Diagnostic utility of 11 C-methionine PET/CT in primary hyperparathyroidism in a UK cohort: A single-centre experience and literature review.

OBJECTIVE: Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear. Here, we report our experience of the diagnostic utility of 11C-methionine PET/CT in a single-center patient cohort (n = 45). DESIGN: Retrospective single-center cohort study. PATIENTS AND MEASUREMENTS: The data of eligible patients that underwent 11C-methionine PET/CT between 2014 and 2022 at Addenbrooke's Hospital (Cambridge, UK) were collected and analyzed. The clinical utility of imaging modalities was determined by comparing the imaging result with histopathological and biochemical outcomes following surgery. RESULTS: In patients with persistent primary hyperparathyroidism following previous surgery, 11C-methionine PET/CT identified a candidate lesion in 6 of 10 patients (60.0%), and histologically confirmed in 5 (50.0%). 11C-methionine PET/CT also correctly identified a parathyroid adenoma in 9 out of 12 patients (75.0%) that failed to be localized on other imaging modalities. 11C-methionine PET/CT had a sensitivity of 70.0% (95% CI 55.8 - 84.2%) for the detection of parathyroid adenomas. CONCLUSIONS: This study highlights a diagnostic role for 11C-methionine PET/CT in patients that have undergone unsuccessful prior surgery or have equivocal or negative prior imaging results, aiding localization and a targeted surgical approach.

The Role of Preoperative Imaging in the Detection of Lateral Lymph Node Metastases in Rectal Cancer: A Systematic Review and Diagnostic Test Meta-analysis.

BACKGROUND: Different techniques exist for the imaging of lateral lymph nodes in rectal cancer. OBJECTIVE: This study aimed to compare the diagnostic accuracy of pelvic MRI, 18 F-FDG-PET/CT, and 18 F-FDG-PET/MRI for the identification of lateral lymph node metastases in rectal cancer. DATA SOURCES: Data sources include PubMed, Embase, Cochrane Library, and Google Scholar. STUDY SELECTION: All studies evaluating the diagnostic accuracy of pelvic MRI, 18 F-FDG-PET/CT, and 18 F-FDG-PET/MRI for the preoperative detection of lateral lymph node metastasis in patients with rectal cancer were selected. INTERVENTIONS: The interventions were pelvic MRI, 18 F-FDG-PET/CT, and/or 18 F-FDG-PET/MRI. MAIN OUTCOME MEASURES: Definitive histopathology was used as a criterion standard. RESULTS: A total of 20 studies (1,827 patients) were included out of an initial search yielding 7,360 studies. The pooled sensitivity of pelvic MRI was 0.88 (95% CI, 0.85-0.91), of 18 F-FDG-PET/CT was 0.83 (95% CI, 0.80-0.86), and of 18 F-FDG-PET/MRI was 0.72 (95% CI, 0.51-0.87) for the detection of lateral lymph node metastasis. The pooled specificity of pelvic MRI was 0.85 (95% CI, 0.78-0.90), of 18 F-FDG-PET/CT was 0.95 (95% CI, 0.86-0.98), and of 18 F-FDG-PET/MRI was 0.90 (95% CI, 0.78-0.96). The area under the curve was 0.88 (95% CI, 0.85-0.91) for pelvic MRI and was 0.83 (95% CI, 0.80-0.86) for 18 F-FDG-PET/CT. LIMITATIONS: Heterogeneity in terms of patients' populations, definitions of suspect lateral lymph nodes, and administration of neoadjuvant treatment. CONCLUSIONS: For the preoperative identification of lateral lymph node metastasis in rectal cancer, this review found compelling evidence that pelvic MRI should constitute the imaging modality of choice. In contrast, to confirm the presence of lateral lymph node metastasis, 18 F-FDG-PET/MRI modalities allow discarding false positive cases because of increased specificity. PROSPERO REGISTRATION NUMBER: CRD42020200319.

Impact of solitary pulmonary nodule size on qualitative and quantitative assessment using 18F-fluorodeoxyglucose PET/CT: the SPUTNIK trial.

PURPOSE: To compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial. METHODS: Patients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles. RESULTS: Three hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules < 12 mm, an SUVmax of 1.75 or visual uptake equal to the mediastinum yielded the highest accuracy. For nodules > 16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate. CONCLUSION: In this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size. TRIAL REGISTRATION: ISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT02013063.

