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BACKGROUND: The PET tracer (4S)-4-(3-[(18)F]fluoropropyl)-l-glutamate ((18)F-FSPG) targets the system x(C)(–) cotransporter, which is overexpressed in various tumors. PURPOSE: To assess the role of (18)F-FSPG PET/CT in intracranial malignancies. MATERIALS AND METHODS: Twenty-six patients (mean age, 54 years ± 12; 17 men; 48 total lesions) with primary brain tumors (n = 17) or brain metastases (n = 9) were enrolled in this prospective, single-center study (ClinicalTrials.gov identifier: NCT02370563) between November 2014 and March 2016. A 30-minute dynamic brain (18)F-FSPG PET/CT scan and a static whole-body (WB) (18)F-FSPG PET/CT scan at 60–75 minutes were acquired. Moreover, all participants underwent MRI, and four participants underwent fluorine 18 ((18)F) fluorodeoxyglucose (FDG) PET imaging. PET parameters and their relative changes were obtained for all lesions. Kinetic modeling was used to estimate the (18)F-FSPG tumor rate constants using the dynamic and dynamic plus WB PET data. Imaging parameters were correlated to lesion outcomes, as determined with follow-up MRI and/or pathologic examination. The Mann-Whitney U test or Student t test was used for group mean comparisons. Receiver operating characteristic curve analysis was used for performance comparison of different decision measures. RESULTS: (18)F-FSPG PET/CT helped identify all 48 brain lesions. The mean tumor-to-background ratio (TBR) on the whole-brain PET images at the WB time point was 26.6 ± 24.9 (range: 2.6–150.3). When (18)F-FDG PET was performed, (18)F-FSPG permitted visualization of non-(18)F-FDG–avid lesions or allowed better lesion differentiation from surrounding tissues. In participants with primary brain tumors, the predictive accuracy of the relative changes in influx rate constant K(i) and maximum standardized uptake value to discriminate between poor and good lesion outcomes were 89% and 81%, respectively. There were significant differences in the (18)F-FSPG uptake curves of lesions with good versus poor outcomes in the primary brain tumor group (P < .05) but not in the brain metastases group. CONCLUSION: PET/CT imaging with (4S)-4-(3-[(18)F]fluoropropyl)-l-glutamate ((18)F-FSPG) helped detect primary brain tumors and brain metastases with a high tumor-to-background ratio. Relative changes in (18)F-FSPG uptake with multi-time-point PET appear to be helpful in predicting lesion outcomes. Clinical trial registration no. NCT02370563 © RSNA, 2022 Online supplemental material is available for this article.

This supplement file contains the identified SUVmax correlated genes in the lung squamous cell carcinoma patients in the RG cohort.

This supplement file contains the identified SUVmax correlated genes in the lung adenocarcinoma patients in the RG cohort.

This supplement file contains a list of de-identified IDs of the patients included in the RG cohort data available online.

This supplement file contains the identified differentially expressed genes (DEGs) between lung adenocarcinoma (AD) and squamous cell carcinoma (SCC) patients.

This supplement file provides additional information and analysis descriptions to the main manuscript ordered as in which they appear in the main text. This supplement file also provides general descriptions and overview to all the supplement materials included. This supplement file also includes Figure S1-S7 and Table S1-S3.

Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non–small cell lung cancer (NSCLC) together with 18FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell–type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFβ treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma.Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445–57. ©2018 AACR.

OBJECTIVE. Differences in the attenuation correction methods used in PET/CT scanners versus the newly introduced whole-body simultaneous PET/MRI reportedly result in differences in standardized upt...

// Ryogo Minamimoto 1 , Mehran Jamali 1 , Olivier Gevaert 1 , Sebastian Echegaray 1 , Amanda Khuong 2 , Chuong D. Hoang 2 , Joseph B. Shrager 2 , Sylvia K. Plevritis 1 , Daniel L. Rubin 1 , Ann N. Leung 1 , Sandy Napel 1 and Andrew Quon 1 1 Department of Radiology, Stanford University, Stanford, CA, USA 2 Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA Correspondence to: Andrew Quon, email: aquon@stanford.edu Keywords: 18 FDG-PET/CT, heterogeneity, KRAS gene mutation, EGFR gene mutation, NSCLC Received: September 16, 2016 Accepted: March 20, 2017 Published: May 10, 2017 ABSTRACT This study investigated the relationship between epidermal growth factor receptor ( EGFR ) and Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations in non-small-cell lung cancer (NSCLC) and quantitative FDG-PET/CT parameters including tumor heterogeneity. 131 patients with NSCLC underwent staging FDG-PET/CT followed by tumor resection and histopathological analysis that included testing for the EGFR and KRAS gene mutations. Patient and lesion characteristics, including smoking habits and FDG uptake parameters, were correlated to each gene mutation. Never-smoker ( P < 0.001) or low pack-year smoking history ( p = 0.002) and female gender ( p = 0.047) were predictive factors for the presence of the EGFR mutations. Being a current or former smoker was a predictive factor for the KRAS mutations ( p = 0.018). The maximum standardized uptake value (SUV max ) of FDG uptake in lung lesions was a predictive factor of the EGFR mutations ( p = 0.029), while metabolic tumor volume and total lesion glycolysis were not predictive. Amongst several tumor heterogeneity metrics included in our analysis, inverse coefficient of variation (1/COV) was a predictive factor ( p < 0.02) of EGFR mutations status, independent of metabolic tumor diameter. Multivariate analysis showed that being a never-smoker was the most significant factor ( p < 0.001) for the EGFR mutations in lung cancer overall. The tumor heterogeneity metric 1/COV and SUV max were both predictive for the EGFR mutations in NSCLC in a univariate analysis. Overall, smoking status was the most significant factor for the presence of the EGFR and KRAS mutations in lung cancer.

An integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) scanner with time of flight (TOF) technology is now available for clinical use. The aim of this study is to evaluate the potential of TOF PET in PET/MRI to reduce artifacts in PET images when compared to non-TOF PET/MRI, TOF PET/X-ray computed tomography (CT), and non-TOF PET/CT.All patients underwent a single 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) injection, followed first by PET/CT, and subsequently by PET/MRI. PET/CT exams were requested as standard-of-care for oncological indications. Using the PET acquisitions datasets, 4 series of images (TOF PET/CT, non-TOF PET/CT, TOF PET/MRI, and non-TOF PET/MRI) were reconstructed. These image series were visually evaluated for: (1) dental metal artifacts, (2) breathing artifacts, and (3) pelvic artifacts due to scatter correction errors from high bladder [(18)F]FDG concentration. PET image quality was assessed by a 3-point scale (1-clinically significant artifact, 2-non clinically significant artifact, and 3-no artifact).Twenty-five patients (mean ± SD age: 56 ± 13 years old; female: 10, male: 15) were enrolled. TOF PET/MRI, non-TOF PET/MRI, TOF PET/CT, and non-TOF PET/CT scores 2.8, 2.5, 2.4, and 2.3, respectively for the presence of dental artifacts, 2.8, 2.5, 2.2, and 1.9, respectively, for the presence of breathing artifacts, and 2.7, 1.7, 2.0, and 1.3, respectively, for the presence of pelvic artifacts TOF PET/MRI images showed the highest image quality scores among the 4 datasets of PET images.The superior timing resolution and resulting TOF capability of the new PET/MRI scanner improved PET image quality in this cohort by reducing artifacts compared to non-TOF PET/MRI, TOF PET/CT, and non-TOF PET/CT.

Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA-11) is a PET tracer that can detect prostate cancer relapses and metastases by binding to the extracellular domain of PSMA. 68Ga-labeled DOTA-4-amino-1-carboxymethyl-piperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (68Ga-RM2) is a synthetic bombesin receptor antagonist that targets gastrin-releasing peptide receptors. We present pilot data on the biodistribution of these PET tracers in a small cohort of patients with biochemically recurrent prostate cancer. Methods: Seven men (mean age ± SD, 74.3 ± 5.9 y) with biochemically recurrent prostate cancer underwent both 68Ga-PSMA-11 PET/CT and 68Ga-RM2 PET/MRI scans. SUVmax and SUVmean were recorded for normal tissues and areas of uptake outside the expected physiologic biodistribution. Results: All patients had a rising level of prostate-specific antigen (mean ± SD, 13.5 ± 11.5) and noncontributory results on conventional imaging. 68Ga-PSMA-11 had the highest physiologic uptake in the salivary glands and small bowel, with hepatobiliary and renal clearance noted, whereas 68Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake outside the expected physiologic biodistribution did not significantly differ between 68Ga-PSMA-11 and 68Ga-RM2; however, 68Ga-PSMA-11 localized in a lymph node and seminal vesicle in a patient with no abnormal 68Ga-RM2 uptake. Abdominal periaortic lymph nodes were more easily visualized by 68Ga-RM2 in two patients because of lack of interference by radioactivity in the small intestine. Conclusion:68Ga-PSMA-11 and 68Ga-RM2 had distinct biodistributions in this small cohort of patients with biochemically recurrent prostate cancer. Additional work is needed to understand the expression of PSMA and gastrin-releasing peptide receptors in different types of prostate cancer.

