Tumors Affect the Metabolic Connectivity of the Human Brain Measured by 18F-FDG PET.

PURPOSE: 18F-FDG PET captures the relationship between glucose metabolism and synaptic activity, allowing for modeling brain function through metabolic connectivity. We investigated tumor-induced modifications of brain metabolic connectivity. PATIENTS AND METHODS: Forty-three patients with left hemispheric tumors and 18F-FDG PET/MRI were retrospectively recruited. We included 37 healthy controls (HCs) from the database CERMEP-IDB-MRXFDG. We analyzed the whole brain and right versus left hemispheres connectivity in patients and HC, frontal versus temporal tumors, active tumors versus radiation necrosis, and patients with high Karnofsky performance score (KPS = 100) versus low KPS (KPS < 70). Results were compared with 2-sided t test (P < 0.05). RESULTS: Twenty high-grade glioma, 4 low-grade glioma, and 19 metastases were included. The patients' whole-brain network displayed lower connectivity metrics compared with HC (P < 0.001), except assortativity and betweenness centrality (P = 0.001). The patients' left hemispheres showed decreased similarity, and lower connectivity metrics compared with the right (P < 0.01), with the exception of betweenness centrality (P = 0.002). HC did not show significant hemispheric differences. Frontal tumors showed higher connectivity metrics (P < 0.001) than temporal tumors, but lower betweenness centrality (P = 4.5-7). Patients with high KPS showed higher distance local efficiency (P = 0.01), rich club coefficient (P = 0.0048), clustering coefficient (P = 0.00032), betweenness centrality (P = 0.008), and similarity (P = 0.0027) compared with low KPS. Patients with active tumor(s) (14/43) demonstrated significantly lower connectivity metrics compared with necroses. CONCLUSIONS: Tumors cause reorganization of metabolic brain networks, characterized by formation of new connections and decreased centrality. Patients with frontal tumors retained a more efficient, centralized, and segregated network than patients with temporal tumors. Stronger metabolic connectivity was associated with higher KPS.

Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications.

Rationale: The in vivo dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence in vivo and for improving their cytotoxic potency in case of treatment failure. Methods: Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer in vivo using Thor-cells in lymphoma models. Results: We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Conclusion: Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies.

Identification of incidental brain tumors in prostate cancer patients via PSMA PET/CT.

PURPOSE: Brain metastases are rare in patients with prostate cancer and portend poor outcome. Prostate-specific membrane antigen positron emission tomography (PSMA PET)/CT scans including the brain have identified incidental tumors. We sought to identify the incidental brain tumor detection rate of PSMA PET/CT performed at initial diagnosis or in the setting of biochemical recurrence. METHODS: An institutional database was queried for patients who underwent 68Ga-PSMA-11 or 18F-DCFPyL (18F-piflufolastat) PET/CT imaging at an NCI-designated Comprehensive Cancer Center from 1/2018 to 12/2022. Imaging reports and clinical courses were reviewed to identify brain lesions and describe clinical and pathologic features. RESULTS: Two-thousand seven hundred and sixty-three patients underwent 3363 PSMA PET/CT scans in the absence of neurologic symptoms. Forty-four brain lesions were identified, including 33 PSMA-avid lesions: 10 intraparenchymal metastases (30%), 4 dural-based metastases (12%), 16 meningiomas (48%), 2 pituitary macroadenomas (6%), and 1 epidermal inclusion cyst (3%) (incidences of 0.36, 0.14, 0.58, 0.07, and 0.04%). The mean parenchymal metastasis diameter and mean SUVmax were 1.99 cm (95%CI:1.25-2.73) and 4.49 (95%CI:2.41-6.57), respectively. At the time of parenchymal brain metastasis detection, 57% of patients had no concurrent extracranial disease, 14% had localized prostate disease only, and 29% had extracranial metastases. Seven of 8 patients with parenchymal brain metastases remain alive at a median 8.8 months follow-up. CONCLUSION: Prostate cancer brain metastases are rare, especially in the absence of widespread metastatic disease. Nevertheless, incidentally detected brain foci of PSMA uptake may represent previously unknown prostate cancer metastases, even in small lesions and in the absence of systemic disease.

