S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study.

OBJECTIVE: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. DESIGN: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. METHODS: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. RESULTS: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. CONCLUSION: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Computed tomography scan can be misleading in the lateralisation of aldosterone excess

Summary: Primary aldosteronism (PA) is characterised by aldosterone hypersecretion and represents a common cause of secondary hypertension. During diagnostic evaluation, it is essential to determine the aetiology of PA since the treatment of unilateral and bilateral disease differs significantly. Adrenal vein sampling (AVS) has been implemented as a gold standard test for the diagnosis of PA subtype. However, due to the AVS complexity, costs and limited availability, many patients with PA are being treated based on the computed tomography (CT) findings. In this article, we present two patients with discrepant CT and AVS results, demonstrating that AVS is the only reliable method for localising the source of aldosterone excess. Learning Points: CT is an unreliable method for distinguishing aldosterone-producing adenoma (APA) from bilateral adrenal hyperplasia (BAH). CT can be misleading in defining lateralisation of the aldosterone excess in case of unilateral disease (APA). AVS is the gold standard test for defining the PA subtype.

LOCALIZATION OF PANCREATIC INSULINOMAS WITH ARTERIAL STIMULATION BY CALCIUM AND HEPATIC VENOUS SAMPLING - PRESENTATION OF A SINGLE CENTRE EXPERIENCE.

CONTEXT: Arterial stimulation and venous sampling (ASVS) is the most sensitive diagnostic method for occult insulinoma localization. We present our experience with this method and modifications used that proved to ensure greater safety and sensitivity with this rare pathology. Relationship between tumour size and changes in peak insulin values and release curves were also tested. SUBJECTS AND METHODS: Six consecutive patients with biochemically established diagnosis of endogenous hyperinsulinism underwent preoperative non-invasive diagnostic tests with sensitivities calculated and compared for all methods. Certain modifications were used in ASVS procedure that included hepatic vein catheterization, order of arterial stimulation, time intervals between each stimulation, diagnostic insulin gradient level and the time frame for diagnostic rise of insulin. Peak insulin values and insulin gradients were compared with tumour size in each patient. RESULTS: In all patients, calcium stimulation accurately localized the insulinoma, with higher sensitivity than any other method. A more than 4-fold increase in insulin level was observed in all patients, after injection into the tumour feeding artery, while 2 to 4-fold increase was observed in the tumour neighbouring areas. Tumour size showed an inversely proportional correlation to peak insulin values in each artery that correctly located the tumour. CONCLUSION: ASVS presents the most accurate and safe method for localization of occult insulinomas. A four-fold insulin gradient can be used as a limit for positive preoperative localization in order to secure a higher specificity.

Clinical features and therapeutic outcomes of patients with acromegaly: single-center experience.

The aim of this study was to review the outcome of acromegaly treatment, as well as co-morbidity and mortality in a series of patients with acromegaly attending a single center in the last 10 yr. In that period, 53 patients were treated for acromegaly. Transsphenoidal operation was applied as the first-line therapy in 94.3% of patients and it led to disease remission in 59.2% of them. The remission criteria included a nadir GH<1 µg/l after glucose load, and normal age-related IGF-I levels. The remission rate after transsphenoidal surgery was significantly higher in the group of patients with microadenoma (76.9%), than in the group of patients with macroadenoma (52.8%). Patients with invasive tumors had remission rate of 16.7% after transsphenoidal surgery. There were no perioperative deaths. As the second-line treatment somatostatin analogues, radiotherapy, and dopaminergic agonists were used. Hypertension and diabetes were the most frequent co-morbidities in the group of patients. After successful treatment, 30% of patients with diabetes or impaired glucose tolerance had significant improvement of glycemic control. Transsphenoidal surgery is the appropriate firstline therapy in patients with somatotropinoma. Medical and radio-therapy should be reserved as the second-line therapy after surgery failure.

Decreased peak bone mass is associated with a 3-bp deletion/insertion of the CYP19 intron 4 polymorphism: preliminary data from the GOOS study.

