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Primary aldosteronism (PA) is a common, potentially reversible, cause of hypertension. Distinguishing unilateral from bilateral PA is critical when deciding who should be offered surgery (unilateral adrenalectomy). Recent studies have shown that PET/CT with [¹¹C]metomidate can accurately identify unilateral PA, with localization of the causative aldosterone-producing adenoma (APA). However, the availability of [¹¹C]metomidate is limited to centers with an on-site cyclotron. Here, we report an early-phase human study with the ¹⁸F-labeled analog, para-chloro-2-[¹⁸F]fluoroethyletomidate ([¹⁸F]CETO).

Methods: We conducted a phase I/IIa, single-center, open-label, microdosing study. The primary objective was to evaluate the safety of up to 2 administrations of [¹⁸F]CETO in 6 patients with PA (3 unilateral disease, 3 bilateral disease) and 5 healthy volunteers. Safety evaluation included assessment of adrenal function after the first [¹⁸F]CETO administration. The biodistribution of [¹⁸F]CETO was assessed in a 90-min dynamic PET acquisition. In patients with PA, the effect of pretreatment with oral dexamethasone on [¹⁸F]CETO uptake by normal adrenal tissue and APAs was also assessed.

Results: Eleven participants were recruited to the trial, including 6 patients and 5 healthy volunteers. No subjects experienced serious adverse events or reactions, and all participants had normal adrenal function after [¹⁸F]CETO administration. [¹⁸F]CETO demonstrated high selectivity for the adrenal glands with low uptake in other tissues. Visualization of APAs was enhanced after dexamethasone pretreatment, which suppressed [¹⁸F]CETO uptake by normal adrenal tissue.

Conclusion: [¹⁸F]CETO is a safe radiopharmaceutical for PET imaging of the adrenal glands, with no observed adverse reactions or impairment of adrenal function in this study. [¹⁸F]CETO demonstrates selective high affinity for adrenal tissue, particularly APAs. Distinction between APAs and normal adrenal tissue is enhanced by dexamethasone pretreatment to suppress [¹⁸F]CETO uptake by normal glands. This positions [¹⁸F]CETO as a promising imaging tool for evaluation in the context of PA.

Assessing the response to systemic therapy in neuroendocrine tumors (NET) is challenging since morphological imaging response is often delayed and not necessarily reflective of clinical benefit. Peptide receptor radionuclide therapy (PRRT) has a complex mechanism of action, further complicating response assessment. In response to these challenges, the European Neuroendocrine Tumor Society (ENETS) Theranostics Task Force conducted a statement-based survey among experts to identify the current landscape and unmet needs in PRRT response assessment. The survey, presented at the 2022 ENETS Advisory Board (AB) meeting in Vienna, was completed by 70% of AB members, most of whom (81%) were from ENETS Centers of Excellence (CoE). It comprised a set of 13 questions with two substatements in three questions. Six (46%) of the statements achieved more than 75% agreement, while five (39%) additional statements reached over 60% consensus. Key points from the survey include: AB members agreed that lesions deemed equivocal on computed tomography (CT) or magnetic resonance imaging (MRI) should be characterized by somatostatin receptor (SST) positron emission tomography (PET)/CT before being designated as target lesions. It was agreed that interim response assessments should occur after the second or third PRRT cycle. Over half (54%) preferred using both conventional cross-sectional imaging (CT and/or MRI) and hybrid imaging (SST PET/CT) for this purpose. Almost all AB members supported further response assessment 3 months after the final PRRT cycle. A majority (62%) preferred using a combination of conventional cross-sectional imaging and SST PET/CT. For cases showing equivocal progression (ambiguous lesions or nontarget lesions) on CT and/or MRI, further confirmation using SST PET/CT was recommended. A significant majority (74%) preferred assessing pseudo-progression and delayed response by combining SST PET with diagnostic CT and/ or MRI. Though just below the 75% consensus threshold, there was substantial agreement on selecting target lesions based on SST PET/CT uptake intensity and homogeneity. Sixty-nine percent noted the importance of documenting and closely following heterogeneity in lesions in liver, lymph nodes, primary tumors, or other organs. As to the statement on parameters for new response criteria, AB members recommended exploring maximum standard unit value, tumor-to-background ratio, Hounsfield Unit (Choi Criteria), total tumor burden, and novel serum or molecular markers for future response evaluation criteria. Sixty-five percent supported the use of a single SST PET/CT for response assessment of NET lesions treated with PRRT. These findings highlight the importance of integrating advanced imaging techniques and recognizing the need for more nuanced criteria in assessing the efficacy of PRRT in NET patients. This approach aims to enhance the accuracy of treatment monitoring and improve patient outcomes.