We report the effect of antiangiogenic therapy on the biodistribution of (18)F-FPPRGD2 (a surrogate biomarker of integrin αvβ3 expression), and the potential of (18)F-FPPRGD2 to predict the prognosis in patients with cervical cancer and ovarian cancer in this clinical scenario.Data from six women, age range 30 - 59 years (mean ± SD 44.0 ± 12.5 years), who had undergone a (18)F-FPPRGD2 PET/CT scan and bevacizumab-containing therapy were prospectively collected and analyzed. We compared baseline (18)F-FPPRGD2 and (18)F-FDG uptake in the lesions and tumor-to-background (T/B) ratios. The maximum and mean (18)F-FPPRGD2 standardized uptake values (SUVmax and SUVmean) were recorded for 13 normal organs, as well as in all the identified malignant lesions on the pretreatment scan and the 1-week post-treatment scan. We also measured changes in (18)F-FPPRGD2 uptake from before to 1 week after treatment, and compared them to the changes in (18)F-FDG uptake from before to 6 weeks after treatment. Treatment outcomes were correlated with these changes.The uptake in lesions and T/B ratio of (18)F-FPPRGD2 were lower than those of (18)F-FDG (SUVmax 3.7 ± 1.3 vs. 6.0 ± 1.8, P 0.001; SUVmean 2.6 ± 0.7 vs. 4.2 ± 1.3, P 0.001; T/B ratio based on SUVmax 2.4 ± 1.0 vs. 2.6 ± 1.0, P 0.04; T/B ratio based on SUVmean 1.9 ± 0.6 vs. 2.4 ± 1.0, P 0.003). One patient did not return for the follow-up scan and in another patient no lesions were identified on the pretreatment scan. (18)F-FPPRGD2 uptake in lesions in the remaining four patients had significantly changed 1 week after treatment (SUVmean 3.3 ± 1.0 vs. 2.7 ± 1.0, P 0.001), while uptake in all normal tissues analyzed was not affected by treatment. One patient with clinical disease progression had a decrease in lesional (18)F-FPPRGD2 SUVmean of 1.6 % and in (18)F-FDG SUVmean of 9.4 %. Two patients with a clinical complete response to treatment had decreases in lesional (18)F-FPPRGD2 SUVmean of 25.2 % and 25.0 % and in (18)F-FDG SUVmean of 6.1 % and 71.8 %. One patient with a clinical partial response had a decrease in lesional (18)F-FPPRGD2 SUVmean of 7.9 % and in (18)F-FDG SUVmean of 76.4 %.This pilot study showed that (18)F-FPPRGD2 and (18)F-FDG provide independent information about the biology of ovarian and cervical cancers. Bevacizumab-containing therapy does not affect (18)F-FPPRGD2 uptake in normal organs, but does result in statistically significant changes in lesions. In addition, (18)F-FPPRGD2 may have potential for early prediction of response to such treatments. These preliminary findings have to be confirmed in larger studies.

Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non–small cell lung cancer (NSCLC) together with 18FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell–type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFβ treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma. Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445–57. ©2018 AACR.

The aim of this study was to investigate the biodistribution of 2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) (18F-FPPRGD2) in cancer patients and to compare its uptake in malignant lesions with 18F-FDG uptake. A total of 35 patients (11 men, 24 women, mean age 52.1 ± 10.8 years) were enrolled prospectively and had 18F-FPPRGD2 PET/CT prior to treatment. Maximum standardized uptake values (SUVmax) and mean SUV (SUVmean) were measured in 23 normal tissues in each patient, as well as in known or suspected cancer lesions. Differences between 18F-FPPRGD2 uptake and 18F-FDG uptake were also evaluated in 28 of the 35 patients. Areas of high 18F-FPPRGD2 accumulation (SUVmax range 8.9 – 94.4, SUVmean range 7.1 – 64.4) included the bladder and kidneys. Moderate uptake (SUVmax range 2.1 – 6.3, SUVmean range 1.1 – 4.5) was found in the choroid plexus, salivary glands, thyroid, liver, spleen, pancreas, small bowel and skeleton. Compared with 18F-FDG, 18F-FPPRGD2 showed higher tumor-to-background ratio in brain lesions (13.4 ± 8.5 vs. 1.1 ± 0.5, P

In this study, we evaluated the biodistribution of the 18F−/18F-FDG administration, compared with separate 18F-NaF and 18F-FDG administrations. We also estimated the interaction of 18F-NaF and 18F-FDG in the 18F−/18F-FDG administration by semiquantitative analysis. Methods: We retrospectively analyzed the data of 49 patients (39 men, 10 women; mean age ± SD, 59.3 ± 15.2 y) who underwent separate 18F-FDG PET/CT and 18F-NaF PET/CT scans as well as 18F−/18F-FDG PET/CT sequentially. The most common primary diagnosis was prostate cancer (n = 28), followed by sarcoma (n = 9) and breast cancer (n = 6). The mean standardized uptake values (SUVs) were recorded for 18 organs in all patients, and maximum SUV and mean SUV were recorded for all the identified malignant lesions. We also estimated the 18F−/18F-FDG uptake as the sum of 18F-FDG uptake and adjusted 18F-NaF uptake based on the ratio of 18F-NaF injected dose in 18F−/18F-FDG PET/CT. Lastly, we compared the results to explore the interaction of 18F-FDG and 18F-NaF uptake in the 18F−/18F-FDG scan. Results: The 18F−/18F-FDG uptake in the cerebral cortex, cerebellum, parotid grand, myocardium, and bowel mostly reflected the 18F-FDG uptake, whereas the uptake in the other analyzed structures was influenced by both the 18F-FDG and the 18F-NaF uptake. The 18F−/18F-FDG uptake in extraskeletal lesions showed no significant difference when compared with the uptake from the separate 18F-FDG scan. The 18F−/18F-FDG uptake in skeletal lesions reflected mostly the 18F-NaF uptake. The tumor-to-background ratio of 18F−/18F-FDG in extraskeletal lesions showed no significant difference when compared with that from 18F-FDG alone (P = 0.73). For skeletal lesions, the tumor-to-background ratio of 18F−/18F-FDG was lower than that from 18F-NaF alone (P