The promise of metabolic imaging in diffuse midline glioma.

Recent insights into histopathological and molecular subgroups of glioma have revolutionized the field of neuro-oncology by refining diagnostic categories. An emblematic example in pediatric neuro-oncology is the newly defined diffuse midline glioma (DMG), H3 K27-altered. DMG represents a rare tumor with a dismal prognosis. The diagnosis of DMG is largely based on clinical presentation and characteristic features on conventional magnetic resonance imaging (MRI), with biopsy limited by its delicate neuroanatomic location. Standard MRI remains limited in its ability to characterize tumor biology. Advanced MRI and positron emission tomography (PET) imaging offer additional value as they enable non-invasive evaluation of molecular and metabolic features of brain tumors. These techniques have been widely used for tumor detection, metabolic characterization and treatment response monitoring of brain tumors. However, their role in the realm of pediatric DMG is nascent. By summarizing DMG metabolic pathways in conjunction with their imaging surrogates, we aim to elucidate the untapped potential of such imaging techniques in this devastating disease.

Interim Analysis of a Prospective Validation of 2 Blood-Based Genomic Assessments (PPQ and NETest) to Determine the Clinical Efficacy of 177Lu-DOTATATE in Neuroendocrine Tumors.

Reliable biomarkers for neuroendocrine tumor (NET) management during peptide receptor radionuclide therapy (PRRT) are lacking. We validated the role of 2 circulating biomarkers: the PRRT prediction quotient (PPQ) as a predictive marker for response and the NETest as a monitoring biomarker. Furthermore, we evaluated whether tissue-based genetic alterations are effective in predicting progression-free survival (PFS). Methods: Data were prospectively collected on patients at the Memorial Sloan Kettering Cancer Center with 177Lu-DOTATATE-treated somatostatin receptor (SSTR)-positive gastroenteropancreatic and lung NETs (n = 67; median age, 66 y; 52% female; 42% pancreatic, 39% small-bowel; 78% grade 1 or 2). All cases were metastatic (89% liver) and had received 1-8 prior treatments (median, 3), including somatostatin analogs (91%), surgery (55%), or chemotherapy (49%). Treatment response included PFS. According to RECIST, version 1.1, responders had stable disease or a partial response (disease-control rate) and nonresponders had progression. Blood was collected before each cycle and at follow-up. Samples were deidentified and assayed and underwent masked analyses. The gene expression assays included RNA isolation, real-time quantitative polymerase chain reaction, and multialgorithm analyses. The PPQ (positive predicts a responder; negative predicts a nonresponder) at baseline was determined. The NETest (0-100 score) was performed. Statistics were analyzed using Mann-Whitney U testing (2-tailed) or Kaplan-Meier survival testing (PFS). In patients with archival tumor tissue, next-generation sequencing was performed through an institutional platform (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets). Results: Forty-one patients (61%) were responders. PPQ accurately predicted 96% (64/67). The hazard ratio for prediction was 24.4 (95% CI, 8.2-72.5). Twelve-month disease control was 97% for PPQ-positive patients versus 26% for PPQ-negative patients (P < 0.0001). Median progression-free survival was not reached in those predicted to respond (PPQ-positive, n = 40) but was 8 mo in those predicted not to respond (PPQ-negative, n = 27). The NETest result in responders was 67 ± 25 at baseline and significantly (P < 0.05) decreased (-37 ± 44%) at follow-up. The NETest result in nonresponders was 44 ± 23 at baseline and significantly (P < 0.05) increased (+76% ± 56%) at progression. Overall, the NETest changes (increases or decreases) were 90% accurate. Thirty patients underwent next-generation sequencing. Tumors were microsatellite-stable, and the median mutational burden was 1.8. Alterations involved mainly the mTOR/PTEN/TSC pathway (30%). No relationship was associated with PRRT response. Conclusion: Our interim analysis confirmed that PPQ is an accurate predictor of 177Lu-DOTATATE responsiveness (radiosensitivity) and that NETest changes accurately correlated with treatment response. Tissue-based molecular genetic information had little value in PRRT prediction. Blood-based gene signatures may improve the management of patients undergoing 177Lu-DOTATATE by providing information on tumor radiosensitivity and disease course, thus allowing individualized strategies.

