Pretreatment and Posttreatment Tumor Metabolic Activity Assessed by FDG-PET/CT as Predictors of Tumor Recurrence and Survival Outcomes in Early-Stage Non-Small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy.

Purpose: Stereotactic body radiation therapy (SBRT) is considered the standard of care for medically inoperable early-stage non-small cell lung cancer. There is mixed evidence on the prognostic significance of tumor metabolic activity assessed by positron emission tomography combined with computed tomography (PET/CT) using F-18 fluorodeoxyglucose (FDG). The objectives of this study were to evaluate the maximum standardized uptake value (SUVmax) pretreatment and at 3 and 6 months after SBRT for prediction of tumor control and survival outcomes. Methods and Materials: Consecutive patients from a single institution with T12N0M0 non-small cell lung cancer receiving primary treatment with SBRT with pretreatment FDG-PET/CT (n = 163) and follow-up FDG-PET/CT at 3 or 6 months (n = 71) were included. Receiver operator characteristic analysis was performed to dichotomize variables for Kaplan-Meier survival analysis. Multivariate analysis was performed with Cox proportional hazards regression. Results: Median follow-up was 19 months. For the whole cohort, 1-year and 2-year local control, progression-free survival (PFS), and overall survival (OS) were 95.0% and 80.3%, 87.1% and 75.4%, and 67.0% and 49.6% respectively. The following pre-SBRT SUVmax cutoffs were significant: SUV > 4.0 for distant failure-free survival (adjusted hazard ratio [aHR], 3.33, P = .006), >12.3 for PFS (aHR, 2.80, P = .011), and >12.6 for OS (aHR, 3.00, P = .003). SUVmax decreases of at least 45% at 3 months (aHR, 0.15, P = .018), and 53% at 6 months (aHR, 0.12, P = .046) were associated with improved local failure-free survival. Conclusions: Pre-SBRT SUVmax cutoffs can predict distant failure, PFS, and OS. At both 3 and 6 months after SBRT, cutoffs for percentage change in SUVmax can potentially stratify risk of local recurrence.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

The predictive impact of dual somatostatin receptor/fluorodeoxyglucose (FDG) positron emission tomography (PET) in metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs): review of literature and a single institution experience.

Treatment with radiolabelled somatostatin analogs, a form of peptide receptor radionuclide therapy (PRRT), has changed the management of patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who have suboptimal benefit and rapidly progress on PRRT, indicating that accurate prognostic and predictive markers are urgently needed. Currently, most of the literature concentrate on the prognostic impact of the dual positron emission tomography (PET) scan with very few information regarding the predictive value. We report a case series and review the literature to summarizes the predictive value of combined somatostatin receptor (SSTR) and fluorodeoxyglucose (FDG) PET in metastatic GEP-NETs. We conducted a review of the literature for data published from 2010 to 2021 in MEDLINE, Embase, the National Institutes of Health trial registry, Cochrane CENTRAL, and published proceedings from major gastrointestinal and neuroendocrine cancer meetings. Our main criteria included all published prospective and retrospective data in which the predictive value of dual PET scans using SSTR and FDG was correlated with PRRT response in patients with metastatic GEP-NETs. We summarized clinical outcomes including progression-free survival (PFS), overall survival (OS), and post-therapy complications associated with PRRT according to FDG avidity. We excluded studies that did not include FDG PET scan, GEP patients, studies with no clear predictive value of the FDG PET scan, and studies that did not report a direct correlation between FDG avidity and primary outcome. Additionally, we summarized our institutional experience in eight patients who progressed during or within the first year of PRRT treatment. Our search identified 1306 articles; most of them showed only the prognostic value of Integrated SSTR/FDG PET imaging biomarker in GEP-NETs. Only three studies (n=75 patients) met our inclusion criteria and retrospectively investigated the predictive value of dual SSTR and FDG imaging in subjects being considered for PRRT. The results confirmed that FDG avidity correlates with advanced NET grades. Lesions that are both SSTR and FDG avid had early disease progression. In one study, at multivariate analysis, FDG PET results were independently predictive of lower PFS for PRRT. In our case series, there were eight patients with metastatic well-differentiated GEP-NETs (grades 2 and 3) who progressed within one year of PRRT. Seven of them had positive FDG PET scan at the time of progression. In conclusion, Dual SSTR/FDG PET imaging has a potential predictive impact for PRRT in GEP-NETs. It permits the capturing of the disease complexity and aggressiveness, which correlates with PRRT response. Therefore, prospective future trials should validate the predictive value of dual SSTRs/FDG PET for better PRRT stratification.

