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OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.
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Paraganglioma , Neoplasias da Bexiga Urinária , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/diagnóstico , Feminino , Masculino , Adulto , Paraganglioma/diagnóstico , Paraganglioma/cirurgia , Europa (Continente) , Estados Unidos , Idoso , ChinaRESUMO
PURPOSE: Transient hypoparathyroidism is the most common complication after total thyroidectomy, and accidental parathyroidectomy (AP) may be a cause. The aim of this study was to investigate the incidence of AP and its impact on postoperative calcemia. MATERIALS AND METHODS: From February 2016 to May 2018, 766 patients undergoing total thyroidectomy were prospectively included. Surgical indications, hormonal status, definitive histology, and postoperative calcium and PTH levels were analyzed. RESULTS: 578/(75.45%) were women and 188/(24.55%) men with mean age of 53.4 years. Parathyroid tissue on the thyroid specimen was observed in 40 (5.2%) patients: 30 APs and 10 parathyroid fragments. Among the 30 APs, 12 glands were intrathyroid and 18 (2.3%) in eutopic location. 97 (12.6%) patients were treated for postoperative hypocalcemia: 90 (11.7%) had transient and 5 (0.6%) definitive hypoparathyroidism; 2 were lost in follow-up. 13/30 (43.3%) with AP had transient hypoparathyroidism. A strong correlation was found (p < 0.0001) between AP and postoperative hypocalcemia. 1/30 (3.3%) patient with APs had definitive hypoparathyroidism. Transient and persistent nerve palsies were found in 10 (1.3%) and 3 (0.4%) patients, respectively. DISCUSSION: A careful examination of the thyroid gland after resection help to identify an AP that could be autotransplanted. Surgeon and hospital activity volume per years seem to reduce the risk of hypoparathyroidism. CONCLUSION: Total thyroidectomy and intrathyroid localization of parathyroid glands are risk factors for the AP. The incidence of AP was 2.3%, and this remains low due to our longstanding experience in thyroid and parathyroid surgery.
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Hipocalcemia , Hipoparatireoidismo , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Paratireoidectomia/efeitos adversos , Tireoidectomia/efeitos adversos , Hipocalcemia/epidemiologia , Incidência , Hipoparatireoidismo/epidemiologia , Hipoparatireoidismo/etiologia , Glândulas Paratireoides/transplante , Complicações Pós-Operatórias/etiologia , Hormônio ParatireóideoRESUMO
CONTEXT: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous. OBJECTIVE: Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. METHODS: The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. RESULTS: PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P = .04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells. CONCLUSION: The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Antígeno B7-H1 , Antígeno CTLA-4 , Receptor de Morte Celular Programada 1 , Humanos , Antígeno CTLA-4/metabolismo , Masculino , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/metabolismo , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/imunologia , Feminino , Receptor de Morte Celular Programada 1/metabolismo , Pessoa de Meia-Idade , Prognóstico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/análise , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Adulto Jovem , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Adolescente , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Measurements of aldosterone by mass spectrometry are more accurate and less prone to interferences than immunoassay measurements, and may produce a more accurate aldosterone:renin ratio (ARR) when screening for primary aldosteronism (PA). METHODS: Differences in diagnostic performance of the ARR using mass spectrometry vs immunoassay measurements of aldosterone were examined in 710 patients screened for PA. PA was confirmed in 153 patients and excluded in 451 others. Disease classifications were not achieved in 106 patients. Areas under receiver-operating characteristic curves (AUROC) and other measures were used to compare diagnostic performance. RESULTS: Mass spectrometry-based measurements yielded lower plasma aldosterone concentrations than immunoassay measurements. For the ARR based on immunoassay measurements of aldosterone, AUROCs were slightly lower (P = 0.018) than those using mass spectrometry measurements (0.895 vs 0.906). The cutoff for the ARR to reach a sensitivity of 95% was 30 and 21.5â pmol/mU by respective immunoassay and mass spectrometry-based measurements, which corresponded to specificities of 57% for both. With data restricted to patients with unilateral PA, diagnostic sensitivities of 94% with specificities >81% could be achieved at cutoffs of 68 and 52â pmol/mU for respective immunoassay and mass spectrometry measurements. CONCLUSIONS: Mass spectrometry-based measurements of aldosterone for the ARR provide no clear diagnostic advantage over immunoassay-based measurements. Both approaches offer limited diagnostic accuracy for the ARR as a screening test. One solution is to employ the higher cutoffs to triage patients likely to have unilateral PA for further tests and possible adrenalectomy, while using the lower cutoffs to identify others for targeted medical therapy.German Clinical Trials Register ID: DRKS00017084.
