Spatial Distribution of Recurrence and Long-Term Toxicity Following Dose Escalation to the Dominant Intra-Prostatic Nodule for Intermediate-High-Risk Prostate Cancer: Insights from a Phase I/II Study.

Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intra-prostatic nodule (DIN). Materials and methods: In 33 patients with intermediate-high-risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25-74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17-76 months), affecting 13 out of 33 patients (39.4%). Intra-prostatic recurrences occurred in 7 patients (21%), with ≥75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patients. Notably, five patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intra-prostatic recurrences. Extended follow-up revealed late grade ≥ 2 GU and GI toxicity in 18% (n = 6) and 6% (n = 2) of the patients. Conclusions: Among patients with intermediate-high-risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: Focal dose-escalated prostate SBRT prevented recurrences in the dominant nodule; however, extra-prostatic recurrence sites were frequent.

Increased [68Ga]Ga-SST uptake in the uncinate pancreatic process in new digital PET/CT machine and potential association with clinical and histologic factors in NET patients.

INTRODUCTION: A physiological increase in the uptake of [68Ga]Ga-labeled somatostatin analogues ([68Ga]Ga-SST) PET tracers has been reported in the uncinate pancreatic process (UP) and might be even higher in latest generation of PET/CT scanners and might be falsely interpreted as NET. We aimed to investigate the uptake of UP in a large population of NET patients who underwent [68Ga]Ga-SST PET/CT with digital SiPM detectors. We also explored potential associations between UP uptake and various clinical, imaging, and pathological factors routinely assessed in NET patients. METHODS: We analyzed all consecutive NET patients from July 2018 to June 2022 in this retrospective, single-center study. All patients underwent a [68Ga]Ga-SST PET/CT scan on a digital SiPM PET/CT scanner. On visual analysis, we distinguished between normal linear and homogenous UP uptake or abnormal if otherwise. We compared SUVmax/mean in patients with normal UP uptake to those with abnormal UP uptake with suspicious NET lesions on contrast-enhanced CT (ce-CT) and according to the site of the primary NET (pancreatic NET vs. other), patient gender (female vs. male) and tumor grade (grade 1-2 vs. 3) using a Mann-Whitney test. We also assessed the correlation between SUVmax/mean values in UP with patients' age, primary NET Ki-67 counting, and its SUVmax/mean, TLA and MTV values. RESULTS: We included 131 NET patients with a total of 34 [68Ga]Ga-DOTATATE PET/CT and 113 [68Ga]Ga-DOTATOC PET/CT scans. An abnormal UP uptake was seen in 32 patients with 65.7% of suspicious NET lesion or extrinsic compression on morphological imaging. Normal UP uptake SUVmax/mean were measured in 115 [68Ga]Ga-SST scans (78.2%) with normal UP uptake and without suspicious lesion on morphological imaging. We found an average SUVmax of 12.3 ± 4.1 for [68Ga]Ga-DOTATATE and 19.8 ± 9.8 g/ml for [68Ga]Ga-DOTATOC, hence higher than those reported in the literature [SUVmax 5 ± 1.6 to 12.6 ± 2.2 g/ml] with significant difference with abnormal UP uptake and between both PET tracers (both p < 0.01). Significant results were a higher UP uptake on [68Ga]Ga-DOTATOC in male patients (p = 0.02) and significant associations between UP uptake on [68Ga]Ga-DOTATOC and SUVmax/mean of the primary tumor (ρ [0.337-0.363]; p [0.01-0.02]). CONCLUSION: We confirmed a higher and very frequent UP uptake in latest SiPM-detector [68Ga]Ga-SST PET/CT with an even higher uptake in patients that had [68Ga]Ga-DOTATOC PET/CT. SUVmean/max were significantly higher in abnormal UP uptake but there were overlaps with UP SUV values for both [68Ga]Ga-SST and a correlation to morphological imaging is crucial. Besides, significant associations between UP uptake and SUVmean/max of the primary NET as well as patients' gender were seen in the larger cohort of [68Ga]Ga-DOTATOC patients suggesting that both physiological and pathological parameters could affect UP uptake.

Natural History of Myocardial αvß3 Integrin Expression After Acute Myocardial Infarction: Correlation with Changes in Myocardial Blood Flow.

