RPS 1106 - Advances in hybrid, molecular and translational imaging

Author Block: S. J. Bartsch¹, K. Brožová¹, V. Ehret¹, J. Friske¹, L. Kenner¹, K. Kratochwill¹, D. Laimer-Gruber¹, T. H. Helbich¹, K. Pinker-Domenig²; ¹Vienna/AT, ²New York, NY/US
Purpose: Tumour neoangiogenesis is an important hallmark of cancer progression, triggered by alternating selective pressures from the hypoxic tumour microenvironment. Multiparametric MRI combining blood oxygen level dependent (BOLD) MRI, depicting blood oxygen saturation, and intravoxel incoherent motion (IVIM) MRI, capturing intravascular and extravascular diffusion, allows insights into tumour progression, capturing tumour oxygenation and neovascularisation simultaneously. The combination of BOLD- and IVIM-MRI may provide non-invasive, non-contrast-enhanced imaging biomarkers of neoangiogenesis for the discrimination of breast cancer (BC) molecular subtypes. We compare our findings to fluorescent multiplexed immunohistochemistry (MP-IHC).
Methods or Background: An in-vivo study on 36 female athymic nude mice, which were inoculated with luminal A, Her2+ and triple negative BC cells, was conducted. MRI was performed using a 9.4T Bruker BioSpec 94/30USR system. Following IVIM-MR imaging, tumour oxygenation was measured at 21% oxygen and 100% oxygen for BOLD measurements. Tumours were resected for MP-IHC staining of CD-31, PDGFR-beta and Hif1-alpha.
Results or Findings: Hyperoxic BOLD MRI discriminates luminal A from Her2+ and triple negative BCs, while the IVIM-derived parameter fIVIM allows the distinction of luminal A and Her2+ from triple negative BCs. A principal component analysis (PCA) of BOLD and IVIM-MRI derived parameters reveals differences between triple negative and other BC molecular subtypes. In a PCA of MP-IHC stains, luminal A BCs clustered separately from other BC molecular subtypes.
Conclusion: Our multivariate analysis of BOLD and IVIM parameters highlights how oxygen delivery is constricted and neoangiogenesis is increased in triple negative BCs. The combined interpretation with MP-IHC provides a holistic view on hypoxia-induced neoangiogenesis in BCs. We conclude that non-contrast-enhanced mpMRI using BOLD and IVIM imaging provides promising imaging biomarkers for an assessment of hypoxia-induced neoangiogenesis in three BC molecular subtypes.
Limitations: No limitations were identified.
Funding for this study: Funding was provided by the Vienna Science and Technology Fund (WWTF), grant no. LS19-018.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This preclinical study was approved by the Austrian Federal Ministry of Education, Science and Research (project number BMFWF-66.009/0284-WF/V/3b/2017).

Author Block: C. Mingels, B. A. Spencer, H. Nalbant, M. Rokni, Y. G. Abdelhafez, F. Sen, R. Badawi, L. Nardo; Sacramento, CA/US
Purpose: Given the increased signal collection efficiency, Total-Body (TB) PET/CT allows for protocol flexibility including acquisition time (AT). This study aimed to define the shortest AT with maintained diagnostic quality to avoid or reduce anaesthesia time in children.
Methods or Background: Twelve oncologic paediatric patients were injected with 4.24 MBq/kg 18F-FDG and scanned in list mode for 20 minutes on uEXPLORER TB-PET/CT after 120 min uptake time. 300s, 150s, 75s, and 37s data sets were extracted and reconstructed with varying iterations (4-6) and filters (4-6mm FWHM Gaussian or Metz) and then compared to the full data set reconstructed with 4 iterations (20 subsets), 256x256 matrix, no smoothing. All reconstructions were simultaneously displayed and independently rated from 1 (best) to 4 (worst) for interpretation/diagnosis by three nuclear medicine physicians. Additionally, signal-to-noise ratio (SNR), tumour-to-background ratio (TBR) and contrast-to-noise ratio (CNR) were calculated using a 30mm diameter sphere in the right liver lobe and tumour lesions segmented using a 40%-iso-contour. Data sets were compared using Student's t-test to the reference data set for changes in semi-quantitative measurements.
Results or Findings: Readers selected the reference reconstruction parameters for the 300s and 150s data sets but preferred additional smoothing for shorter data sets. Liver, blood-pool and bone SNR decreased with shortened AT. TBR and CNR were not significantly different between 20 min, 300 s and 150 s. Compared to 20 min TBR and CNR reduced significantly in 75 s and 37 s reconstructions (TBR 20 min: 3.64; 75 s: 2.40, p <0.05 and 37 s: 2.09, p <0.05; CNR 20 min: 11.29; 75 s: 2.36, p=0.01 and 37 s: 1.77, p=0.01).
Conclusion: 150 s paediatric acquisitions on TB-PET/CT obtained after 120 minutes uptake time show no significant semi-quantitative image quality reduction compared to 20 min scans and may decrease or avoid the need of anaesthesia.
Limitations: The study featured a small cohort.
Funding for this study: Funding was received from the US National Institutes of Health R01-CA249422;R01-CA206187.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The evaluation was approved by the hospital committee.

