Logo: to the web site of Uppsala University

Early detection of metastases and timely surgical intervention play a crucial role in the management of neuroendocrine tumors. In large-sized pheochromocytomas and sympathetic paragangliomas (PPGL), functional imaging with positron emission tomography (PET) is recommended, as it improves the detection of metastases, which may go undetected on conventional radiologic imaging. ¹¹C-hydroxyephedrine binds to the norepinephrine transporter receptor and is detected by PET/CT (HED-PET/CT). It has previously demonstrated high accuracy in detecting primary and metastatic PPGL; however, its impact on preoperative staging is unclear. In this study, we retrospectively analyzed a selected cohort of 44 patients with large PPGL to evaluate whether HED-PET/CT influences preoperative clinical decision-making. All patients who underwent HED-PET/CT at Uppsala University Hospital between 2004 and 2024 were screened for inclusion. In total, 44 patients with pheochromocytomas >5 cm and paragangliomas >4 cm were included. HED-PET/CT results were compared with CT/MR findings, and a final consensus was reached on whether preoperative HED-PET/CT would have altered clinical decision-making. HED-PET/CT identified previously undetected metastatic disease in three patients (6.8%), which had not been visualized on CT/MR. Additionally, two patients had discordant findings, where HED-PET/CT revealed additional metastases. In one case, a liver metastasis was identified postoperatively with HED-PET/CT, leading to a metastasectomy that could have potentially been avoided. These findings suggest that HED-PET/CT is highly accurate in detecting metastases; however, its routine preoperative use may be limited and appears to provide significant clinical benefit only in selected patients.

Aim: To explore the optimal use of MRI including time point to predict early treatment response during definitive chemoradiotherapy in cervical carcinoma.

Methods: Pilot study including 15 patients with cervical carcinoma stage IIB-IIIB (FIGO 2009) scheduled for chemoradiotherapy. All patients underwent four MRI examinations (at baseline, 3 weeks, 5 weeks, and 12 weeks after treatment start). Maximum tumor size, size change (Delta size), visibility on diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) mean and change in ADC (Delta ADC) at the different time points were recorded.

Results: 7/15 patients relapsed during the study period, referred to as "poor prognosis" (PP) and the remaining 8/15 are referred to as "good prognosis" (GP). At all four time points, the tumors in the PP patients were larger than in the GP patients. Tumor size did change between the time point but this was not significant between the groups. Visible tumor on high b-value DWI reached a sensitivity and specificity for predicting prognostic group being highest at 5 weeks, 83 % (5/6) and 63 % (5/ 8), respectively. The combination of tumor size at baseline and visible tumor on DWI at 5 weeks, resulted in an area under the curve (AUC) = 0.83. At 12 weeks, no GP patients, but 2/7 PP patients showed visible tumor on DWI. Addition of ADC-values in the analysis did not improve the predictive value at any time point.

Conclusion: This pilot study indicates that the tumor size on baseline MRI, combined with tumor visibility on DWI at 5 weeks, may predict outcome of chemoradiotherapy.

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.

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.

We aimed to assess the symptoms and impact on overall survival (OS) from bone metastases (BM) diagnosed on Gallium-68-labelled DOTA tyrosine octreotide positron emission tomography with computed tomography (⁶⁸Ga-DOTATOC-PET/CT) in patients with well-differentiated small intestinal neuroendocrine tumours (Si-NETs). Patients with well-differentiated Si-NETs, who underwent ⁶⁸Ga-DOTATOC-PET/CT between 2010 and 2023 at two tertiary referral centres in Sweden, were included. Their number of BM, ≤5 BM versus >5 BM, symptoms and need for analgesics were recorded. To further assess the impact of BM on OS, we used a control group of age- and sex-matched Si-NET patients with liver metastases (Stage IV disease) but without BM. The prevalence of BM in Si-NET patients was 23% (175/753); among these, complete clinical data were available in 138 patients. Synchronous BM were found in 33% (46/138). Sixty-one patients (44%) showed >5 BM at the time of BM detection. Fractures were diagnosed in 4% (n = 6) and 14% (n = 20) needed analgesics for BM-associated pain. In univariable analysis, patients with >5 BM experienced shorter OS from the time of BM detection compared to those with ≤5 BM (18 months vs. 75 months, p < .001). Among patients with Stage IV disease with and without BM, OS was shorter in patients with BM compared to patients with no BM (72 months vs. 288 months, p = .002). In multivariable analysis of patients with BM, higher Ki-67% (hazard ratio [HR] = 1.06, p = .007), older age (HR = 1.07, p < .01), presence of >5 BM (HR = 1.93, p = .021) and synchronous BM (HR = 2.14, p = .016) were identified as independent prognostic factors for shorter OS. In the matched cohort of patients with Stage IV disease with and without BM, presence of BM (HR = 1.94, p = .009), age at diagnosis of Stage IV (HR = 1.08, p < .001) and locoregional surgical resection (HR = 0.47, p = .015) were independent prognostic factors for survival. BM are detected in approximately 25% of Si-NET patients subjected to ⁶⁸Ga-DOTATOC-PET/CT. Pain occurs in approximately 14% and fractures in 4%. The presence of BM among Stage IV patients, the extent of bone disease (>5 BM) and synchronous BM are independent prognostic factors for shorter OS.