Angiogenesis is an essential part of the cardiac repair process after myocardial infarction, but its spatiotemporal dynamics remain to be fully deciphered.68Ga-NODAGA-Arg-Gly-Asp (RGD) is a PET tracer targeting αvß3 integrin expression, which is a marker of angiogenesis. Methods: In this prospective single-center trial, we aimed to monitor angiogenesis through myocardial integrin αvß3 expression in 20 patients with ST-segment elevation myocardial infarction (STEMI). In addition, the correlations between the expression levels of myocardial αvß3 integrin and the subsequent changes in 82Rb PET/CT parameters, including rest and stress myocardial blood flow (MBF), myocardial flow reserve (MFR), and wall motion abnormalities, were assessed. The patients underwent 68Ga-NODAGA-RGD PET/CT and rest and stress 82Rb-PET/CT at 1 wk, 1 mo, and 3 mo after STEMI. To assess 68Ga-NODAGA-RGD uptake, the summed rest 82Rb and 68Ga-NODAGA-RGD images were coregistered, and segmental SUVs were calculated (RGD SUV). Results: At 1 wk after STEMI, 19 participants (95%) presented increased 68Ga-NODAGA-RGD uptake in the infarcted myocardium. Seventeen participants completed the full imaging series. The values of the RGD SUV in the infarcted myocardium were stable 1 mo after STEMI (1 wk vs. 1 mo, 1.47 g/mL [interquartile range (IQR), 1.37-1.64 g/mL] vs. 1.47 g/mL [IQR, 1.30-1.66 g/mL]; P = 0.9), followed by a significant partial decrease at 3 mo (1.32 g/mL [IQR, 1.12-1.71 g/mL]; P = 0.011 vs. 1 wk and 0.018 vs. 1 mo). In segment-based analysis, positive correlations were found between RGD SUV at 1 wk and the subsequent changes in stress MBF (Spearman ρ: r = 0.17, P = 0.0033) and MFR (Spearman ρ: r = 0.31, P < 0.0001) at 1 mo. A negative correlation was found between RGD SUV at 1 wk and the subsequent changes in wall motion abnormalities at 3 mo (Spearman ρ: r = -0.12, P = 0.035). Conclusion: The present study found that αvß3 integrin expression is significantly increased in the infarcted myocardium 1 wk after STEMI. This expression remains stable after 1 mo and partially decreases after 3 mo. Initial αvß3 integrin expression at 1 wk is significantly weakly correlated with subsequent improvements in stress MBF, MFR, and wall motion analysis.

Comparing various AI approaches to traditional quantitative assessment of the myocardial perfusion in [82Rb] PET for MACE prediction.

Assessing the individual risk of Major Adverse Cardiac Events (MACE) is of major importance as cardiovascular diseases remain the leading cause of death worldwide. Quantitative Myocardial Perfusion Imaging (MPI) parameters such as stress Myocardial Blood Flow (sMBF) or Myocardial Flow Reserve (MFR) constitutes the gold standard for prognosis assessment. We propose a systematic investigation of the value of Artificial Intelligence (AI) to leverage [ 82 Rb] Silicon PhotoMultiplier (SiPM) PET MPI for MACE prediction. We establish a general pipeline for AI model validation to assess and compare the performance of global (i.e. average of the entire MPI signal), regional (17 segments), radiomics and Convolutional Neural Network (CNN) models leveraging various MPI signals on a dataset of 234 patients. Results showed that all regional AI models significantly outperformed the global model ( p < 0.001 ), where the best AUC of 73.9% (CI 72.5-75.3) was obtained with a CNN model. A regional AI model based on MBF averages from 17 segments fed to a Logistic Regression (LR) constituted an excellent trade-off between model simplicity and performance, achieving an AUC of 73.4% (CI 72.3-74.7). A radiomics model based on intensity features revealed that the global average was the least important feature when compared to other aggregations of the MPI signal over the myocardium. We conclude that AI models can allow better personalized prognosis assessment for MACE.

Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma.

Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor-reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

Anatomical Quantitative Volumetric Evaluation of Liver Segments in Hepatocellular Carcinoma Patients Treated with Selective Internal Radiation Therapy: Key Parameters Influencing Untreated Liver Hypertrophy.