PET-guided repeat transsphenoidal surgery for previously deemed unresectable lateral disease in acromegaly.

OBJECTIVE: The object of this study was to determine if revision transsphenoidal surgery (TSS), guided by 11C-methionine PET/CT coregistered with volumetric MRI (Met-PET/MRCR), can lead to remission in patients with persistent acromegaly due to a postoperative lateral disease remnant. METHODS: The authors identified 9 patients with persistent acromegaly following primary intervention (TSS ± medical therapy ± radiotherapy) in whom further surgery had initially been discounted because of equivocal MRI findings with suspected lateral sellar and/or parasellar disease (cases with clear Knosp grade 4 disease were excluded). All patients underwent Met-PET/MRCR. Scan findings were used by the pituitary multidisciplinary team to inform decision-making regarding repeat surgery. Revision TSS was performed with wide lateral exploration as guided by the PET findings. Endocrine reassessment was performed at 6-10 weeks after surgery, with longitudinal follow-up thereafter. RESULTS: Met-PET/MRCR revealed focal tracer uptake in the lateral sellar and/or parasellar region(s) in all 9 patients, which correlated with sites of suspected residual tumor on volumetric MRI. At surgery, tumor was identified and resected in 5 patients, although histological analysis confirmed somatotroph tumor in only 4 cases. In the other 4 patients, no definite tumor was seen, but equivocal tissue was removed. Despite the uncertainty at surgery, all patients showed immediate significant improvements in clinical and biochemical parameters. In the 8 patients for whom long-term follow-up data were available, insulin-like growth factor 1 (IGF-1) was ≤ 1.2 times the upper limit of normal (ULN) in all subjects and ≤ 1 times the ULN in 6 subjects, and these findings have been maintained for up to 28 months (median 8 months, mean 13 months) with no requirement for adjunctive medical therapy or radiotherapy. No patient suffered any additional pituitary deficit or other complication of surgery. CONCLUSIONS: This study provides proof of concept that Met-PET/MRCR can be helpful in the evaluation of residual lateral sellar/parasellar disease in persistent acromegaly and facilitate targeted revision TSS in a subgroup of patients.

11 C-Metomidate PET/CT is a useful adjunct for lateralization of primary aldosteronism in routine clinical practice.

OBJECTIVE: To describe clinical practice experience of 11 C-Metomidate PET/CT as an adjunct to adrenal vein sampling (AVS) in the lateralization of aldosterone-producing adenomas (APA) in primary aldosteronism (PA). CONTEXT: Accurate lateralization of APA in the setting of PA offers the potential for surgical cure and improved long-term cardiovascular outcomes. Challenges associated with AVS, the current gold standard lateralization modality, mean that only a small proportion of potentially eligible patients currently make it through to surgery. This has prompted consideration of alternative strategies for lateralization, including the application of novel molecular PET tracers such as 11 C-Metomidate. DESIGN: Clinical Service Evaluation/Retrospective audit. PATIENTS: Fifteen individuals with a confirmed diagnosis of PA, undergoing lateralization with 11 C-Metomidate PET/CT prior to final clinical decision on surgical vs medical management. MEASUREMENTS: All patients underwent screening aldosterone renin ratio (ARR), followed by confirmatory testing with the seated saline infusion test, according to Endocrine Society Clinical Practice Guidelines. Adrenal glands were imaged using dedicated adrenal CT. 11 C-Metomidate PET/CT was undertaken due to equivocal or failed AVS. Management outcomes were assessed by longitudinal measurement of blood pressure, ARR, number of hypertensive medications following adrenalectomy or institution of medical therapy. RESULTS: We describe the individual lateralization and clinical outcomes for 15 patients with PA. CONCLUSION: 11 C-Metomidate PET/CT in conjunction with adrenal CT and AVS provided useful information which aided clinical decision-making for PA within a multidisciplinary hypertension clinic.

Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.

BACKGROUND: Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. METHODS: Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/- Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. RESULTS: The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. CONCLUSIONS: Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.

Improved long-term survival after resection of colorectal liver metastases following staging with FDG positron emission tomography.