Finding that estrogen plays an important role in bone homeostasis in men prompted research on relationship of polymorphism at the CYP19 gene and the bone mass. Therefore, influence of 3-bp deletion/insertion polymorphism of CYP19 (TTTA)7 allele on the peak bone mass attainment in males was studied. Fifty-eight unrelated male participants, aged 21-35, were selected depending on the presence of (TTTA)7 (no.=19) or (TTTA)7-3 (no.=39) alleles from the initial cohort of 92 young males. Heterozygotes (TTTA)7/(TTTA)7-3 (no.=13) were not included in the analysis. Serum levels of estradiol, free testosterone, 25-hydroxyvitamin D, bone alkaline phosphatase, osteocalcin, and beta-crosslaps were measured. Bone mass was measured by DXA at the hip and at the spine. (TTTA)7-3 allele was associated with significantly lower femoral neck bone mineral density (BMD) (p=0.02). Logistic regression model indicated strong association of (TTTA)7-3 allele with low BMD in the range of osteopenia/osteoporosis (p=0.014, odds ratio 12.36, confidence intervals 1.65-92.46). In the present study association of 3-bp deletion polymorphism of the (TTTA)7 allele with decreased peak bone mass in males is reported for the first time. However, further studies are necessary to elucidate the functional relevance of this polymorphism.

Discriminatory ability of calcaneal quantitative ultrasound in the assessment of bone status in patients with inflammatory bowel disease.

A high incidence of bone disease in patients with inflammatory bowel disease (IBD) requires frequent monitoring of skeletal status and, for that reason, evaluation of radiation-free technology is an issue of interest. Our objective was to appraise the parameters of calcaneal quantitative ultrasound (QUS): broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (QUI), and establish their t-score values to investigate discriminatory ability of QUS in IBD patients with metabolic bone disease. The study included 126 patients (Crohn's disease [n = 94] and ulcerative colitis [n = 32]), and 228 age- and sex-matched healthy volunteers. Bone status was evaluated on the same day by calcaneal QUS and dual-energy x-ray absorptiometry (DXA) at spine (L1-L4) and total hip. All QUS measurements were lower in patients compared with healthy controls (BUA p < 0.001; SOS p < 0.001; QUI p < 0.001) and correlated significantly but inversely with disease duration (r = -0.3, p = 0.002). There was no difference with respect to type of disease (Crohn's disease or ulcerative colitis) or corticosteroid therapy. All three QUS t-scores were significantly lower in patients who had previously sustained fragile fractures (n = 28) than in those without fracture in their history (n = 98) (t-scores: BUA -2.0 vs. -1.3, p = 0.008; SOS -2.1 vs. -1.4, p = 0.02: QUI -2.3 vs. -1.5, p = 0.009). Axial DXA was not significantly different between the fracture and nonfracture patients (-1.7 vs. -1.2, p = 0.1), whereas total hip DXA showed a discriminatory power between the two (-1.6 vs. -0.7, p = 0.001). Patients with t-score < -1.0 scanned by DXA were classified as bone disease. The sensitivity of QUS to identify bone disease was 93% and specificity 63%. The sensitivity of QUS to detect osteopenia was 84% and 72% for osteoporosis. Alternatively, lower negative QUS t-score cutoff

Calcaneus ultrasound in males: normative data in the Croatian population (ECUM study).

Limited number of dual X-ray absorptiometry (DXA) devices in Croatia makes this diagnostic technique unavailable to the majority of the population. Quantitative ultrasound (QUS) of the calcaneus could be an alternative tool for assessing fracture risk. However, age-specific normative data should be obtained before using the QUS in everyday clinical practice. The aim of our Epidemiology of Calcaneus Ultrasound in Males (ECUM) study is to establish the normative QUS data in a healthy sample of Croatian males. A total of 1002 male participants, aged 20-99, recruited in different Croatian counties, were included in the study. In each subject broadband ultrasound attenuation (BUA), speed of sound (SOS) and quantitative ultrasound index (QUI) of the left calcaneus were measured using the Sahara ultrasound device (Hologic). The coefficients of variation were 2.85 for BUA, 0.37 for SOS and 2.49 for QUI. Significant declining with age was found for all three parameters, BUA (p<0.001), SOS (p<0.001) and QUI (p<0.001), with respective r values 0.14, 0.27 and 0.23. The peak SOS (1,562.8+/-28.5 m/sec) and QUI (103.6+/-16.5) values were observed in the third decade, whereas the peak BUA value (86.2+/-19.2 db/MHz) was observed in the fourth decade. A subgroup of 103 participants, aged 20-29, was used to estimate young adult mean and SD for QUI and calculate the T-scores. Using the World Health Organization diagnostic criteria the rates of osteoporosis (T-score<-2.5) in the males aged 50 and older was 5.8%. However, when we used the cut-off value of the T-score<-1.8, as previously suggested, prevalence of osteoporosis in Croatian males >50 yr was 16.2%. Although further studies might improve our understanding of the QUS role in the fracture prediction, we hope that the results presented here will improve the clinical management of osteoporosis in males.