Background: Factors affecting morphological changes in the liver following selective internal radiation therapy (SIRT) are unclear, and the available literature focuses on non-anatomical volumetric assessment techniques in a lobar treatment setting. This study aimed to investigate quantitative changes in the liver post-SIRT using an anatomical volumetric approach in hepatocellular carcinoma (HCC) patients with different levels of treatment selectivity and evaluate the parameters affecting those changes. This retrospective, single-institution, IRB-approved study included 88 HCC patients. Whole liver, liver segments, tumor burden, and spleen volumes were quantified on MRI at baseline and 3/6/12 months post-SIRT using a segmentation-based 3D software relying on liver vascular anatomy. Treatment characteristics, longitudinal clinical/laboratory, and imaging data were analyzed. The Student's t-test and Wilcoxon test evaluated volumetric parameters evolution. Spearman correlation was used to assess the association between variables. Uni/multivariate analyses investigated factors influencing untreated liver volume (uLV) increase. Results: Most patients were cirrhotic (92%) men (86%) with Child-Pugh A (84%). Absolute and relative uLV kept increasing at 3/6/12 months post-SIRT vs. baseline (all, p ≤ 0.005) and was maximal during the first 6 months. Absolute uLV increase was greater in Child-Pugh A5/A6 vs. ≥B7 at 3 months (A5, p = 0.004; A6, p = 0.007) and 6 months (A5, p = 0.072; A6, p = 0.031) vs. baseline. When the Child-Pugh class worsened at 3 or 6 months post-SIRT, uLV did not change significantly, whereas it increased at 3/6/12 months vs. baseline (all p ≤ 0.015) when liver function remained stable. The Child-Pugh score was inversely correlated with absolute and relative uLV increase at 3 months (rho = -0.21, p = 0.047; rho = -0.229, p = 0.048). In multivariate analysis, uLV increase was influenced at 3 months by younger age (p = 0.013), administered 90Y activity (p = 0.003), and baseline spleen volume (p = 0.023). At 6 months, uLV increase was impacted by younger age (p = 0.006), whereas treatment with glass microspheres (vs. resin) demonstrated a clear trend towards better hypertrophy (f = 3.833, p = 0.058). The amount (percentage) of treated liver strongly impacted the relative uLV increase at 3/6/12 months (all f ≥ 8.407, p ≤ 0.01). Conclusion: Liver function (preserved baseline and stable post-SIRT) favored uLV hypertrophy. Younger patients, smaller baseline spleen volume, higher administered 90Y activity, and a larger amount of treated liver were associated with a higher degree of untreated liver hypertrophy. These factors should be considered in surgical candidates undergoing neoadjuvant SIRT.

Factors Impacting Survival After Transarterial Radioembolization in Patients with Unresectable Intrahepatic Cholangiocarcinoma: A Combined Analysis of the Prospective CIRT Studies.

PURPOSE: Transarterial radioembolization (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). However, optimising the timing of TARE in relation to systemic therapies and patient selection remains challenging. We report here on the effectiveness, safety, and prognostic factors associated with TARE for ICC in a combined analysis of the prospective observational CIRT studies (NCT02305459 and NCT03256994). METHODS: A combined analysis of 174 unresectable ICC patients enrolled between 2015 and 2020 was performed. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every follow-up visit. Log-rank tests and a multivariable Cox proportional hazard model were used to identify prognostic factors. RESULTS: Patients receiving a first-line strategy of TARE in addition to any systemic treatment had a median OS and PFS of 32.5 months and 11.3 months. Patients selected for first-line TARE alone showed a median OS and PFS of 16.2 months and 7.4 months, whereas TARE as 2nd or further treatment-line resulted in a median OS and PFS of 12 and 9.3 months (p = 0.0028), and 5.1 and 3.5 months (p = 0.0012), respectively. Partition model dosimetry was an independent predictor for better OS (HR 0.59 [95% CI 0.37-0.94], p = 0.0259). No extrahepatic disease, no ascites, and < 6.1 months from diagnosis to treatment were independent predictors for longer PFS. CONCLUSION: This combined analysis indicates that in unresectable ICC, TARE in combination with any systemic treatment is a promising treatment option. LEVEL OF EVIDENCE: level 3, Prospective observational.

Contrast enhanced CT on PET/CT imaging in clinical routine: an international survey.

Aim: To perform an international survey about PET/CT imaging with contrast enhanced CT (PET/ceCT) in clinical routine worldwide. Methods: A questionnaire of ten questions was prepared for health professionals, addressing the following issues: (1) general demographic, hospital, and department information; (2) use and diffusion of PET/ceCT worldwide; (3) factors influencing the use of PET/ceCT. An invitation to the survey was sent to the corresponding authors of NM scientific articles indexed in SCOPUS in 2022 and dedicated to PET/CT imaging. Data were analysed per individual responder. Results: 191 individual responders worldwide participated in this survey. Most of the responders are using PET/ceCT in their center (74%). Interestingly, the relative use of PET/ceCT over the total PET/CT scans has an anti-Gaussian distribution (<20% ceCT and > 80% ceCT were most represented). Most of responders are using PET/ceCT in oncological settings (62%) and irrespectively from radiopharmaceuticals (62%). In most cases, PET/ceCT scans are reported by NM physicians alone or together by NM physicians and radiologists with an integrated report (31%). Conclusion: PET/ceCT imaging is largely used worldwide. Local factors can affect the choice of PET/ceCT in respect to conventional PET/CT imaging. Further cost-benefit analysis could be useful to consider other possible influencing variables, such as technologies, dosimetry, department organization and economics.