BACKGROUND AND OBJECTIVES: Actual long-term survival of patients with colorectal liver metastases staged by PET CT has not been reported. Objectives were to investigate whether PET CT staging results in actual improved long-term survival, to examine outcome in patients with 'equivocal' PET CT scans, and those excluded from hepatectomy by PET CT. METHODS: A retrospective analysis of patients undergoing hepatectomy for colorectal liver metastases between March 1998 and September 2008. RESULTS: Overall 5- and 10-year survival was 44.8% and 23.9%. PET CT staging resulted in management changes in 23% of patients. PET CT staged patients showed significantly better survival than those staged by CT alone at 3 years (79.8% vs. 54.1%) and at 5 years (54.1% vs. 37.3%) with median survivals of 6.4 years versus 3.9 years (log rank P = 0.018). Patients with equivocal PET CT scans showed worse median survival than those with favourable PET CT (log rank P = 0.002), but may include a subpopulation whose prognosis trends towards a more favourable outcome than those excluded from liver resection by PET CT, whose median survival remains limited to 21 months. CONCLUSIONS: Staging of patients with colorectal liver metastases by PET CT is associated with significantly improved actual long-term survival, and provides valuable prognostic information which guides surgical and oncological treatments.

Real-world experience with 11C-methionine positron emission tomography in the management of acromegaly.

BACKGROUND: L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly. METHODS: A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%). RESULTS: A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery. CONCLUSION: In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.

Clinical Utility of 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) in Multivisceral Transplant Patients.

Multivisceral transplant (MVTx) refers to a composite graft from a cadaveric donor, which often includes the liver, the pancreaticoduodenal complex, and small intestine transplanted en bloc. It remains rare and is performed in specialist centres. Post-transplant complications are reported at a higher rate in multivisceral transplants because of the high levels of immunosuppression used to prevent rejection of the highly immunogenic intestine. In this study, we analyzed the clinical utility of 28 18F-FDG PET/CT scans in 20 multivisceral transplant recipients in whom previous non-functional imaging was deemed clinically inconclusive. The results were compared with histopathological and clinical follow-up data. In our study, the accuracy of 18F-FDG PET/CT was determined as 66.7%, where a final diagnosis was confirmed clinically or via pathology. Of the 28 scans, 24 scans (85.7%) directly affected patient management, of which 9 were related to starting of new treatments and 6 resulted in an ongoing treatment or planned surgery being stopped. This study demonstrates that 18F-FDG PET/CT is a promising technique in identifying life-threatening pathologies in this complex group of patients. It would appear that 18F-FDG PET/CT has a good level of accuracy, including for those MVTx patients suffering from infection, post-transplant lymphoproliferative disease, and malignancy.

Molecular Imaging of Pituitary Tumors.

Tumors of the pituitary gland, although mostly benign adenomas, are a cause of significant morbidity and even excess mortality due to local compressive effects (eg visual loss, hypopituitarism) and unregulated hormone secretion (eg acromegaly or Cushing Disease). Surgery, radiotherapy, and medical management (sometimes in combination) may be needed to mitigate the effects of tumor expansion and endocrine dysfunction. Magnetic resonance imaging (MRI) plays a central role in treatment planning for most patients. However, it does not always reliably identify the site(s) of primary or recurrent disease, especially where post-treatment remodeling results in indeterminate anatomical appearances. In these contexts, molecular imaging is a potential game-changer, allowing precise localization of sites of active disease and enabling safe and effective targeted intervention when patients would otherwise be consigned to expensive life-long medication. For pituitary and parasellar imaging, PET is the preferred modality due to its superior spatial resolution and sensitivity compared with SPECT, and an array of PET radioligands have been studied in different pituitary adenoma (PA) subtypes. While 18F-fluorodeoxyglucose (18F-FDG) is widely available, significant heterogeneity in tumoral uptake has limited its use. Instead, ligands targeting specific molecular pathways relevant to PA biology (eg somatostatin or dopamine receptor expression, amino acid uptake) are increasingly preferred and are beginning to find application in routine clinical practice. In addition, novel approaches to distinguish adenomatous tissue from normal gland (eg through comparison of images obtained with different radiotracers) and increase confidence that a suspected abnormal focus is indeed pathological (eg through subtraction imaging) have been proposed. It is likely therefore that molecular imaging will continue to find increasing application in the management of pituitary tumors just as it already does in other endocrine disorders.

Development of a bespoke phantom to optimize molecular PET imaging of pituitary tumors.