Author Block: M. Winkelmann, V. Blumenberg, K. Rejeski, V. Bücklein, F. Dekorsy, J. Ricke, M. Subklewe, W. G. Kunz; Munich/DE
Purpose: Chimeric antigen receptor T-cell therapy (CART) is approved for relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL). Recently, the international prognostic metabolic index (IMPI), which is composed of metabolic tumour volume (MTV), age, and Ann Arbor stage, was introduced. As higher patient age is a positive prognostic factor and higher MTV is a negative prognostic factor in the context of CART, we compared the predictive value of each component of the IMPI and its prognostic value for progression-free survival (PFS) and overall survival (OS).
Methods or Background: Consecutive r/r NHL patients and 18F-FDG PET/CT imaging at baseline were selected. Ann Arbor stage and patient age were calculated at the time of lymphodepletion. MTV was calculated with an absolute SUV cut-off of 4.
Results or Findings: 43 patients were included (37% female, 63% male) with a median age of 66 years and baseline MTV of 276 cm2. Ann Arbor stage was 1 in four patients, 2 in 11 patients, 3 in eight patients, and 4 in patients.
Splitting patients by median IMPI showed minor differences in median PFS and OS, which were statistically not significant. Dichotomisation by median MTV alone revealed a larger, statistically significant difference in median PFS and a larger nonsignificant difference in OS. Patients with an older age demonstrated a slightly longer PFS and OS, whereas there was no relevant difference between the two Ann Arbor risk groups.
Conclusion: For r/r NHL patients undergoing CAR T-cell therapy, IMPI represents a promising tool for risk assessment. However, in our study MTV alone was superior in PFS and OS stratification. A larger cohort should be used to assess whether MTV alone or in combination with measurement of tumour dissemination can improve survival prediction.
Limitations: This was a single centre study with a limited patient population.
Funding for this study: Funding for this study was received from Bayrisches Zentrum für Krebsforschung (BZKF) as well as Förderung für Forschung und Lehre der LMU (FöFoLe).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: All medical records and imaging studies were reviewed with the approval of the LMU Munich Institutional Review Board (LMU Ethics Committee, project number 19-817). Informed consent was obtained from all individual participants included in the study.