Direct comparison and reproducibility of two segmentation methods for multicompartment dosimetry: round robin study on radioembolization treatment planning in hepatocellular carcinoma.

PURPOSE: Investigate reproducibility of two segmentation methods for multicompartment dosimetry, including normal tissue absorbed dose (NTAD) and tumour absorbed dose (TAD), in hepatocellular carcinoma patients treated with yttrium-90 (90Y) glass microspheres. METHODS: TARGET was a retrospective investigation in 209 patients with < 10 tumours per lobe and at least one tumour ≥ 3 cm ± portal vein thrombosis. Dosimetry was compared using two distinct segmentation methods: anatomic (CT/MRI-based) and count threshold-based on pre-procedural 99mTc-MAA SPECT. In a round robin substudy in 20 patients with ≤ 5 unilobar tumours, the inter-observer reproducibility of eight reviewers was evaluated by computing reproducibility coefficient (RDC) of volume and absorbed dose for whole liver, whole liver normal tissue, perfused normal tissue, perfused liver, total perfused tumour, and target lesion. Intra-observer reproducibility was based on second assessments in 10 patients ≥ 2 weeks later. RESULTS: 99mTc-MAA segmentation calculated higher absorbed doses compared to anatomic segmentation (n = 209), 43.9% higher for TAD (95% limits of agreement [LoA]: - 49.0%, 306.2%) and 21.3% for NTAD (95% LoA: - 67.6%, 354.0%). For the round robin substudy (n = 20), inter-observer reproducibility was better for anatomic (RDC range: 1.17 to 3.53) than 99mTc-MAA SPECT segmentation (1.29 to 7.00) and similar between anatomic imaging modalities (CT: 1.09 to 3.56; MRI: 1.24 to 3.50). Inter-observer reproducibility was better for larger volumes. Perfused normal tissue volume RDC was 1.95 by anatomic and 3.19 by 99mTc-MAA SPECT, with corresponding absorbed dose RDC 1.46 and 1.75. Total perfused tumour volume RDC was higher, 2.92 for anatomic and 7.0 by 99mTc-MAA SPECT with corresponding absorbed dose RDC of 1.84 and 2.78. Intra-observer variability was lower for perfused NTAD (range: 14.3 to 19.7 Gy) than total perfused TAD (range: 42.8 to 121.4 Gy). CONCLUSION: Anatomic segmentation-based dosimetry, versus 99mTc-MAA segmentation, results in lower absorbed doses with superior reproducibility. Higher volume compartments, such as normal tissue versus tumour, exhibit improved reproducibility. TRIAL REGISTRATION: NCT03295006.

Lung CT stabilization with high-frequency non-invasive ventilation (HF-NIV) and breath-hold (BH) in lung nodule assessment by PET/CT.

PURPOSE: To evaluate the effect of lung stabilization using high-frequency non-invasive ventilation (HF-NIV) and breath-hold (BH) techniques on lung nodule detection and texture assessment in PET/CT compared to a free-breathing (FB) standard lung CT acquisition in PET/CT. MATERIALS AND METHODS: Six patients aged 65 ± 7 years, addressed for initial assessment of at least one suspicious lung nodule with 18F-FDG PET/CT, underwent three consecutive lung PET/CT acquisitions with FB, HF-NIV and BH. Lung nodules were assessed on all three CT acquisitions of the PET/CT and characterized for any size, volume and solid/sub-solid nature. RESULTS: BH detected a significantly higher number of nodules (n = 422) compared to HF-NIV (n = 368) and FB (n = 191) (p < 0.001). The mean nodule size (mm) was 2.4 ± 2.1, 2.6 ± 1.9 and 3.2 ± 2.4 in BH, HF-NIV and FB, respectively, for long axis and 1.5 ± 1.3, 1.6 ± 1.2 and 2.1 ± 1.7 in BH, HF-NIV and FB, respectively, for short axis. Long- and short-axis diameters were significantly different between BH and FB (p < 0.001) and between HF-NIV and FB (p < 0.001 and p = 0.008), but not between BH and HF-NIV. A trend for higher volume was shown in FB compared to BH (p = 0.055) and HF-NIV (p = 0.068) without significant difference between BH and HF-NIV (p = 1). We found a significant difference in detectability of sub-solid nodules between the three acquisitions, with BH showing a higher number of sub-solid nodules (n = 128) compared to HF-NIV (n = 72) and FB (n = 44) (p = 0.002). CONCLUSION: We observed a higher detection rate of pulmonary nodules on CT under BH or HF-NIV conditions applied to PET/CT than with FB. BH and HF-NIV demonstrated comparable texture assessment and performed better than FB in assessing size and volume. BH showed a better performance for detecting sub-solid nodules compared to HF-NIV and FB. The addition of BH or HF-NIV to PET/CT can help improve the detection and texture characterization of lung nodules by CT, therefore improving the accuracy of oncological lung disease assessment. The ease of use of BH and its added value should prompt its use in routine practice.

