The Diagnostic Value of 18F-FDG PET/CT Scan in Characterizing Adrenal Tumors

CONTEXT: Imaging plays an important role in the characterization of adrenal tumors, but findings might be inconclusive. The clinical question is whether 18F fluodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is of diagnostic value in this setting.OBJECTIVE: This meta-analysis was aimed at the diagnostic value of 18F-FDG PET/CT in differentiating benign from malignant adrenal tumors discovered either as adrenal incidentaloma or during staging or follow-up of oncologic patients.DATA SOURCES: PubMed, EMBASE, Web of Science, and Cochrane Library were searched to select articles between 2000 and 2021.STUDY SELECTION: We included studies describing the diagnostic value of 18F-FDG PET/CT in adult patients with an adrenal tumor. Exclusion criteria were 10 or fewer participants, insufficient data on histopathology, clinical follow-up, or PET results. After screening of title and abstract by 2 independent reviewers, 79 studies were retrieved, of which 17 studies met the selection criteria.DATA EXTRACTION: Data extraction using a protocol and quality assessment according to QUADAS-2 was performed independently by at least 2 authors.DATA SYNTHESIS: A bivariate random-effects model was applied using R (version 3.6.2.). Pooled sensitivity and specificity of 18F-FDG PET/CT for identifying malignant adrenal tumors was 87.3% (95% CI, 82.5%-90.9%) and 84.7% (95% CI, 79.3%-88.9%), respectively. The pooled diagnostic odds ratio was 9.20 (95% CI, 5.27-16.08; P &lt; .01). Major sources of heterogeneity (I2, 57.1% [95% CI, 27.5%-74.6%]) were in population characteristics, reference standard, and interpretation criteria of imaging results.CONCLUSIONS: 18F-FDG PET/CT had good diagnostic accuracy for characterization of adrenal tumors. The literature, however, is limited, in particular regarding adrenal incidentalomas. Large prospective studies in well-defined patient populations with application of validated cutoff values are needed.</p

NMDA and GABAB (KIR) conductances: The "perfect couple" for bistability

Networks that produce persistent firing in response to novel input patterns are thought to be important in working memory and other information storage functions. One possible mechanism for maintaining persistent firing is dendritic voltage bistability in which the depolarized state depends on the voltage dependence of the NMDA conductance at recurrent synapses. In previous models, the hyperpolarized state is dependent on voltage-independent conductances, including GABAA. The interplay of these conductances leads to bistability, but its robustness is limited by the fact that the conductance ratio must be within a narrow range. The GABAB component of inhibitory transmission was not considered in previous analyses. Here, we show that the voltage dependence of the inwardly rectifying potassium (KIR) conductance activated by GABAB receptors adds substantial robustness to network simulations of bistability and the persistent firing that it underlies. The hyperpolarized state is robust because, at hyperpolarized potentials, the GABAB/KIR conductance is high and the NMDA conductance is low; the depolarized state is robust because, at depolarized potentials, the NMDA conductance is high and the GABAB/KIR conductance is low. Our results suggest that this complementary voltage dependence of GABAB/KIR and NMDA conductances makes them a “perfect couple” for producing voltage bistability

Intricacies of the Molecular Machinery of Catecholamine Biosynthesis and Secretion by Chromaffin Cells of the Normal Adrenal Medulla and in Pheochromocytoma and Paraganglioma

The adrenal medulla is composed predominantly of chromaffin cells producing and secreting the catecholamines dopamine, norepinephrine, and epinephrine. Catecholamine biosynthesis and secretion is a complex and tightly controlled physiologic process. The pathways involved have been extensively studied, and various elements of the underlying molecular machinery have been identified. In this review, we provide a detailed description of the route from stimulus to secretion of catecholamines by the normal adrenal chromaffin cell compared to chromaffin tumor cells in pheochromocytomas. Pheochromocytomas are adrenomedullary tumors that are characterized by uncontrolled synthesis and secretion of catecholamines. This uncontrolled secretion can be partly explained by perturbations of the molecular catecholamine secretory machinery in pheochromocytoma cells. Chromaffin cell tumors also include sympathetic paragangliomas originating in sympathetic ganglia. Pheochromocytomas and paragangliomas are usually locally confined tumors, but about 15% do metastasize to distant locations. Histopathological examination currently poorly predicts future biologic behavior, thus long term postoperative follow-up is required. Therefore, there is an unmet need for prognostic biomarkers. Clearer understanding of the cellular mechanisms involved in the secretory characteristics of pheochromocytomas and sympathetic paragangliomas may offer one approach for the discovery of novel prognostic biomarkers for improved therapeutic targeting and monitoring of treatment or disease progression

Outcomes after Surgical Treatment of Metastatic Disease in the Adrenal Gland; Valuable for the Patient?