PET Imaging of Hepatocellular Carcinoma Using ZD2-(68Ga-NOTA).

Purpose: We tested a recently developed short peptide radioligand for PET imaging of hepatocellular carcinoma (HCC) by targeting an oncoprotein, extra-domain B fibronectin (EDB-FN) in the tumor microenvironment. Methods: The radioligand consists of a small linear peptide ZD2 with 68Ga-NOTA chelator, and specifically binds to EDB-FN. PET images were acquired dynamically for 1 hour after intravenously (i.v.) injecting 37 MBq (1.0 mCi) of the radioligand into the woodchuck model of naturally occurring HCC. Woodchuck HCC originated from chronic viral hepatitis infection, which recapitulates the corresponding human primary liver cancer. The animals were euthanized post-imaging for tissue collection and validation. Results: For ZD2 avid liver tumors, the radioligand accumulation plateaued a few minutes after injection, while the liver background uptake stabilized 20 min post-injection. The status of EDB-FN in woodchuck HCC was confirmed by histology and validated by PCR and western blocking. Conclusion: We have showed the viability of using the ZD2 short peptide radioligand targeting EDB-FN in liver tumor tissue for PET imaging of HCC, which can potentially impact the clinical care for HCC patients.

Abdominopelvic MR to CT registration using a synthetic CT intermediate.

Accurate coregistration of computed tomography (CT) and magnetic resonance (MR) imaging can provide clinically relevant and complementary information and can serve to facilitate multiple clinical tasks including surgical and radiation treatment planning, and generating a virtual Positron Emission Tomography (PET)/MR for the sites that do not have a PET/MR system available. Despite the long-standing interest in multimodality co-registration, a robust, routine clinical solution remains an unmet need. Part of the challenge may be the use of mutual information (MI) maximization and local phase difference (LPD) as similarity metrics, which have limited robustness, efficiency, and are difficult to optimize. Accordingly, we propose registering MR to CT by mapping the MR to a synthetic CT intermediate (sCT) and further using it in a sCT-CT deformable image registration (DIR) that minimizes the sum of squared differences. The resultant deformation field of a sCT-CT DIR is applied to the MRI to register it with the CT. Twenty-five sets of abdominopelvic imaging data are used for evaluation. The proposed method is compared to standard MI- and LPD-based methods, and the multimodality DIR provided by a state of the art, commercially available FDA-cleared clinical software package. The results are compared using global similarity metrics, Modified Hausdorff Distance, and Dice Similarity Index on six structures. Further, four physicians visually assessed and scored registered images for their registration accuracy. As evident from both quantitative and qualitative evaluation, the proposed method achieved registration accuracy superior to LPD- and MI-based methods and can refine the results of the commercial package DIR when using its results as a starting point. Supported by these, this manuscript concludes the proposed registration method is more robust, accurate, and efficient than the MI- and LPD-based methods.

