Dimitra Christodoulou's research while affiliated with Guy's and St Thomas' NHS Foundation Trust and other places

Bladder paragangliomas (bPGL) are rare neuroendocrine tumors arising from the sympathetic paraganglia present in the bladder wall. Bladder PGLs are typically submucosal or intramural but when subserosal may not be readily visible at cystoscopy. The average size at presentation is 3.9 cm (range 1.0–9.1 cm). When small, bPGL are usually spherical, well-marginated and homogeneous. Larger bPGL are typically more complex with peri- and intra-tumoral neovascularity and central necrosis. On ultrasound, increased color Doppler signal is typical. The increased soft tissue resolution of MRI enables localization of bPGL within the bladder wall more accurately than CT. Restricted diffusion and avid contrast enhancement help differentiate small bPGLs from leiomyomas, which have similar appearances on ultrasound and CT. Nuclear medicine techniques identify bPGLs and their metastases with high specificity, ⁶⁸Ga-DOTATATE PET/CT having largely replaced ¹²³I-mIBG SPECT/CT as the first line functional investigation. Imaging is essential to aid surgical planning, as endoscopic resection is often not possible or incomplete due to tumor location. For patients with advanced disease, ⁶⁸Ga-DOTATATE PET/CT and ¹²³I-mIBG SPECT/CT assess suitability for peptide receptor radionuclide therapy. Up to 63% of bPGL patients have a germline mutation, most commonly in the SDHB subunit gene, increasing their risk of developing pheochromocytomas and further paragangliomas; lifelong annual biochemical and periodic imaging screening from skull base to pelvis is therefore recommended. Graphical abstract

Objective : Succinate dehydrogenase subunit ( SDHx ) pathogenic variants predispose to phaeochromocytoma and araganglioma (PPGL). Lifelong surveillance is recommended for all patients to enable prompt detection and treatment. There is currently limited evidence for optimal surveillance strategies in hereditary PPGL. We aim to detail the clinical presentation of PPGL in our cohort of non-index SDHB and SDHD pathogenic variant carriers. Methods : Retrospective analysis of medical and genetic records from a single tertiary referral centre identified SDHB or SDHD pathogenic variants in 74 non-index cases (56 SDHB , 18 SDHD ). Surveillance screening for asymptomatic relatives consisted of annual plasma metanephrine measurement and whole-body MRI with contrast at 3-5 yearly intervals. Results : 23 out of 74 non-index patients (10 SDHB , 13 SDHD ) were diagnosed with PPGL, 17 patients through surveillance screening (24 tumours in total) and 6 diagnosed prior to commencement of cascade screening with symptomatic presentation. MRI with contrast identified PPGL in 18/24 screen-detected tumours and 5/24 tumours had elevated plasma metanephrine levels. Penetrance in non-index family members was 15.2% and 47.2% for SDHB carriers and 71.6% and 78.7% for SDHD carriers at age 50 and 70 years respectively. Conclusion : Surveillance screening with combined biochemical testing and imaging enables early detection of PPGL in asymptomatic relatives with SDHx pathogenic variants. The presence of disease at first screen was significant in our cohort and hence further multi-centre long term data is needed to inform counselling of family members undergoing lifelong surveillance.

Objectives The ATTIS study aimed to investigate whether substituting almonds for typical snacks (high in refined starch, free sugars and saturated fats, and low in fibre) influenced cardiometabolic risk factors. Primary outcomes, endothelial function and liver fat, were measured in healthy adults aged 30–70 y who were habitual snackers and at moderate risk of developing cardiovascular disease (CVD). It was hypothesized that snacking on almonds would improve endothelial function and decrease liver fat. Methods Following a 2-week run-in period consuming control snacks, a 6-week parallel arm trial was conducted where participants were randomized to isoenergetic treatments: 1) control snacks (mini-muffins) replicating an average snack nutrient profile, calculated from snack foods identified in 4-d food diaries from a national dietary intake database, or 2) dry-roasted whole almonds, providing 20% estimated energy requirement. Endothelial function (via flow-mediated dilation (FMD)); abdominal subcutaneous and visceral fat, and liver, muscle and pancreatic fat (via MRI/MRS); day- and night-time heart rate variability (HRV) and 24 h ambulatory blood pressure (ABP); blood biomarkers of insulin sensitivity and lipid profile; and fecal short chain fatty acids (SCFA) were assessed at baseline and endpoint. A total of 107 participants (75 F, 32 M; mean age 56.2 y, SD 10.4) were randomized and 105 subjects completed the trial. Results Almonds significantly increased FMD (mean difference 4.1%, 95% CI 2.2, 5.9), the long-phase HRV index, night-time very-low frequency power (mean difference 337 ms2, 95% CI 12, 661) and plasma oleic acid levels (mean difference 228 μmol, 95% CI 7, 449) relative to control adjusted for baseline BMI and baseline dependent outcome values, but there were no treatment differences in ABP and subcutaneous, visceral, liver, muscle and pancreatic fat. Plasma LDL cholesterol levels were significantly decreased by almonds (mean difference −0.25 mmol/L, 95% CI −0.45, −0.04), but no differences were found in other blood lipids, insulin sensitivity, nor fecal SCFA levels. Conclusions These novel findings suggest almonds may be cardioprotective by increasing availability of nitric oxide and improving cardiac autonomic function, in addition to their well-established LDL cholesterol-lowering properties. Funding Sources Almond Board of California.