BACKGROUND: Image optimization is a key step in clinical nuclear medicine, and phantoms play an essential role in this process. However, most phantoms do not accurately reflect the complexity of human anatomy, and this presents a particular challenge when imaging endocrine glands to detect small (often subcentimeter) tumors. To address this, we developed a novel phantom for optimization of positron emission tomography (PET) imaging of the human pituitary gland. Using radioactive 3D printing, phantoms were created which mimicked the distribution of 11C-methionine in normal pituitary tissue and in a small tumor embedded in the gland (i.e., with no inactive boundary, thereby reproducing the in vivo situation). In addition, an anatomical phantom, replicating key surrounding structures [based on computed tomography (CT) images from an actual patient], was created using material extrusion 3D printing with specialized filaments that approximated the attenuation properties of bone and soft tissue. RESULTS: The phantom enabled us to replicate pituitary glands harboring tumors of varying sizes (2, 4 and 6 mm diameters) and differing radioactive concentrations (2 ×, 5 × and 8 × the normal gland). The anatomical phantom successfully approximated the attenuation properties of surrounding bone and soft tissue. Two iterative reconstruction algorithms [ordered subset expectation maximization (OSEM); Bayesian penalized likelihood (BPL)] with a range of reconstruction parameters (e.g., 3, 5, 7 and 9 OSEM iterations with 24 subsets; BPL regularization parameter (ß) from 50 to 1000) were tested. Images were analyzed quantitatively and qualitatively by eight expert readers. Quantitatively, signal was the highest using BPL with ß = 50; noise was the lowest using BPL with ß = 1000; contrast was the highest using BPL with ß = 100. The qualitative review found that accuracy and confidence were the highest when using BPL with ß = 400. CONCLUSIONS: The development of a bespoke phantom has allowed the identification of optimal parameters for molecular pituitary imaging: BPL reconstruction with TOF, PSF correction and a ß value of 400; in addition, for small (< 4 mm) tumors with low contrast (2:1 or 5:1), sensitivity may be improved using a ß value of 100. Together, these findings should increase tumor detection and confidence in reporting scans.

[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.

Localization of TSH-secreting pituitary adenoma using 11C-methionine image subtraction.

BACKGROUND: Pituitary adenomas (PA) affect ~ 1:1200 of the population and can cause a wide range of symptoms due to hormone over-secretion, loss of normal pituitary gland function and/or compression of visual pathways, resulting in significantly impaired quality of life. Surgery is potentially curative if the location of the adenoma can be determined. However, standard structural (anatomical) imaging, in the form of MRI, is unable to locate all tumors, especially microadenomas (< 1 cm diameter). In such cases, functional imaging [11C-methionine PET/CT (Met-PET)] can facilitate tumor detection, although may be inconclusive when the adenoma is less metabolically active. We, therefore, explored whether subtraction imaging, comparing findings between two Met-PET scans with medical therapy-induced suppression of tumor activity in the intervening period, could increase confidence in adenoma localization. In addition, we assessed whether normalization to a reference region improved consistency of pituitary gland signal in healthy volunteers who underwent two Met-PET scans without medical suppression. RESULTS: We found that the mean percentage differences in maximum pituitary uptake between two Met-PET scans in healthy volunteers were 2.4% for (SUVr) [cerebellum], 8.8% for SUVr [pons], 5.2% for SUVr [gray matter] and 23.1% for the SUVbw [no region]. Laterality, as measured by contrast-noise ratio (CNR), indicated the correct location of the adenoma in all three image types with mean CNR values of 6.2, 8.1 and 11.1 for SUVbw, SUVbwSub and SUVrSub [cerebellum], respectively. Subtraction imaging improved CNR in 60% and 100% of patients when using images generated from SUVbw [no region] and SUVr [cerebellum] scans compared to standard clinical SUVbw imaging. CONCLUSIONS: Met-PET scans should be normalized to the cerebellum to minimize the effects of physiological variation in pituitary gland uptake of 11C-methionine, especially when comparing serial imaging. Subtraction imaging following endocrine suppression of tumor function improved lateralization of PA when compared with single time point clinical Met-PET but, importantly, only if the images were normalized to the cerebellum prior to subtraction.

Low-dose interleukin 2 for the reduction of vascular inflammation in acute coronary syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial.