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Aldosterona , Hiperaldosteronismo , Espectrometria de Massas , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/sangue , Aldosterona/sangue , Imunoensaio/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Espectrometria de Massas/métodos , Sensibilidade e Especificidade , Curva ROC , Adulto , Renina/sangue , Idoso , Programas de Rastreamento/métodosRESUMO
BACKGROUND: Diagnosis of primary aldosteronism (PA) is complicated by the need to withdraw antihypertensive medications that interfere with test results, particularly renin. This study examined whether machine learning-based steroid-probability scores offer a renin measurement-independent approach for testing less prone to interference than the aldosterone-to-renin ratio (ARR). METHODS: This prospective multicenter cohort study involved the use of plasma steroidomics and the ARR in 839 patients tested for PA, including 190 with and 578 without PA (71 indeterminate). Receiver operating characteristic curves for steroid-probability scores and the ARR were examined with and without interfering medications. Impacts of individual medications on plasma aldosterone, 18-oxocortisol, 18-hydroxycortisol, steroid-probability scores, renin, and ARRs were examined by multivariable and paired analyses in patients with and without PA. RESULTS: Receiver operating characteristic curves indicated a significant impact of interfering antihypertensive medications on the diagnostic performance of the ARR and minimal impact on steroid-probability scores. Mineralocorticoid receptor antagonists increased plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol in patients without PA and resulted in false-positive test results for steroid-probability scores and false-negative results for the ARR. Diuretics increased aldosterone, 18-oxocortisol, and steroid-probability scores in patients without PA, whereas angiotensin-converting enzyme inhibitors decreased aldosterone, steroid-probability scores, and ARRs. Beta-adrenoceptor blockers, dihydropyridine calcium channel blockers, and angiotensin receptor blockers had negligible impact on mineralocorticoids and steroid-probability scores. CONCLUSIONS: Among antihypertensive drugs that impact plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol, mineralocorticoid receptor antagonists stood out as a cause of false-positive results for derived steroid-probability scores. Other antihypertensives have minimal or no impact, an advantage for use of steroid-probability scores over the ARR when those medications cannot be withdrawn. REGISTRATION: URL: https://drks.de/; Unique identifier: DRKS00017084.
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Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.
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Neoplasias das Glândulas Suprarrenais , Cortisona , Síndrome de Cushing , Diabetes Mellitus , Hipertensão , Paraganglioma , Feocromocitoma , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Hidrocortisona/metabolismo , Estudos Retrospectivos , Síndrome de Cushing/complicações , Esteroides , Neoplasias das Glândulas Suprarrenais/complicações , Hipertensão/complicações , Feocromocitoma/complicações , Paraganglioma/complicações , Catecolaminas , DesidroepiandrosteronaRESUMO
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.
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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: Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking. Methods: Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl. Results: A total of 260 patients were enrolled (147 women (56.5%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0%) and PACS (21.9%) than in NFA (8.1%). Over time, 40/124 (32.3%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing's syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9%; PACS, 24.0%; ACS, 39.0%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3% vs. 81.9% and 92.0%; p<0.05), diabetes (23.8% vs. 35.6% and 40.0%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95%-CI 0.89-13.29; ACS: HR 5.96, 95%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95%-CI 0.94-5.32; ACS: HR 2.60, 95%-CI 0.87-7.79; p=0.1). Twenty-five (12.6%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0% at diagnosis to 61.7% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group. Conclusion: Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).