Author Block: I. Horvat Menih, J. Birchall, M. McLean, M. Zamora-Morales, A. Bebb, J. Kaggie, A. Warren, G. Stewart, F. A. Gallagher; Cambridge/UK
Purpose: Renal cell carcinoma (RCC) poses a significant clinical challenge. Accurate early detection is hindered by limitations in current diagnostic methods. This study investigates the potential of 23Na-MRI to noninvasively differentiate kidney tumour subtypes, shedding light on sodium regulation in renal cancer.
Methods or Background: Eight patients with kidney tumours underwent 23Na-MRI. Total sodium concentration (TSC) was calculated based on an 80mM 23Na-phantom. Regions of interest were drawn on TSC maps. Histopathology was determined on renal mass biopsy or surgical specimen. Immunohistochemical markers (CD31, Ki67) were assessed in a separate patient cohort. RNAseq counts for NHE3 and Na+/K+-ATPase were obtained from online databases. Statistical analyses were performed in Graphpad Prism.
Results or Findings: 7 renal oncocytomas (RO), 2 chromophobe RCCs (chRCC) and 2 clear cell RCCs (ccRCC) were identified in the 8 participants. 4 participants are undergoing active surveillance, and 4 underwent nephrectomy.
TSC was highest in ccRCC, and lowest in chRCC, while normal tissue and RO had comparable values. The main Na+ transporter in the kidney, NHE3, was highest in ccRCC and downregulated in chRCC. By contrast, ATPase was highest in chRCC, followed by ccRCC and RO. As expected, the ccRCC as the most aggressive kidney tumour subtype, exhibited highest vascularity (CD31) and highest proliferation rate (Ki67), which may have further contributed to the increased sodium signal detected on imaging.
Conclusion: We have shown feasibility for 23Na-MRI to noninvasively detect sodium concentration differences across kidney tumours, and associated findings with molecular markers of sodium handling. This prepares the ground for future research and shows potential to improve the clinical management of kidney cancer.
Limitations: It was not possible to quantify intracellular/extracellular sodium. There was no separation of cortex and medulla, and no correction for cystic/necrotic areas.
Funding for this study: This work is supported by the Cancer Research UK Cambridge Centre (RQAG/119) as well as the NIHR Cambridge Biomedical Research Centre.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The investigation of the differential biology of benign and malignant renal masses using advanced magnetic resonance imaging techniques (IBM-Renal) was approved by the Cambridge research ethics committee, no.: 22/EE/0136.

Author Block: R. Ebner, A-K. Lohse, M. P. Fabritius, J. Rübenthaler, P. Bartenstein, J. Ricke, F. Grawe; Munich/DE
Purpose: Somatostatin receptor positron emission tomography/computed tomography (SSTR-PET/CT) using [68Ga]-labelled tracers is a widely used imaging modality for neuroendocrine tumours (NET). Recently, [18F]SiTATE has shown great potential due to its favourable clinical characteristics. We aimed to evaluate the reproducibility of SSTR-RADS 1.0 for structured interpretation and treatment planning of NETs using [18F]SiTATE.
Methods or Background: Four readers assessed [18F]SiTATE-PET/CT of 95 patients according to the SSTR-RADS 1.0 criteria at two different time points. Each reader selected and evaluated up to 5 target lesions per scan. Overall scan score and the decision on peptide receptor radionuclide therapy (PRRT) were considered. Inter- and intrareader agreement was determined using the intraclass correlation coefficient (ICC).
Results or Findings: Interreader agreement for identical target lesions (ICC≥85%), overall scan score (ICC≥90%) and decision to recommend PRRT (ICC≥85%) showed excellent agreement. However, significant differences were observed in recommending PRRT within ERs (p =0.020) and IRs (p =0.004). Compartment-based analysis demonstrated good to excellent interreader agreement for most organs (ICC≥74%), except for lymph nodes (ICC≥52%).
Conclusion: SSTR-RADS 1.0 represents an accurate and reproducible framework system for stratifying [18F]SiTATE-PET/CTs as an alternative for [68Ga]-labelled PET/CTs in NET-imaging. However, excellent interreader agreement on the overall scan score and the decision for PRRT was observed, there were variations in PRRT recommendations, highlighting the complexity of such decisions, suggesting the need for multidisciplinary input. Compartment-based assessments demonstrated excellent interreader agreement for the liver, soft tissue, and skeleton, with varying agreement for lymph nodes, emphasising the importance of functional imaging for small lesions.
Limitations: The absence of histopathological confirmation for each target lesion and blinding of readers to patients' clinical status may have influenced inter- and intrareader agreement, indicating the need to integrate clinical information into the interpretation of [18F]SiTATE-PET/CT scans.
Funding for this study: No funding was received for this study.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The analysis of the data was approved by the institutional ethics board of LMU Munich (IRB 20-1077).