The recent introduction of hybrid PET/MRI scanners in clinical practice has shown promising initial results for several clinical scenarios. However, the first generation of combined PET/MRI lacks time-of-flight (TOF) technology. Here we report the results of the first patients to be scanned on a completely novel fully integrated PET/MRI scanner with TOF.We analyzed data from patients who underwent a clinically indicated F FDG PET/CT, followed by PET/MRI. Maximum standardized uptake values (SUVmax) were measured from F FDG PET/MRI and F FDG PET/CT for lesions, cerebellum, salivary glands, lungs, aortic arch, liver, spleen, skeletal muscle, and fat. Two experienced radiologists independently reviewed the MR data for image quality.Thirty-six patients (19 men, 17 women, mean [±standard deviation] age of 61 ± 14 years [range: 27-86 years]) with a total of 69 discrete lesions met the inclusion criteria. PET/CT images were acquired at a mean (±standard deviation) of 74 ± 14 minutes (range: 49-100 minutes) after injection of 10 ± 1 mCi (range: 8-12 mCi) of F FDG. PET/MRI scans started at 161 ± 29 minutes (range: 117 - 286 minutes) after the F FDG injection. All lesions identified on PET from PET/CT were also seen on PET from PET/MRI. The mean SUVmax values were higher from PET/MRI than PET/CT for all lesions. No degradation of MR image quality was observed.The data obtained so far using this investigational PET/MR system have shown that the TOF PET system is capable of excellent performance during simultaneous PET/MR with routine pulse sequences. MR imaging was not compromised. Comparison of the PET images from PET/CT and PET/MRI show no loss of image quality for the latter. These results support further investigation of this novel fully integrated TOF PET/MRI instrument.

Differences in the attenuation correction methods used in PET/CT scanners versus the newly introduced whole-body simultaneous PET/MRI reportedly result in differences in standardized uptake values (SUVs) in the normal skeleton. The aim of the study was to compare the semiquantitative FDG uptake in the normal skeleton using time-of-flight (TOF) PET/MRI versus PET/CT with and without TOF.Participants received a single FDG injection and underwent non-TOF and TOF PET/CT (n = 23) or non-TOF PET/CT and TOF PET/MRI (n = 50). Mean SUV (SUVThe SUVIn the normal skeleton, SUV

The purpose of this study was to compare combined PET/MRI with PET/CT and cardiac MRI in the evaluation of cardiac sarcoidosis and myocarditis.Ten patients (4 men and 6 women; 56.1 ± 9.6 years old) were prospectively enrolled for evaluation of suspected cardiac sarcoidosis or myocarditis. Written informed consent was obtained. Following administration of 9.9 ± 0.9 mCi F-FDG, patients underwent standard cardiac PET/CT followed by combined PET/MRI using a simultaneous 3-T scanner. Cardiac MRI sequences included ECG-triggered cine SSFP, T2-weighted, and late gadolinium-enhanced imaging. Myocardial involvement was assessed with separate analysis of combined PET/MRI, PET/CT, and cardiac MRI data using dedicated postprocessing software. Estimates of radiation dose were derived from the applied doses of F-FDG and CT protocol parameters.Imaging was acquired with a delay from F-FDG injection of 90.2 ± 27.4 minutes for PET/CT and 207.7 ± 40.3 minutes for PET/MRI. Total scan time for PET/MRI was significantly longer than for PET/CT (81.4 ± 14.8 vs 12.0 minutes, P0.001). Total effective radiation dose was significantly lower for PET/MRI compared with PET/CT (6.9 ± 0.6 vs 8.2 ± 1.1 mSv, P = 0.007). There was no significant difference in the number of positive cases identified between combined PET/MRI (n = 10 [100%]), PET/CT (n = 6 [60%]), and cardiac MRI (n = 8 [80%]), P = 0.091.Simultaneous cardiac PET/MRI is feasible in the evaluation of cardiac sarcoidosis and myocarditis achieving diagnostic image quality.

Introduction Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non–small-cell lung cancer (NSCLC) patients undergoing imaging evaluation. Methods First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUV max ]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group. Results We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value=0.001) and for stage I patients alone (AUC = 0.87, p value=0.002). Conclusion CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.

Circulating tumor cells (CTCs) are established cancer biomarkers for the “liquid biopsy” of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non–small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.

As quantitative F-FDG PET numbers and pooling of results from different PET/CT scanners become more influential in the management of patients, it becomes imperative that we fully interrogate differences between scanners to fully understand the degree of scanner bias on the statistical power of studies.Participants with body mass index (BMI) greater than 25, scheduled on a time-of-flight (TOF)-capable PET/CT scanner, had a consecutive scan on a non-TOF-capable PET/CT scanner and vice versa. SUVmean in various tissues and SUVmax of malignant lesions were measured from both scans, matched to each subject. Data were analyzed using a mixed-effects model, and statistical significance was determined using equivalence testing, with P0.05 being significant.Equivalence was established in all baseline organs, except the cerebellum, matched per patient between scanner types. Mixed-effects method analysis of lesions, repeated between scan types and matched per patient, demonstrated good concordance between scanner types.Patients could be scanned on either a TOF or non-TOF-capable PET/CT scanner without clinical compromise to quantitative SUV measurements.

Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)] ((68)Ga-PSMA-11) is a PET tracer that can detect prostate cancer relapses and metastases by binding to the extracellular domain of PSMA. (68)Ga-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 ((68)Ga-RM2) is a synthetic bombesin receptor antagonist that targets gastrin-releasing peptide receptors. We present pilot data on the biodistribution of these PET tracers in a small cohort of patients with biochemically recurrent prostate cancer.Seven men (mean age ± SD, 74.3 ± 5.9 y) with biochemically recurrent prostate cancer underwent both (68)Ga-PSMA-11 PET/CT and (68)Ga-RM2 PET/MRI scans. SUVmax and SUVmean were recorded for normal tissues and areas of uptake outside the expected physiologic biodistribution.All patients had a rising level of prostate-specific antigen (mean ± SD, 13.5 ± 11.5) and noncontributory results on conventional imaging. (68)Ga-PSMA-11 had the highest physiologic uptake in the salivary glands and small bowel, with hepatobiliary and renal clearance noted, whereas (68)Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake outside the expected physiologic biodistribution did not significantly differ between (68)Ga-PSMA-11 and (68)Ga-RM2; however, (68)Ga-PSMA-11 localized in a lymph node and seminal vesicle in a patient with no abnormal (68)Ga-RM2 uptake. Abdominal periaortic lymph nodes were more easily visualized by(68)Ga-RM2 in two patients because of lack of interference by radioactivity in the small intestine.(68)Ga-PSMA-11 and (68)Ga-RM2 had distinct biodistributions in this small cohort of patients with biochemically recurrent prostate cancer. Additional work is needed to understand the expression of PSMA and gastrin-releasing peptide receptors in different types of prostate cancer.

We prospectively evaluated the use of combined (18)F-NaF/(18)F-FDG PET/CT in patients with breast and prostate cancer and compared the results with those for (99m)Tc-MDP bone scintigraphy and whole-body MRI.Thirty patients (15 women with breast cancer and 15 men with prostate cancer) referred for standard-of-care bone scintigraphy were prospectively enrolled in this study. (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI were performed after bone scintigraphy. The whole-body MRI protocol consisted of both unenhanced and contrast-enhanced sequences. Lesions detected with each test were tabulated, and the results were compared.For extraskeletal lesions, (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI had no statistically significant differences in sensitivity (92.9% vs. 92.9%, P = 1.00), positive predictive value (81.3% vs. 86.7%, P = 0.68), or accuracy (76.5% vs. 82.4%, P = 0.56). However, (18)F-NaF/(18)F-FDG PET/CT showed significantly higher sensitivity and accuracy than whole-body MRI (96.2% vs. 81.4%, P0.001, 89.8% vs. 74.7%, P = 0.01) and bone scintigraphy (96.2% vs. 64.6%, P0.001, 89.8% vs. 65.9%, P0.001) for the detection of skeletal lesions. Overall, (18)F-NaF/(18)F-FDG PET/CT showed higher sensitivity and accuracy than whole-body MRI (95.7% vs. 83.3%, P0.002, 87.6% vs. 76.0%, P0.02) but not statistically significantly so when compared with a combination of whole-body MRI and bone scintigraphy (95.7% vs. 91.6%, P = 0.17, 87.6% vs. 83.0%, P = 0.53). (18)F-NaF/(18)F-FDG PET/CT showed no significant difference from a combination of (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI. No statistically significant differences in positive predictive value were noted among the 3 examinations.(18)F-NaF/(18)F-FDG PET/CT is superior to whole-body MRI and (99m)Tc-MDP scintigraphy for evaluation of skeletal disease extent. Further, (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI detected extraskeletal disease that may change the management of these patients. (18)F-NaF/(18)F-FDG PET/CT provides diagnostic ability similar to that of a combination of whole-body MRI and bone scintigraphy in patients with breast and prostate cancer. Larger cohorts are needed to confirm these preliminary findings, ideally using the newly introduced simultaneous PET/MRI scanners.

Recently, a whole-body, simultaneous positron emission tomography - magnetic resonance imaging (PET-MRI) system combing MRI with time-of-flight (TOF) PET has been developed. We present our initial experience with human clinical studies using 18Ffluorodeoxyglucase (FDG) with this scanner, in comparison to PET-CT. All patients underwent a single-injection of 18F-FDG, with a dual-imaging protocol consisting of PET-CT followed by PET-MRI scan. PET-MR attenuation correction used a two point Dixon fat-water separated method for the body, combined with registration to an atlas for the head. Two radiologists evaluated MRI image quality using the following scale (0 non-diagnostic; 1 poor; 2 good; 3 excellent). PET-MRI and PET-CT images were reviewed for FDG uptake thought to be consistent with malignancy by two readers independently, and categorized into 5 groups (1 both PETMRI and PET-CT positive, 2 PET-MRI positive, PET-CT positive in retrospect; 3 PET-CT positive, PET-MRI positive in retrospect; 4: PET-MRI positive, PET-CT negative; 5: PET-MRI negative, PET-CT positive) by consensus.