TriDFusion (3DF) image viewer.

BACKGROUND: An open-source, extensible medical viewing platform is described, called the TriDFusion image viewer (3DF). The 3DF addresses many broad unmet needs in nuclear medicine research; it provides a viewer with several tools not available in commercial nuclear medicine workstations, yet invaluable for imaging in research studies. RESULTS: The 3DF includes an image integration platform to register images from multiple imaging modalities together with delineated volumes of interest (VOIs), structures and dose distributions. It can process images from different vendors' systems and is therefore vendor neutral. The 3DF also provides a convenient tool for performing multi-modality image analysis and fusion. The functional components currently being distributed is open-source code that includes: (1) a high quality viewer that can display axial, coronal, and sagittal tomographic images, maximum intensity projection images, structure contours, and isointensity contour lines or dose colorwash, (2) multi-image fusion allowing multiple images to be fused with VOI and dose distributions, (3) a suite of segmentation tools to edit and/or create tumor and organ VOIs, (4) dosimetry tools for several radioisotopes, (5) clinical tools for correcting acquisition errors, including patient orientation, and (6) the ability to save the resultant image and VOI as DICOM files or to export the numerical results as comma separated values files. Because the code is written in MATLAB™, it is highly readable and is easier for the coder to make changes compared to languages such as C or C++. In what follows, we describe the content of the new TriDFusion (3DF) image viewer software platform using examples of a number of clinical research workflows. Such examples vary in complexity but illustrate the main attributes of the software. CONCLUSIONS: In summary, 3DF provides a powerful, convenient, easy-to-use suite of open-source imaging research tools for the nuclear medicine community that allows physicians, medical physicists, and academic researchers to display, manipulate, and analyze images.

Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.

BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue. METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity. FINDINGS: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition. CONCLUSION: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research. FUNDING: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund.

Salvage resection plus cesium-131 brachytherapy durably controls post-SRS recurrent brain metastases.

BACKGROUND: Salvage of recurrent previously irradiated brain metastases (rBrM) is a significant challenge. Resection without adjuvant re-irradiation is associated with a high local failure rate, while reirradiation only partially reduces failure but is associated with greater radiation necrosis risk. Salvage resection plus Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced normal brain dose versus re-irradiation, however data are limited. METHODS: A prospective registry of consecutive patients with post-stereotactic radiosurgery (SRS) rBrM undergoing resection plus implantation of collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies) prescribed to 60 Gy at 5 mm from the cavity was analyzed. RESULTS: Twenty patients underwent 24 operations with Cs131 implantation in 25 tumor cavities. Median maximum preoperative diameter was 3.0 cm (range 1.1-6.3). Gross- or near-total resection was achieved in 80% of lesions. A median of 16 Cs131 seeds (range 6-30), with a median air-kerma strength of 3.5 U/seed were implanted. There was one postoperative wound dehiscence. With median follow-up of 1.6 years for survivors, two tumors recurred (one in-field, one marginal) resulting in 8.4% 1-year progression incidence (95%CI = 0.0-19.9). Radiographic seed settling was identified in 7/25 cavities (28%) 1.9-11.7 months post-implantation, with 1 case of distant migration (4%), without clinical sequelae. There were 8 cases of radiation necrosis, of which 4 were symptomatic. CONCLUSIONS: With > 1.5 years of follow-up, intraoperative brachytherapy with commercially available Cs131 implants was associated with favorable local control and toxicity profiles. Weak correlation between preoperative tumor geometry and implanted tiles highlights a need to optimize planning criteria.

Positron emission tomography and magnetic resonance imaging in primary central nervous system lymphoma-a narrative review.