Imaging of Tumor-Associated Vascular Prostate-Specific Membrane Antigen in Woodchuck Model of Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Radiolabeled short peptide ligands targeting prostate-specific membrane antigen (PSMA) were developed initially for imaging and treatment of prostate cancers. While many nonprostate solid tumors including hepatocellular carcinoma (HCC) express little PSMA, their neovasculature expresses a high level of PSMA, which is avid for Gallium-68-labeled PSMA-targeting radio-ligand (68Ga-PSMA-11) for positron emission tomography (PET). However, the lack of a spontaneous animal model of tumor-associated vascular PSMA overexpression has hindered the development and assessment of PSMA-targeting radioligands for imaging and therapy of the nonprostatic cancers. We identified detectable indigenous PSMA expression on tumor neovascular endothelia in a naturally occurring woodchuck model of HCC. METHODS: Molecular docking was performed with 3 bait PSMA ligands and compared between human and woodchuck PSMA. Initially, PET images were acquired dynamically after intravenously injecting 37 MBq (1.0 mCi) of 68Ga-PSMA-11 into woodchuck models of HCC. Subsequently, 10-minute static PET scans were conducted for other animals 1-hour after injection due to HCC and liver background uptake stabilization at 30-45 minutes after injection. Liver tissue samples were harvested after imaging, fresh-frozen for quantitative reverse transcription polymerase chain reaction and western blot for validation, or fixed for histology for correlation. RESULTS: Our preclinical studies confirmed the initial clinical findings of 68Ga-PSMA-11 uptake in HCC. The agents (ligands and antibodies) developed against human PSMA were found to be reactive against the woodchuck PSMA. CONCLUSION: This animal model offers a unique opportunity for investigating the biogenesis of tumor-associated vascular PSMA, its functional role(s), and potentials for future treatment strategies targeting tumor vascular PSMA using already developed PSMA-targeting agents.

The Role of the Microbiome in Gastroentero-Pancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, CA, USA). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

Diagnosis and staging of hepatobiliary malignancies: Potential incremental value of (18)F-FDG-PET/MRI compared to MRI of the liver.

OBJECTIVE: The purpose of the study was to investigate the potential added value of 18F-FDG-PET/MRI (functional information derived from PET) over standard diagnostic liver MRI (excellent soft tissue characterization) in diagnosing and staging suspected primary hepatobiliary malignancies including extrahepatic cholangiocarcinoma (ECC), intrahepatic cholangiocellular carcinoma (ICC) and gallbladder cancer (GBCA). METHODS: Twenty consecutive patients with suspected hepatobiliary malignancy were included in this retrospective study. All patients underwent combined whole-body (WB) 18F-FDG-PET/MRI including contrast-enhanced MRI of the liver, contrast-enhanced WB-MRI and WB 18F-FDG-PET. Two experienced readers staged hepatobiliary disease using TNM criteria: first based on MRI alone and then based on combined 18F-FDG-PET/MRI. Subsequently, the impact of FDG-PET/MRI on clinical management compared to MRI alone was recorded. Histopathologic proof served as the reference standard. RESULTS: Hepatobiliary neoplasms were present in 16/20 patients (ECC n = 3, ICC n = 8, GBCA n = 5), two patients revealed benign disease, two were excluded. TNM staging with 18F-FDG-PET/MRI was identical to MRI alone in 11/18 (61.1 %) patients and correctly changed the stage in 4/18 (22.2 %), resulting in a change in management for 2/4 patients (11.1 %). 18F-FDG-PET/MRI was false-positive in 3/18 cases (16.7 %). Both MRI and 18F-FDG-PET/MRI were falsely positive in 1 case without malignancy. CONCLUSIONS: A small incremental benefit of 18F-FDG-PET/MRI over standard MRI of the liver was observed. However, in some cases 18F-FDG-PET/MRI may lead to false-positive findings. Overall there is seemingly limited role of 18F-FDG-PET/MRI in patients with suspected hepatobiliary malignancy.

PET/CT Variants and Pitfalls in Breast Cancers.

There are a number of normal variants and pitfalls which are important to consider when evaluating F-18 Fluorodeoxyglucose (FDG) with Positron Emission Tomography (PET) in breast cancer patients. Although FDG-PET is not indicated for the initial diagnosis of breast cancer, focally increased glucose metabolism within breast tissue represents a high likelihood for a neoplastic process and requires further evaluation. Focally increased glucose metabolism is not unique to breast cancer. Other malignancies such as lymphoma, metastases from solid tumors as well as inflammatory changes also may demonstrate increased glucose metabolism either within the breast or at other sites throughout the body. Importantly, benign breast disease may also exhibit increased glucose metabolism, limiting the specificity of FDG-PET. Breast cancer has a wide range of metabolic activity attributed to tumor heterogeneity and breast cancer subtype. Intracellular signaling pathways regulating tumor glucose utilization contribute to these pitfalls of PET/CT in breast cancer. The evaluation of axillary lymph nodes by FDG-PET is less accurate than sentinel lymph node procedure, however is very accurate in identifying level II and III axillary lymph node metastases or retropectoral metastases. It is important to note that non-malignant inflammation in lymph nodes are often detected by modern PET/CT technology. Therefore, particular consideration should be given to recent vaccinations, particularly to COVID-19, which can commonly result in increased metabolic activity of axillary nodes. Whole body FDG-PET for staging of breast cancer requires specific attention to physiologic variants of FDG distribution and a careful comparison with co-registered anatomical imaging. The most important pitfalls are related to inflammatory changes including sarcoidosis, sarcoid like reactions, and other granulomatous diseases as well as secondary neoplastic processes.

