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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, [ 11 C]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. Comparison of non-invasive [ 11 C]metomidate PET-CT with adrenal vein sampling for predicting biochemical remission of primary aldosteronism showed non-superiority, suggesting that the non-invasive method is suitable for the diagnosis of unilateral primary aldosteronism.

Unilateral aldosterone-producing adrenal adenomas (APAs) are the potentially curable cause of 5% of all cases of hypertension. Their localisation (via adrenal vein sampling [AVS]) and removal (by laparoscopic adrenalectomy) require invasive procedures that are unattractive to patients. Molecular imaging-located, endoscopic ultrasound-guided trans-gastric radiofrequency ablation (EUS-RFA) is a potential novel, minimally invasive alternative to AVS and total adrenalectomy for the treatment of APAs in the left adrenal gland, which is very close to the stomach. We aimed to determine whether EUS-RFA can safely target a heterogeneous set of such tumours without damaging the rest of the adrenal gland or adjacent organs. We conducted a three-centre feasibility study in the UK of EUS-RFA as a non-surgical, adrenal-sparing treatment for left-sided APAs. Eligible participants were men and women aged 18 years or older, with a diagnosis of primary aldosteronism under the Endocrine Society's criteria, and with evidence of a left-sided APA, diagnosed by AVS or PET-CT. Recruitment was done in three groups, with data from the first four patients in the previously recruited group being reviewed by an independent Safety Committee before proceeding. We performed molecular imaging on two occasions, first to diagnose and locate the APA, and later to quantify the degree of ablation. Following a fine-needle biopsy for later confirmation of APA diagnosis, ablation was performed using a 19G ablation catheter. Its manipulation under continuous ultrasound guidance permitted an incremental number of 10–20 s treatments (also known as burns) as the study progressed. The primary endpoint was safety, judged by the occurrence of prespecified major hazards (gastric and adrenal puncture: perforation, haemorrhage, or infarction of major organs) 24 h or 48 h post-ablation. Secondary endpoints were reductions in the proportion of radiotracer uptake by the ablated APA compared with the contralateral adrenal on molecular imaging at 3 months, and international consensus criteria for biochemical and clinical success (reductions in plasma aldosterone to renin ratio and blood pressure 6 months post-RFA). Between Feb 21, 2018, and Feb 10, 2023, 44 patients were screened and 28 participants were recruited (21 [75%] male and seven [25%] female, mean age 57·7 years [SD 10·3]; 16 [57%] White, 11 [39%] Black, and one [4%] Asian). The 28 participants underwent 35 ablations on one (21 [75%]) or two (seven [25%]) occasions. All PET-CT-positive nodules were identified by the endoscopic ultrasound probe and successfully penetrated by biopsy and ablation catheters. None of the prespecified major hazards occurred in any patient. Localised reduction of radiotracer uptake by the PET-CT-positive APAs at 3 months was associated with complete or partial biochemical cure in 21 participants (75% [95% CI 55–91]), and with complete or partial cure of hypertension (clinical cure) in 12 participants (43% [24–61]). In four participants, disappearance of the APA on molecular imaging was associated with a systolic blood pressure under 135 mm Hg and diastolic blood pressure under 85 mm Hg off all antihypertensive treatment. EUS-RFA appears a safe alternative to total adrenalectomy for the treatment of left-sided APAs and has the potential to completely cure primary aldosteronism and hypertension when most of the APA is ablated. These findings have informed the design of a pivotal study of thermal ablation versus surgery, which will determine the full benefits of EUS-RFA. National Institute for Health and Care Research Biomedical Research Centres at Barts, University College Hospitals, and Cambridge University Hospitals, Barts Charity, and British Heart Foundation.

IntroductionInflammation 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 analysisIn 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 disseminationThe 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 numberNCT04241601.

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. 11 C-methionine PET/CT) may help with tumor localisation, although interpretation of these 2D images can be challenging. 3D printing of anatomical 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 anatomical 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.

BackgroundPituitary 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.ResultsWe 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.ConclusionsMet-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.

The main objective of this study was to assess the quality of CT pulmonary angiography (CTPA) for suspected pulmonary embolus (PE) in the pregnant population. We retrospectively identified 40 consecutive pregnant patients who underwent CTPA from January 2005 to December 2006. Forty consecutive age-matched non-pregnant women were used as a control group. Studies were subjectively graded according to overall image quality by two readers in consensus, in randomised and blinded manner. Moreover, contrast enhancement of pulmonary arteries was subjectively and objectively evaluated. The proportion of sub-optimal studies was more than three times higher in the pregnant group (27.5%, n = 11) compared with the non-pregnant group (7.5%, n = 3; p = 0.015). Mean contrast enhancement was consistently higher in the non-pregnant group compared with pregnant group, both subjectively and objectively. The percentage of inadequately opacified vascular segments was more than two times higher in the pregnant group (28.7%, n = 264) than in the non-pregnant group (13.3%, n = 122; p = 0.0001). The incidence of sub-optimal CTPA studies is higher in pregnancy when compared with an age-matched non-pregnant control group. In addition to radiation issues, this should also be considered when implementing diagnostic strategies for suspected PE in pregnancy.

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.

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 .

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 [sup.18] F-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 [sup.18] F-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 [sup.18] F-FDG PET/CT is a promising technique in identifying life-threatening pathologies in this complex group of patients. It would appear that [sup.18] F-FDG PET/CT has a good level of accuracy, including for those MVTx patients suffering from infection, post-transplant lymphoproliferative disease, and malignancy.

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.AimsTo 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.ConclusionsOur 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.