Tc-99m mebrofenin hepatobiliary scintigraphy to assess future liver remnant function before major liver surgery.

BACKGROUND AND OBJECTIVES: Assessment of liver function is paramount before hepatectomy. This study aimed to assess future liver remnant function (FLR-F) using hepatobiliary scintigraphy (HBS) and to compare it to FLR volume (FLR-V) in the prediction of posthepatectomy liver failure (PHLF). The impact of volume and function gains were also assessed in patients undergoing portal vein embolization (PVE) or liver venous deprivation (LVD). METHODS: All consecutive patients undergoing major hepatectomy between 02/2018 and 09/2021 with preoperative HBS were included. FLR-V was expressed as percentage of total liver volume and analyzed using preoperative computed tomography. FLR-V and FLR-F gains after embolization were expressed in percentage. Receiver operating characteristic analysis was performed to compare both methods in predicting PHLF. RESULTS: Thirty-six patients were included. PVE and LVD were performed in 4 (11%) and 28 patients (78%), respectively. Overall, PHLF occurred in eight patients (22%). FLR-F gain after embolization showed significant ability to predict PHLF (area under the curve [AUC] = 0.789), with cut-off value of 150% showing a sensitivity of 1.00, a specificity of 0.42, and a negative predictive value of 1.00. CONCLUSION: Preoperative HBS shows a high sensitivity to predict PHLF when HBS is performed twice to measure the function gain after venous embolization.

99mTc-macroaggregated albumin SPECT/CT predictive dosimetry and dose-response relationship in uveal melanoma liver metastases treated with first-line selective internal radiation therapy.

First-line selective internal radiation therapy (SIRT) showed promising outcomes in patients with uveal melanoma liver metastases (UMLM). Patient survival depends on liver's disease control. SIRT planning is essential and little is known about dosimetry. We investigated whether 99mTc-MAA-SPECT/CT dosimetry could predict absorbed doses (AD) evaluated on 90Y-PET/CT and assess the dose-response relationship in UMLM patients treated with first-line SIRT. This IRB-approved, single-center, retrospective analysis (prospectively collected cohort) included 12 patients (median age 63y, range 43-82). Patients underwent MRI/CT, 18F-FDG-PET/CT before and 3-6 months post-SIRT, and 90Y-PET/CT immediately post-SIRT. Thirty-two target lesions were included. AD estimates in tumor and non-tumor liver were obtained from 99mTc-MAA-SPECT/CT and post-SIRT 90Y-PET/CT, and assessed with Lin's concordance correlation coefficients (ρc and Cb), Pearson's coefficient correlation (ρ), and Bland-Altman analyses (mean difference ± standard deviation; 95% limits-of-agreement (LOA)). Influence of tumor characteristics and microsphere type on AD was analyzed. Tumor response was assessed according to size-based, enhancement-based and metabolic response criteria. Mean target lesion AD was 349 Gy (range 46-1586 Gy). Concordance between 99mTc-MAA-SPECT/CT and 90Y-PET/CT tumor dosimetry improved upon dose correction for the recovery coefficient (RC) (ρ = 0.725, ρc = 0.703, Cb = 0.969) with good agreement (mean difference: - 4.93 ± 218.3 Gy, 95%LOA: - 432.8-422.9). Without RC correction, concordance was better for resin microspheres (ρ = 0.85, ρc = 0.998, Cb = 0.849) and agreement was very good between predictive 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (mean difference: - 4.05 ± 55.9 Gy; 95%LOA: - 113.7-105.6). After RC correction, 99mTc-MAA-SPECT/CT dosimetry overestimated AD (- 70.9 ± 158.9 Gy; 95%LOA: - 382.3-240.6). For glass microspheres, concordance markedly improved with RC correction (ρ = 0.790, ρc = 0.713, Cb = 0.903 vs without correction: ρ = 0.395, ρc = 0.244, Cb = 0.617) and 99mTc-MAA-SPECT/CT dosimetry underestimated AD (148.9 ± 267.5 Gy; 95%LOA: - 375.4-673.2). For non-tumor liver, concordance was good between 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (ρ = 0.942, ρc = 0.852, Cb = 0.904). 99mTc-MAA-SPECT/CT slightly overestimated liver AD for resin (3.4 ± 3.4 Gy) and glass (11.5 ± 13.9 Gy) microspheres. Tumor AD was not correlated with baseline or post-SIRT lesion characteristics and no dose-response threshold could be identified. 99mTc-MAA-SPECT/CT dosimetry provides good estimates of AD to tumor and non-tumor liver in UMLM patients treated with first-line SIRT.