Here we evaluated the potential of TOF PET/MRI to reduce various PET image artifacts, by comparing the images to non-TOF PET/MRI, TOF PET/CT and non-TOF PET/CT.

The aim of this study was to investigate the biodistribution of 2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) ((18)F-FPPRGD2) in cancer patients and to compare its uptake in malignant lesions with (18)F-FDG uptake.A total of 35 patients (11 men, 24 women, mean age 52.1 ± 10.8 years) were enrolled prospectively and had (18)F-FPPRGD2 PET/CT prior to treatment. Maximum standardized uptake values (SUVmax) and mean SUV (SUVmean) were measured in 23 normal tissues in each patient, as well as in known or suspected cancer lesions. Differences between (18)F-FPPRGD2 uptake and (18)F-FDG uptake were also evaluated in 28 of the 35 patients.Areas of high (18)F-FPPRGD2 accumulation (SUVmax range 8.9 - 94.4, SUVmean range 7.1 - 64.4) included the bladder and kidneys. Moderate uptake (SUVmax range 2.1 - 6.3, SUVmean range 1.1 - 4.5) was found in the choroid plexus, salivary glands, thyroid, liver, spleen, pancreas, small bowel and skeleton. Compared with (18)F-FDG, (18)F-FPPRGD2 showed higher tumor-to-background ratio in brain lesions (13.4 ± 8.5 vs. 1.1 ± 0.5, P 0.001), but no significant difference in body lesions (3.2 ± 1.9 vs. 4.4 ± 4.2, P = 0.10). There was no significant correlation between the uptake values (SUVmax and SUVmean) for (18)F FPPRGD2 and those for (18)F-FDG.The biodistribution of (18)F-FPPRGD2 in cancer patients is similar to that of other RGD dimer peptides and it is suitable for clinical use. The lack of significant correlation between (18)F-FPPRGD2 and (18)F-FDG uptake confirms that the information provided by each PET tracer is different.

In this study, we evaluated the biodistribution of the (18)F(-)/(18)F-FDG administration, compared with separate (18)F-NaF and (18)F-FDG administrations. We also estimated the interaction of (18)F-NaF and (18)F-FDG in the (18)F(-)/(18)F-FDG administration by semiquantitative analysis.We retrospectively analyzed the data of 49 patients (39 men, 10 women; mean age ± SD, 59.3 ± 15.2 y) who underwent separate (18)F-FDG PET/CT and (18)F-NaF PET/CT scans as well as (18)F(-)/(18)F-FDG PET/CT sequentially. The most common primary diagnosis was prostate cancer (n = 28), followed by sarcoma (n = 9) and breast cancer (n = 6). The mean standardized uptake values (SUVs) were recorded for 18 organs in all patients, and maximum SUV and mean SUV were recorded for all the identified malignant lesions. We also estimated the (18)F(-)/(18)F-FDG uptake as the sum of (18)F-FDG uptake and adjusted (18)F-NaF uptake based on the ratio of (18)F-NaF injected dose in (18)F(-)/(18)F-FDG PET/CT. Lastly, we compared the results to explore the interaction of (18)F-FDG and (18)F-NaF uptake in the (18)F(-)/(18)F-FDG scan.The (18)F(-)/(18)F-FDG uptake in the cerebral cortex, cerebellum, parotid grand, myocardium, and bowel mostly reflected the (18)F-FDG uptake, whereas the uptake in the other analyzed structures was influenced by both the (18)F-FDG and the (18)F-NaF uptake. The (18)F(-)/(18)F-FDG uptake in extraskeletal lesions showed no significant difference when compared with the uptake from the separate (18)F-FDG scan. The (18)F(-)/(18)F-FDG uptake in skeletal lesions reflected mostly the (18)F-NaF uptake. The tumor-to-background ratio of (18)F(-)/(18)F-FDG in extraskeletal lesions showed no significant difference when compared with that from (18)F-FDG alone (P = 0.73). For skeletal lesions, the tumor-to-background ratio of (18)F(-)/(18)F-FDG was lower than that from (18)F-NaF alone (P0.001); however, this difference did not result in missed skeletal lesions on the (18)F(-)/(18)F-FDG scan.The understanding of the biodistribution of radiopharmaceuticals and the lesion uptake of the (18)F(-)/(18)F-FDG scan as well as the variations compared with the uptake on the separate (18)F-FDG PET/CT and (18)F-NaF PET/CT are valuable for more in-depth evaluation of the combined scanning technique.

