Timo Sane’s research while affiliated with University of Helsinki and other places

PurposeEctopic ACTH syndrome (EAS) is rare. We established a national cohort to increase awareness and address unmet needs.Methods The Finnish national EAS cohort includes 60 patients diagnosed in 1997–2016. We assessed clinical features, diagnostic work-ups, treatments, incidence, and outcomes of subgroups occult tumor (OT), well-differentiated neuroendocrine tumor G1/G2 (NETG1/G2) and NET G3/neuroendocrine carcinoma (NETG3/NEC).ResultsThe distribution of OT, NETG1/G2, and NETG3/NEC was 10 (17%), 20 (33%), and 30 (50%), respectively; and median follow-up 22 months (0–249). Annual incidence (0.20–0.93 per million inhabitants) and tumor subgroups (OT vs. NEC) varied across the country. The longest diagnostic delay from EAS onset to radiological tumor identification was 48 months. In NET/NEC, 6/50 (12%) were diagnosed 1–24 years before EAS onset. Osteoporotic fractures (32%) and severe infections (55%) were common. The CRH stimulation test accurately diagnosed EAS in 25/31 (81%). Metyrapone (≤6 g daily, prescribed in 88%) was well tolerated. In NETG1/G2, 13/20 (65%) underwent curative resection of the primary tumor; four experienced recurrence within 2–12 years. In OT, 70% underwent bilateral adrenalectomy. Five-year overall survival in OT, NETG1/G2, and NETG3/NEC was 90%, 55%, and 0%, respectively (P < 0.001). Morning cortisol, hypokalemia, infections, metastatic disease, and acute onset were negative, whereas resection of the primary tumor and bilateral adrenalectomy were positive predictors of survival.ConclusionsNET/NEC may precede EAS onset by several years. In NETG1/G2, recurrences may occur > 10 years after successful primary surgery. Tumor subgroup (OT, NETG1/G2, NEC) was an independent predictor of survival.

Objective: Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging of adrenal cortex with ¹¹ C-metomidate ( ¹¹ C-MTO) could offer a noninvasive alternative to AVS in the subtype classification of PA. Design: We prospectively recruited 58 patients with confirmed PA who were eligible for adrenal surgery. Methods: Subjects underwent AVS and ¹¹ C-MTO positron emission tomography (PET) without dexamethasone pretreatment in random order. The lateralization of ¹¹ C-MTO-PET and adrenal computed tomography (CT) were compared with AVS in all subjects and in a prespecified adrenalectomy subgroup in which the diagnosis was confirmed with immunohistochemical staining for CYP11B2. Results: In the whole study population, the concordance of AVS and ¹¹ C-MTO-PET was 51% and did not differ from that of AVS and adrenal CT (53%). The concordance of AVS and ¹¹ C-MTO-PET was 55% in unilateral and 44% in bilateral PA. In receiver operating characteristics analysis, the maximum standardized uptake value ratio of 1.16 in ¹¹ C-MTO-PET had an AUC of 0.507 (P=n.s.) to predict allocation to adrenalectomy or medical therapy with sensitivity of 55% and specificity of 44%. In the prespecified adrenalectomy subgroup, AVS and ¹¹ C-MTO-PET were concordant in 10 of 19 subjects with CYP11B2-positive adenoma and in 6 of 10 with CYP11B2-positivity without an adenoma. Conclusions: The concordance of ¹¹ C-MTO-PET with AVS was clinically suboptimal, and did not outperform adrenal CT. In a subgroup with CYP11B2-positive adenoma, ¹¹ C-MTO-PET identified 53% of cases. ¹¹ C-MTO-PET appeared to be inferior to AVS for subtype classification of PA.