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Neoplasias das Glândulas Suprarrenais , Doenças Cardiovasculares , Síndrome de Cushing , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Hidrocortisona , Estudos Retrospectivos , Estudos de Coortes , DexametasonaRESUMO
BACKGROUND: Given their neuroendocrine origin, head and neck paragangliomas (HNPGLs) can be imaged with somatostatin receptor (SSTR)-directed PET/CT. We aimed to determine whether the in vivo PET signal can differentiate between varying HNPGL subtypes. PATIENTS AND METHODS: Fourteen patients with HNPGL received pretherapeutic SSTR-PET/CTs using 68 Ga-DOTATOC. Six (42.9%) patients had a jugular paraganglioma (PGL-J), 5 (35.7%) were diagnosed with carotid paraganglioma (PGL-Cs), and the remaining 3 patients (21.4%) had PGL-C with pathogenic SDHx germline variants (PGL-C-SDH). A visual and quantitative assessment of the primary tumor on SSTR-PET was performed, including SUV max and target-to-background ratio (TBR). Quantitative values were then compared between subgroups of patients affected with different HNPGL entities. RESULTS: On visual assessment, all primary HNPGLs could be identified on SSTR-PET/CT. Quantification of HNPGL revealed substantially elevated SUV max in PGL-J (101.7 ± 58.5) when compared with PGL-C-SDH (13.4 ± 5.6, P < 0.05), but not when compared with PGL-C (66.7 ± 27.3, P = 0.4; PGL-C vs PGL-C-SDH, P = 0.2). TBR of PGL-J (202.9 ± 82.2), however, further differentiated between PGL-C (95.7 ± 45.4, P < 0.05) and PGL-C-SDH (20.4 ± 12.2, P < 0.01; PGL-C vs PGL-C-SDH, P = 0.3). Moreover, whole-body readout revealed metastases in 2/3 (66.7%) of PGL-C-SDH patients, with a single SSTR-expressing skeletal lesion in one subject and bipulmonary lesions in the other patient. CONCLUSIONS: In patients with HNPGL, SSTR-PET/CT identified the primary and metastatic disease and provides substantially elevated TBR, indicating excellent image contrast. PET-based quantification can also differentiate between varying HNPGL subtypes.
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Neoplasias de Cabeça e Pescoço , Paraganglioma Extrassuprarrenal , Paraganglioma , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptores de Somatostatina , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Paraganglioma Extrassuprarrenal/patologia , Paraganglioma/diagnóstico por imagemRESUMO
CONTEXT: Long-term follow-up has been recommended for patients with pheochromocytoma or paraganglioma (PPGL) due to potential for recurrent disease. However, the need to follow patients with sporadic PPGL has recently become controversial. OBJECTIVE: To investigate the prevalence of recurrence among patients with sporadic compared with hereditary PPGL and to identify predictors of recurrence for sporadic disease. METHODS: This multicenter study included retrospective data from 1127 patients with PPGL. In addition to sex and age at primary tumor diagnosis, clinical information included location, size, and catecholamine phenotype of primary tumors, genetic test results, and subsequent development of recurrent and/or metastatic disease. Patients with sporadic PPGL were defined as those with negative genetic test results. RESULTS: Prevalence of recurrence among patients with sporadic PPGL (14.7%) was lower (P < 0.001) than for patients with pathogenic variants that activate pseudohypoxia pathways (47.5%), but similar to those with variants that activate kinase pathways (14.9%). Among patients with sporadic recurrent PPGL, 29.1% and 17.7% were respectively diagnosed at least 10 and 15 years after first diagnosis. Multivariable regression analysis showed that a noradrenergic/dopaminergic phenotype (HR 2.73; 95% CI, 1.553-4.802; P < 0.001), larger size (HR 1.82; 95% CI, 1.113-2.962; P = 0.017) and extra-adrenal location (HR 1.79; 95% CI, 1.002-3.187; P = 0.049) of primary tumors were independent predictors of recurrence in sporadic PPGL. CONCLUSION: Patients with sporadic PPGL require long-term follow-up, as supported by the 14.7% prevalence of recurrent disease, including recurrences at more than 10 years after first diagnosis. The nature of follow-up could be individualized according to tumor size, location, and biochemical phenotype.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/diagnóstico , Feocromocitoma/epidemiologia , Feocromocitoma/genética , Estudos Retrospectivos , Recidiva Local de Neoplasia/epidemiologia , Paraganglioma/epidemiologia , Paraganglioma/genética , Paraganglioma/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/diagnósticoRESUMO
