed WHO grade II-IV gliomas. AMT-accumulating grade I meningiomas were used to define an AMT uptake cutoff threshold that detects the tumor but excludes peri-meningioma vasogenic edema. Tumor infiltration in AMT-accumulating areas was studied in stereotactically-resected specimens from patients with glioblastoma. In the 28 gliomas, mean AMT-PET-defined tumor volumes were greater than the contrast-enhancing volume, but smaller than T2 abnormalities. Volume of AMT-accumulating tissue outside MRI abnormalities increased with higher tumor proliferative index and was the largest in glioblastomas. Tumor infiltration was confirmed by histopathology from AMT-positive regions outside contrast-enhancing glioblastoma mass, while no or minimal tumor cells were found in AMT-negative specimens. These results demonstrate that increased AMT accumulation on PET detects glioma-infiltrated brain tissue extending beyond the contrast-enhanced tumor mass. While tryptophan uptake is low in peritumoral vasogenic edema, AMT-PET can detect tumor-infiltrated brain outside T2-lesions. Thus, AMT-PET may assist pretreatment delineation of tumor infiltration, particularly in high-grade gliomas.

Evaluation of age-related changes in translocator protein (TSPO) in human brain using (11)C-[R]-PK11195 PET.

BACKGROUND: We studied the distribution and expression of translocator protein in the human brain using (11)C-[R]-PK-11195 positron emission tomography (PK11195 PET) and evaluated age-related changes. METHODS: A dynamic PK11195 PET scan was performed in 15 normal healthy adults (mean age: 29 ±8.5 years (range: 20 to 49); 7 males) and 10 children (mean age: 8.8 ±5.2 years (range: 1.2 to 17); 5 males), who were studied for potential neuroinflammation but showed no focally increased PK11195 binding. The PET images were evaluated by calculating standard uptake values and regional binding potential, based on a simplified reference region model, as well as with a voxel-wise analysis using statistical parametric mapping. RESULTS: PK11195 uptake in the brain is relatively low, compared with the subcortical structures, and symmetrical. The overall pattern of PK11195 distribution in the brain does not change with age. PK11195 uptake was lowest in the frontal-parietal-temporal cortex and highest in the pituitary gland, midbrain, thalamus, basal ganglia, occipital cortex, hippocampus and cerebellum, in descending order. White matter showed negligible PK11195 uptake. Overall, brain PK11195 uptake increased with age, with midbrain and thalamus showing relatively higher increases with age compared with other brain regions. CONCLUSIONS: The brain shows low PK11195 uptake, which is lower in the cortex and cerebellum compared with subcortical structures, suggesting a low level of translocator protein expression. There is no hemispheric asymmetry in PK11195 uptake and the overall pattern of PK11195 distribution in the brain does not change with age. However, brain PK11195 uptake increases with age, with the thalamus and midbrain showing relatively higher increases compared with other brain regions. This increase in uptake suggests an age-related increase in translocator protein expression or the number of cells expressing these receptors or both.

Quantitative PET imaging of tryptophan accumulation in gliomas and remote cortex: correlation with tumor proliferative activity.

PURPOSE: PET studies with α[C-11]methyl-L-tryptophan (AMT) have shown decreased serotonin synthesis based on a decrease of the unidirectional uptake rate (K-complex) in neuropsychiatric conditions such as autism and depression. Increased AMT K-complex in tumors can indicate increased tryptophan metabolism via the immunosuppressive kynurenine pathway. Moreover, apparent AMT volume of distribution (VD') reflects net tryptophan transport from blood to tissue. We evaluated if kinetic parameters (K-complex, VD') of AMT, measured by PET, can predict the proliferative activity of glioma, and if these AMT parameters are altered in the remote cortex. METHODS: We evaluated dynamic AMT PET images of 30 adult patients with grade 2 to 4 gliomas according to the World Health Organization's classification to determine tumoral AMT VD' and K-complex values, which were correlated with tumor proliferative activity as assessed by the Ki-67 labeling index in resected tumor specimens. We also compared cortical VD' and K-complex values between patients with glioma and healthy controls. RESULTS: Both VD' and K-complex values were significantly higher in gliomas than in the contralateral cortex (VD', P < 0.001; K-complex, P < 0.001). Tumoral VD' values and tumor/cortex VD' ratios, but not the K-complex, showed strong positive correlations with the proliferative activity of glioma (P ≤ 0.001). The contralateral frontal cortex showed decreased AMT VD' and K-complex in patients with glioma compared with those in controls (P ≤ 0.01). CONCLUSIONS: Increased net amino acid transport into tumor tissue, quantified by PET, can serve as an imaging marker of the proliferative activity of glioma. The data also suggest a glioma-induced down-regulation of cortical serotonin synthesis, likely mediated by shunting of tryptophan from serotonin synthesis to kynurenine metabolism.