Background Non-small cell lung cancer (NSCLC) is a common neoplasm with poor prognosis in advanced stages. The clinical work-up in patients with locally advanced NSCLC mostly includes F-18-fluorodeoxyglucose positron emission tomography computed tomography (F-18-FDG PET/CT) because of its high sensitivity for malignant lesion detection; however, specificity is lower. Diverging results exist whether whole-body MRI (WB-MRI) improves the staging accuracy in advanced lung cancer. Considering WB-MRI being a more time-consuming examination compared to brain MRI, it is important to establish whether or not additional value is found in detecting and characterizing malignant lesions. The purpose of this study is to investigate the value of additional whole-body magnetic resonance imaging, instead of only brain MRI, together with F-18-FDG PET/CT in staging patients with advanced NSCLC planned for curative treatment. Material and methods In a prospective single center study, 28 patients with NSCLC stage 3 or oligometastatic disease were enrolled. In addition to F-18-FDG PET/CT, they underwent WB-MRI including the thorax, abdomen, spine, pelvis, and contrast-enhanced examination of the brain and liver. F-18-FDG PET/CT and WB-MRI were separately evaluated by two blinded readers, followed by consensus reading in which the likelihood of malignancy was assessed in detected lesions. Imaging and clinical follow-up for at least 12 months was used as reference standard. Statistical analyses included Fischer's exact test and Clopped-Pearson. Results 28 patients (mean age +/- SD 70.5 +/- 8.4 years, 19 women) were enrolled. WB-MRI and FDG-PET/CT both showed maximum sensitivity and specificity for primary tumor diagnosis and similar sensitivity (p = 1.00) and specificity (p = 0.70) for detection of distant metastases. For diagnosis of lymph node metastases, WB-MRI showed lower sensitivity, 0.65 (95% CI: 0.38-0.86) than FDG-PET/CT, 1.00 (95% CI: 0.80-1.00) (p < 0.05), but similar specificity (p = 0.59). Conclusions WB-MRI in conjunction with F-18-FDG PET/CT provides no additional value over MRI of the brain only, in staging patients with advanced NSCLC. Trial registration Registered locally and approved by the Uppsala University Hospital committee, registration number ASMR020.

Background

Historically, patient selection for peptide receptor radionuclide therapy (PRRT) has been performed by virtue of somatostatin receptor scintigraphy (SRS). In recent years, somatostatin receptor positron emission tomography (SSTR-PET) has gradually replaced SRS because of its improved diagnostic capacity, creating an unmet need for SSTR-PET-based selection criteria for PRRT. Tumor-to-blood ratio (TBR) measurements have shown high correlation with the net influx rate Ki, reflecting the tumor somatostatin receptor expression, to a higher degree than standardized uptake value (SUV) measurements. TBR may therefore predict treatment response to PRRT. In addition, changes in semiquantitative SSTR-PET parameters have been shown to predate morphological changes, making them a suitable metric for response assessment.

Methods

The institutional database of the Department of Nuclear Medicine (University Hospital Essen) was searched for NET patients undergoing ≥ 2 PRRT cycles with available baseline and follow-up SSTR-PET. Two blinded independent readers reported the occurrence of new lesions quantified tumor uptake of up to nine lesions per patient using SUV and TBR. The association between baseline TBR and changes in uptake/occurrence of new lesions with progression-free survival (PFS) and overall survival (OS) was tested by use of a Cox regression model and log-rank test.

Results

Patients with baseline TBR in the 1st quartile had a shorter PFS (14.4 months) than those in the 3rd (23.7 months; p = 0.03) and 4th (24.1 months; p = 0.02) quartile. Similarly, these patients had significantly shorter OS (32.5 months) than those with baseline TBR in the 2nd (41.8 months; p = 0.03), 3rd (69.2 months; p < 0.01), and 4th (42.7 months; p = 0.03) quartile. Baseline to follow-up increases in TBR were independently associated with shorter PFS when accounting for prognostic markers, e.g., RECIST response (hazard ratio = 2.91 [95%CI = 1.54–5.50]; p = 0.01). This was confirmed with regard to OS (hazard ratio = 1.64 [95%CI = 1.03–2.62]; p = 0.04). Changes in SUVmean were not associated with PFS or OS.

Conclusions

Baseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

Background: Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation.

Methods: This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1^st, 2018 and December 31^st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy.

Results: We screened 48 patients diagnosed with NEC between January 1^st, 2018 and December 31^st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months.

Conclusions: BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.