OBJECTIVE: Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting. DESIGN: Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at 6 German reference centres between 2016 and 2022. METHODS: Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAE) were assessed. RESULTS: In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR was 24% (16-41). PFS was 3.0 months (95% CI, 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs 2.5 (2.0-3.0) months (HR 0.29, 95% CI, 0.13-0.66, P = 0.001) and OS of 28.2 (9.5-46.8) vs 7.0 (4.1-10.2) months (HR 0.34, 95% CI, 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs 2.3 (1.6-3.0, P < 0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab. CONCLUSIONS: In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Estudos Retrospectivos , Carcinoma Adrenocortical/tratamento farmacológico , Antígeno B7-H1/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias do Córtex Suprarrenal/tratamento farmacológicoRESUMO
The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/genética , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias das Glândulas Suprarrenais/genética , Paraganglioma/genética , EpinefrinaRESUMO
BACKGROUND: Pheochromocytomas and paragangliomas have up to a 20% rate of metastatic disease that cannot be reliably predicted. This study prospectively assessed whether the dopamine metabolite, methoxytyramine, might predict metastatic disease, whether predictions might be improved using machine learning models that incorporate other features, and how machine learning-based predictions compare with predictions made by specialists in the field. METHODS: In this machine learning modelling study, we used cross-sectional cohort data from the PMT trial, based in Germany, Poland, and the Netherlands, to prospectively examine the utility of methoxytyramine to predict metastatic disease in 267 patients with pheochromocytoma or paraganglioma and positive biochemical test results at initial screening. Another retrospective dataset of 493 patients with these tumors enrolled under clinical protocols at National Institutes of Health (00-CH-0093) and the Netherlands (PRESCRIPT trial) was used to train and validate machine learning models according to selections of additional features. The best performing machine learning models were then externally validated using data for all patients in the PMT trial. For comparison, 12 specialists provided predictions of metastatic disease using data from the training and external validation datasets. FINDINGS: Prospective predictions indicated that plasma methoxytyramine could identify metastatic disease at sensitivities of 52% and specificities of 85%. The best performing machine learning model was based on an ensemble tree classifier algorithm that used nine features: plasma methoxytyramine, metanephrine, normetanephrine, age, sex, previous history of pheochromocytoma or paraganglioma, location and size of primary tumours, and presence of multifocal disease. This model had an area under the receiver operating characteristic curve of 0·942 (95% CI 0·894-0·969) that was larger (p<0·0001) than that of the best performing specialist before (0·815, 0·778-0·853) and after (0·812, 0·781-0·854) provision of SDHB variant data. Sensitivity for prediction of metastatic disease in the external validation cohort reached 83% at a specificity of 92%. INTERPRETATION: Although methoxytyramine has some utility for prediction of metastatic pheochromocytomas and paragangliomas, sensitivity is limited. Predictive value is considerably enhanced with machine learning models that incorporate our nine recommended features. Our final model provides a preoperative approach to predict metastases in patients with pheochromocytomas and paragangliomas, and thereby guide individualised patient management and follow-up. FUNDING: Deutsche Forschungsgemeinschaft.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Estados Unidos , Humanos , Feocromocitoma/diagnóstico , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Estudos Retrospectivos , Estudos Prospectivos , Estudos Transversais , Paraganglioma/diagnóstico , Paraganglioma/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Aprendizado de MáquinaRESUMO