The purpose of this study was to analyze the distribution of 18F Sodium Fluoride (18F-NaF) uptake in the normal skeleton, benign and malignant bone lesions, and extraskeletal tissues, using semiquantitative SUV measurements.We retrospectively analyzed data from 129 patients who had 18F-NaF PET/CT at our institution for an oncological diagnosis between 2007 and 2014. There were 99 men and 30 women, 19 to 90 years old (mean [SD], 61.5 [15.5]). The range, average, and SD of SUV were measured for normal bone and extraskeletal tissues uptake for the entire patient population. A separate statistical analysis was performed to compare group A, which corresponds to the population of patient with no 18F-NaF-avid metastatic lesions, and group B, which corresponds to the population of patient with 18F-NaF-avid metastatic lesions. We also measured SUV max and SUV mean for bony metastases and degenerative changesThe PET/CT images were acquired at 30 to 169 minutes (mean [SD], 76.5 [22.8]) after injection of 3.9 to 13.6 mCi (mean [SD], 7.3 [2.4]) of 18F-NaF. The range and mean (SD) of SUV max for 18F-NaF-avid metastasis were 4.5 to 103.3 and 25.9 (16.6) and for 18F-NaF-avid degenerative changes were 3.3 to 52.1 and 16.5 (7.9), respectively.Various skeletal sites have different normal SUVs. Skeletal metastases have different SUVs when compared with benign findings such as degenerative changes.

Introduction Metabolic reprogramming is a cancer hallmark that is not fully understood. Moreover, increasing evidence suggests that metabolic dysregulation is histology-specific, particularly in the case of non-small cell lung cancer (NSCLC). In this study, we investigated the differences in glucose metabolism between the two major histology subtypes of NSCLC, namely adenocarcinoma (AD) and squamous cell carcinoma (SQ). We explored transcriptomics in association with FDG-PET SUVmax (maximum standardized uptake value), a common clinical marker of glucose uptake in cancer. Methods We identified metabolically-associated differentially expressed genes (DEGs) by histology subtypes using RNAseq data from resected tumors in our study cohort of 127 NSCLC patients (96 AD and 31 SQ) and validated the DEGs on The Cancer Genome Atlas. We also identified gene-enriched cellular processes correlated with SUVmax separately for AD and SQ. We validated our findings in public domain cell line microarray data. In a separate cohort of 40 NSCLC patients (20 patients overlap with study cohort) whose tumors were sorted by cell type (cancer, endothelial, fibroblast and immune cells), we identified specific cell types where the genes of interest were expressed. Results Metabolically-associated DEGs in AD were enriched in the hexosamine biosynthesis pathway (HBP), which is involved in glycosylating proteins related to invasion. SUVmax correlated genes in AD were enriched for epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling. In particular, GFPT2 (the rate-limiting gene in HBP) and 4 EMT-related glycoprotein genes were highly correlated with SUVmax, suggesting potency of HBP for EMT related glucose metabolic reprogramming. We validated the findings on cell line microarray data (GSE49644) before and after TGF-β induced EMT, showing that many genes in HBP increased after induced EMT, while genes in the glycolysis pathway and the pentose phosphate pathway (PPP) were unchanged or reduced. HBP genes and many SUVmax correlated EMT genes were most highly expressed in tumor-associated fibroblasts compared to other cells in the tumor microenvironment. In SQ, metabolically-associated DEGs were enriched in the glycolysis pathway and PPP. SUVmax correlated genes were enriched for cell development. Conclusion An integrative analysis of PET-RNAseq showed that in AD glucose uptake was related to invasion through metabolic reprogramming of HBP. In SQ, glucose uptake was associated with glycolysis and higher proliferation potential. Our work confirms that metabolic dysregulation in NSCLC is histology-specific and extends the finding to identify cellular processes associated with FDG uptake that differ by histology as well. Understanding histology-specific differences of tumor metabolism provides new insights into tumor behavior that can have implications for anti-cancer therapy. Citation Format: Weiruo Zhang, Gina Bouchard, Alice Yu, Majid Shafiq, Mehran Jamali, Joseph Shrager, Kelsey Ayers, Viswam S. Nair, Andrew Gentles, Maximilian Diehn, Andrew Quon, Sandy Napel, Sylvia Plevritis. FDG uptake in human lung adenocarcinoma associated with invasion through the hexosamine biosynthesis pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4403. doi:10.1158/1538-7445.AM2017-4403

PURPOSETo compare the conspicuity of malignant lesions between FDG PET/CT and a new simultaneous, time-of-flight (TOF) enabled PET/MRI scanner.METHODSAll patients underwent a single-injection of FDG, followed by a dual imaging protocol consisting of PET/CT followed by TOF PET/MRI. PET/CT and PET/MRI images were evaluated by two readers independently for areas of FDG uptake compatible with malignancy, and then categorized into 5 groups (1: PET/MRI and PET/CT positive; 2: PET/MRI positive, PET/CT positive in retrospect; 3: PET/CT positive, PET/MRI positive in retrospect; 4: PET/MRI positive, PET/CT negative; 5: PET/MRI negative, PET/CT positive) by consensus. Patients with no lesions on either study or greater than 10 lesions based on either modality were excluded from the study.RESULTSFifty-two patients (mean±SD age: 58±14 years) underwent the dual imaging protocol; of these, 29 patients with a total of 93 FDG-avid lesions met the inclusion criteria. The majority of lesions (56%) were recorded prospectively in the same location on PET/CT and PET/MRI. About an equal small fraction of lesions were seen on PET/CT but only retrospectively on PET/MRI (9%) and vice versa (12%). More lesions were identified only on PET/MRI but not on PET/CT, even in retrospect (96% vs. 81%, respectively; p = 0.003). Discrepant lesions had lower maximum standardized uptake value (SUVmax) than concordant lesions on both modalities (pCONCLUSIONSWhile most lesions were identified prospectively on both modalities, significantly more lesions were identified with PET/MRI than with PET/CT.