Author Block: P. Summer¹, N. Gallon¹, N. Bulmer¹, S. Prabhu¹, P. Heidari², U. Mahmood²; ¹Charlestown, MA/US, ²Boston, MA/US
Purpose: This study aims to evaluate whether a novel human granzyme B PET imaging agent CYT-200 (Cytosite) labelled with 68Ga can be used as a reliable, non-invasive biomarker for detecting intratumoural granzyme B levels, while evaluating the efficacy of immune checkpoint inhibitor therapy in vivo.
Methods or Background: Melanoma-bearing humanised NSG mice were randomly assigned to receive either anti-PD1/CTLA4 combined, anti-PD1 alone or saline (controls) 9, 12 and 15 days after tumour implantation. PET imaging was performed prior to treatment initiation (baseline), such as on days 4, 7 and 14 after the first treatment dose. Tumour-bearing mice were injected with 68Ga-CYT-200 labelled 1h prior to PET/CT imaging. Intra-tumoural T-cell activity was determined by tumour to blood ratio (TBR), calculated by the standard uptake values (SUVs) of the tumours normalised against the heart blood pool. Treatment response was assessed by tumour growth measurements over 35 days after the first treatment dose.
Results or Findings: PET imaging on day 4 after treatment initiation showed the highest TBR compared to the baseline (3.08±0.98 vs. 1.22±0.48) with a gradual decrease of the TBRs on day 7 (2.76±1.85), and 14 (1.91±0.23). Anti-PD1/CTLA4 decreased the tumour size on days 4 and 7 after treatment initiation (336±38 mm3 vs.154±31 mm3 and 131±129 mm3, respectively). However, tumour growth recurred up to the final time point, 12 days after treatment initiation (181±112 mm3), correlating with the T-cell activity measured through in vivo PET imaging using CYT-200.
Conclusion: CYT-200 labelled with 68Ga can detect intra-tumoural T-cell activity associated with tumour killing following immune checkpoint inhibitor therapy in a humanised mouse model for melanoma.
Limitations: The study may have a limited number of mice, which could affect the generalisability and statistical power of the findings.
Funding for this study: Funding for this study was received by the National Institutes of Health.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: All animal studies were approved and conducted according to the IACUC guidelines.

Author Block: P. Summer¹, N. Bulmer¹, N. Gallon¹, S. Prabhu¹, P. Heidari², U. Mahmood²; ¹Charlestown, MA/US, ²Boston, MA/US
Purpose: The purpose of this study is to determine whether granzyme B PET imaging can predict treatment response to CAR T-cell therapy while evaluating the efficacy of CAR T-cell therapy for melanoma.
Methods or Background: Chimeric antigen receptor (CAR) T-cell therapy is a novel cell-based immunotherapy that urgently requires a reliable tool to determine patient response rapidly and accurately. Four days after melanoma cell implantation, tumour-bearing NSG mice received either 2x10^6 CAR T-cells (n=9) or vehicle (controls; n=8) intravenously. Treatment response was evaluated by tumour growth measurements up to 35 days post-treatment. A human granzyme-B-specific agent, CYT-200, labelled with 68Ga was used for PET imaging to assess intra-tumoural T-cell activity on days 2, 7 and 14 after treatment. Further, liver and colon uptake were compared between the groups to evaluate granzyme B expression within different organs.
Results or Findings: Tumoural 68Ga-hGZP uptake was significantly greater in the CAR T group 2 (3.1 ± 1.2 vs. 1.1 ± 0.4, P = 0.0017) and 7 (2.0 ± 1.1 vs. 1.1 ± 0.1, P = 0.0111) days after treatment, much earlier than when CAR T treated mice first presented with significantly lower tumour volumes eleven days after tumour implantation (61.8 mm3 ± 8.7 vs. 287.1 mm3 ± 157.6, P = 0.0455).
Conclusion: Quantitative in vivo imaging of intratumoural granzyme B provides early prediction of treatment response as early as 2 days after treatment. With the recent translation of granzyme B PET imaging to cancer patients treated with checkpoint-inhibitors, these findings may help inform CAR T response assessment in patients.
Limitations: The study may have a limited number of mice, which could affect the generalisability and statistical power of the findings.
Funding for this study: Funding for this study was received from the National Insitutes of Health.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: IACUC approval was obtained.