OBJECTIVE: The therapeutic options for metastatic pheochromocytomas/paragangliomas (mPPGLs) include chemotherapy with cyclophosphamide/vincristine/dacarbazine (CVD), temozolomide monotherapy, radionuclide therapies, and tyrosine kinase inhibitors such as sunitinib. The objective of this multicenter retrospective study was to evaluate and compare the responses of mPPGLs including those with pathogenic variants in succinate dehydrogenase subunit B (SDHB), to different systemic treatments. DESIGN: This is a retrospective analysis of treatment responses of mPPGL patients (n = 74) to systemic therapies. METHODS: Patients with mPPGLs treated at 6 specialized national centers were selected based on participation in the ENSAT registry. Survival until detected progression (SDP) and disease-control rates (DCRs) at 3 months were evaluated based on imaging reports. RESULTS: For the group of patients with progressive disease at baseline (83.8% of 74 patients), the DCR with first-line CVD chemotherapy was 75.0% (n = 4, SDP 11 months; SDHB [n = 1]: DCR 100%, SDP 30 months), with somatostatin peptide receptor-based radionuclide therapy (PPRT) 85.7% (n = 21, SDP 17 months; SDHB [n = 10]: DCR 100%, SDP 14 months), with 131I-meta-iodobenzylguanidine (131I-MIBG) 82.6% (n = 23, SDP 43 months; SDHB [n = 4]: DCR 100%, SDP 24 months), with sunitinib 100% (n = 7, SDP 18 months; SDHB [n = 3]: DCR 100%, SDP 18 months), and with somatostatin analogs 100% (n = 4, SDP not reached). The DCR with temozolomide as second-line therapy was 60.0% (n = 5, SDP 10 months; SDHB [n = 4]: DCR 75%, SDP 10 months). CONCLUSIONS: We demonstrate in a real-life clinical setting that all current therapies show reasonable efficacy in preventing disease progression, and this is equally true for patients with germline SDHB mutations.
Assuntos
Neoplasias das Glândulas Suprarrenais , Neoplasias Encefálicas , Doenças Cardiovasculares , Segunda Neoplasia Primária , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/patologia , Radioisótopos do Iodo/uso terapêutico , Estudos Retrospectivos , Estudos de Coortes , Temozolomida/uso terapêutico , Sunitinibe/uso terapêutico , Paraganglioma/genética , Succinato Desidrogenase/genética , Neoplasias das Glândulas Suprarrenais/patologia , Somatostatina/uso terapêuticoRESUMO
CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.
Assuntos
Neoplasias das Glândulas Suprarrenais , Segunda Neoplasia Primária , Paraganglioma , Feocromocitoma , Humanos , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapia , Neoplasias das Glândulas Suprarrenais/metabolismo , Paraganglioma/genética , Paraganglioma/terapia , Paraganglioma/metabolismo , Feocromocitoma/genética , Feocromocitoma/terapia , Feocromocitoma/metabolismo , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Estudos Retrospectivos , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismoRESUMO
Adrenal masses are common incidental findings on imaging procedures.In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but in up to 20â% they require therapeutic intervention. The aim of this article is to provide essential guidance for clinicians regarding clinical management of patients with adrenal incidentalomas based on the respective current clinical guidelines. The following main questions are addressed: How to distinguish a nonfunctioning incidentaloma from a functioning one and how to assess risk of malignancy? How to define and manage low-level autonomous cortisol secretion, formerly called "subclinical" Cushing's syndrome? Which patients have to be treated surgically and which approach should be used? What follow-up is indicated if the adrenal incidentaloma is not surgically removed?