INTRODUCTION: Inflammation plays a critical role in the pathogenesis of atherosclerosis, the leading cause of ischaemic heart disease (IHD). Studies in preclinical models have demonstrated that an increase in regulatory T cells (Tregs), which have a potent immune modulatory action, led to a regression of atherosclerosis. The Low-dose InterLeukin 2 (IL-2) in patients with stable ischaemic heart disease and Acute Coronary Syndromes (LILACS) study, established the safety of low-dose IL-2 and its biological efficacy in IHD. The IVORY trial is designed to assess the effects of low-dose IL-2 on vascular inflammation in patients with acute coronary syndromes (ACS). METHODS AND ANALYSIS: In this study, we hypothesise that low-dose IL-2 will reduce vascular inflammation in patients presenting with ACS. This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Patients will be recruited across two centres, a district general hospital and a tertiary cardiac centre in Cambridge, UK. Sixty patients with ACS (unstable angina, non-ST elevation myocardial infarction or ST elevation myocardial infarction) with high-sensitivity C reactive protein (hsCRP) levels >2 mg/L will be randomised to receive either 1.5×106 IU of low-dose IL-2 or placebo (1:1). Dosing will commence within 14 days of admission. Dosing will comprise of an induction and a maintenance phase. 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography/CT (PET/CT) scans will be performed before and after dosing. The primary endpoint is the change in mean maximum target to background ratios (TBRmax) in the index vessel between baseline and follow-up scans. Changes in circulating T-cell subsets will be measured as secondary endpoints of the study. The safety and tolerability of extended dosing with low-dose IL-2 in patients with ACS will be evaluated throughout the study. ETHICS AND DISSEMINATION: The Health Research Authority and Health and Care Research Wales, UK (19/YH/0171), approved the study. Written informed consent is required to participate in the trial. The results will be reported through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT04241601.

An Approach to a Patient With Primary Hyperparathyroidism and a Suspected Ectopic Parathyroid Adenoma.

Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia driven by excess parathyroid hormone (PTH) secretion. PHPT is a common endocrine condition with a prevalence of 1 to 7 cases per 1000 adults. PHPT typically presents in the fifth or sixth decade and shows significant female preponderance. Solitary hyperfunctioning parathyroid adenomas account for 85% to 90% of PHPT cases. The remaining 10% to 15% include cases of multiglandular disease (multiple adenomas or hyperplasia) and, rarely, parathyroid carcinoma (1%). Ectopic parathyroid adenomas may arise due to abnormal embryological migration of the parathyroid glands and can be difficult to localize preoperatively, making surgical cure challenging on the first attempt. The potential existence of multiglandular disease should be considered in all patients in whom preoperative localization fails to identify a target adenoma or following unsuccessful parathyroidectomy. Risk factors for multiglandular disease include underlying genetic syndromes (eg, MEN1/2A), lithium therapy, or previous radiotherapy. In addition to multifocal disease, the possibility of an ectopic parathyroid gland should also be considered in patients requiring repeat parathyroid surgery. In this article, we use illustrative clinical vignettes to discuss the approach to a patient with primary hyperparathyroidism (PHPT) and a suspected ectopic parathyroid adenoma.

The emerging role of cell surface receptor and protein binding radiopharmaceuticals in cancer diagnostics and therapy.

Targeting specific cell membrane markers for both diagnostic imaging and radionuclide therapy is a rapidly evolving field in cancer research. Some of these applications have now found a role in routine clinical practice and have been shown to have a significant impact on patient management. Several molecular targets are being investigated in ongoing clinical trials and show promise for future implementation. Advancements in molecular biology have facilitated the identification of new cancer-specific targets for radiopharmaceutical development.

Methods of 3D printing models of pituitary tumors.