Author Block: M. Radzina¹, L. Saule¹, E. Mamis¹, E. Pajuste¹, T. E. Coccolios², T. Stora³; ¹Riga/LV, ²Brussels/BE, ³Geneva/CH
Purpose: The study aimed to understand the current status and future perspectives of novel radionuclides in Europe, through a survey. In order to support the ongoing research across Europe and to facilitate access to novel radionuclides, the PRISMAP consortium (European medical radionuclides programme) was established.
Methods or Background: A consortium questionnaire was disseminated among 30 countries. We received 114 respondents through the PRISMAP consortium and user community, professional associations and preclinical/clinical end users in Europe and the current status of clinical end users in nuclear medicine was identified.
Results or Findings: A total of 40 preclinical/clinical users institutions took part in the survey. Clinical end users currently use the following radionuclides in their studies: 177 Lu, 68 Ga, 111 In, 90 Y, other alpha emitters, 225 Ac, 64 Cu, and Terbium isotopes. Radionuclides that would be of interest for users within the next 2 to 5 years are 64 Cu, Terbium radionuclide “family” and alpha emitters, such as 225 Ac. Active industry involvement in joint outreach activities will provide access to new radionuclides and new purity grades for medical research. This will enhance clarity and regulatory procedures to foster research with radiopharmaceuticals and improve the delivered radionuclide data and regulation, along with biomedical research capacity.
Conclusion: The current perspective shows that nuclear medicine specialists/clinical end users from broad parts of Europe are not only interested in new radionuclides for diagnostics, but also in therapy and technology advancements that confirm their interest in development. This study was preliminary and should be extended outside the PRISMAP consortium.
Limitations: Not all European countries were covered - the majority of responses came from Western Europe, most notably the Benelux, France and Italy. More emphasis is needed to reach respondents from South-Eastern Europe.
Funding for this study: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101008571 (PRISMAP). This document reflects only the view of the author(s). The funding agenc(y/ies) is/are not responsible for any use that may be made of the information it contains.
Has your study been approved by an ethics committee? Not applicable
Ethics committee - additional information: Not applicable.

Author Block: L. Brizzi, L. Preda, C. Bortolotto, D. Gioacchino; Pavia/IT
Purpose: Radiomic analysis holds the potential to revolutionise lung cancer management by providing nuanced insights into tumour characteristics, ultimately aiding in early detection and personalised treatment, thus reducing mortality rates significantly. This study aims to investigate correlations between radiomic features in images obtained both from conventional spiral-CT and micro-CT scans of post-surgical anatomical specimens extracted from lung cancer patients.
Methods or Background: Three patients with lung cancer (pT2-3N0-1M0) underwent conventional in vivo spiral-CT before surgery. After surgery, post-surgical specimens were scanned using both spiral-CT (slice 0.3 mm) and micro-CT (slice thickness 40 μm). Tumour lesions from in vivo CT and within the specimens were segmented manually and semi-automatically using ITK-SNAP. A comparative radiomic analysis using Pyradiomics software was conducted, comparing features (shape and II order) from both image modalities before and after surgery, using ICC for assessing agreement.
Results or Findings: Concordance statistics for the 107 extracted radiomic features between image modalities revealed the following percentages of agreement: 79% when comparing micro-CT scans and conventional CT scans of the anatomical specimens, 74% when comparing micro-CT scans of the anatomical specimens and conventional in vivo CT scans, and 95% when comparing conventional CT images of the anatomical specimens with conventional in vivo CT scans. Among all the extracted features the highest degree of concordance was found in GLCM (Gray Level Co-occurrence Matrix; variation between 0.06-7.97%) and shape-based features (0.01-0.92%).
Conclusion: These preliminary findings indicate good to excellent concordance of radiomic features extracted from micro-CT and conventional CT scans, both in vivo and ex vivo. These results establish micro-CT as a possible tool for investigating the biological basis of radiomic features. In clinical practice, the diagnostic potential of micro-CT could be expanded to the point of performing "virtual biopsies".
Limitations: The possible limitations are the small sample size, and the feasibility of the study.
Funding for this study: Funding was received from Ricerca Corrente Founding.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: 1. Patients' consent was acquired by signing standard forms according to hospital protocol.