Assuntos
Neoplasias das Glândulas Suprarrenais , Síndrome de Cushing , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/terapia , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/terapia , Diagnóstico Diferencial , Humanos , Hidrocortisona , Achados IncidentaisRESUMO
Objective: Endogenous hypercortisolism predisposes to impaired immune function and infections. To date, however, it is unknown whether there is a subtype-specific pattern in white blood cell (WBC) and WBC differential (WBCD) count. Methods: A retrospective monocentric cohort study was carried out in patients with overt endogenous Cushing's syndrome (CS) or adrenal incidentalomas and autonomous cortisol secretion (ACS), with WBC/WBCD analysis at initial diagnosis and after biochemical remission. Cut-offs were obtained by receiver-operating characteristics analysis. Results: In total, 253 patients were analyzed (Cushing's disease (CD); n = 88; ectopic CS (ECS), n = 31; cortisol-producing adrenal adenomas (CPA), n = 40; ACS, n = 45; adrenocortical carcinomas (ACC), n = 49). Total leukocytes and neutrophils correlated positively with serum cortisol after 1-mg dexamethasone (r = 0.314 and r = 0.428), while a negative correlation was observed for lymphocytes and eosinophils (r = -0.374 and r= -0.380) (each P < 0.0001). Similar observations were made for 24 h-urinary free cortisol. CD and ECS differed in numbers of neutrophils and lymphocytes (P < 0.0001) and were well differentiated at a cut-off of 6.1 for the neutrophil/lymphocyte ratio (sensitivity 90.0%, specificity 89.4%, and areas under the curve (AUC) 0.918). For adrenocorticotropic hormone (ACTH)-independent CS, the best diagnostic outcome was obtained for the discrimination of CPA and ACC at a cut-off of 187.9 for the platelet/lymphocyte ratio (sensitivity 59.6%, specificity 80.6%, and AUC 0.713). For ECS, CPA, and CD, neutrophils decreased (delta -47.0, -29.7, and -26.2%) and lymphocytes increased (+123.2, +78.1, and +17.7%) already 3 months after remission. Conclusion: Most immune cells correlate with the degree of hypercortisolism and differ among CS subtypes. WBCD changes are already identified 3 months after remission from endogenous hypercortisolism.
Assuntos
Neoplasias do Córtex Suprarrenal , Neoplasias das Glândulas Suprarrenais , Carcinoma Adrenocortical , Síndrome de Cushing , Hipersecreção Hipofisária de ACTH , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Estudos de Coortes , Diagnóstico Diferencial , Humanos , Hidrocortisona , Leucócitos , Hipersecreção Hipofisária de ACTH/diagnóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Moderately elevated plasma normetanephrine (NMN) levels are frequent among patients with suspected pheochromocytoma and paraganglioma (PPGL). Clonidine suppression testing (CST) is recommended to distinguish patients with from those without PPGL. We aimed at evaluating the diagnostic outcome of CST in patients with moderate NMN elevations. METHODS: Data from patients participating in the PMT study (Prospective Monoamine-Producing Tumor) and the ENSAT (European Network for the Study of Adrenal Tumours) registry in 6 European reference centers were analyzed retrospectively. Eighty-nine patients with suspected PPGL and moderate NMN elevations upon screening were included. During follow-up, PPGL was confirmed in 16 and excluded in 73 cases. Plasma NMN was measured by liquid chromatography tandem mass spectrometry before and 180 minutes after oral clonidine. Receiver operating characteristic analysis was performed to identify optimal cutoffs. RESULTS: If published diagnostic criteria for CST (ie, NMN ≥112 ng/L and NMN suppression <40%) were applied, a sensitivity of 88% (CI, 61%-98%) and a specificity of 97% (CI, 90%-100%) were observed. An improved cutoff for plasma NMN 180 minutes after clonidine was established at 80% of the age-related upper limit of normal, resulting in a sensitivity of 94% and a specificity of 97%. False-negative CST results occurred in 2 patients with small PPGL. CONCLUSIONS: This study, involving one of the largest cohorts of patients with suspected PPGL and moderately elevated NMN, confirmed the diagnostic accuracy of CST. The application of an adapted cutoff further improved sensitivity.