[Low-renin hypertension and inherited mineralocorticoid diseases]. / Niskoreninska hipertenzija i nasljedne bolesti mineralokortikoida.

Liddle's syndrome, apparent mineralocorticoid excess (AME) and glucocorticoid remediable aldosteronism (GRA) are inherited diseases characterized by hypertension and low plasma renin activity. Constitutive activation of distal renal epithelial sodium channel (Liddle's syndrome), defect in 11 beta-hydroxysteroid dehydrogenase activity (AME) and unequal crossing over, fusing regulatory sequences of 11 beta-hydroxylase gene to coding sequences of aldosterone synthase gene and forming a new chimeric gene (GRA), cause apparent or real mineralocorticoid excess. This diseases are often being unrecognized and classified as essential hypertension, especially in patients with normal serum potassium level. Family history of hypertension and characteristic serum and urine++ steroid profile direct us to diagnosis, and genetic analysis will confirm it.

High resolution molecular typing of HLA class II region in the population of the island of Krk, Croatia.

The HLA class II alleles (DRB1, DRB3, DRB5, DQA1, and DQB1) and haplotypic associations were studied in the population of the island of Krk using the PCR-SSOP method and the 12th International Histocompatibility Workshop primers and probes. Allele and haplotypic frequencies were compared with the general Croatian population. Significant differences were observed between the population of the island of Krk and Croatians for: a) three broad specificities at DRB1 locus (DRB1*01, *15, and *07), b) one allele at DRB3 locus (DRB3*0301), c) one allele at DQA1 locus (DQA1*0201), d) one allele at DQB1 locus (DQB1*0303). Four unusual haplotypic associations, which have not yet been described in the Croatian population, DRB1*1301-DQA1*0103-DQB1*0607, DRB1*1302-DQA1*0102-DQB1*0605, DRB1*1305-DQA1*0102-DQB1*0605 and DRB1*1305-DQA1*0103-DQB1*0603 were observed in the population from the island of Krk.

HLA class II gene and haplotype diversity in the population of the island of Hvar, Croatia.

The DRB1, DRB3, DRB5, DQA1 and DQB1 allele polymorphisms were analysed in 3 western and 3 eastern villages of the island of Hvar using PCR-SSOP method and 12th International Workshop primers and probes. Three DQB1 alleles (*0304, *0305, *0607) detected in the population of the island of Hvar (HP) have not yet been observed in general Croatian population (GCP). Significant differences were observed between two regions of Hvar for: a) DRB1*0701 allele (p < 0.001), b) DQA1*0201 allele (p < 0.01), and c) DRB1*0101-DQA1*0101-DQB1*0501 haplotypic association (p < 0.05). Two unusual haplotypic associations, which have not yet been described in general Croatian population (GCP), DRB1*0101-DQA1*0102-DQB1*0501 and DRB1*1501-DQA1 *0102-DQB1*0604 were observed in the population from the island of Hvar (HP). Measures of genetic kinship and genetic distances revealed isolation and clusterization which coincides with the known ethnohistorical, as well as biological and biocultural data obtained from a series of previous investigations. The five studied village subpopulations formed two clusters (East-West) to which the far eastern village (with the highest rii of 0.0407) joined later, thus indicating possible impact of historical immigrations from the mainland.

[Turner's syndrome--case report of a female patient with chromosome mosaicism]. / Turnerov sindrom--prikaz bolesnice s kromosomskim mozaicizmom.

A 45-year old woman with the typical Turner's phenotype (short stature, short and broad neck, shield chest and low hairline) and signs of ovarian failure started at the age of 37 with menopause at the age of 44, is presented. The cytogenetic analysis showed the presence of three different cell lines with 45,X, 46,XX and 47,XXX karyotypes. It is a rare type of mosaicism, combining Turner's and triple-X syndrome. Interestingly, the became pregnant and gave birth to a healthy child. Second pregnancy resulted in a miscarriage in the first trimester.