| 1. |
- Taïeb, David, et al.
(författare)
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Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants : an international expert Consensus statement
- 2024
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Ingår i: Nature Reviews Endocrinology. - : Springer Nature. - 1759-5029 .- 1759-5037. ; 20:3, s. 168-184
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Forskningsöversikt (refereegranskat)abstract
- Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
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| 2. |
- Bushnell, David L., et al.
(författare)
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90Y-edotreotide for metastatic carcinoid refractory to octreotide
- 2010
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 28:10, s. 1652-1659
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors. PATIENTS AND METHODS: Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. RESULTS: Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. CONCLUSION: (90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.
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| 3. |
- Alexandraki, Krystallenia I., et al.
(författare)
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Changing biological behaviour of NETs during the evolution of the disease : progress on progression
- 2021
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Ingår i: Endocrine-Related Cancer. - : BioScientifica Ltd.. - 1351-0088 .- 1479-6821. ; 28:5, s. R121-R140
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Forskningsöversikt (refereegranskat)abstract
- Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.
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| 4. |
- Alexandraki, Krystallenia I., et al.
(författare)
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Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
- 2020
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Ingår i: Trends in endocrinology and metabolism. - : Elsevier. - 1043-2760 .- 1879-3061. ; 31:3, s. 239-255
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Tidskriftsartikel (refereegranskat)abstract
- Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.
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| 5. |
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| 6. |
- Asa, Sylvia L., et al.
(författare)
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Pituitary neuroendocrine tumors : a model for neuroendocrine tumor classification
- 2021
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Ingår i: Modern Pathology. - : Springer Nature. - 0893-3952 .- 1530-0285. ; 34:9, s. 1634-1650
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Forskningsöversikt (refereegranskat)abstract
- The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.
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| 7. |
- Chahal, Harvinder S., et al.
(författare)
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Brief Report : AIP Mutation in Pituitary Adenomas in the 18th Century and Today
- 2011
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 364:1, s. 43-50
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Tidskriftsartikel (refereegranskat)abstract
- Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, *RF 1-3* he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.
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| 8. |
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| 9. |
- Fu, Yi-Ping, et al.
(författare)
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The 19q12 Bladder Cancer GWAS Signal : Association with Cyclin E Function and Aggressive Disease
- 2014
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 74:20, s. 5808-5818
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Tidskriftsartikel (refereegranskat)abstract
- A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P-trend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
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| 10. |
- Igreja, Susana, et al.
(författare)
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Assessment of p27 (cyclin-dependent kinase inhibitor 1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes in multiple endocrine neoplasia (MEN1) syndrome patients without any detectable MEN1 gene mutations
- 2009
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Ingår i: Clinical Endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 70:2, s. 259-264
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in the MEN1 gene predispose to the multiple endocrine neoplasia (MEN1) syndrome; however, approximately 10-20% of patients with MEN1 do not have a detectable MEN1 mutation. A rat strain with multiple endocrine tumours, a phenotypic overlap of both MEN1 and MEN2, has been reported to have a homozygous germline p27 (CDKN1B) mutation. Recently, two MEN1 mutation-negative MEN1 syndrome patients have been identified to harbour a germline CDKN1B mutation. The recently identified gene AIP can also cause familial isolated pituitary adenoma, but no other specific tumour is associated with this syndrome. The objective of this study was to evaluate the possible contribution of CDKN1B and AIP germline mutations in a cohort of MEN1 mutation-negative MEN1 syndrome patients. Eighteen sporadic and three familial cases of MEN1 mutation-negative MEN1 syndrome were studied (18 pituitary adenomas, 12 hyperparathyroidism, 10 neuroendocrine tumours including 2 ACTH-secreting lesions and one adrenal nodular hyperplasia). Clinical data and genomic DNA were analysed for mutations in the CDKN1B and AIP genes. There were no mutations in the coding region or exon/intron junction of the CDKN1B and AIP genes in any patient. Although we have a limited number of patients in our cohort, our data is consistent with others in the literature suggesting that CDKN1B and AIP mutations are extremely rare in MEN1 syndrome. Our results suggest that mutations in the CDKN1B and AIP genes are relatively uncommon in MEN1 mutation-negative MEN1 syndrome patients.
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| 11. |
- Kaltsas, Gregory, et al.
(författare)
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Current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms
- 2014
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 81:2, s. 157-168
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Forskningsöversikt (refereegranskat)abstract
- The vast majority of gastrin-related gastrointestinal neuroendocrine neoplasms (GI-NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastric NENs type 1 (GNEN1) and have recently been shown to constitute the commonest GI-NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management of GI-NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long-term follow-up and potential comorbidities of GNEN1s.
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| 12. |
- Sorbye, Halfdan, et al.
(författare)
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Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)
- 2019
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 108:1, s. 54-62
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Tidskriftsartikel (refereegranskat)abstract
- Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.
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| 13. |
- Wang, Katharina, et al.
(författare)
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Targeted Therapies in Pheochromocytoma and Paraganglioma
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 107:11, s. 2963-2972
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Forskningsöversikt (refereegranskat)abstract
- Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but remain difficult to treat. This mini-review provides an overview of established molecular targeted therapies in present use, and perspectives on those currently under development and evaluation in clinical trials. Recently published research articles, guidelines, and expert views on molecular targeted therapies in PPGLs are systematically reviewed and summarized. Some tyrosine kinase inhibitors (sunitinib, cabozantinib) are already in clinical use with some promising results, but without formal approval for the treatment of PPGLs. Sunitinib is the only therapeutic option which has been investigated in a randomized placebo-controlled clinical trial. It is clinically used as a first-, second-, or third-line therapeutic option for the treatment of progressive metastatic PPGLs. Some other promising molecular targeted therapies (hypoxia-inducible factor 2 alpha [HIF2 alpha] inhibitors, tumor vaccination together with checkpoint inhibitors, antiangiogenic therapies, kinase signaling inhibitors) are under evaluation in clinical trials. The HIF2 alpha inhibitor belzutifan may prove to be particularly interesting for cluster 1B-/VHL/EPAS1-related PPGLs, whereas antiangiogenic therapies seem to be primarily effective in cluster 1A-/SDHx-related PPGLs. Some combination therapies currently being evaluated in clinical trials, such as temozolomide/olaparib, temozolomide/talazoparib, or cabozantinib/atezolizumab, will provide data for novel therapy for metastatic PPGLs. It is likely that advances in such molecular targeted therapies will play an essential role in the future treatment of these tumors, with more personalized therapy options paving the way towards improved therapeutic outcomes.
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