Transforming UTE-mDixon MR Abdomen-Pelvis Images Into CT by Jointly Leveraging Prior Knowledge and Partial Supervision.

Computed tomography (CT) provides information for diagnosis, PET attenuation correction (AC), and radiation treatment planning (RTP). Disadvantages of CT include poor soft tissue contrast and exposure to ionizing radiation. While MRI can overcome these disadvantages, it lacks the photon absorption information needed for PET AC and RTP. Thus, an intelligent transformation from MR to CT, i.e., the MR-based synthetic CT generation, is of great interest as it would support PET/MR AC and MR-only RTP. Using an MR pulse sequence that combines ultra-short echo time (UTE) and modified Dixon (mDixon), we propose a novel method for synthetic CT generation jointly leveraging prior knowledge as well as partial supervision (SCT-PK-PS for short) on large-field-of-view images that span abdomen and pelvis. Two key machine learning techniques, i.e., the knowledge-leveraged transfer fuzzy c-means (KL-TFCM) and the Laplacian support vector machine (LapSVM), are used in SCT-PK-PS. The significance of our effort is threefold: 1) Using the prior knowledge-referenced KL-TFCM clustering, SCT-PK-PS is able to group the feature data of MR images into five initial clusters of fat, soft tissue, air, bone, and bone marrow. Via these initial partitions, clusters needing to be refined are observed and for each of them a few additionally labeled examples are given as the partial supervision for the subsequent semi-supervised classification using LapSVM; 2) Partial supervision is usually insufficient for conventional algorithms to learn the insightful classifier. Instead, exploiting not only the given supervision but also the manifold structure embedded primarily in numerous unlabeled data, LapSVM is capable of training multiple desired tissue-recognizers; 3) Benefiting from the joint use of KL-TFCM and LapSVM, and assisted by the edge detector filter based feature extraction, the proposed SCT-PK-PS method features good recognition accuracy of tissue types, which ultimately facilitates the good transformation from MR images to CT images of the abdomen-pelvis. Applying the method on twenty subjects' feature data of UTE-mDixon MR images, the average score of the mean absolute prediction deviation (MAPD) of all subjects is 140.72 ± 30.60 HU which is statistically significantly better than the 241.36 ± 21.79 HU obtained using the all-water method, the 262.77 ± 42.22 HU obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method, and the 197.05 ± 76.53 HU obtained via the conventional SVM method. These results demonstrate the effectiveness of our method for the intelligent transformation from MR to CT on the body section of abdomen-pelvis.

Liver background uptake of [18F]FLT in PET imaging.

High liver uptake presents a problem for 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) as a radiotracer for imaging cellular proliferation in the liver with positron emission tomography (PET). This investigation re-visited some issues related to the high liver background uptake of [18F]FLT with an animal model of woodchucks. Several enzymes involved in the hepatic catabolism of FLT, thymidine phosphorylase (TP, TYMP), uridine 5'-diphospho-glucuronosyl-transferases (UDP-GTs, short for UGTs), and ß-glucuronidase (GUSB), their homology as well as hepatic expression between the human and the woodchuck was examined. Inhibitors of these enzymes, TP inhibitor (TPI) tipiracil hydrochloride, UGT inhibitor probenecid, ß-glucuronidase inhibitor L-aspartate, were administered to the animals at human equivalent doses either intravenously (i.v.) and orally before the injection of tracer-dose [18F]FLT for PET imaging to examine any changes in liver uptake. Liver tissue samples were harvested from the animals after PET imaging and used to perform polymerase chain reaction (PCR) for TP expression or assays for enzymatic activities of TP and ß-glucuronidase. Non-radiolabeled (cold) FLT was also applied for enzyme saturation. Animals administered with TPI displayed lower radioactivity in the liver in comparison with the baseline scan. The application of probenecid did not change [18F]FLT liver uptake even though it reduced renal uptake. L-aspartate reduced the liver background uptake of [18F]FLT slightly. The application of cold FLT reduced overall uptake of [18F]FLT including the liver background. Therefore, the combined application of cold FLT and [18F]FLT merits further clinical investigation for reducing liver background uptake of [18F]FLT.

