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Abstract Adrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.

Abstract Context Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X 2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.

While multiple studies have demonstrated that minimally invasive surgical (MIS) techniques are a safe and efficacious approach to adrenalectomy for pheochromocytomas (PC), these studies have only been small comparative studies. The aim of this multi-institutional study is to compare perioperative outcomes between open and MIS, stratified by robotic and conventional laparoscopic, techniques in the surgical management of PC. We retrospectively evaluated patients who underwent adrenalectomy for PCs from 2000 to 2017 at three different institutions. Clinical, perioperative, and pathologic parameters were analyzed using t test, Chi square, and Fisher exact statistical measures. Of the 156 adrenalectomy cases performed, 26 (16.7%) were with an open approach and 130 (83.3%) using MIS techniques. Of the MIS procedures, 41 (31.5%) were performed robotically and 89 (68.5%) performed laparoscopically without robotic assistance. Demographic and clinical parameters were similar between the open and MIS groups. Patients, who underwent MIS procedure had a lower complication rate ( p  = 0.04), shorter hospitalization ( p  = 0.02), shorter operative time ( p  < 0.001), and less blood loss ( p  = 0.002) than those who underwent open surgical resection. Conventional laparoscopic and robotic operative approaches resulted in similar complication rates, length of hospitalization, and blood loss. Our study is one of the largest cohorts comparing the perioperative outcomes between conventional laparoscopic and robotic adrenalectomies in patients with PC. Our results support that MIS techniques have potentially lower morbidity compared to open techniques, while laparoscopic and robotic approaches have similar perioperative outcomes.

Abstract Context Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require a hospital environment due to the risks involved. Objective To evaluate the efficacy of oral furosemide as a new confirmatory test for PA diagnosis. Methods We prospectively evaluated the diagnostic performance of 80 mg of oral furosemide in 64 patients with PA and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, and 2 hours and 3 hours after the oral furosemide. In addition, the oral furosemide test was compared with 2 other confirmatory tests: the furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all patients with PA. Results The cut-off of 7.6 µU/mL for DRC at 2 hours after oral furosemide had a sensitivity of 92%, specificity of 82%, and accuracy of 90% for PA diagnosis. In 5 out of 6 controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these 6 controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2 hours after oral furosemide had a sensitivity of 95.3%, specificity of 93.7% and accuracy of 95% for PA diagnosis. DRC after 3 hours of oral furosemide did not improve diagnostic performance. Using the cut-off of 10 µU/mL, the oral furosemide test and the FUT were concordant in 62 out of 64 (97%) patients with PA. Only 4 out of 64 cases with PA (6.4%) ended the oral furosemide test with potassium <3.5 mEq/L. Hypotension was not evidenced in any patient with PA during the test. Conclusion The oral furosemide test was safe, well-tolerated and represents an effective strategy for PA investigation.

Abstract Context Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. Objective To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. Methods We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. Results KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). Conclusion The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA. The impact of KCNJ5 somatic mutations on hypertension remission after adrenalectomy brings new insight into the postoperative follow-up of patients with PA.

Abstract Context Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using immunoassay. Objective To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening. Methods A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings. Results The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level <15 ng/dL, 19.9% had at least 2 aldosterone levels <15 ng/dL, and 16.2% had mean aldosterone levels <15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC >2 ng/dL/µIU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements. Conclusion Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements.

Abstract Context The role of hormone parameters at adrenal venous sampling (AVS) in predicting clinical and biochemical outcomes remains controversial. Objective To investigate the impact of hormone parameters at AVS under cosyntropin stimulation on lateralization and on complete biochemical and clinical outcomes. Methods We retrospectively evaluated 150 sequential AVS under cosyntropin infusion. The bilateral successful cannulation rate was 83.3% (n = 140), 47.9% bilateral and 52.1% unilateral. The lateralization index, aldosterone/cortisol ratio (A/C) in the dominant adrenal vein (AV), and relative aldosterone secretion index (RASI = A/C in AV divided by A/C in inferior vena cava) were assessed. The contralateral suppression (CS) percentage was defined by (1 − nondominant RASI) * 100. Results A nondominant RASI <0.5 (CS >50%) had 86.84% sensitivity and 92.96% specificity to predict contralateral lateralization. An A/C ratio in dominant AV >5.9 (74.67% sensitivity and 80% specificity) and dominant RASI >4.7 (35.21% sensitivity and 88.06% specificity) had the worst performance to predict ipsilateral lateralization. Complete biochemical and clinical cure was significantly more frequent in the patients with CS >50% [98.41% vs 42.86% (P < .001) and 41.94% vs 0% (P < .001)]. CS correlated with high aldosterone at diagnosis (P < .001) and low postoperative aldosterone levels at 1 month (P = .019). Postoperative biochemical hypoaldosteronism was more frequent in patients with CS >50% (70% vs 16.67%, P = .014). In multivariable analysis, a CS >50% was associated with complete biochemical cure [odds ratio (OR) 125, 95% confidence interval (CI) 11.904-5000; P = .001] and hypertension remission (OR 12.19, 95% CI 2.074-250; P = .023). Conclusion A CS >50% was an independent predictor of complete clinical and biochemical cure. Moreover, it can predict unilateral primary aldosteronism and postoperative biochemical hypoaldosteronism. Our findings underscore the usefulness of CS for clinical decision-making.