BACKGROUND: Pituitary adenomas can give rise to a variety of clinical disorders and surgery is often the primary treatment option. However, preoperative magnetic resonance imaging (MRI) does not always reliably identify the site of an adenoma. In this setting molecular (functional) imaging (e.g. 11C-methionine PET/CT) may help with tumor localisation, although interpretation of these 2D images can be challenging. 3D printing of anatomicalal models for other indications has been shown to aid surgical planning and improve patient understanding of the planned procedure. Here, we explore the potential utility of four types of 3D printing using PET/CT and co-registered MRI for visualising pituitary adenomas. METHODS: A 3D patient-specific model based on a challenging clinical case was created by segmenting the pituitary gland, pituitary adenoma, carotid arteries and bone using contemporary PET/CT and MR images. The 3D anatomical models were printed using VP, MEX, MJ and PBF 3D printing methods. Different anatomicalal structures were printed in color with the exception of the PBF anatomical model where a single color was used. The anatomical models were compared against the computer model to assess printing accuracy. Three groups of clinicians (endocrinologists, neurosurgeons and ENT surgeons) assessed the anatomical models for their potential clinical utility. RESULTS: All of the printing techniques produced anatomical models which were spatially accurate, with the commercial printing techniques (MJ and PBF) and the consumer printing techniques (VP and MEX) demonstrating comparable findings (all techniques had mean spatial differences from the computer model of < 0.6 mm). The MJ, VP and MEX printing techniques yielded multicolored anatomical models, which the clinicians unanimously agreed would be preferable to use when talking to a patient; in contrast, 50%, 40% and 0% of endocrinologists, neurosurgeons and ENT surgeons respectively would consider using the PBF model. CONCLUSION: 3D anatomical models of pituitary tumors were successfully created from PET/CT and MRI using four different 3D printing techniques. However, the expert reviewers unanimously preferred the multicolor prints. Importantly, the consumer printers performed comparably to the commercial MJ printing technique, opening the possibility that these methods can be adopted into routine clinical practice with only a modest investment.

The role of [68 Ga]Ga-DOTATATE PET/CT in wild-type KIT/PDGFRA gastrointestinal stromal tumours (GIST).

BACKGROUND: [68 Ga]Ga-DOTATATE PET/CT is now recognised as the most sensitive functional imaging modality for the diagnosis of well-differentiated neuroendocrine tumours (NET) and can inform treatment with peptide receptor radionuclide therapy with [177Lu]Lu-DOTATATE. However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [68 Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours. Molecular profiling of gastrointestinal stromal tumours that lack activating somatic mutations in KIT or PDGFRA or so-called 'wild-type' GIST (wtGIST) has demonstrated that wtGIST and NET have overlapping molecular features and has encouraged exploration of shared therapeutic targets, due to a lack of effective therapies currently available for metastatic wtGIST. AIMS: To investigate (i) the diagnostic role of [68 Ga]Ga-DOTATATE PET/CT; and, (ii) to investigate the potential of this imaging modality to guide treatment with [177Lu]Lu-DOTATATE in patients with wtGIST. METHODS: [68 Ga]Ga-DOTATATE PET/CT was performed on 11 patients with confirmed or metastatic wtGIST and one patient with a history of wtGIST and a mediastinal mass suspicious for metastatic wtGIST, who was subsequently diagnosed with a metachronous mediastinal paraganglioma. Tumour expression of somatostatin receptor subtype 2 (SSTR2) using immunohistochemistry was performed on 54 tumour samples including samples from 8/12 (66.6%) patients who took part in the imaging study and 46 tumour samples from individuals not included in the imaging study. RESULTS: [68 Ga]Ga-DOTATATE PET/CT imaging was negative, demonstrating that liver metastases had lower uptake than background liver for nine cases (9/12 cases, 75%) and heterogeneous uptake of somatostatin tracer was noted for two cases (16.6%) of wtGIST. However, [68 Ga]Ga-DOTATATE PET/CT demonstrated intense tracer uptake in a synchronous paraganglioma in one case and a metachronous paraganglioma in another case with wtGIST. CONCLUSIONS: Our data suggest that SSTR2 is not a diagnostic or therapeutic target in wtGIST. [68 Ga]Ga-DOTATATE PET/CT may have specific diagnostic utility in differentiating wtGIST from other primary tumours such as paraganglioma in patients with sporadic and hereditary forms of wtGIST.

Modern imaging of pituitary adenomas.

Decision-making in pituitary disease is critically dependent on high quality imaging of the sella and parasellar region. Magnetic resonance imaging (MRI) is the investigation of choice and, for the majority of patients, combined T1 and T2 weighted sequences provide the information required to allow surgery, radiotherapy (RT) and/or medical therapy to be planned and long-term outcomes to be monitored. However, in some cases standard clinical MR sequences are indeterminate and additional information is needed to help inform the choice of therapy for a pituitary adenoma (PA). This article reviews current recommendations for imaging of PA, examines the potential added value that alternative MR sequences and/or CT can offer, and considers how the use of functional/molecular imaging might allow definitive treatment to be recommended for a subset of patients who would otherwise be deemed unsuitable for (further) surgery and/or RT.