In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology.

17ß-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18F-fluoroestradiol (18F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women's health.

In vivo Brain Estrogen Receptor Expression By Neuroendocrine Aging And Relationships With Gray Matter Volume, Bio-Energetics, and Clinical Symptomatology.

17ß-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women's health.

ß3 -Adrenoceptor as a potential immuno-suppressor agent in melanoma.

BACKGROUND AND PURPOSE: Stress-related catecholamines have a role in cancer and ß-adrenoceptors; specifically, ß2 -adrenoceptors have been identified as new targets in treating melanoma. Recently, ß3 -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which ß3 -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of ß3 -adrenoceptors in immune-tolerance regulation. EXPERIMENTAL APPROACH: A mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of ß-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with ß-blockers (propranolol and SR59230A) and specific ß-adrenoceptor siRNAs targeting ß2 - or ß3 -adrenoceptors were used. KEY RESULTS: Only ß3 -, but not ß2 -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and ß3 -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and ß3 -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes. CONCLUSIONS AND IMPLICATIONS: Our data suggest that ß3 -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

The use of Deauville 5-point score could reduce the risk of false-positive fluorodeoxyglucose-positron emission tomography in the posttherapy evaluation of patients with primary bone lymphomas.

Primary bone lymphoma (PBL) is a rare disease. Little is reported about response evaluation procedures in these patients. Our aim was to evaluate response to therapy according to fluorodeoxyglucose-positron emission tomography (FDG-PET) results, and in particular to test the Deauville 5-point scale as compared to the visual evaluation of FDG-PET scans in PBL. In this single-center study, we diagnosed 31 consecutive patients with PBL, of which 24 were evaluated with end-of-treatment FDG-PET. Patients' ages ranged from 19 to 82 years. Six patients were treated with chemotherapy, 24 with chemotherapy and radiotherapy, and one patient with radiotherapy alone. Six patients were affected by a pathological fracture. Four patients died within the range of 3 to 36 months after diagnosis. The average follow-up of the remaining patients was 70 (24-173) months. Overall survival was 87% at 5 years. The only positive prognostic factor was complete remission after chemotherapy. According to visual criteria, end-of-treatment FDG-PET was evaluated in 24 patients and it was positive in 11 (46%) and negative in 13 patients. We organized a retrospective central-blinded revision of end-of-therapy FDG-PET scans using the 5-point Deauville Score (DS). We reviewed 17 out of 24 patients and obtained the following results: at the end of therapy, 12 patients with DS score 2, three patients with DS score 3, one patient with DS score 4, and none with DS score 5. Considering that all the 24 patients achieved complete remission after treatment, visual interpretation produced 11/24 false-positive results, and DS interpretation produced 1/17 false-positive results, thus significantly reducing the number of false positives. In PBL, the final evaluation at the end of therapy with FDG-PET should be evaluated using Deauville 5-point scale in order to significantly reduce the risk of false-positive scans.

Synthesis of Novel c(AmpRGD)-Sunitinib Dual Conjugates as Molecular Tools Targeting the αvß3 Integrin/VEGFR2 Couple and Impairing Tumor-Associated Angiogenesis.

On the basis of a previously discovered anti-αVß3 integrin peptidomimetic (c(AmpRGD)) and the clinically approved antiangiogenic kinase inhibitor sunitinib, three novel dual conjugates were synthesized (compounds 1-3), featuring the covalent and robust linkage between these two active modules. In all conjugates, the ligand binding competence toward αVß3 (using both isolated receptors and αVß3-overexpressing endothelial progenitor EP cells) and the kinase inhibitory activity (toward both isolated kinases and EPCs) remained almost untouched and comparable to the activity of the single active units. Compounds 1-3 showed interesting antiangiogenesis properties in an in vitro tubulogenic assay; furthermore, dimeric-RGD conjugate 3 strongly inhibited in vivo angiogenesis in Matrigel plug assays in FVB mice. These results offer proof-of-concept of how the covalent conjugation of two angiogenesis-related small modules may result in novel and stable molecules, which impair tumor-related angiogenesis with equal or even superior ability as compared to the single modules or their simple combinations.

Radiosynthesis and micro-SPECT analysis of triazole-based RGD integrin ligands as non-peptide molecular imaging probes for angiogenesis.

Taking advantage of click chemistry, we synthesized triazole-containing RGD peptidomimetics capable of binding to αvß3 integrin with diverse potency, and selected (125)I-labeled compounds proved to interact in vitro and in vivo with αvß3 integrin expressed by melanoma cells. Two (125)I-compounds containing either 2-aminobenzimidazole or 2-aminopyridine groups as the arginine bioisostere with the capacity to selectively bind cells of highly expressing αvß3 melanoma xenografts were found using micro-SPECT imaging studies.

A PPAR-gamma agonist attenuates pulmonary injury induced by irradiation in a murine model.

