RESUMO
Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications. Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset. In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled. SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0-246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309-0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410-0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877-0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396-0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405-0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274-0.718]; P = .001) were associated with a reduced risk of death. SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasias Ósseas , Paraganglioma , Feocromocitoma , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Ósseas/secundário , Neoplasias Ósseas/complicações , Feocromocitoma/complicações , Feocromocitoma/patologia , Feocromocitoma/mortalidade , Estudos Retrospectivos , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/mortalidade , Neoplasias das Glândulas Suprarrenais/terapia , Adulto , Idoso , Paraganglioma/complicações , Paraganglioma/patologia , Paraganglioma/mortalidade , Adulto Jovem , Compressão da Medula Espinal/etiologia , Fraturas Ósseas/etiologia , Adolescente , Idoso de 80 Anos ou mais , Hipercalcemia/etiologia , Fatores de Risco , Conservadores da Densidade Óssea/uso terapêutico , PrognósticoRESUMO
BACKGROUND: Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes. RESULTS: Out of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1. CONCLUSIONS: Combined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/genética , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Histonas/genética , Histonas/metabolismo , Metilação de DNA , Paraganglioma/genética , Paraganglioma/patologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Perfilação da Expressão GênicaRESUMO
Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs's cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew's Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Succinato Desidrogenase , Humanos , Neoplasias das Glândulas Suprarrenais/genética , Alelos , Mutação em Linhagem Germinativa , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Padrões de HerançaRESUMO
Introduction: The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. Methods: Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. Results: Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an "intermediate signature" to suggest that both variants had a pathological role in tumour development. Discussion: In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/patologia , Predisposição Genética para Doença , Paraganglioma/patologia , Mutação , Neoplasias das Glândulas Suprarrenais/diagnósticoRESUMO
CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.
Assuntos
Síndrome de Nelson/diagnóstico , Síndrome de Nelson/terapia , Adenoma Hipofisário Secretor de ACT/diagnóstico , Adenoma Hipofisário Secretor de ACT/epidemiologia , Adenoma Hipofisário Secretor de ACT/terapia , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/terapia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Nelson/epidemiologia , Terapia Neoadjuvante , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido/epidemiologia , Adulto JovemRESUMO
CONTEXT: Differentiated thyroid cancer (DTC) is usually treated by thyroidectomy followed by radioiodine ablation and generally has a good prognosis. It may now be possible to limit the amount of treatment without impacting on efficacy. It is not known whether coexistent thyroiditis impacts on radioiodine uptake or on its potential efficacy, but this could provide a rationale for modification to current therapeutic protocols. DESIGN: This was a retrospective cohort study of radioiodine uptake on imaging after radioiodine ablation for DTC in patients with and without concurrent thyroiditis. All patients with histologically confirmed DTC treated with radioiodine ablation after thyroidectomy in a single centre from 2012 to 2015 were included. The primary outcome assessed was the presence of low or no iodine uptake on post-ablation scan, as reported by a nuclear medicine physician blinded to the presence or absence of thyroiditis. RESULTS: One hundred thirty patients with available histopathology results were included. Thyroiditis was identified in 42 post-operative specimens and 15 of these patients had low or no iodine uptake on post-ablation scan, compared to only 2 of 88 patients without thyroiditis (P < 0.0001) with further data analysis dividing the groups by ablation activity received (1100 MBq or 3000 MBq). CONCLUSIONS: Concurrent thyroiditis may impair the uptake of radioactive iodine in management of DTC. Given that patients with DTC and thyroiditis already have a good prognosis, adopting a more selective approach to this step in therapy may be indicated. Large, longitudinal studies would be required to determine if omitting radioactive iodine therapy from those patients with concurrent thyroiditis has a measurable impact on mortality from thyroid cancer.
RESUMO
OBJECTIVE: To determine whether short-term changes in liver tests (bilirubin, albumin, gamma glutamyl transferase, alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase) predict 12-month mortality and, if so, which test is most informative. DESIGN: Retrospective review of general medicine inpatients at a tertiary hospital (2005-2012) identified non-elective admissions of minimum 7â days' duration. Patients with liver disease, malignancy, admission to the intensive care unit or inpatient mortality were excluded. Linear spline modelled the vector of intra-admission change from admission. The association between 12-month mortality and admission and intra-admission changes in liver tests was assessed by logistic regression modelling, adjusted for age, gender, comorbidity index and heart failure. RESULTS: 12-month mortality was 17% in 4160 patients analysed. 12-month mortality for patients with abnormally low albumin at admission was 5% higher per 1â g/L below 34â g/L (OR 0.95, 95% CI 0.93 to 0.98, p<0.001). Albumin and ALT were the only tests for which an intra-admission change significantly predicted mortality; the predictive effects were additive. 12-month mortality was greater by 4% per 1â g/L intra-admission decrement in albumin (OR 1.04, 95% CI 1.02 to 1.06, p<0.001) and 6% per 100 IU/L intra-admission increment in ALT (OR 1.06, 95% CI 1.02 to 1.1, p=0.005). Intra-admission changes were superior to admission values in predicting mortality. CONCLUSIONS: Changes in liver tests predict long-term mortality better than a single value and provide prognostic information more quickly than long-term monitoring. In the absence of known liver disease, albumin predicts long-term mortality better than transaminases. The patient whose albumin decreases in the short term is at high risk of death within 1 year, even from a normal baseline.