MCT4 regulates de novo pyrimidine biosynthesis in GBM in a lactate-independent manner.

BACKGROUND: Necrotic foci with surrounding hypoxic cellular pseudopalisades and microvascular hyperplasia are histological features found in glioblastoma (GBM). We have previously shown that monocarboxylate transporter 4 (MCT4) is highly expressed in necrotic/hypoxic regions in GBM and that increased levels of MCT4 are associated with worse clinical outcomes. METHODS: A combined transcriptomics and metabolomics analysis was performed to study the effects of MCT4 depletion in hypoxic GBM neurospheres. Stable and inducible MCT4-depletion systems were used to evaluate the effects of and underlining mechanisms associated with MCT4 depletion in vitro and in vivo, alone and in combination with radiation. RESULTS: This study establishes that conditional depletion of MCT4 profoundly impairs self-renewal and reduces the frequency and tumorigenicity of aggressive, therapy-resistant, glioblastoma stem cells. Mechanistically, we observed that MCT4 depletion induces anaplerotic glutaminolysis and abrogates de novo pyrimidine biosynthesis. The latter results in a dramatic increase in DNA damage and apoptotic cell death, phenotypes that were readily rescued by pyrimidine nucleosides supplementation. Consequently, we found that MCT4 depletion promoted a significant prolongation of survival of animals bearing established orthotopic xenografts, an effect that was extended by adjuvant treatment with focused radiation. CONCLUSIONS: Our findings establish a novel role for MCT4 as a critical regulator of cellular deoxyribonucleotide levels and provide a new therapeutic direction related to MCT4 depletion in GBM.

mDixon-Based Synthetic CT Generation for PET Attenuation Correction on Abdomen and Pelvis Jointly Using Transfer Fuzzy Clustering and Active Learning-Based Classification.

We propose a new method for generating synthetic CT images from modified Dixon (mDixon) MR data. The synthetic CT is used for attenuation correction (AC) when reconstructing PET data on abdomen and pelvis. While MR does not intrinsically contain any information about photon attenuation, AC is needed in PET/MR systems in order to be quantitatively accurate and to meet qualification standards required for use in many multi-center trials. Existing MR-based synthetic CT generation methods either use advanced MR sequences that have long acquisition time and limited clinical availability or use matching of the MR images from a newly scanned subject to images in a library of MR-CT pairs which has difficulty in accounting for the diversity of human anatomy especially in patients that have pathologies. To address these deficiencies, we present a five-phase interlinked method that uses mDixon MR acquisition and advanced machine learning methods for synthetic CT generation. Both transfer fuzzy clustering and active learning-based classification (TFC-ALC) are used. The significance of our efforts is fourfold: 1) TFC-ALC is capable of better synthetic CT generation than methods currently in use on the challenging abdomen using only common Dixon-based scanning. 2) TFC partitions MR voxels initially into the four groups regarding fat, bone, air, and soft tissue via transfer learning; ALC can learn insightful classifiers, using as few but informative labeled examples as possible to precisely distinguish bone, air, and soft tissue. Combining them, the TFC-ALC method successfully overcomes the inherent imperfection and potential uncertainty regarding the co-registration between CT and MR images. 3) Compared with existing methods, TFC-ALC features not only preferable synthetic CT generation but also improved parameter robustness, which facilitates its clinical practicability. Applying the proposed approach on mDixon-MR data from ten subjects, the average score of the mean absolute prediction deviation (MAPD) was 89.78±8.76 which is significantly better than the 133.17±9.67 obtained using the all-water (AW) method (p=4.11E-9) and the 104.97±10.03 obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method (p=0.002). 4) Experiments in the PET SUV errors of these approaches show that TFC-ALC achieves the highest SUV accuracy and can generally reduce the SUV errors to 5% or less. These experimental results distinctively demonstrate the effectiveness of our proposed TFCALC method for the synthetic CT generation on abdomen and pelvis using only the commonly-available Dixon pulse sequence.