Aims Widespread use of high-resolution imaging techniques and thus increased prevalence of adrenal lesions has made diagnostics of adrenocortical tumours an increasingly important clinical issue. In non-metastatic tumours, diagnosis is based on histology. New or enhanced information for clinicopathological diagnosis, revealing the malignant potential of the tumour, could emerge by means of biomarkers. The connection of proto-oncogene c-myc to adrenocortical neoplasias is poorly known, although the Wnt/beta-catenin pathway, one of the signalling pathways leading to induction of c-myc expression, has been connected to development of adrenocortical neoplasias. We studied c-myc expression in adrenocortical tumours and investigated molecules associated with the signalling pathway of c-myc, including cell cycle-related proteins p27, cyclin E and cyclin D1. Methods We studied 195 consecutive adult patients with 197 primary adrenocortical tumours. Histopathological diagnosis was determined by Weiss score and the novel Helsinki score. C-myc, cyclin D1, cyclin E and p27 expressions were determined by immunohistochemistry. Results Benign adenomas showed prominent nuclear c-myc expression comparable to that of normal adrenocortical cells, whereas carcinomas showed increased cytoplasmic expression. Strong cytoplasmic and weak nuclear c-myc expressions associated with malignancy and adverse outcome. C-myc staining did not correlate with cyclin E. Cyclin D1 correlated with cytoplasmic c-myc expression and to a lesser extent with nuclear c-myc. P27 correlated with cytoplasmic c-myc, but not with nuclear c-myc. P27 correlated with cyclin E. Conclusions Strong cytoplasmic c-myc expression and weak nuclear expression in adrenocortical tumours associated with malignancy and shorter survival.

Background: Few studies have examined weight loss sustainability after sleeve gastrectomy (SG). The purpose of this study was to determine long-term outcome after SG and gastric bypass (GBP) and learn whether preoperative weight loss and binge eating behavior can be used to predict outcome. Materials and methods: Together, 257 patients (64 % women) were operated, 163 by GBP and 94 by SG. Binge eating was assessed by binge eating scale (BES) and preoperative weight loss was advised to all, including very low-calorie diet for 5 weeks. Postoperative visits took place at 1 and 2 years, and long-term outcome was at median 5 years (range 2.29-6.85). Multivariate linear regression analysis was used to predict outcome at 2-year and long-term control. Results: Median age was 48 years, weight 141.1 kg, and BMI 48.2 kg/m(2). Preoperative weight loss was median 4.9 % before GBP and 3.8 % before SG, P = 0.04. Total weight loss at year one was 24.1 % in GBP and 23.7 % in SG (P = 0.40), at year two 24.4 and 23.4 % (P = 0.26), and at long-term control 23.0 and 20.2 % (P = 0.006), respectively. Weight was analyzed in 93, 88, and 89 % of those alive, respectively. BES did not predict weight outcome, but larger preoperative weight loss predicted less postoperative weight loss at 2 years. Conclusion: On long term, weight loss was better maintained after GBP compared with SG. Binge eating behavior was not a significant predictor, but larger preoperative weight loss predicted less postoperative weight loss for the next 2 years.

Background: Current guidelines for follow-up of adrenal incidentalomas are extensive and hampered by lack of follow-up studies. We tested the hypothesis that small lipid-rich adrenal incidentalomas, initially characterized by tumor size < 40 mm and < 10 Hounsfield Units (HU) on unenhanced computed tomography (CT) may not demon-strate excessive growth / hormonal hypersecretion on follow-up. Methods: Sixty-nine incidentalomas in 56 patients were restudied with unenhanced CT and screening for hypercortisolism (dexamethasone suppression test (DST), plasma ACTH) and pheochromocytoma (24hr urinary metanephrines and normetanephrines) 5 years later. Primary hyperaldosteronism was excluded at baseline. Results: Tumor (n=69) size was similar before and after 5 yrs follow-up (19 ± 6 mm vs 20 ± 7 mm). Mean tumor growth was 1 ± 2 mm. Largest increase in tumor size was 8 mm, this tumor was surgically removed and histopathology confirmed cortical adenoma. DST was normal in 54 patients and two (3.6%) patients were still characterized by subclinical hypercortisolism. Initial tumor size was > 20 mm for the patient with largest tumor growth and those with subclinical hypercortisolism. All patients had normal 24hr urinary metanephrines and normetanephrines. Low attenuation (< 10 HU) was demonstrated in 97% of 67 masses re-evaluated with unenhanced CT. Conclusion: None of the patients developed clinically relevant tumor growth or new subclinical hypercortisolism. Biochemical screening for pheochromocytoma in incidentalomas demonstrating < 10 HU on unenhanced CT is not needed. For such incidentalomas < 40 mm, it seems sufficient to perform control CT and screen for hypercortisolism after 5 yrs.