Purpose: MicroRNAs (miRNAs) are being investigated as stable, non-invasive, circulating biomarkers for detecting human disease, including cancer. We sought to determine whether select, circulating miRNAs can define a “footprint” for circulating tumor cells (CTCs) in the blood of lung cancer patients. Methods: We analyzed plasma from patients with non-small cell lung cancer (NSCLC) for nine candidate miRNAs using Taqman™ qRT-PCR primers in duplicate and normalized by spiked-in synthetic cel-miR-39. We then associated miRNA expression levels with CTCs using a morphometric assay that is independent of Epithelial Cell Adhesion Molecule (EpCAM) and designed for the ultra-sensitive detection of individual CTCs and tumor cell clusters. We chose candidate plasma miRNA markers based on criteria including low or absent expression in other blood components, epithelial-specific expression, and/or significance in the literature. This included miRs -21, -135b, -141, -200a/b/c, -205, -210 and -429. We analyzed Pearson and Spearman rank correlations and associations by group using ANOVA with Bonferonni adjustments for multiple comparisons. Lastly, we integrated patients' clinical and tumors' imaging data for modeling using multiple logistic regression to assess how miRNAs associated with CTCs. Results: We evaluated 68 patients with predominantly stage I disease (75%) and adenocarcinoma histology (69%). Median CTC/mL was 4.2 (Interquartile Range [IQR] 0-19), 49% (33/68) of patients had more than 5 CTCs/mL and 51% (35/68) of these patients also had tumor clusters present. MiRNAs were only weakly correlated with absolute CTC/mL levels in the circulation but at a threshold of 5 CTCs/mL there was a strong relationship with miR-141 (p-value = 0.0004, adj p-value = 0.004). Several miRNAs were associated with the presence of tumor clusters, including miR-205 (p-value = 0.007; adj p-value = 0.06) and miR-429 (p-value = 0.006, adj p-value = 0.05). A logistic model integrating clinical, imaging and miRNA features selected several miRNAs preferentially to predict the presence of tumor clusters (miR-21, miR-200b, miR-205, and miR-429). Conclusion: Circulating oncomiRs may indirectly associate with CTCs and tumor clusters in patients with NSCLC. Our “footprint” is concordant with one previous investigation in metastatic breast cancer showing common results for miR-141 and the miR-200-429 cluster. Further investigations examining miRNAs expressed directly in CTCs would be useful to determine the origin of circulating cancer-associated miRNAs. Citation Format: Viswam S. Nair, Maria Giraldez, Madelyn Luttgen, Khun Visith Keu, Minal Vasanawala, George Horng, Mehran Jamali, Anand Kolatkar, Ware Kuschner, Peter Kuhn, Sanjiv Sam Gambhir, Muneesh Tewari. MicroRNA footprints of circulating tumor cells in patients with non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4006. doi:10.1158/1538-7445.AM2014-4006

1416 Objectives We previously reported the pilot evaluation of a simultaneous PET/MRI scanner with TOF capability (1), as well as the use of combined 18F NaF/18F FDG PET/CT in cancer patients (2,3). Here we prospectively compared the combined 18F NaF/18F FDG PET/ MRI against 99mTc-MDP bone scintigraphy in patients with breast and prostate cancers. Methods 30 patients referred for 99mTc-MDP bone scans were prospectively enrolled from Oct 2014 to Jan 2016. The cohort included 23 men with prostate cancer and 7 women with breast cancer, 41 - 85 year-old (average 65 ± 11). 18F NaF (0.7-2.2 mCi, mean: 1.1 mCi) and 18F FDG (3.6-5.5 mCi, mean: 4.2 mCi) were subsequently injected from separate syringes. The PET/MRI was done 6-30 days (average 9.3 ± 3.2) after bone scan. The whole body MRI protocol consisted of MRAC, T2-weighted, DWI, and contrast-enhanced T1-weighted imaging. Lesions detected with each test were tabulated and the results were compared. Results All patients tolerated the PET/MRI exam and PET image quality was diagnostic despite the marked reduction in the administered dosage of radiopharmaceuticals (80% less for 18F NaF and 67% less for 18F FDG compared to standard PET/CT protocols). 11 patientshad no bone metastases identified on either scans. Bone scintigraphy and PET/MRI showed osseous metastases in 16 patients, but more numerous bone findings were noted on PET/MRI than on bone scintigraphy in 8 of these patients. 1 patient had a negative bone scan, but bone metastases were seen on PET/MRI. Lesions outside the skeleton were identified by PET/MRI in 3 patients. Conclusions The combined 18F NaF/18F FDG PET/MRI is superior to 99mTc-MDP scintigraphy for evaluation of skeletal disease extent. Further, it detected extra-skeletal disease that may change the management of these patients, while allowing a significant reduction in radiation exposure from lower dosages of PET radiopharmaceuticals administered. 18F NaF/18F FDG PET/MRI appears well suited for detection of metastases in patients with breast and prostate cancers.