Synthesis and assessment of ZD2-(68Ga-NOTA) specific to extradomain B fibronectin in tumor microenvironment for PET imaging of pancreatic cancer.

Patients diagnosed with pancreatic cancer at a late stage have a dismal survival rate. Accurate early detection of pancreatic cancer with a size of 10 mm or less could dramatically improve patient survival after timely treatments. We have developed a new PET probe ZD2-(68Ga-NOTA) specific to extradomain-B fibronectin (EDB-FN), an oncoprotein in tumor microenvironment, for sensitive molecular imaging and early diagnosis of pancreatic cancer. A targeted ligand ZD2-NOTA is synthesized by conjugation of a macrocyclic ligand NOTA via a 6-aminohexanoic acid spacer to a linear ZD2 peptide (Thr-Val-Arg-Thr-Ser-Ala-Asp). ZD2-(68Ga-NOTA) is synthesized by relabeling of ZD2-NOTA with 68GaCl3 in a high purity under GMP conditions. The expression of EDB-FN is demonstrated in BxPC3 and Capan-1 human pancreatic cancer cells and tumor xenografts in mice. ZD2-(68Ga-NOTA) results in significantly higher uptake in the both BxPC3 and Capan-1 tumor xenografts than normal organs and tissues, including the brain, heart, liver and muscle, at 1 hr postinjection in mice. The tumor to muscle uptake ratio is at least 5 folds for the tracer in both tumors. ZD2-(68Ga-NOTA) is able to clearly delineate the PaCa tumors with a size of 10 mm or less with minimal background noise in normal tissues, including the liver. Substantial tumor uptake is still visible at 2 hr post-injection. The results suggest that the ZD2 peptide targeted PET probe has a potential for sensitive molecular imaging of EDB-FN and early detection of pancreatic cancer to improve healthcare of the patients diagnosed with the disease.

Chemoradiotherapy-related carotid artery inflammation in head and neck cancer patients quantified by [18F]FDG PET/CT.

OBJECTIVES: Radiotherapy (RT) is associated with an increased risk of cardiovascular disease (CVD), but little is known about the mechanism for vascular injury and methods for early detection. MATERIALS AND METHODS: We conducted a prospective, pilot study of carotid artery inflammation using 18F-labeled 2-fluoro-2-deoxy-d-glucose ([18F]FDG) PET/CT imaging pre- and 3 months post-RT in head-and-neck cancer (HNC) patients. [18F]FDG uptake by the carotid arteries was measured by the maximum and mean target to background ratio (TBRMAX, TBRMEAN) and the mean partial volume corrected standardized uptake value (pvcSUVMEAN). RESULTS: Of the 22 patients who completed both pre and post-RT scans, the majority (82%) had stage III or stage IV disease and received concurrent chemotherapy. TBRMAX, TBRMEAN, and pvcSUVMEAN were all significantly higher 3 months after RT versus before RT with mean difference values (95% CI; p-value) of 0.17 (0.1-0.25; 0.0001), 0.19 (0.12-0.25; 0.0001), and 0.31 g/ml (0.12-0.5; 0.002), respectively. Fifteen patients (68%) had HPV-positive tumors, which were associated with lower pre-RT [18F]FDG signal, but a greater increase in TBRMAX (19% vs 5%), TBRMEAN (21% vs 11%) and pvcSUVMEAN (20% increase vs 3% decrease), compared to HPV negativity. CONCLUSION: There is a significant increase in carotid artery inflammation in HNC patients due to CRT that amounts to a degree that has previously been associated with higher risk for future CVD events. The subset of patients with HPV-positive tumors experienced the greatest increases in vascular inflammation due to CRT. Carotid [18F]FDG uptake may be an early biomarker of RT-related vascular injury.

UTE-mDixon-based thorax synthetic CT generation.