Abstract Disclosure: E.Z. Kawahara: None. J. Okubo: None. T.S. Goldbaum: None. F.L. Ledesma: None. J.L. Chambo: None. L.A. Bortolotto: None. A. Pio-Abreu: None. G.V. Silva: None. L.F. Drager: None. M.C. Fragoso: None. W.C. Nahas: None. M.N. Zerbini: None. A. Latronico: None. B.B. Mendonca: None. M.Q. Almeida: None. Background: Approximately 25% of patients with primary aldosteronism (PA) exhibit mild autonomous cortisol secretion (MACS). Patients with PA and MACS have an increased incidence of cardiovascular events compared to patients with PA without MACS. However, the characterization of aldosterone lateralization, histopathology, and outcomes among patients with PA and MACS is not well established. Aims: To evaluate the origins of aldosterone and cortisol secretion in patients with PA and MACS who underwent adrenalectomy, and to compare clinical and biochemical aspects, histology and outcomes between PA patients with and without MACS. Methods: We conducted a cohort study including 197 patients with PA who underwent investigation for MACS using a 1 mg dexamethasone suppression test at a single tertiary center. MACS was characterized by cortisol ≥ 1.8 mcg/dL with dexamethasone levels > 130 ng/dL. Histology was investigated using CYP11B2 and CYP11B1 immunostaining in adrenal lesions. Results: MACS was diagnosed in 52 (26.4%) out of 197 patients with PA. Among the 52 patients with MACS, 29 (55.8%) underwent adrenal venous sampling (AVS) under cosyntropin stimulation, and 25 (48.1%) underwent surgical treatment. Patients with PA and MACS were statistically significantly older at the time of PA diagnosis compared to patients with isolated PA (57.15 [33 - 74] vs. 52.58 [20 - 76] years; p = 0.014). Other clinical and biochemical features at diagnosis and PASO outcomes were not different between the two groups. Moreover, the frequency of unilateral and bilateral PA was 48,3% and 51,7% in patients with PA and MACS, respectively. Interestingly, aldosterone and cortisol were produced by different adrenal lesions in 6 (33.3%) out of 18 cases. This included five cases with a unilateral cortisol-producing adenoma (negative for CYP11B2) and bilateral aldosterone-producing nodules or micronodules (positive only for CYP11B2), and one case with bilateral adenomas (one was positive for CYP11B1 and the contralateral was positive for CYP11B2). The remaining 12 (66.6%) patients had a unilateral adenoma producing both aldosterone and cortisol. Conclusion: For the first time, we demonstrate that aldosterone and cortisol originate from distinct adrenal lesions one-third of patients with PA and MACS. This finding has critical implications for the interpretation of AVS and the planning of surgical treatment. Support: Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6 (to M.Q.A.) Presentation: Saturday, July 12, 2025

