Marcus Quinkler

Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification.

Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification. However, to date, the prognostic value of the proposed classification has not been evaluated.

Combination chemotherapy in advanced adrenocortical carcinoma

BACKGROUND Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

Integrated genomic characterization of adrenocortical carcinoma

Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.

Prevalence, Clinical, and Molecular Correlates of KCNJ5 Mutations in Primary Aldosteronism

Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, n=380) and peripheral (APA, n=344; bilateral adrenal hyperplasia, n=174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; P<10−3) and in younger patients (42.1±1.0 versus 47.6±0.7 years; P<10−3) and were associated with higher preoperative aldosterone levels (455±26 versus 376±17 ng/L; P=0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism.

Cardiovascular and Cerebrovascular Comorbidities of Hypokalemic and Normokalemic Primary Aldosteronism: Results of the German Conn’s Registry

CONTEXT Primary aldosteronism (PA) is associated with vascular end-organ damage. OBJECTIVE Our objective was to evaluate differences regarding comorbidities between the hypokalemic and normokalemic form of PA. DESIGN AND SETTING This was a retrospective cross-sectional study collected from six German centers (German Conns registry) between 1990 and 2007. PATIENTS Of 640 registered patients with PA, 553 patients were analyzed. MAIN OUTCOME MEASURES Comorbidities depending on hypokalemia or normokalemia were examined. RESULTS Of the 553 patients (61 +/- 13 yr, range 13-96), 56.1% had hypokalemic PA. The systolic (164 +/- 29 vs. 155 +/- 27 mm Hg; P < 0.01) and diastolic (96 +/- 18 vs. 93 +/- 15 mm Hg; P < 0.05) blood pressures were significantly higher in hypokalemic patients than in those with the normokalemic variant. The prevalence of cardiovascular events (angina pectoris, myocardial infarction, chronic cardiac insufficiency, coronary angioplasty) was 16.3%. Atrial fibrillation occurred in 7.1% and other atrial or ventricular arrhythmia in 5.2% of the patients. Angina pectoris and chronic cardiac insufficiency were significantly more prevalent in hypokalemic PA (9.0 vs. 2.1%, P < 0.001; 5.5 vs. 2.1%, P < 0.01). Overall, cerebrovascular comorbidities were not different between hypokalemic and normokalemic patients, however, stroke tended to be more prevalent in normokalemic patients. CONCLUSIONS Our data indicate a high prevalence of comorbidities in patients with PA. The hypokalemic variant is defined by a higher morbidity than the normokalemic variant regarding some cardiovascular but not cerebrovascular events. Thus, PA should be sought not only in hypokalemic but also in normokalemic hypertensives because high-excess morbidity occurs in both subgroups.

The Adrenal Vein Sampling International Study (AVIS) for Identifying the Major Subtypes of Primary Aldosteronism

CONTEXT In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.

Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies

OBJECTIVE Adrenal crisis (AC) is a life-threatening complication of adrenal insufficiency (AI). Here, we evaluated frequency, causes and risk factors of AC in patients with chronic AI. METHODS In a cross-sectional study, 883 patients with AI were contacted by mail. Five-hundred and twenty-six patients agreed to participate and received a disease-specific questionnaire. RESULTS Four-hundred and forty-four datasets were available for analysis (primary AI (PAI), n=254; secondary AI (SAI), n=190). Forty-two percent (PAI 47% and SAI 35%) reported at least one crisis. Three hundred and eighty-four AC in 6092 patient years were documented (frequency of 6.3 crises/100 patient years). Precipitating causes were mainly gastrointestinal infection and fever (45%) but also other stressful events (e.g. major pain, surgery, psychic distress, heat and pregnancy). Sudden onset of apparently unexplained AC was also reported (PAI 6.6% and SAI 12.7%). Patients with PAI reported more frequent emergency glucocorticoid administration (42.5 vs 28.4%, P=0.003). Crisis incidence was not influenced by educational status, body mass index, glucocorticoid dose, DHEA treatment, age at diagnosis, hypogonadism, hypothyroidism or GH deficiency. In PAI, patients with concomitant non-endocrine disease were at higher risk of crisis (odds ratio (OR)=2.02, 95% confidence interval (CI) 1.05-3.89, P=0.036). In SAI, female sex (OR=2.18, 95% CI 1.06-4.5, P=0.035) and diabetes insipidus (OR=2.71, 95% CI 1.22-5.99, P=0.014) were associated with higher crisis incidence. CONCLUSION AC occurs in a substantial proportion of patients with chronic AI, mainly triggered by infectious disease. Only a limited number of risk factors suitable for targeting prevention of AC were identified. These findings indicate the need for new concepts of crisis prevention in patients with AI.

Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma

Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to targeted treatment options.

Adrenal Venous Sampling Evaluation of the German Conn's Registry

In patients with primary aldosteronism, adrenal venous sampling is helpful to distinguish between unilateral and bilateral adrenal diseases. However, the procedure is technically challenging, and selective bilateral catheterization often fails. The aim of this analysis was to evaluate success rate in a retrospective analysis and compare data with procedures done prospectively after introduction of measures designed to improve rates of successful cannulation. Patients were derived from a cross-sectional study involving 5 German centers (German Conns registry). In the retrospective phase, 569 patients with primary aldosteronism were registered between 1990 and 2007, of whom 230 received adrenal venous sampling. In 200 patients there were sufficient data to evaluate the procedure. In 2008 and 2009, primary aldosteronism was diagnosed in 156 patients, and adrenal venous sampling was done in 106 and evaluated prospectively. Retrospective evaluation revealed that 31% were bilaterally selective when a selectivity index (cortisol adrenal vein/cortisol inferior vena cava) of ≥2.0 was applied. Centers completing <20 procedures had success rates between 8% and 10%. Overall success rate increased in the prospective phase from 31% to 61%. Retrospective data demonstrated the pitfalls of performing adrenal venous sampling. Even in specialized centers, success rates were poor. Marked improvements could be observed in the prospective phase. Selected centers that implemented specific measures to increase accuracy, such as rapid-cortisol-assay and introduction of standard operating procedures, reached success rates of >70%. These data demonstrate the importance of throughput, expertise, and various potentially beneficial measures to improve adrenal vein sampling.