PURPOSE: Accurate photon attenuation assessment from MR data remains an unmet challenge in the thorax due to tissue heterogeneity and the difficulty of MR lung imaging. As thoracic tissues encompass the whole physiologic range of photon absorption, large errors can occur when using, for example, a uniform, water-equivalent or a soft-tissue-only approximation. The purpose of this study was to introduce a method for voxel-wise thoracic synthetic CT (sCT) generation from MR data attenuation correction (AC) for PET/MR or for MR-only radiation treatment planning (RTP). METHODS: Acquisition: A radial stack-of-stars combining ultra-short-echo time (UTE) and modified Dixon (mDixon) sequence was optimized for thoracic imaging. The UTE-mDixon pulse sequence collects MR signals at three TE times denoted as UTE, Echo1, and Echo2. Three-point mDixon processing was used to reconstruct water and fat images. Bias field correction was applied in order to avoid artifacts caused by inhomogeneity of the MR magnetic field. ANALYSIS: Water fraction and R2* maps were estimated using the UTE-mDixon data to produce a total of seven MR features, that is UTE, Echo1, Echo2, Dixon water, Dixon fat, Water fraction, and R2*. A feature selection process was performed to determine the optimal feature combination for the proposed automatic, 6-tissue classification for sCT generation. Fuzzy c-means was used for the automatic classification which was followed by voxel-wise attenuation coefficient assignment as a weighted sum of those of the component tissues. Performance evaluation: MR data collected using the proposed pulse sequence were compared to those using a traditional two-point Dixon approach. Image quality measures, including image resolution and uniformity, were evaluated using an MR ACR phantom. Data collected from 25 normal volunteers were used to evaluate the accuracy of the proposed method compared to the template-based approach. Notably, the template approach is applicable here, that is normal volunteers, but may not be robust enough for patients with pathologies. RESULTS: The free breathing UTE-mDixon pulse sequence yielded images with quality comparable to those using the traditional breath holding mDixon sequence. Furthermore, by capturing the signal before T2* decay, the UTE-mDixon image provided lung and bone information which the mDixon image did not. The combination of Dixon water, Dixon fat, and the Water fraction was the most robust for tissue clustering and supported the classification of six tissues, that is, air, lung, fat, soft tissue, low-density bone, and dense bone, used to generate the sCT. The thoracic sCT had a mean absolute difference from the template-based (reference) CT of less than 50 HU and which was better agreement with the reference CT than the results produced using the traditional Dixon-based data. CONCLUSION: MR thoracic acquisition and analyses have been established to automatically provide six distinguishable tissue types to generate sCT for MR-based AC of PET/MR and for MR-only RTP.

Post-radiotherapy PET/CT for predicting treatment outcomes in head and neck cancer after postoperative radiotherapy.

PURPOSE: The purpose of this study was to retrospectively review the role of post-treatment (post-tx) FDG-PET/CT scans in patients receiving postoperative intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Eighty-two patients with HNSCC treated with surgery and postoperative IMRT with or without chemotherapy from October 15, 2008 to December 31, 2014 that had post-tx PET/CT within 6 months of completing IMRT were included. PET/CT was considered positive based on multi-disciplinary review integrating clinical information. Survival analysis was performed using the Kaplan-Meier method. Categorical and continuous predictors of positive post-tx PET/CT were evaluated using Fisher's exact test and logistic regression, respectively. Predictors for survival outcomes were evaluated with log-rank testing. A p ≤ 0.05 was considered statistically significant. RESULTS: Median follow-up was 3.88 years. For all patients, 3-year overall survival (OS) and recurrence-free survival (RFS) were 71.8% and 61.3%, respectively. Patients with positive post-tx PET/CT had worse OS compared to those with negative post-tx PET/CT (log rank p < 0.001). For patients with positive post-tx PET/CT, 3-year OS was 11.2% compared to 89.9% for patients with negative post-tx PET/CT. The positive predictive value (PPV) of PET/CT was 100% for local recurrence (LR), regional recurrence (RR) and distant metastasis (DM). The negative predictive values (NPV) for LR, RR and DM were 89.0%, 89.2%, and 85.9%, respectively. Perineural invasion (p = 0.009), p16 status (p = 0.009), non-oropharyngeal primary site (p = 0.002), and the use of chemotherapy (p = 0.01) were independent predictors of positive PET/CT. CONCLUSIONS: Post-tx PET/CT after postoperative radiation is prognostic for survival outcomes. The PPV of post-tx PET for recurrence was excellent, allowing for early detection of recurrent disease. Post-tx PET/CT should be considered after postoperative radiation.