Interdisciplinary Swiss consensus recommendations on staging and treatment of advanced prostate cancer.

The management of prostate cancer is undergoing rapid changes in all disease settings. Novel imaging tools for diagnosis have been introduced, and the treatment of high-risk localized, locally advanced and metastatic disease has changed considerably in recent years. From clinical and health-economic perspectives, a rational and optimal use of the available options is of the utmost importance. While international guidelines list relevant pivotal trials and give recommendations for a variety of clinical scenarios, there is much room for interpretation, and several important questions remain highly debated. The goal of developing a national consensus on the use of these novel diagnostic and therapeutic strategies in order to improve disease management and eventually patient outcomes has prompted a Swiss consensus meeting. Experts from several specialties, including urology, medical oncology, radiation oncology, pathology and nuclear medicine, discussed and voted on questions of the current most important areas of uncertainty, including the staging and treatment of high-risk localized disease, treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and use of new options to treat metastatic castration-resistant prostate cancer (mCRPC).

Response heterogeneity as a new biomarker of treatment response in patients with neuroendocrine tumors.

Aim: The RAISE project aimed to find a surrogate end point to predict treatment response early in patients with enteropancreatic neuroendocrine tumors (NET). Response heterogeneity, defined as the coexistence of responding and non-responding lesions, has been proposed as a predictive marker for progression-free survival (PFS) in patients with NETs. Patients & methods: Computerized tomography scans were analyzed from patients with multiple lesions in CLARINET (NCT00353496; n = 148/204). Cox regression analyses evaluated association between response heterogeneity, estimated using the standard deviation of the longest diameter ratio of target lesions, and NET progression. Results: Greater response heterogeneity at a given visit was associated with earlier progression thereafter: week 12 hazard ratio (HR; 95% confidence interval): 1.48 (1.20-1.82); p < 0.001; n = 148; week 36: 1.72 (1.32-2.24); p < 0.001; n = 108. HRs controlled for sum of longest diameter ratio: week 12: 1.28 (1.04-1.59); p = 0.020 and week 36: 1.81 (1.20-2.72); p = 0.005. Conclusion: Response heterogeneity independently predicts PFS in patients with enteropancreatic NETs. Further validation is required.

Neuroendocrine tumors (NET) are rare, slow-growing cancers that can grow in various parts of the body. By understanding how NETs are responding to treatment, doctors can choose the best treatment for a patient and monitor whether the treatment needs to be changed. Treatment response is determined using 'Response Evaluation Criteria in Solid Tumors (RECIST)': a technique which measures the size of tumors to assess whether they are shrinking. However, RECIST is not always useful in NETs, which grow slowly and rarely shrink. 'Response heterogeneity' describes the situation in which some tumors respond well to treatment, while other tumors in the same patient do not. Response heterogeneity may be important in understanding how tumors are responding to treatment and predicting outcomes for patients. Until now, the link between response heterogeneity and treatment response has not been studied in patients with NETs. The RAISE project examined data from a clinical trial of patients with NETs treated with lanreotide. In RAISE, response heterogeneity was estimated using imaging scans of NETs. Response heterogeneity was compared with factors such as tumor size and amounts of certain molecules found in the blood, to see how well response heterogeneity could predict outcomes for patients with NETs. In this study, response heterogeneity was linked with worse outcomes for patients. Therefore, it may be useful in understanding how NETs respond to treatment. Further research is needed in a different group of patients with NETs, and in patients receiving other treatments, to better understand response heterogeneity.

The use of deep learning models to predict progression-free survival in patients with neuroendocrine tumors.

Aim: The RAISE project assessed whether deep learning could improve early progression-free survival (PFS) prediction in patients with neuroendocrine tumors. Patients & methods: Deep learning models extracted features from CT scans from patients in CLARINET (NCT00353496) (n = 138/204). A Cox model assessed PFS prediction when combining deep learning with the sum of longest diameter ratio (SLDr) and logarithmically transformed CgA concentration (logCgA), versus SLDr and logCgA alone. Results: Deep learning models extracted features other than lesion shape to predict PFS at week 72. No increase in performance was achieved with deep learning versus SLDr and logCgA models alone. Conclusion: Deep learning models extracted relevant features to predict PFS, but did not improve early prediction based on SLDr and logCgA.