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/patologia , Clonidina , Humanos , Metanefrina , Normetanefrina , Paraganglioma/diagnóstico , Paraganglioma/patologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Pheochromocytomas (PCCs) are rare but potentially lethal tumors that arise from the adrenal medulla. The clinical suspicion and diagnosis of PCC can be challenging due to the non-specific nature of signs and symptoms. In many patients, infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could lead to long-term symptoms including fatigue, headaches, and cognitive dysfunction. Here, we present the case of a patient incidentally diagnosed with an adrenal mass that proved to be a PCC after imaging was performed due to persisting complaints after coronavirus disease 2019 (COVID-19) infection. A 37-year-old male patient was referred to our center because of a right-sided inhomogeneous adrenal mass, incidentally found during a computed tomographic scan of the thorax performed due to cough and dyspnea that persisted after COVID-19 infection. Other complaints that were present prior to COVID-19 infection included profuse sweating, dizziness, exhaustion with chronic fatigue, and concentration difficulties. The patient had no history of hypertension, his blood pressure was normal, and the 24-h ambulatory blood pressure monitoring confirmed normotension but with the absence of nocturnal dipping. Plasma normetanephrine was 5.7-fold above the upper limit (UL) of reference intervals (738 pg/ml, UL = 129 pg/ml), whereas plasma metanephrine and methoxytyramine were normal at 30 pg/ml (UL = 84 pg/ml) and <4 pg/ml (UL = 16 pg/ml), respectively. Preoperative preparation with phenoxybenzamine was initiated, and a 4-cm tumor was surgically resected. Profuse sweating as well as dizziness was resolved after adrenalectomy pointing toward PCC and not COVID-19-associated patient concerns. Altogether, this case illustrates the difficulties in recognizing the possibility of PCC due to the non-specific nature of signs and symptoms of the tumor, which in this case did not include hypertension and coincided with some of the symptoms of long COVID-19.
Assuntos
Neoplasias das Glândulas Suprarrenais , COVID-19 , Hipertensão , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Monitorização Ambulatorial da Pressão Arterial , COVID-19/complicações , Tontura/complicações , Humanos , Hipertensão/complicações , Masculino , Metanefrina , Normetanefrina , Fenoxibenzamina , Feocromocitoma/complicações , Feocromocitoma/diagnóstico , Feocromocitoma/cirurgia , SARS-CoV-2 , Síndrome de COVID-19 Pós-AgudaRESUMO
CONTEXT: Diagnosis of primary aldosteronism (PA) for many patients depends on positive results for the saline infusion test (SIT). Plasma aldosterone is often measured by immunoassays, which can return inaccurate results. OBJECTIVE: This study aimed to establish whether differences in aldosterone measurements by immunoassay versus mass spectrometry (MS) might impact confirmatory testing for PA. METHODS: This study, involving 240 patients tested using the SIT at 5 tertiary care centers, assessed discordance between immunoassay and MS-based measurements of plasma aldosterone. RESULTS: Plasma aldosterone measured by Liaison and iSYS immunoassays were respectively 86% and 58% higher than determined by MS. With an immunoassay-based SIT cutoff for aldosterone of 170 pmol/L, 78 and 162 patients had, respectivel, negative and positive results. All former patients had MS-based measurements of aldosteroneâ <â 117 pmol/L, below MS-based cutoffs of 162 pmol/L. Among the 162 patients with pathogenic SIT results, MS returned nonpathologic results in 62, including 32 under 117 pmol/L. Repeat measurements by an independent MS method confirmed nonpathogenic results in 53 patients with discordant results. Patients with discordant results showed a higher (Pâ <â 0.0001) prevalence of nonlateralized than lateralized adrenal aldosterone production than patients with concordant results (83% vs 28%). Among patients with nonlateralized aldosterone production, 66% had discordant results. Discordance was more prevalent for the Liaison than iSYS immunoassay (32% vs 16%; Pâ =â 0.0065) and was eliminated by plasma purification to remove interferents. CONCLUSION: These findings raise concerns about the validity of immunoassay-based diagnosis of PA in over 60% of patients with presumed bilateral disease. We provide a simple solution to minimize immunoassay inaccuracy-associated misdiagnosis of PA.