Background: Presurgical treatment with an alpha-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced alpha-adrenergic receptor mediated vasoconstriction in patients... Show moreBackground: Presurgical treatment with an alpha-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced alpha-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 alpha-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the alpha 1A, alpha 1B, alpha 1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and alpha 2A, alpha 2B 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 alpha-adrenergic receptor blocker (p < 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 alpha-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to alpha-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations. Show less
Simple Summary: Patients with the rare cancer adrenocortical carcinoma are exposed to many symptoms and treatment side-effects. Research on how this can affect their health-related quality of life ... Show moreSimple Summary: Patients with the rare cancer adrenocortical carcinoma are exposed to many symptoms and treatment side-effects. Research on how this can affect their health-related quality of life (HRQoL) is limited, however. This article includes the first assessment of HRQoL in a population-based cohort of patients with adrenocortical carcinoma with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire and the newly developed disease-specific additional questionnaire ACC-QOL. The ACC-QOL has good psychometric properties in terms of validity, reliability, and responsiveness. Patients diagnosed more than 5 years ago reported a relatively good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients after additional surgery reported a slightly lower HRQoL due to physical limitations. Patients who had recently received mitotane or chemotherapy reported a worse HRQoL and problems in many domains. This knowledge and the new disease-specific questionnaire can aid future research, side-effect monitoring, treatment guidance, and shared decision making. We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties. Show less
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in... Show moreFibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics. Show less
Background: Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the... Show moreBackground: Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large 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 cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection. Methods: Study subjects participated in PRESCRIPT, a randomized controlled 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 during surgery as well as the occurrence of perioperative cardiovascular events. Results: A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41-0.63) nmol/L and 68.7 (27.9-150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive 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 biomarkers 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. Show less
Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We... Show moreOsteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI. Show less
Simple Summary Adrenocortical carcinoma is a rare and aggressive cancer. Great variability in clinical course is observed, ranging from patients with extreme long survival to aggressive tumors with... Show moreSimple Summary Adrenocortical carcinoma is a rare and aggressive cancer. Great variability in clinical course is observed, ranging from patients with extreme long survival to aggressive tumors with prompt fatal outcome. This heterogeneity in survival makes it complicated to tailor treatment strategies for an individual patient. Therefore we sought to identify prognostic factors associated with ACC specific mortality. We analyzed the data of 160 ACC patients and developed a clinical prediction model including age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. This easy-to-use prediction model for ACC-specific mortality has the potential to guide clinical decision making if externally validated. Adrenocortical carcinoma (ACC) has an incidence of about 1.0 per million per year. In general, survival of patients with ACC is limited. Predicting survival outcome at time of diagnosis is a clinical challenge. The aim of this study was to develop and internally validate a clinical prediction model for ACC-specific mortality. Data for this retrospective cohort study were obtained from the nine centers of the Dutch Adrenal Network (DAN). Patients who presented with ACC between 1 January 2004 and 31 October 2013 were included. We used multivariable Cox proportional hazards regression to compute the coefficients for the prediction model. Backward stepwise elimination was performed to derive a more parsimonious model. The performance of the initial prediction model was quantified by measures of model fit, discriminative ability, and calibration. We undertook an internal validation step to counteract the possible overfitting of our model. A total of 160 patients were included in the cohort. The median survival time was 35 months, and interquartile range (IQR) 50.7 months. The multivariable modeling yielded a prediction model that included age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. The c-statistic was 0.77 (95% Confidence Interval: 0.72, 0.81), indicating good predictive performance. We developed a clinical prediction model for ACC-specific mortality. ACC mortality can be estimated using a relatively simple clinical prediction model with good discriminative ability and calibration. Show less
Context: Pretreatment with alpha-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).Objective:... Show moreContext: Pretreatment with alpha-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).Objective: To determine which type of alpha-adrenergic receptor blocker provides the best efficacy.Design: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898)Setting: Multicenter study including 9 centers in The Netherlands.Patients: 134 patients with nonmetastatic PPGL.Intervention: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. lntraoperative hemodynamic management was standardized.Main Outcome Measures: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.Results: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.Conclusions: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome. Show less
Sanchez Duffhues, G.; Mikkers, H.; Jong, D. de; Szuhai, K.; Vries, T.J. de; Freund, C.; ... ; Dijke, P. ten 2019
Fibrodysplasia ossificans progressiva (FOP) is a very rare devastating heterotopic ossification disorder, classically caused by a heterozygous single point mutation (c.617G>A) in the ACVR1gene,... Show moreFibrodysplasia ossificans progressiva (FOP) is a very rare devastating heterotopic ossification disorder, classically caused by a heterozygous single point mutation (c.617G>A) in the ACVR1gene, encoding the Bone morphogenetic protein (BMP) type I receptor, also termed activin receptor-like kinase (ALK)2. FOP patients develop heterotopic ossification episodically in response to inflammatory insults, thereby compromising tissue sampling and the development of in vitro surrogate models for FOP. Here we describe the generation and characterization of a control and a classical FOP induced pluripotent stem cell (iPSC) line derived from periodontal ligament fibroblast cells using Sendai virus vectors. Show less
Context: Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite... Show moreContext: Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite levels are within the reference range.Participants: We report a series of 10 patients carrying pathogenic variants in the SDHD gene from five tertiary referral centers for paraganglioma (PGL) in the Netherlands, who presented with a sympathetic PGL (sPGL), pheochromocytoma (PHEO), or metastases outside the head and neck region in the absence of excessive catecholamine production. Two of six patients with a biochemically silent sPGL/PHEO developed metastatic disease. Additionally, four patients were found to have metastases outside the head and neck region from head and neck PGL. The average interval between the initial diagnosis and discovery of the silent lesions was 10 (range, 0 to 32) years.Conclusions: The absence of excessive catecholamine production does not exclude the presence of manifestations of SDHD outside the head and neck region. These findings suggest that a more extensive imaging strategy in SDHD mutation carriers may be warranted for detection of biochemically silent lesions. Show less
Objective: Familial Paget's disease of bone is inherited as an autosomal-dominant trait and mutations in the sequestosome 1 (SQSTM1) gene have been reported with variable frequency in patients with... Show moreObjective: Familial Paget's disease of bone is inherited as an autosomal-dominant trait and mutations in the sequestosome 1 (SQSTM1) gene have been reported with variable frequency in patients with familial disease. The natural history, however, of the disease in family members with or without SQSTM1 mutations is unknown.Methods: To address this question, we investigated members of families with Paget's disease identified and genotyped in 2000 in The Netherlands without clinical, biochemical or radiological signs of Paget's disease. Seventy-five subjects, median age 56 years (range 44-93), with or without SQSTM1 mutations participated in the present study. Medical history was obtained and clinical examination and laboratory investigations were performed in all. When serum biochemical markers of bone turnover were increased, skeletal scintigraphy with SPECT-CT was performed.Results: After a mean period of 15.9 +/- 0.32 (SD) years no subject without SQSTM1 mutations (either from positive or negative families) developed Paget's disease. Of 14 carriers of SQSTM1 mutations, Paget's disease of the pelvis was diagnosed in a 74-year old asymptomatic woman.Conclusion: The incidence of new Paget's disease in SQSTM1 positive subjects was 7.1% and no mutation-negative subject developed the disease within 16 years of follow-up. Subjects without SQSTM1 mutations can be reassured whereas mutation carriers should consider screening. Our findings should be confirmed in other populations as currently unknown environmental factors that might be involved in the development of the disease may differ. Show less