Several inflammation scores have shown association with survival outcomes for patients with neuroendocrine tumours (NET) treated with peptide receptor radionuclide therapy (PRRT). However, whether these scores add value to established prognostic factors remains unknown. In this retrospective, cohort study of 557 NET patients undergoing PRRT in a tertiary referral centre from 2005 to 2015, we examined inflammatory markers and scores previously associated with cancer outcomes, using Cox proportional hazard models and Akaike's information criterion. Lower albumin (hazard ratio [95% confidence interval], .91 [.87-.95] per unit), as well as higher C-reactive protein (CRP; 1.02 [1.01-1.02]), Glasgow Prognostic Score (GPS; 1 vs. 0: 1.67 [1.14-2.44], 2 vs. 0 3.60 [2.24-5.79]), CRP/albumin ratio (1.84 [1.43-2.37]) and platelet count (Plt) x CRP, but not white blood cell, neutrophil and thrombocyte counts or derived neutrophil to lymphocyte ratio (dNLR), were associated with shorter median overall survival (OS) in an adjusted analysis. The addition of parameters based on albumin and CRP, but not dNLR, to a base model including age, chromogranin A, the cell proliferation marker Ki-67, performance status, tumour site and previous treatments improved the predictive accuracy of the base model. In an exploratory analysis of patients with available erythrocyte sedimentation rate (ESR) and CRP, ESR emerged as the most powerful predictor. When added to a prognostic model for OS in NET patients treated with PRRT, most inflammation scores further improved the model. Albumin was the single marker adding most value to the set of established prognostic markers, whereas dNLR did not seem to improve the model's prognostic ability.

Precise anatomic localization of insulinomas is crucial for surgical treatment. Current routine noninvasive imaging techniques, including CT, MRI, and ⁶⁸Ga-DOTA-somatostatin analog (DOTA-SSA) PET/CT, have limited sensitivity. Endoscopic ultrasound is highly sensitive but invasive. In this prospective multicenter study, we compared the diagnostic accuracy of ⁶⁸Ga-NODAGA-exendin-4 (exendin) PET/CT with all routine imaging procedures for the localization of insulinomas.

Methods: Sixty-nine adults with biochemically proven adult endogenous hyperinsulinemic hypoglycemia underwent exendin PET/CT and current routine imaging. Images were evaluated in a clinical reading and in an expert reading. Image quality was determined by quantitative analysis.

Results: Based on clinical readings, the accuracy of exendin PET/CT (94.4%; 95% CI, 84.6%–98.8%) was greater than that of DOTA-SSA PET/CT (64.8%; 95% CI, 50.6%–77.3%), contrast-enhanced CT/contrast-enhanced diffusion-weighted imaging-MRI (83.3%; 95% CI, 70.7%–92.1%), and endoscopic ultrasound (82.8%; 95% CI, 64.1%–94.1%). In 13% of patients, a correct diagnosis was only reached after exendin PET/CT. Interobserver agreement between readings was higher for exendin PET/CT than for DOTA-SSA PET/CT and contrast-enhanced CT/contrast-enhanced diffusion-weighted imaging-MRI (Cohen κ, 1.0 vs. 0.5 and 0.55). Exendin PET/CT provided a higher insulinoma-to-background ratio (15.3 ± 6.7 vs. 5.2 ± 3.0) and contrast-to-noise ratio (22.6 ± 11.1 vs. 5.1 ± 3.7) than did DOTA-SSA PET/CT.

Conclusion: This study demonstrates the superiority of exendin PET/CT in a unique prospective comparison to all current routine imaging modalities for preoperative localization of benign insulinomas, providing the level of evidence needed for clinical implementation.

Aims/hypothesis

Compromised pancreatic sympathetic innervation has been suggested as a factor involved in both immune-mediated beta cell destruction and endocrine dysregulation of pancreatic islets. To further explore these intriguing findings, new techniques for in vivo assessment of pancreatic innervation are required. This is a retrospective study that aimed to investigate whether the noradrenaline (norepinephrine) analogue ¹¹C-hydroxy ephedrine (¹¹C-HED) could be used for quantitative positron emission tomography (PET) imaging of the sympathetic innervation of the human pancreas.

Methods

In 25 individuals with type 2 diabetes and 64 individuals without diabetes, all of whom had previously undergone ¹¹C-HED-PET/CT because of pheochromocytoma or paraganglioma (or suspicion thereof), the ¹¹C-HED standardised uptake value (SUV_mean), ¹¹C-HED specific binding index (SBI), pancreatic functional volume (FV, in ml), functional neuronal volume (FNV, calculated as SUV_mean × FV), specific binding index with functional volume (SBI FV, calculated as SBI × FV) and attenuation on CT (HU) were investigated in the entire pancreas, and additionally in six separate anatomical pancreatic regions.