Background: There is convincing evidence that daily whole almond consumption lowers blood LDL cholesterol concentrations, but effects on other cardiometabolic risk factors such as endothelial function and liver fat are still to be determined. Objectives: We aimed to investigate whether isoenergetic substitution of whole almonds for control snacks with the macronutrient profile of average snack intakes, had any impact on markers of cardiometabolic health in adults aged 30-70 y at above-average risk of cardiovascular disease (CVD). Methods: The study was a 6-wk randomized controlled, parallel-arm trial. Following a 2-wk run-in period consuming control snacks (mini-muffins), participants consumed either whole roasted almonds (n = 51) or control snacks (n = 56), providing 20% of daily estimated energy requirements. Endothelial function (flow-mediated dilation), liver fat (MRI/magnetic resonance spectroscopy), and secondary outcomes as markers of cardiometabolic disease risk were assessed at baseline and end point. Results: Almonds, compared with control, increased endothelium-dependent vasodilation (mean difference 4.1%-units of measurement; 95% CI: 2.2, 5.9), but there were no differences in liver fat between groups. Plasma LDL cholesterol concentrations decreased in the almond group relative to control (mean difference -0.25 mmol/L; 95% CI: -0.45, -0.04), but there were no group differences in triglycerides, HDL cholesterol, glucose, insulin, insulin resistance, leptin, adiponectin, resistin, liver function enzymes, fetuin-A, body composition, pancreatic fat, intramyocellular lipids, fecal SCFAs, blood pressure, or 24-h heart rate variability. However, the long-phase heart rate variability parameter, very-low-frequency power, was increased during nighttime following the almond treatment compared with control (mean difference 337 ms2; 95% CI: 12, 661), indicating greater parasympathetic regulation. Conclusions: Whole almonds consumed as snacks markedly improve endothelial function, in addition to lowering LDL cholesterol, in adults with above-average risk of CVD.This trial was registered at clinicaltrials.gov as NCT02907684.

Introduction: Bladder Paragangliomas (PGLs) are rare neuroendocrine tumors derived from sympathetic paraganglionic tissue within the bladder wall, accounting for <1% of all Pheochromocytomas and Paragangliomas (PPGLs). >40% of PPGLs are associated with inherited syndromes through mutations affecting citric acid cycle enzymes (commonly SDH). Susceptibility gene identification has important implications for long-term care and facilitates targeted cascade genetic screening. Functional imaging using MIBG, Gallium DOTATATE and FDG-PET have become important tools in both diagnosis and treatment (Peptide Receptor Radionuclide Therapy). Clinical Cases: We report the demographics, clinical characteristics and novel features of 7 patients with bladder PGLs. The series includes 2 females and 5 males, median age 38 years (range 14-68). 5 presented with hematuria and 2 were detected incidentally (1 found on radiological imaging and the other during cystoscopy surveillance). Other symptoms reported were headaches, sweating and palpitations which were relieved by urination. Only 1/7 had a known family history of PGLs. 5/7 patients had elevated plasma normetadrenaline levels and 2 had non-elevated catecholamine metabolites (these 2 patients were asymptomatic). 6/7 patients had genetic testing performed and pathogenic variants were identified in 4 (Fumarate hydratase (FH), SDHA, SDHB*2 genes) and no pathogenic variant identified in 2 patients in our genetic panel of 10 PPGL genes. All primary tumors demonstrated MIBG avidity and in 2 patients assessed there was PGL FDG-PET avidity. Metastatic disease was present in 2 patients (2 SDHB mutations; with 1 MIBG avid bone and 1 FDG-PET avid nodal metastasis). SDHB immunostaining on resected histology was available for 3 cases - absent SDHB immunostaining in the patient with SDHA mutation and strongly positivity in 2 patients (1 with no genetic mutation and in 1 with FH mutation). Conclusions: The majority (>65%) of patients with bladder PGL have a germ line mutation in a susceptibility gene involving the citric acid cycle. An extended gene panel should be performed in all patients diagnosed with bladder PGLs including SDHA and FH gene mutations. SDH immunostaining of tumour can indicate SDHx gene defects but can be normal in FH mutations. SDHB is associated with increased risk of malignant/metastatic behavior. All 3 modalities of functional imaging (Ga DOTATATE, FDG PET, & MIBG) have a role in the assessment and treatment decision making in the management of bladder PGLs.

Pheochromocytoma (PC) and paraganglioma (PGL) are rare neu- roendocrine tumors that occur throughout the body from the base of the skull to the pelvis. Sympathetic catecholamine-secreting tu- mors may be associated with hyperadrenergic symptoms and long- term morbidity if they are untreated.Typically biochemically silent, head and neck PGLs may result in cranial nerve palsies and symp- toms due to localized mass effect.Tumors can arise sporadically or as part of an inheritable PC-PGL syndrome. Up to 40% of tumors are recognized to be associated with germline mutations in an in- creasing array of susceptibility genes, including those that appear to arise sporadically. Most commonly, up to 25% of all PC-PGLs are associated with mutations in one of the succinate dehydrogenase (SDH) enzyme subunit genes.The resulting familial PC-PGL syn- drome varies according to the affected enzyme subunit (most com- monly SDHB and SDHD mutations) with respect to tumor preva- lence, location, age of onset, and risk of malignancy. Patients with SDH enzyme mutations have increased lifetime risk of developing multifocal tumors and malignancy. Early recognition of individu- als at high risk, genetic testing, screening of family members, and lifelong surveillance programs are recommended, but not without health, economic, and psychologic implications. Anatomic and functional imaging is key to diagnosis, staging, treatment planning, and lifelong surveillance of these individuals. Radiologists must be aware of the imaging appearance of these varied tumors.