Abstract Disclosure: T.S. Goldbaum: None. F.L. Ledesma: None. A.G. Guimaraes: None. J. Okubo: None. E.Z. Kawahara: None. V. Calsavara: None. L.A. Bortolloto: None. J.L. Chambo: None. M.B. Fragoso: None. M.A. Pereira: None. A. Pio-Abreu: None. G.V. Silva: None. J.V. Silveira: None. F. Consolim-Colombo: None. L.F. Drager: None. W.C. Nahas: None. A. Latronico: None. B.B. Mendonca: None. M.Q. Almeida: None. M.N. Zerbini: None. Background: The effectiveness of histopathological classification using CYP11B2 immunostaining in unilateral primary aldosteronism (PA) for predicting clinical and biochemical outcomes following adrenalectomy remains a topic of debate. To date, no studies have conclusively shown that HISTALDO influences hypertension remission, and its effect on biochemical success varies among different ethnic groups. Methods: We conducted a cohort study involving 131 consecutive patients with unilateral PA who underwent unilateral adrenalectomy. Aldosterone-producing adrenal lesions were classified according to the HISTALDO criteria. Biochemical and clinical outcomes were assessed using the PASO criteria. Results: Among the 131 adrenal lesions, classical and non-classical histology were identified in 101 (77.09%) and 30 (22.91%) cases, respectively. In the classical group, 89 cases were classified as aldosterone-producing adenoma (APA), and 12 as aldosterone-producing nodule (APN). Within the non-classical group, 27 cases (90%) had multiple aldosterone-producing micronodules (APM), and 3 cases (30%) had multiple APNs. Patients with classical histology were younger (p = 0.028) and predominantly female (p = 0.028) compared to those with non-classical histology. Classical histology was associated with higher rates of complete biochemical success (97.03% vs. 68.97%, p < 0.001) and complete hypertension remission (34.34% vs. 10.71%, p < 0.001) compared to non-classical histology. Although clinical and biochemical outcomes were similar between APA and APN, their immunohistological characteristics differed (fewer clear cells and stronger CYP11B2 staining in APN). In multivariable analysis, classical histology remained independently associated with complete biochemical (p < 0.001) and clinical (p = 0.037) success. Conclusion: Classical histology was an independent variable associated with more severe PA, complete biochemical and hypertension remission in surgically treated patients with unilateral PA. Moreover, the distinction between APA and APN did not differentiate outcome. Support: This work was supported by the Sao Paulo Research Foundation (FAPESP), process number 2019/15873-6 (to M.Q. Almeida), FAPESP fellowship 2021/09879-1 (to A.A.W.M.) and 2021/10101-5 (to A.G.G.). M.Q.A was also supported by National Council for Scientific and Technological Development (CNPq) 304091/2021-9. Presentation: Monday, July 14, 2025

Disclosure: H.L. Charchar: None. A.W. Kuhn: None. B.M. Mariani: None. M.Y. Nishi: None. F.L. Ledesma: None. M.C. Zerbini: None. F.Y. Tanno: None. V. Srougi: None. J.L. Chambo: None. M.Q. Almeida: None. B.B. Mendonca: None. M.C. Fragoso: None. Background: The clinical evolution of primary macronodular adrenal hyperplasia (PMAH) is usually slow over many years and is related to the insidious progression of hypercortisolism. The disease presents an autosomal dominant inheritance pattern with incomplete penetrance. Germline heterozygous mutations in the ARMC5 are present in 10% to 55% of the patients. The long-term follow-up of patients harboring germline ARMC5 pathogenic variants with normal evaluation will provide us with important insights regarding the outcomes. Clinical case: A 53-year-old man (index-case) was referred by the cardiologist to our service in October 2012, due to resistant hypertension (HTA), type 2 diabetes mellitus, dyslipidemia, and BMI of 32.4 kg/m2. Hormonal data: low ACTH (<5 pg/mL) and no suppression of cortisol after the overnight DST-1mg (22.7 µg/dL); late-night salivary cortisol, urinary free cortisol, aldosterone/renin ratio and plasma metanephrines were in the normal range. A CT scan showed bilateral enlargement of the adrenals associated with multiple macronodules. He underwent an adrenal-sparing surgery (total adrenalectomy of the left adrenal and partial adrenalectomy of the right adrenal). The macroscopic and histological appearance was consistent with PMAH. Leucocyte DNA genotyping identified the germline heterozygous ARMC5 pathogenic variant in exon 1 c.280del, p.(Ser94Argfs*43). This variant was identified in 3 of the 10 relatives investigated (son#1, daughter#2 and grandson#3). In 2021, the 37-year-old son#1 presented with a BMI of 32.6 kg/m2. Autonomous cortisol secretion was confirmed (cortisol after DST-1mg = 6.7 µg/dL). CT scan showed bilateral enlargement of the adrenals, similar to his father (index-case), with a larger left adrenal. Unilateral left adrenalectomy was performed, and PMAH was histologically confirmed. In 2018, the 21-year-old daugher#2 had normal adrenal function. More recently, in December 2022, she presented with an important weight gain (44kg in 4 years), without any specific signs and symptoms of hypercortisolism. Hormonal investigation showed a possible autonomous cortisol secretion (cortisol after DST-1mg = 2.2 µg/dL); the CT scan demonstrated an adrenal diffusely thickened with several nodules, especially on the left side, as the other relatives. Up to now, she has been using ketoconazole. All of them did not present meningioma of CNS. The grandson#3 with 11-year-old, is asymptomatic so far. Clinical Lesson: PMAH is a heterogenous and underdiagnosed disorder and is more genetically associated than previously thought. Therefore, a careful hormonal-genetic-clinical-radiological study of the relatives of index cases permits the diagnosis of many unsuspected familial-cases, including asymptomatic patients. Surgical or medical treatment should be considered for these patients to avoid progression to a possible overt Cushing syndrome. Presentation: Friday, June 16, 2023