Results

Generally, ¹¹C-HED uptake in the pancreas was high, with marked individual variation, suggesting variability in sympathetic innervation. Moreover, pancreatic CT attenuation (HU) (p<0.001), ¹¹C-HED SBI (p=0.0049) and SBI FV (p=0.0142) were lower in individuals with type 2 diabetes than in individuals without diabetes, whereas ¹¹C-HED SUV_mean (p=0.15), FV (p=0.73) and FNV (p=0.30) were similar.

Conclusions/interpretation

We demonstrate the feasibility of using ¹¹C-HED-PET for non-invasive assessment of pancreatic sympathetic innervation in humans. These findings warrant further prospective evaluation, especially in individuals with theoretical defects in pancreatic sympathetic innervation, such as those with type 1 diabetes.

Metastases outside the liver and abdominal/retroperitoneal lymph nodes are nowadays detected frequently in patients with neuroendocrine tumours (NETs), owing to the high sensitivity of positron emission tomography (PET) with Gallium-68-DOTA-somatostatin analogues (⁶⁸Ga-SSA) and concomitant diagnostic computed tomography (CT). Our aim was to determine the prevalence of extra-abdominal metastases on ⁶⁸Ga-DOTATOC-PET/CT in a cohort of patients with small intestinal (Si-NET) and pancreatic NET (Pan-NET), as well as that of pancreatic metastasis in patients with Si-NET. Among 2090 patients examined by ⁶⁸Ga-DOTATOC-PET/CT at two tertiary referral centres, a total of 1177 patients with a history of Si- or Pan-NET, were identified. The most recent ⁶⁸Ga-DOTATOC-PET/CT report for each patient was reviewed, and the location and number of metastases of interest were recorded. Lesions outside the liver and abdominal nodes were found in 26% of patients (n = 310/1177), of whom 21.5% (255/1177) were diagnosed with Si-NET and 4.5% (55/1177) Pan-NET. Bone metastases were found in 18.4% (215/1177), metastases to Virchow's lymph node in 7.1% (83/1177), and lung/pleura in 4.8% (56/1177). In the subset of 255 Si-NET patients, 5.4% (41/255) manifested lesions in the pancreas, 1.5% in the breast (18/255), 1.3% in the heart (15/255) and 1% in the orbita (12/255). In Si-NET patients, the Ki-67 proliferation index was higher in those with ≥2 metastatic sites of interest, than with 1 metastatic site, (p <0.001). Overall, extra-abdominal or pancreatic metastases were more often found in patients with Si-NET (34%) than in those with Pan-NET (13%) (p <0.001). Bone metastases were 2.6 times more frequent in patients with Si-NET compared to Pan-NET patients (p <0.001). Lesions to the breast and orbita were encountered in almost only Si-NET patients. In conclusion, lesions outside the liver and abdominal nodes were detected in as many as 26% of the patients, with different prevalence and metastatic patterns in patients with Si-NET compared to Pan-NET. The impact of such metastases on overall survival and clinical decision-making needs further evaluation.

Background [C-11]metomidate, a methyl ester analogue of etomidate, is used for positron emission tomography of adrenocortical cancer, and has been tested in recent clinical trials for lateralization in primary aldosteronism (PA). However, in PA, visualization as well as uptake quantification are hampered by the tracer's rather high non-specific liver uptake, and its overall clinical usefulness is also limited by the short 20-minute half-life of carbon-11. Therefore, we evaluated para-chloro-2-[F-18]fluoroethyl-etomidate, [F-18]CETO, a fluorine-18 (T-1/2=109.8 min) analogue, as a potential new adrenocortical PET tracer. The aim of this study was to assess radiation dosimetry of [F-18]CETO. Results [F-18]CETO showed a high uptake in adrenal glands, still increasing at 5 h post injection. Adrenal glands (absorbed dose coefficients 0.100 +/- 0.032 mGy/MBq in males and 0.124 +/- 0.013 mGy/MBq in females) received the highest absorbed dose. The effective dose coefficient was 20 mu Sv/MBq. Conclusions[F-18]CETO has a favourable biodistribution in humans for adrenal imaging. The effective dose for a typical clinical PET examination with 200 MBq [F-18]CETO is 4 mSv. Trial registration ClinicalTrials.gov, NCT05361083 Retrospectively registered 29 April 2022. at, URL: https://clinicaltrials.gov/ct2/show/NCT05361083.