From bench to bedside: 64Cu/177Lu 1C1m-Fc anti TEM-1: mice-to-human dosimetry extrapolations for future theranostic applications.

The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of 64Cu/177Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [64Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [177Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5-10 GBq and 25-30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [64Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [177Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals' models such as dogs before moving into the clinic.

Parathyroid Imaging.

Primary hyperparathyroidism (1° HPT) is a relatively common endocrine disorder usually caused by autonomous secretion of parathormone by one or several parathyroid adenomas. 1° HPT causing hypercalcemia, kidney stones and/or osteoporosis should be treated whenever possible by parathyroidectomy. Accurate preoperative location of parathyroid adenomas is crucial for surgery planning, mostly when performing minimally invasive surgery. Cervical ultrasonography (US) is usually performed to localize parathyroid adenomas as a first intention, followed by 99mTc- sestamibi scintigraphy with SPECT/CT whenever possible. 4D-CT is a possible alternative to 99mTc- sestamibi scintigraphy. Recently, 18F-fluorocholine positron emission tomography/computed tomography (18F-FCH PET/CT) has made its way in the clinics as it is the most sensitive method for parathyroid adenoma detection. It can eventually be combined to 4D-CT to increase its diagnostic performance, although this results in higher dose exposure to the patient. Other forms of hyperparathyroidism consist in secondary (2° HPT) and tertiary hyperparathyroidism (3° HPT). As parathyroidectomy is not usually part of the management of patients with 2° HPT, parathyroid imaging is not routinely performed in these patients. In patients with 3° HPT, total or subtotal parathyroidectomy is often performed. Localization of hyperfunctional glands is an important aid to surgery planning. As 18F-FCH PET/CT is the most sensitive modality in multigland disease, it is the preferred imaging technic in 3° HPT patients, although its cost and availability may limit its widespread use in this setting.

Predictive Factors for Adverse Event Outcomes After Transarterial Radioembolization with Yttrium-90 Resin Microspheres in Europe: Results from the Prospective Observational CIRT Study.

BACKGROUND: Using data collected in the prospective observational study CIRSE Registry for SIR-Spheres Therapy, the present study aimed at identifying predictors of adverse events (AEs) following transarterial radioembolization (TARE) with Yttrium-90 resin microspheres for liver tumours. METHODS: We analysed 1027 patients enrolled between January 2015 and December 2017 and followed up for 24 months. Four hundred and twenty-two patients with hepatocellular carcinoma (HCC), 120 with intrahepatic carcinoma (ICC), 237 with colorectal liver metastases and 248 with liver metastases from other primaries were included. Prognostic factors were calculated with a univariable analysis by using the overall AEs burden score (AEBS). RESULTS: All-cause AEs were reported in 401/1027 (39.1%) patients, with AEs associated with TARE, such as abdominal pain (16.6%), fatigue (17%), and nausea (11.7%) reported most frequently. Grade 3 or higher AEs were reported in 92/1027 (9%) patients. Reports on grade ≥ 3 gastrointestinal ulcerations (0.4%), gastritis (0.3%), radiation cholecystitis (0.2%) or radioembolization-induced liver disease (0.5%) were uncommon. Univariable analysis showed that in HCC, AEBS increased for Eastern Cooperative Oncology Group (ECOG) 0 (p = 0.0045), 1 tumour nodule (0.0081), > 1 TARE treatment (p = 0.0224), no prophylactic embolization (p = 0.0211), partition model dosimetry (p = 0.0007) and unilobar treatment target (0.0032). For ICC, > 1 TARE treatment was associated with an increase in AEBS (p = 0.0224), and for colorectal liver metastases, ECOG 0 (p = 0.0188), > 2 prior systemic treatments (p = 0.0127), and 1 tumour nodule (p = 0.0155) were associated with an increased AEBS. CONCLUSION: Our study confirms that TARE is a safe treatment with low toxicity and a minimal impact on quality of life.

The diagnostic performance of functional dopaminergic scintigraphic imaging in the diagnosis of dementia with Lewy bodies: an updated systematic review.