Histopathologic diagnosis of adrenocortical tumors is based on adverse features that indicate malignant potential. Proliferation index has served as a supplemental tool in assessing the malignant potential of adrenocortical tumors. None of the current histologic classification systems can sufficiently accurately predict tumors' metastatic potential. We studied 177 consecutive adult patients with primary adrenocortical tumors operated on at Helsinki University Central Hospital between 1990 and 2003, all patients with a minimum follow-up of 5 years. We determined for each tumor the Weiss score and the Weiss revisited score by Aubert. Proliferation index was measured by computer-assisted image analysis. Each of the 9 Weiss criteria and the proliferation index were then used to establish a scoring system to predict the metastatic potential of adrenocortical tumors. Use of stepwise regression analysis led us to propose a calculation: 3 × mitotic rate (>5/50 high-power fields) + 5 × presence of necrosis + proliferation index in the most proliferative area of the tumor. Using a cutoff value of 8.5, the new scoring system was able to diagnose metastatic adrenocortical carcinoma with 100% sensitivity (confidence interval [CI], 76.8%-100%) and 99.4% specificity (CI, 96.6%-100%). The corresponding sensitivity of the Weiss system was 100% (CI, 76.8%-100%), and specificity, 90.2% (CI, 84.6%-94.3%), with sensitivity of the Weiss revisited system at 100% (CI, 76.8%-100%) and specificity at 96.9% (CI, 93.0%-99.0%). The new Helsinki score thus was accurate in predicting the metastatic potential of adrenocortical tumors. Copyright © 2015 Elsevier Inc. All rights reserved.

Introduction: Dietary serotonin increases urinary secretion of 5-HIAA. A falsely elevated 5-HIAA may lead to incorrect suspicion of a neuroendocrine tumour. Therefore, we determined the effect and duration of dietary serotonin on serum 5-HIAA concentration. We also studied the distribution of 5-HIAA in serum fractions. Methods: We used serum samples from healthy volunteers (31 women and four men). All test subjects avoided serotonin-containing foods for three days before sample collection. They then ate either pineapple, banana, kiwi fruit, tomato or walnuts and additional blood samples were taken after 2, 4, 6, 24, 48 and 72 h. To study the distribution of 5-HIAA in serum, samples from a healthy individual, a test person who had ingested walnuts, and from a neuroendocrine tumour patient were fractionated by gel filtration chromatography. The fractions were analysed for 5-HIAA. Results: Serum 5-HIAA concentration increased significantly (P ≤ 0.001) within 2 h after ingestion of serotonin-containing food. After 2 h, 5-HIAA concentration started to decrease and reached the baseline concentration within 24 h. A calculated half-life of 5-HIAA in circulation was 1.3 h. In fractionated serum, 5-HIAA was found not only in free form but also in the albumin and α2-globulin fractions. Conclusions: The increase of serum 5-HIAA caused by dietary serotonin is significant but transient. Therefore, serotonin-containing foods should be avoided for one day before blood sampling. In serum, 5-HIAA is free and apparently bound to albumin. Minor amounts were also found in the α2-globulin fraction. Our liquid chromatography tandem mass spectrometry assay measures free 5-HIAA in serum.