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial.

IMPORTANCE: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. OBJECTIVE: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. INTERVENTIONS: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. RESULTS: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. CONCLUSIONS AND RELEVANCE: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01279967.

Altered glutamine metabolism in platinum resistant ovarian cancer.

Ovarian cancer is characterized by an increase in cellular energy metabolism, which is predominantly satisfied by glucose and glutamine. Targeting metabolic pathways is an attractive approach to enhance the therapeutic effectiveness and to potentially overcome drug resistance in ovarian cancer. In platinum-sensitive ovarian cancer cell lines the metabolism of both, glucose and glutamine was initially up-regulated in response to platinum treatment. In contrast, platinum-resistant cells revealed a significant dependency on the presence of glutamine, with an upregulated expression of glutamine transporter ASCT2 and glutaminase. This resulted in a higher oxygen consumption rate compared to platinum-sensitive cell lines reflecting the increased dependency of glutamine utilization through the tricarboxylic acid cycle. The important role of glutamine metabolism was confirmed by stable overexpression of glutaminase, which conferred platinum resistance. Conversely, shRNA knockdown of glutaminase in platinum resistant cells resulted in re-sensitization to platinum treatment. Importantly, combining the glutaminase inhibitor BPTES with platinum synergistically inhibited platinum sensitive and resistant ovarian cancers in vitro. Apoptotic induction was significantly increased using platinum together with BPTES compared to either treatment alone. Our findings suggest that targeting glutamine metabolism together with platinum based chemotherapy offers a potential treatment strategy particularly in drug resistant ovarian cancer.

Radiomics Analysis on FLT-PET/MRI for Characterization of Early Treatment Response in Renal Cell Carcinoma: A Proof-of-Concept Study.

Studying early response to cancer treatment is significant for patient treatment stratification and follow-up. Although recent advances in positron emission tomography (PET) and magnetic resonance imaging (MRI) allow for evaluation of tumor response, a quantitative objective assessment of treatment-related effects offers localization and quantification of structural and functional changes in the tumor region. Radiomics, the process of computerized extraction of features from radiographic images, is a new strategy for capturing subtle changes in the tumor region that works by quantifying subvisual patterns which might escape human identification. The goal of this study was to demonstrate feasibility for performing radiomics analysis on integrated PET/MRI to characterize early treatment response in metastatic renal cell carcinoma (RCC) undergoing sunitinib therapy. Two patients with advanced RCC were imaged using an integrated PET/MRI scanner. [18 F] fluorothymidine (FLT) was used as the PET radiotracer, which can measure the degree of cell proliferation. Image acquisitions included test/retest scans before sunitinib treatment and one scan 3 weeks into treatment using [18 F] FLT-PET, T2-weighted (T2w), and diffusion-weighted imaging (DWI) protocols, where DWI yielded an apparent diffusion coefficient (ADC) map. Our framework to quantitatively characterize treatment-related changes involved the following analytic steps: 1) intraacquisition and interacquisition registration of protocols to allow voxel-wise comparison of changes in radiomic features, 2) correction and pseudoquantification of T2w images to remove acquisition artifacts and examine tissue-specific response, 3) characterization of information captured by T2w MRI, FLT-PET, and ADC via radiomics, and 4) combining multiparametric information to create a map of integrated changes from PET/MRI radiomic features. Standardized uptake value (from FLT-PET) and ADC textures ranked highest for reproducibility in a test/retest evaluation as well as for capturing treatment response, in comparison to high variability seen in T2w MRI. The highest-ranked radiomic feature yielded a normalized percentage change of 63% within the RCC region and 17% in a spatially distinct normal region relative to its pretreatment value. By comparison, both the original and postprocessed T2w signal intensity appeared to be markedly less sensitive and specific to changes within the tumor. Our preliminary results thus suggest that radiomics analysis could be a powerful tool for characterizing treatment response in integrated PET/MRI.