Small intestinal neuroendocrine tumors are often diagnosed at an advanced stage, with up to 70% of patients presenting with stage IV disease. While some guidelines recommend prophylactic resection of the primary tumor and mesenteric lymph node metastasis in patients without abdominal symptoms at diagnosis to prevent future abdominal complications, the benefit of this approach remains uncertain.This retrospective cohort study included 44 asymptomatic patients with stage IV small intestinal neuroendocrine tumors treated at Uppsala University Hospital between 2014 and 2019. Additional ten symptomatic patients who underwent at least two computed tomography scans before planned surgery were included in the analysis of mesenteric metastasis volume change and tumor growth rate. The primary outcomes were abdominal symptoms development requiring surgical intervention and the assessment of mesenteric metastasis size progression. During a 10-year follow-up, only four initially asymptomatic patients (9%) developed symptoms leading to surgery. Among all 54 patients, the median volume change in mesenteric metastases was -298 mm3 (IQR: -2,785-1,294), with no significant difference between baseline and most recent scans (P = 0.38). The median interval between scans was 29 months, and the median tumor growth rate was -0.6% per month (IQR: -3.6-1.9%). Similar results were observed in the asymptomatic group. These findings suggest that a non-operative management in stage IV patients without abdominal symptoms is associated with a low incidence of symptom development and limited progression of mesenteric metastases.

Background

In several countries, whole-body imaging has been introduced in the routine follow-up of individuals with high-risk cutaneous malignant melanoma after surgery. However, there is scarce evidence that earlier detection of recurrent disease by regular scanning improves survival. In this interim analysis, we investigated whether imaging in the follow-up programme for high-risk cutaneous malignant melanoma improves survival and assessed whether the study should continue to include participants.

Methods

TRIM is a multicentre, randomised, phase 3 trial in Sweden. Eligible participants are aged 18 years and older with sufficient renal function for intravenously contrast-enhanced CT and are expected to be fit for treatment in case of recurrence. After radical surgery of stage IIB–C and III cutaneous malignant melanoma, participants were randomly assigned (1:1, stratified by tumour stage and method of radiological assessment) to 3 years of follow-up by physical examinations alone (standard group) or to physical examinations plus whole-body imaging with CT or [¹⁸F]fluorodeoxyglucose-PET-CT at baseline, 6, 12, 24, and 36 months (experimental group). The goal is to include 1300 participants. The primary endpoint is overall survival at 5 years and will be reported in the final analysis when data are mature. In this interim report, no endpoints were predefined; we present overall survival, relapse-free survival, locoregional relapse-free survival, and distant metastasis-free survival, analysed by intention to intervene. This study is registered with ClinicalTrials.gov, NCT03116412, and recruitment is ongoing.

Findings

Between June 8, 2017, and July 28, 2023, 983 participants were randomly allocated to the standard (n=498; 296 [59%] male, 202 [41%] female) or experimental (n=485; 309 [64%] male, 176 [36%] female) group. There were no statistically significant differences in overall survival (not reached [NR; 95% CI NR–NR] vs NR [NR–NR]; hazard ratio [HR] 1·04 [95% CI 0·71–1·51], p=0·85) or distant metastasis-free survival (NR [NR–NR] vs NR [NR–NR]; HR 1·20 [0·89–1·64], p=0·24) between the groups at a median follow-up time of 33·6 months (IQR 16·3–49·8). 3-year overall survival rates were 88·2% (95% CI 85·0–91·6) in the standard group versus 87·7% (84·3–91·3) in the experimental group and distant metastasis-free survival was 81·6% (77·9–85·6) in the standard group versus 79·3% (75·3–83·5) in the control group.

Interpretation

This interim analysis indicated that there is no benefit from imaging in the follow-up programme for individuals with high-risk cutaneous malignant melanoma. However, only a few participants have completed the follow-up time of 5 years, and the numerical difference between the study groups in distant metastasis-free survival motivates us to continue the study according to protocol.

The biology of metastatic pancreatic neuroendocrine tumors (panNET) may alter over time. It remains to be defined if, how, and when this patient group should be recommended to re-evaluate the characteristics of their disease. This prospective single-center, longitudinal cohort study at Uppsala University Hospital, Sweden (NCT03130205), included metastatic panNET patients with progressive disease to participate in a standardized re-characterization protocol: clinical and biochemical analyses, core-needle biopsy, and dual-positron emission tomography/computed tomography (PET/CT) (¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and Gallium-68 DOTATOC (⁶⁸Ga-DOTATOC)) with NETPET score assessments. At further disease progression, a second re-characterization was offered. The proportion of patients with a clinically significant change is reported and defined as information that could lead to a change in the therapeutic algorithm proposed in the European Neuroendocrine Tumor Society (ENETS) guidelines. Between 2017 and 2021, 21 patients with progressive metastatic panNETs were included. Before inclusion, 19 tumors were grade (G) 1 or 2, and two were G3. Sixteen patients underwent biopsy with collection of adequate tumor material, of whom 81.3% (n = 13/16) displayed an increase in the Ki-67 index, with transition from G2 to G3 in 50% (n = 8/16). Twelve and 15 patients were positive on ¹⁸F-FDG- and ⁶⁸Ga-DOTATOC-positron emission tomography (PET), respectively. This corresponded to NETPET grades P1 (n = 2), P2b (n = 12), and P3b (n = 1). A clinically significant change was noted among 62% (n = 13/21) of patients at first re-characterization, leading to therapy change in 7 positron emission tomography/computed tomography (PET/CT) patients. After the second re-characterization, a significant clinical change occurred in 43% (n = 3/7) with a shift in therapy for one patient. This study shows that a considerable number of progressive metastatic panNETs experience significant changes in their disease characteristics over time. This may result in a revised treatment plan and highlights the need to re-evaluate all relevant aspects of panNET disease. Such comprehensive re-characterization is particularly crucial in the context of clinical trial inclusion.

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.