Author Block: D. Kifjak, M. J. Hochmair, J. Klinger, K. Sinn, A. Hoda, R-I. Milos, A. Haug, H. Prosch, L. Beer; Vienna/AT
Purpose: The aim of this study was to evaluate the association between 18-FDG-PET CT quantitative imaging markers and histological responses from patients with operable non-small cell lung cancer (NSCLC) treated with neo-adjuvant immuno-chemotherapy.
Methods or Background: This prospective, single-centre study included 22 patients (7 male, 15 female) with NSCLC who were treated with neo-adjuvant immuno-chemotherapy and underwent preoperative 18F-FDG-PET-CT. We semi-automatically extracted the standardised uptake value (SUVmax) and metabolic tumour volume (MTV). The histological results were retrieved from patients’ records. Patients were assigned to either complete pathologic response (cPR) or non-cPR groups. A Mann-Whitney-U-Test was calculated to determine if there were differences between SUVmax, MTV and histologic response.
Results or Findings: Eleven patients had a cPR, while eleven had a non-cPR. The SUVmax was lower in patients with cPR compared to those without cPR (median: 4.69 (IQR 5.7) vs. 9.9 (IQR 19.3)), p=0.049. The MTV was not significantly different between the two groups (median: 16.9 (IQR) 71.4, 29.2 (IQR 110.7)) p=0.0622.
Conclusion: Presurgical SUVmax was associated with cPR in NSCLC patients receiving immuno-chemotherapy. However, cPR can also be observed in patients with high SUVmax values.
Limitations: This study is a single-centre study with a small sample size.
Funding for this study: Funding was received from the Austrian Federal Ministry for Digital and Economic Affairs, the National Foundation for Research, Technology and Development and the Christian Doppler Research Association.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: EC number 1521/2015

Author Block: A. Chuprin, J. Young, M. K. Jain, M. Mahowald, F. Kestel, Amyloid research group; Jacksonville, FL/US
Purpose: Pittsburgh B Compound (PiB) is one of the newer investigational radiotracers studied for use in evaluation of cardiac amyloid. Potential advantages include the ability to distinguish between types of cardiac amyloid (ATTR vs AL), additional prognostic information, and monitoring of treatment response. Most if not all studies have quantified cardiac PiB uptake using standardized uptake value (SUV) metrics. We investigate applications of volumetric analysis of PiB PET and compare it to SUV metrics.
Methods or Background: Retrospective, blinded, case-cohort study on eight patients with biopsy proven ATTR (n=5) and AL (n=3) amyloidosis with cardiac involvement who had a PiB PET/CT.
Results or Findings: Compared with ATTR cardiac amyloidosis, AL amyloidosis showed higher mean PiB volumetric uptake (246 mL vs 29.5 mL, p = 0.0005), mean SUVmax (7.3 vs 5.5, p = 0.085) and mean SUVmean (4.3 vs 3.7, p = 0.191. There was no overlap between ranges of volumetric PiB uptake in cases of cardiac AL amyloidosis and cardiac ATTR amyloidosis (162.6 - 316.1 mL vs. 0 - 60.7 mL), unlike with SUVmax (6.6-8.1 vs. 2.9-8) and SUVmean (2-5.2 vs. 4.1-4.7).
Conclusion: Volumetric PiB PET analysis shows unique application for distinguishing AL from ATTR cardiac amyloidosis. Given increasingly sophisticated PACS paving the way for more feasible volumetric analysis, we expect volumetric PET analysis to be more readily available for clinical application. However, further analysis with a larger cohort is needed to confirm these findings and explore any association with volumetric PiB uptake and clinical outcomes.
Limitations: The limitation of this study is the sample size.
Funding for this study: Funding was received from the Mayo Internal Funding-Clinical Research Operations Group (CROG).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This study was approved by the Institutional Research Ethics Board.