This review addresses the challenges of primary central nervous system (CNS) lymphoma diagnosis, assessment of treatment response, and detection of recurrence. Primary CNS lymphoma is a rare form of extra-nodal non-Hodgkin lymphoma that can involve brain, spinal cord, leptomeninges, and eyes. Primary CNS lymphoma lesions are most commonly confined to the white matter or deep cerebral structures such as basal ganglia and deep periventricular regions. Contrast-enhanced magnetic resonance imaging (MRI) is the standard diagnostic modality employed by neuro-oncologists. MRI often shows common morphological features such as a single or multiple uniformly well-enhancing lesions without necrosis but with moderate surrounding edema. Other brain tumors or inflammatory processes can show similar radiological patterns, making differential diagnosis difficult. [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) has selected utility in cerebral lymphoma, especially in diagnosis. Primary CNS lymphoma can sometimes present with atypical findings on MRI and FDG PET, such as disseminated disease, non-enhancing or ring-like enhancing lesions. The complementary strengths of PET and MRI have led to the development of combined PET-MR systems, which in some cases may improve lesion characterization and detection. By highlighting active developments in this field, including advanced MRI sequences, novel radiotracers, and potential imaging biomarkers, we aim to spur interest in sophisticated imaging approaches.

Prognostic value of [18F]FDG PET/CT in patients with CNS lymphoma receiving ibrutinib-based therapies.

PURPOSE: Current clinical and imaging tools remain suboptimal for predicting treatment response and prognosis in CNS lymphomas. We investigated the prognostic value of baseline [18F]FDG PET in patients with CNS lymphoma receiving ibrutinib-based treatments. METHODS: Fifty-three patients enrolled in a prospective clinical trial and underwent brain PET before receiving single-agent ibrutinib or ibrutinib in combination with methotrexate with or without rituximab. [18F]FDG uptake in these lesions was quantified by drawing PET volumes of interest around up to five [18F]FDG-avid lesions per patient (with uptake greater than surrounding brain). We measured standardized uptake values (SUVmax), metabolic tumor volumes, total lesion glycolysis (TLG), and the sum thereof in these lesions. We analyzed the relationship between PET parameters and mutation status, overall response rates, and progression-free survival (PFS). RESULTS: Thirty-eight patients underwent single-agent therapy and 15 received combination therapy. On PET, 15/53 patients had no measurable disease. In the other 38 patients, a total of 71 lesions were identified on PET. High-intensity [18F]FDG uptake and a larger volume of [18F]FDG-avid disease were inversely related to treatment outcome (p ≤ 0.005). In univariable analysis, PFS was linearly correlated with all PET parameters, with stronger association when sum-values were used. A multivariable model showed that risk of progression increased by 9% for every 5-unit increase in sumSUVmax (hazard ratio = 1.09 [95% CI: 1.04 to 1.14]). CONCLUSION: Higher lesional metabolic parameters are inversely related to outcome in patients undergoing ibrutinib-based therapies, and sumSUVmax emerged as a strong independent prognostic factor. TRIAL REGISTRATION: NCT02315326; https://clinicaltrials.gov/ct2/show/NCT02315326?term=NCT02315326&draw=2&rank=1.

Patient Size-Dependent Dosimetry Methodology Applied to 18F-FDG Using New ICRP Mesh Phantoms.

Despite the known influence of anatomic variability on internal dosimetry, dosimetry for 18F-FDG and other diagnostic radiopharmaceuticals is routinely derived using reference phantoms, which embody population-averaged morphometry for a given age and sex. Moreover, phantom format affects dosimetry estimates to varying extent. Here, we applied newly developed mesh format reference phantoms and a patient-dependent phantom library to assess the impact of height, weight, and body contour variation on dosimetry of 18F-FDG. We compared the mesh reference phantom dosimetry estimates with corresponding estimates from common software to identify differences related to phantom format or software implementation. Our study serves as an example of how more precise patient size-dependent dosimetry methodology could be performed. Methods: Absorbed dose coefficients were computed for the adult mesh reference phantoms and derivative patient-dependent phantom series by Monte Carlo simulation using the PHITS radiation transport code within PARaDIM software. The dose coefficients were compared with reference absorbed dose coefficients obtained from ICRP Publication 128, or generated using software including OLINDA 2.1, OLINDA 1.1, and IDAC-dose 2.1. Results: Differences in dosimetry arising from anatomical variations were shown to be significant, with detriment-weighted dose coefficients for the percentile-specific phantoms varying by up to ±40% relative to the corresponding reference phantom effective dose coefficients, irrespective of phantom format. Similar variations were seen in the individual organ absorbed dose coefficients for the percentile-specific phantoms relative to the reference phantoms. The effective dose coefficient for the mesh reference adult was 0.017 mSv/MBq, which was 5% higher than estimated by a corresponding voxel phantom, and 10% lower than estimated by the stylized phantom format. Conclusion: We observed notable variability in 18F-FDG dosimetry across morphometrically different patients, supporting the use of patient-dependent phantoms for more accurate dosimetric estimations relative to standard reference dosimetry. These data may help in optimizing imaging protocols and research studies, in particular when longer-lived isotopes are employed.

Engineered Cells as a Test Platform for Radiohaptens in Pretargeted Imaging and Radioimmunotherapy Applications.

Pretargeted imaging and radioimmunotherapy approaches are designed to have superior targeting properties over directly targeted antibodies but impose more complex pharmacology, which hinders efforts to optimize the ligands prior to human applications. Human embryonic kidney 293T cells expressing the humanized single-chain variable fragment (scFv) C825 (huC825) with high-affinity for DOTA-haptens (293T-huC825) in a transmembrane-anchored format eliminated the requirement to use other pretargeting reagents and provided a simplified, accelerated assay of radiohapten capture while offering normalized cell surface expression of the molecular target of interest. Using binding assays, ex vivo biodistribution, and in vivo imaging, we demonstrated that radiohaptens based on benzyl-DOTA and a second generation "Proteus" DOTA-platform effectively and specifically engaged membrane-bound huC825, achieving favorable tumor-to-normal tissue uptake ratios in mice. Furthermore, [86Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [177Lu]Lu-DOTA-Bn and [225Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.

Effects of a workplace physical activity intervention on cognitive determinants of physical activity: a randomized controlled trial.

OBJECTIVE: The present randomized controlled trial evaluated if a workplace physical activity (PA) program that comprises both a PA component and a psychological coaching component (PA + C) is more effective in changing cognitive determinants of PA than a PA program without coaching component. Design:N = 213 employees were cluster-randomly assigned to two groups: the PA + C group received the MoVo-work intervention, combining a psychological coaching component and a PA component. The PA group received the PA component without psychological coaching. Main Outcome Measures: Strength of goal intention, self-efficacy, outcome expectations, action planning and barrier management were assessed at five time points (before and at the end of the intervention, as well as 6 weeks, 6 months and 12 months after the intervention). Results: After six weeks and one year, respectively, the PA + C group showed significantly higher goal intentions (p = .018) and self-efficacy beliefs (p = .006) than the PA group; and, at a descriptive level, a clear tendency towards better barrier management. Conclusions: The results indicate that a workplace PA program, including psychological coaching, may partially improve the effects of a pure PA program on critical motivational and volitional determinants of PA behavioural change among employees.

CAR Chase: Where Do Engineered Cells Go in Humans?

Chimeric antigen receptor (CAR) - and T-cell receptor (TCR) - modified T-cells are rapidly emerging as a viable treatment option for cancer patients. While initial clinical trials for these CAR T cells showed response rates of over 90% in some cases, retrospective studies have revealed a wide variability in patient responses as well as a significant proportion of patients relapsing after an initial response. In addition, patients often have severe adverse reactions to this therapy (e.g., cytokine release and neurologic syndromes). As a result, much research is still needed to be able to predict both therapeutic outcomes and possible toxicities. Furthermore, little success has been seen in treating solid tumors with engineered T cells and uncovering modes of failure is a topic of much research. Finally, little is known about the T cells' pharmacokinetics after infusion into the patient, as standard methods of tracking the cells analyze peripheral blood and tumor biopsies - both of which lack spatiotemporal information. Herein, we propose that reporter gene-based imaging of engineered T cells in humans would be tremendously valuable in elucidating the fate of the transplanted T cells and would greatly facilitate clinical translation of new CAR and TCR technologies. Currently, there are no FDA-approved reporter genes and few methods have advanced to human studies. Herein, we outline current reporter gene approaches to track engineered cells in vivo, analyze why current reporter genes have not progressed into the clinic, and propose "rules" for designing a widely applicable reporter gene for use in humans.