INTRODUCTION: Dopaminergic scintigraphic imaging is a cornerstone to support the diagnosis in dementia with Lewy bodies. To clarify the current state of knowledge on this imaging modality and its impact on clinical diagnosis, we performed an updated systematic review of the literature. METHODS: This systematic review was carried out according to PRISMA guidelines. A comprehensive computer literature search of PubMed/MEDLINE, EMBASE, and Cochrane Library databases for studies published through June 2022 was performed using the following search algorithm: (a) "Lewy body" [TI] OR "Lewy bodies" [TI] and (b) ("DaTscan" OR "ioflupane" OR "123ip" OR "123?ip" OR "123 ip" OR "123i-FP-CIT" OR "FPCIT" OR "FP-CIT" OR "beta?CIT" OR "beta CIT" OR "CIT?SPECT" OR "CIT SPECT" OR "Dat?scan*" OR "dat scan*" OR "dat?spect*" OR "SPECT"). Risk of bias and applicability concerns of the studies were evaluated using the QUADAS-2 tool. RESULTS: We performed a qualitative analysis of 59 studies. Of the 59 studies, 19 (32%) addressed the diagnostic performance of dopamine transporter imaging, 15 (25%) assessed the identification of dementia with Lewy bodies in the spectrum of Lewy body disease and 18 (31%) investigated the role of functional dopaminergic imaging in distinguishing dementia with Lewy bodies from other dementias. Dopamine transporter loss was correlated with clinical outcomes in 19 studies (32%) and with other functional imaging modalities in 15 studies (25%). Heterogeneous technical aspects were found among the studies through the use of various radioligands, the more prevalent being the [123I]N­ω­fluoropropyl­2ß­carbomethoxy­3ß­(4­iodophenyl) nortropane (123I-FP-CIT) in 54 studies (91.5%). Image analysis used visual analysis (9 studies, 15%), semi-quantitative analysis (29 studies, 49%), or a combination of both (16 studies, 27%). CONCLUSION: Our systematic review confirms the major role of dopaminergic scintigraphic imaging in the assessment of dementia with Lewy bodies. Early diagnosis could be facilitated by identifying the prodromes of dementia with Lewy bodies using dopaminergic scintigraphic imaging coupled with emphasis on clinical neuropsychiatric symptoms. Most published studies use a semi-quantitative analytical assessment of tracer uptake, while there are no studies using quantitative analytical methods to measure dopamine transporter loss. The superiority of a purely quantitative approach to assess dopaminergic transmission more accurately needs to be further clarified.

Factors impacting survival after transarterial radioembolization in patients with hepatocellular carcinoma: Results from the prospective CIRT study.

Background & Aims: Transarterial radioembolization (TARE) with Yttrium-90 resin microspheres is an established treatment option for patients with hepatocellular carcinoma (HCC). However, optimising treatment application and patient selection remains challenging. We report here on the effectiveness, safety and prognostic factors, including dosing methods, associated with TARE for HCC in the prospective observational CIRT study. Methods: We analysed 422 patients with HCC enrolled between Jan 2015 and Dec 2017, with follow-up visits every 3 months for up to 24 months after first TARE. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every 3-month follow-up visit. We used the multivariable Cox proportional hazard model and propensity score matching to identify independent prognostic factors for effectiveness outcomes. Results: The median OS was 16.5 months, the median PFS was 6.1 months, and the median hepatic PFS was 6.7 months. Partition model dosimetry resulted in improved OS compared to body surface area calculations on multivariable analysis (hazard ratio 0.65; 95% CI 0.46-0.92; p = 0.0144), which was confirmed in the exact matching propensity score analysis (hazard ratio 0.56; 95% CI 0.35-0.89; p = 0.0136). Other independent prognostic factors for OS were ECOG-performance status >0 (p = 0.0018), presence of ascites (p = 0.0152), right-sided tumours (p = 0.0002), the presence of portal vein thrombosis (p = 0.0378) and main portal vein thrombosis (p = 0.0028), ALBI grade 2 (p = 0.0043) and 3 (p = 0.0014). Adverse events were recorded in 36.7% of patients, with 9.7% of patients experiencing grade 3 or higher adverse events. Conclusions: This large prospective observational dataset shows that TARE is an effective and safe treatment in patients with HCC. Using partition model dosimetry was associated with a significant improvement in survival outcomes. Impact and implications: Transarterial radioembolization (TARE) is a form of localised radiation therapy and is a potential treatment option for primary liver cancer. We observed how TARE was used in real-life clinical practice in various European countries and if any factors predict how well the treatment performs. We found that when a more complex but personalised method to calculate the applied radiation activity was used, the patient responded better than when a more generic method was used. Furthermore, we identified that general patient health, ascites and liver function can predict outcomes after TARE. Clinical trial number: NCT02305459.