| 1. |
- Bausch, Birke, et al.
(författare)
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Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:7, s. 2784-92
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.
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| 2. |
- Gimm, Oliver, et al.
(författare)
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Malignant pheochromocytomas and paragangliomas: a diagnostic challenge
- 2012
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Ingår i: Langenbeck's archives of surgery (Print). - : Springer Verlag (Germany). - 1435-2443 .- 1435-2451. ; 397:2, s. 155-177
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Forskningsöversikt (refereegranskat)abstract
- Introduction Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare disorders arising from the adrenal gland, from the glomera along parasympathetic nerves or from paraganglia along the sympathetic trunk. According to the WHO classification, malignancy of PCCs and PGLs is defined by the presence of metastases at non-chromaffin sites distant from that of the primary tumor and not by local invasion. The overall prognosis of metastasized PCCs/PGLs is poor. Surgery offers currently the only change of cure. Preferably, the discrimination between malignant and benign PCCs/PGLs should be made preoperatively. less thanbrgreater than less thanbrgreater thanMethods This review summarizes our current knowledge on how benign and malignant tumors can be distinguished. less thanbrgreater than less thanbrgreater thanConclusion Due to the rarity of malignant PCCs/PGLs and the obvious difficulties in distinguishing benign and malignant PCCs/PGLs, any patient with a PCC/PGL should be treated in a specialized center where a multidisciplinary setting with specialized teams consisting of radiologists, endocrinologist, oncologists, pathologists and surgeons is available. This would also facilitate future studies to address the existing diagnostic and/or therapeutic obstacles.
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| 3. |
- Nomine-Criqui, Claire, et al.
(författare)
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Role of hospital and patient factors in the outcome of reoperations for primary hyperparathyroidism : a retrospective multicenter cohort study
- 2023
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Ingår i: International journal of surgery (London, England). - 1743-9159. ; 109:11, s. 3441-3449
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are few data on outcomes after reintervention for persistent or recurrent primary hyperparathyroidism (PHPT). The authors hypothesized that the variation in outcomes at the hospital level after reoperation would be significant. After accounting for this variability, some patient-level clinical criteria could be identified to help inform treatment decisions in this patient population. The aim of this study was to determine whether there is significant variation in outcomes after reoperation for PHPT between hospitals (hospital-level analysis) and identify clinical factors (patient-level analysis) that influence postoperative outcomes. MATERIALS AND METHODS: This retrospective multicenter cohort study was performed using the Eurocrine registry. Data from 11 countries and 76 hospitals from January 2015 to October 2020 were extracted. A generalized linear mixed model was used to assess the variation in outcomes at the hospital level and to identify risk factors of postoperative outcomes at the patient level. The primary endpoint (textbook outcome) was achieved when all six of the following postoperative conditions were met: no hypocalcemia or persistent hypercalcemia, no laryngeal nerve injury, no negative exploration, no normal parathyroid gland only on histopathology, and no postoperative death. RESULTS: Among 13 593 patients who underwent parathyroidectomy for PHPT, 617 (4.5%) underwent reoperative parathyroidectomy. At follow-up, 231 patients (37.4%) were hypocalcemic, 346 (56.1%) were normocalcemic without treatment, and 40 (6.5%) had persistent hypercalcemia. Textbook outcomes were achieved in 321 (52.0%) patients. The hospital-level variation in textbook outcome rates was significant ( P <0.001), and this variation could explain 29.1% of the observed outcomes. The criterion that remained significant after controlling for inter-hospital variation was 'a single lesion on sestamibi scan or positron emission tomography (PET) imaging' (odds ratio 2.08, 95% confidence interval 1.24-3.48; P =0.005). CONCLUSION: Outcomes after reoperation are significantly associated with hospital-related factors. A 'single lesion observed on preoperative sestamibi scan or PET' appears relevant to select patients before reoperation.
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| 4. |
- Stenman, Adam, et al.
(författare)
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HRAS mutation prevalence and associated expression patterns in pheochromocytoma
- 2016
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Ingår i: Genes, Chromosomes and Cancer. - : WILEY-BLACKWELL. - 1045-2257 .- 1098-2264. ; 55:5, s. 452-459
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene was screened, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R, and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase-signaling pathways.
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| 5. |
- Tabebi, Mouna, et al.
(författare)
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Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation.Material: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression.Results: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction.Conclusion: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis.
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| 6. |
- Vatansever, Safa, et al.
(författare)
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Robot-assisted versus conventional laparoscopic adrenalectomy : Results from the EUROCRINE Surgical Registry
- 2022
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Ingår i: Surgery (United States). - : Elsevier BV. - 0039-6060. ; 171:5, s. 1224-1230
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adrenalectomy is routinely performed via the minimally invasive approach. Safety of adrenalectomy using the robot-assisted technique has been widely demonstrated by several series, but the literature is scarce regarding the comparison of conventional laparoscopic versus robot-assisted approach. We decided to carry out a multicenter study to compare clinical and surgical outcomes between laparoscopic and robotic adrenalectomy. Methods: This is a retrospective case-control study, including data from centers affiliated to the Surgical Registry EUROCRINE. Patients undergoing laparoscopic surgery for adrenal tumors and registered between 2015 and 2018 were included. Robot-assisted versus laparoscopic adrenalectomy was compared. All comparisons were carried out in terms of complication rate, conversion rate and duration of stay. Results: A total of 1,005 patients from 46 clinics underwent robotic or conventional laparoscopic adrenalectomy. Median age was 55 (interquartile range: 45−65) years. Robotic adrenalectomy was performed in 189 (18.8%) patients. According to Clavien-Dindo classification, complication rate was lower in the robotic surgery group (1.6% vs 16.5%, P <.001). Laparoscopic surgery and active hormonal status were significantly correlated with complications, both in univariate and multivariate analysis. There was no significant difference between laparoscopic and robotic surgery groups, in terms of conversion rate (2.1% vs 0.5%, respectively, P =.147). Duration of stay was shorter in the robotic adrenalectomy group (82.1% vs 28.8%, P <.001). Conclusion: Analysis of the EUROCRINE database supports that robotic adrenalectomy resulted in a lower complication rate and shorter duration of stay, compared with laparoscopic adrenalectomy. Granular data to support this is warranted.
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| 7. |
- Welander, Jenny, et al.
(författare)
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Activating FGFR1 mutations in sporadic pheochromocytoma
- 2018
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Ingår i: World Journal of Surgery. - : Springer. - 0364-2313 .- 1432-2323. ; 42:2, s. 482-489
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas are neuroendocrine tumors of the adrenal glands that cause hypertension. More than a third of the cases are associated with hereditary mutations in a growing list of susceptibility genes, some of which are also somatically altered in sporadic pheochromocytomas. However, for the majority of sporadic pheochromocytomas, a genetic explanation is still lacking. Here we investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples, and discovered on average 33 non-silent somatic mutations per tumor. One of the recurrently mutated genes was FGFR1, encoding the fibroblast growth factor receptor 1, which was recently revealed as an oncogene in pilocytic astrocytoma and childhood glioblastoma. Including a subsequent analysis of a larger cohort, activating FGFR1 mutations were detected in three of 80 sporadic pheochromocytomas (3.8%). Gene expression microarray profiling showed that these tumors clustered with NF1- RET- and HRAS-mutated pheochromocytomas, indicating activation of the MAPK and PI3K-AKT signal transduction pathways. The results advance our biological understanding of pheochromocytoma and suggest that somatic FGFR1 activation is an important event in a subset of these tumors.
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