SIMPLE SUMMARY: Adrenal glands are common dissemination sites for metastases of various solid tumors. The rapid development of new treatment strategies, such as targeted therapy and immunotherapy for different cancer types, has led to increased metastatic adrenalectomies. Therefore, clear communication between oncologists and adrenal gland specialists has become increasingly important to outweigh surgical risks versus oncological advantages of adrenalectomies in these patients. This study assesses trends in diagnosis, type of surgery, and short-term and long-term surgical outcomes of patients who underwent metastatic adrenalectomy. We included a total of 95 patients with an adrenal metastasis of non-adrenal primary tumors, most often colorectal or lung cancer, who underwent (minimal invasive) adrenalectomy. 37.9% of the patients experienced one or more complications after adrenalectomy. Within our patient cohort, an increased demand for metastatic adrenalectomy was observed over the past years, which might be associated with the rise of targeted- and immunotherapy. Our data aims to assist multidisciplinary teams with weighing the pros and cons of resection of the metastasized adrenal gland of cancer patients. ABSTRACT: The adrenal glands are common dissemination sites for metastasis of various solid tumors. Surgical treatment is often recommended because targeted therapies and immunotherapy are frequently ineffective for adrenal metastasis. We report the experience with short-term and long-term surgical outcomes of patients undergoing surgery for adrenal metastasis in two hospitals. A retrospective, multicenter study was performed to analyze patient characteristics, tumor-related data, perioperative outcomes, and oncological outcomes. Postoperative complications that occurred within 30 days were scored according to the Clavien Dindo classification. Metastatic adrenalectomy was performed in 95 patients. We observed an increase from an average of 3 metastatic adrenalectomies per year between 2001–2005 to 10 between 2015–2019. The most frequent underlying malignancies were colorectal and lung cancer. In 55.8%, minimal invasive adrenalectomy was performed, including six conversions to open surgery. A total of 37.9% of patients had postoperative complications, of which ileus or gastroparesis, wound problems, pneumonia, and heart arrhythmias were the most occurring complications. Improved cancer care has led to an increased demand for metastatic adrenalectomy over the past years. Complication rates of 37.9% are significant and cannot be neglected. Therefore, multidisciplinary teams should weigh the decision to perform metastatic adrenalectomy for each patient individually, taking into account the drawbacks of the described morbidity versus the potential benefits

Recurrent Disease in Patients With Sporadic Pheochromocytoma and Paraganglioma

Supplemental Appendix for manuscript 'Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Determinants of disease-specific survival in patients with and without metastatic pheochromocytoma and paraganglioma

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) have a heterogeneous prognosis, the basis of which remains unclear. We, therefore, assessed disease-specific survival (DSS) and potential predictors of progressive disease in patients with PPGLs and head/neck paragangliomas (HNPGLs) according to the presence or absence of metastases. METHODS: This retrospective study included 582 patients with PPGLs and 57 with HNPGLs. DSS was assessed according to age, location and size of tumours, recurrent/metastatic disease, genetics, plasma metanephrines and methoxytyramine. RESULTS: Among all patients with PPGLs, multivariable analysis indicated that apart from older age (HR = 5.4, CI = 2.93-10.29, P < 0.0001) and presence of metastases (HR = 4.8, CI = 2.41-9.94, P < 0.0001), shorter DSS was also associated with extra-adrenal tumour location (HR = 2.6, CI = 1.32-5.23, P = 0.0007) and higher plasma methoxytyramine (HR = 1.8, CI = 1.11-2.85, P = 0.0170) and normetanephrine (HR = 1.8, CI = 1.12-2.91, P = 0.0160). Among patients with HNPGLs, those with metastases presented with longer DSS compared to patients with metastatic PPGLs (33.4 versus 20.2 years, P < 0.0001) and only plasma methoxytyramine (HR = 13, CI = 1.35-148, P = 0.0380) was an independent predictor of DSS. For patients with metastatic PPGLs, multivariable analysis revealed that apart from older age (HR = 6.2, CI = 3.20-12.20, P < 0.0001), shorter DSS was associated with the presence of synchronous metastases (HR = 4.9, CI = 2.78-8.80, P < 0.0001), higher plasma methoxytyramine (HR = 2.4, CI = 1.44-4.14, P = 0.0010) and extensive metastatic burden (HR = 2.1, CI = 1.07-3.79, P = 0.0290). CONCLUSIONS: DSS among patients with PPGLs/HNPGLs relates to several presentations of the disease that may provide prognostic markers. In particular, the independent associations of higher methoxytyramine with shorter DSS in patients with HNPGLs and metastatic PPGLs suggest the utility of this biomarker to guide individualized management and follow-up strategies in affected patients

Influence of Receptor Polymorphisms on the Response to alpha-Adrenergic Receptor Blockers in Pheochromocytoma Patients

Background: Presurgical treatment with an α-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced α-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in α-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the α1A, α1B, α1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and α2A, α2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of α-adrenergic receptor blocker (p &lt; 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of α-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to α-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations

Circulating adrenomedullin and B-type natriuretic peptide do not predict blood pressure fluctuations during pheochromocytoma resection:a cross-sectional study

Background: Despite adequate presurgical management, blood pressure fluctua tions are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a larg e extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B -type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of card iovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with bl ood pressure fluctuations during PPGL resection. Methods: Study subjects participated in PRESCRIPT, a randomized control led trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents duri ng surgery as well as the occurrence of perioperative cardiovascular events. Results: A total of 126 PPGL patients were included. Median plasma conc entrations of MR-proADM and NT-proBNP were 0.51 (0.41-0.63) nmol/L and 68.7 (27.9-150.4) ng/L, respec tively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positiv e correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P = 0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P = 0.013 and OR: 1.54, P = 0.017, respectively). Conclusions: Plasma MR-proADM or NT-proBNP should not be considered as biom arkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk