Recurrent Disease in Patients With Sporadic Pheochromocytoma and Paraganglioma

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

A comparison of high‑throughput plasma NMR protocols for comparative untargeted metabolomics (Metabolomics

Following publication of the original article, the authors would like to correct a sentence in the paragraph “1H-NMR spectra were recorded at 298 K…” under the heading “NMR experiments”. The sentence currently reads: “The LED pulse sequence had the form -RD-901-G1- 1801-G1-901-G2-T-901-G1-1801-G1-901-G2-t-901-acquire FID, where RD is a relaxation delay, 901 is a 901 RF pulse, G1 is the pulsed-field gradient that is applied to allow editing, 1801 is a 1801 RF pulse, G2 is a spoil gradient applied to remove unwanted magnetization components. The diffusion delay Δ is the time during which the molecules are allowed to diffuse—this is the period (901-G1-1801-G1- 901-G2-T-); and t is a delay to allow the longitudinal eddy currents caused within the sample to decay (Beckonert et al. 2007).” The sentence should read: “The LED pulse sequence had the form -RD-90°-G1- 180°-G1-90°-G2-T-90°-G1-180°-G1-90°-G2-t-90°-acquire FID, where RD is a relaxation delay, 90° is a 90° RF pulse, G1 is the pulsed-field gradient that is applied to allow editing, 180° is a 180° RF pulse, G2 is a spoil gradient applied to remove unwanted magnetization components. The diffusion delay ? is the time during which the molecules are allowed to diffuse—this is the period (90°-G1-180°-G1-90°-G2 T-); and t is a delay to allow the longitudinal eddy currents caused within the sample to decay (Beckonert et al. 2007).” This has been corrected with this erratum.</p

Metabolic subtyping of pheochromocytoma and paraganglioma by 18F-FDG pharmacokinetics using dynamic PET/CT scanning

Static single–time-frame 18F-FDG PET/CT is useful for the localization and functional characterization of pheochromocytomas and paragangliomas (PPGLs). 18F-FDG uptake varies between PPGLs with different genotypes, and the highest SUVs are observed in cases of succinate dehydrogenase (SDH) mutations, possibly related to enhanced aerobic glycolysis in tumor cells. The exact determinants of 18F-FDG accumulation in PPGLs are unknown. We performed dynamic PET/CT scanning to assess whether in vivo 18F-FDG pharmacokinetics has added value over static PET to distinguish different genotypes. Methods: Dynamic 18F-FDG PET/CT was performed on 13 sporadic PPGLs and 13 PPGLs from 11 patients with mutations in SDH complex subunits B and D, von Hippel-Lindau (VHL), RET, and neurofibromin 1 (NF1). Pharmacokinetic analysis was performed using a 2-tissue-compartment tracer kinetic model. The derived transfer rate-constants for transmembranous glucose flux (K1 [in], k2 [out]) and intracellular phosphorylation (k3), along with the vascular blood fraction (Vb), were analyzed using nonlinear regression analysis. Glucose metabolic rate (MRglc) was calculated using Patlak linear regression analysis. The SUVmax of the lesions was determined on additional static PET/CT images. Results: Both MRglc and SUVmax were significantly higher for hereditary cluster 1 (SDHx, VHL) tumors than for hereditary cluster 2 (RET, NF1) and sporadic tumors (P, 0.01 and P, 0.05, respectively). Median k3 was significantly higher for cluster 1 than for sporadic tumors (P, 0.01). Median Vb was significantly higher for cluster 1 than for cluster 2 tumors (P, 0.01). No statistically significant differences in K1 and k2 were found between the groups. Cutoffs for k3 to distinguish between cluster 1 and other tumors were established at 0.015 min−1 (100% sensitivity, 15.8% specificity) and 0.636 min−1 (100% specificity, 85.7% sensitivity). MRglc significantly correlated with SUVmax (P 5 0.001) and k3 (P 5 0.002). Conclusion: In vivo metabolic tumor profiling in patients with PPGL can be achieved by assessing 18F-FDG pharmacokinetics using dynamic PET/CT scanning. Cluster 1 PPGLs can be reliably identified by a high 18F-FDG phosphorylation rate

SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma

Contains fulltext : 97331.pdf (publisher's version ) (Closed access)PURPOSE: Hereditary head and neck paraganglioma (HNPGL) syndromes are associated with mutations in the SDHD(PGL1), SDHC(PGL3), and SDHB(PGL4) genes encoding succinate dehydrogenase subunits. We recently described mutations in a previously uncharacterized human gene, now called SDHAF2, and showed that this was the long-sought "imprinted" PGL2 gene. Here, we present a new branch of the Dutch SDHAF2 (PLG2-SDH5) family. EXPERIMENTAL DESIGN: The SDHAF2 family has been collected over a 30-year period. The family described here was linked to PGL2 and at-risk family members were invited to participate in this study. Patients were investigated and treated dependent on tumor size and localization. All family members have now been analyzed for the SDHAF2 mutation status. RESULTS: Among the 57 family members, 23 were linkage positive including 7 risk-free carriers (maternal imprinting). Of the 16 at-risk individuals, 11 had a total of 24 tumors with primarily carotid (71%) and vagal locations (17%). Multifocality of tumors was prominent (91%). Malignancy was not detected. The average age at onset was 33 years, and many patients (42%) were asymptomatic prior to screening. SDHAF2 mutation analysis confirmed the findings of the previously performed linkage analysis without detection of discrepancies. CONCLUSIONS: We established the SDHAF2 mutation status of PGL2 family members. Phenotypic characterization of this family confirms the currently exclusive association of SDHAF2 mutations with HNPGL. This SDHAF2 family branch shows a young age at onset and very high levels of multifocality. A high percentage of patients were asymptomatic at time of detection

The influence of the exclusion of central necrosis on [¹⁸F]FDG PET radiomic analysis

Background: Central necrosis can be detected on [18F]FDG PET/CT as a region with little to no tracer uptake. Currently, there is no consensus regarding the inclusion of regions of central necrosis during volume of interest (VOI) delineation for radiomic analysis. The aim of this study was to assess how central necrosis affects radiomic analysis in PET. Methods: Forty-three patients, either with non-small cell lung carcinomas (NSCLC, n = 12) or with pheochromocytomas or paragangliomas (PPGL, n = 31), were included retrospectively. VOIs were delineated with and without central necrosis. From all VOIs, 105 radiomic features were extracted. Differences in radiomic features between delineation methods were assessed using a paired t-test with Benjamini-Hochberg multiple testing correction. In the PPGL cohort, performances of the radiomic models to predict the noradrenergic biochemical profile were assessed by comparing the areas under the receiver operating characteristic curve (AUC) for both delineation methods. Results: At least 65% of the features showed significant differences between VOIvital-tumour and VOIgross-tumour (65%, 79% and 82% for the NSCLC, PPGL and combined cohort, respectively). The AUCs of the radiomic models were not significantly different between delineation methods. Conclusion: In both tumour types, almost two-third of the features were affected, demonstrating that the impact of whether or not to include central necrosis in the VOI on the radiomic feature values is significant. Nevertheless, predictive performances of both delineation methods were comparable. We recommend that radiomic studies should report whether or not central necrosis was included during delineation.Biomechanical Engineerin

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

Population Pharmacokinetic and Pharmacogenetic Analysis of Mitotane in Patients with Adrenocortical Carcinoma: Towards Individualized Dosing

Background: Mitotane is the only approved treatment for patients with adrenocortical carcinoma (ACC). A better explanation for the variability in the pharmacokinetics (PK) of mitotane, and the optimization and individualization of mitotane treatment, is desirable for patients. Objectives: This study aims to develop a population PK (PopPK) model to characterize and predict the PK profiles of mitotane in patients with ACC, as well as to explore the effect of genetic variation on mitotane clearance. Ultimately, we aimed to facilitate mitotane dose optimization and individualization for patients with ACC. Methods: Mitotane concentration and dosing data were collected retrospectively from the medical records of patients with ACC taking mitotane orally and participating in the Dutch Adrenal Network. PopPK modelling analysis was performed using NONMEM (version 7.4.1). Genotypes of drug enzymes and transporters, patient demographic information, and clinical characteristics were investigated as covariates. Subsequently, simulations were performed for optimizing treatment regimens. Results: A two-compartment model with first-order absorption and elimination best described the PK data of mitotane collected from 48 patients. Lean body weight (LBW) and genotypes of CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to significantly affect mitotane clearance (CL/F), which decreased the coefficient of variation (CV%) of the random inter-individual variability of CL/F from 67.0 to 43.0%. Fat amount (i.e. body weight − LBW) was found to significantly affect the central distribution volume. Simulation results indicated that determining the starting dose using the developed model is beneficial in terms of shortening the period to reach the therapeutic target and limit the risk of toxicity. A regimen that can effectively maintain mitotane concentration within 14–20 mg/L was established. Conclusions: A two-compartment PopPK model well-characterized mitotane PK profiles in patients with ACC. The CYP2C19 enzyme and SLCO1B1 and SLCO1B3 transporters may play roles in mitotane disposition. The developed model is beneficial in terms of optimizing mitotane treatment schedules and individualizing the initial dose for patients with ACC. Further validation of these findings is still required

Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome

Objective: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment. Design and methods: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition. Results: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2 ±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency. Conclusion: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe

Clinical aspects of SDHA-related pheochromocytoma and paraganglioma: A nationwide study

Copyright © 2018 Endocrine Society. Context: Paraganglioma (PGL) has the highest degree of heritability among human neoplasms. Current clinical understanding of germline SDHA mutation carriers is limited. Objective: To estimate the contribution of SDHA mutations in PGL and to assess clinical manifestations and age-related penetrance. Design: Nationwide retrospective cohort study. Setting: Tertiary referral centers in the Netherlands (multicenter). Patients: Germline SDHA analysis was performed in 393 patients with genetically unexplained PGL. Subsequently, 30 index SDHA mutation carriers and 56 nonindex carriers were studied. Main Outcome Measures: SDHA mutation detection yield, clinical manifestations, and SDHArelated disease penetrance. Results: Pathogenic germline SDHA variants were identified in 30 of the 393 referred patients with PGL (7.6%), who had head and neck PGL (21 of 174 [12%] ), pheochromocytoma (4 of 191 [2%]), or sympathetic PGL (5 of 28 [18%] ). The median age at diagnosis was 43 years (range, 17 to 81 years) in index SDHA mutation carriers compared with 52 years (range, 7 to 90 years) in nonmutation carriers (P = 0.002). The estimated penetrance of any SDHA-related manifestation was 10% at age 70 years (95% confidence interval, 0% to 21%) in nonindex mutation carriers. Conclusion: Germline SDHA mutations are relatively common (7.6%) in patients with genetically unexplained PGL. Most index patients presented with apparently sporadic PGL. In this SDHA series, the largest assembled so far, we found the lowest penetrance of all major PGL predisposition genes. This suggests that recommendations for genetic counseling of at-risk relatives and stringency of surveillance for SDHA mutation carriers might need to be reassessed