PURPOSE/OBJECTIVE(S): Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR-γ agonist rosiglitazone is of interest in the prevention and therapy of radiation-induced pulmonary injury. We evaluated the radioprotective effects of rosiglitazone in a murine model of pulmonary damage to determine whether radioprotection was selective for normal and tumor tissues. METHODS: Lungs in C57BL/6J mice were irradiated (19 Gy) with or without rosiglitazone (RGZ, 5mg/kg/day for 16 weeks, oral gavage). Computed tomography (CT) was performed and Hounsfield Units (HU) were determined during the observation period. Histological analysis and evaluation of fibrosis/inflammatory markers by western blot were performed at 16 weeks. A549 tumor-bearing CD1 mice were irradiated (16 Gy) with or without RGZ, and tumor volumes were measured at 35 days. RESULTS: Rosiglitazone reduced radiologic and histologic signs of fibrosis, inflammatory infiltrate, alterations to alveolar structures, and HU lung density that was increased due to irradiation. RGZ treatment also significantly decreased Col1, NF-kB and TGF-ß expression and increased Bcl-2 protein expression compared to the irradiation group and reduced A549 clonogenic survival and xenograft tumor growth. CONCLUSIONS: Rosiglitazone exerted a protective effect on normal tissues in radiation-induced pulmonary injury, while irradiated lung cancer cells were not protected in vivo and in vitro. Thus, rosiglitazone could be proposed as a radioprotective agent in the treatment of lung cancer.

Prostate-specific antigen kinetics parameters are predictive of positron emission tomography features worsening in patients with biochemical relapse after prostate cancer treatment with radical intent: Results from a longitudinal cohort study.

OBJECTIVE: The aim of this study was to identify prostate-specific antigen (PSA) kinetics parameters predictive of [(18)F]fluorocholine positron emission tomography/computed tomography ((18)FC PET/CT) features worsening in a cohort of patients with biochemical failure after prostate cancer treatment. MATERIAL AND METHODS: This longitudinal cohort study comprised 103 consecutive patients. All patients underwent two (18)FC PET/CT scans: one at baseline (PET1) and one after 6 months (PET2). Total PSA (tPSA), PSA velocity (vPSA), PSA doubling time (PSAdt), absolute variation in PSA values between PET2 and PET1 (ΔPSA), and percentage variation in PSA between the two PSA measurements (PSA%) were measured in each patient. Progression of disease on (18)FC PET/CT findings was compared with the PSA kinetics parameters. The major outcome measure was disease progression at PET2. RESULTS: (18)FC PET/CT progression between PET1 and PET2 was reported in 64 patients (62.1%), while in 39 cases it remained unvaried. The following PSA kinetic parameters correlated with worsened (18)FC PET/CT findings: ΔPSA >5 ng/ml [odds ratio (OR = 6.44, 95% confidence interval (CI) 1.04-39.6; p = 0.04], vPSA >6 ng/ml/month (OR = 5.2, 95% CI 0.9-29.8; p = 0.05) and PSAdt <6 months (OR = 5.2, 95% CI 0.4-5.4; p = 0.03). From receiver operating characteristics (ROC) analysis, the combination with the three PSA kinetics parameters for predicting worsened (18)FC PET/CT findings resulted in a sensitivity of 86% (95% CI 77-92%) and specificity of 77% (95% CI 65-85%). CONCLUSION: PSA kinetics is strictly related to (18)FC PET/CT findings. In patients with biochemical relapse, ΔPSA >5 ng/ml, PSAdt <6 months and vPSA >6 ng/ml/month are highly predictive of (18)FC PET/CT features worsening, independently from the treatment received.

Predictive factors of [18F]-Choline PET/CT in 170 patients with increasing PSA after primary radical treatment.

AIM: The purpose of this study was to evaluate the potential usefulness of [18F]-Choline PET/CT in the restaging of prostate cancer patients, who presented a rising PSA. MATERIALS AND METHODS: We evaluated 170 prostate cancer patients, previously radically treated, that were referred for restaging with [18F]-Choline PET/CT. RESULTS: A total of 129 patients (median PSA 4.29 ng/ml at relapse) showed one or more areas of high uptake on PET/CT scan, while 41 patients with a median PSA of 1.07 ng/ml at relapse showed negative PET/CT scans. No false negative was found, while 31 patients were identified as false positive. Specificity of Choline PET/CT in our series was 56.9 %, while sensibility was 100 %. At the time of restaging, a PSA value superior or equal to 1 ng/ml was found to be a statistically significant predictive factor of PET positivity, either at the univariate (p < 0.0001) and at the multivariate analysis (p < 0.0001). CONCLUSIONS: Based on our findings, [18F]-Choline PET/CT is confirmed as a useful diagnostic tool to detect early recurrence, in patients with increasing PSA after primary treatment. However, in case of a mild increase in PSA, positive results must be validated with other techniques, as specificity and positive predictive value of [18F]-Choline PET/CT decrease with the lower values of PSA.

¹²5I-radiolabeled morpholine-containing arginine-glycine-aspartate (RGD) ligand of αvß3 integrin as a molecular imaging probe for angiogenesis.

In this paper, using a hybrid small-animal Micro SPECT/CT imaging system, we report that a new (125)I-Cilengitide-like RGD-cyclopentapeptide, containing d-morpholine-3-carboxylic acid, interacts in vivo with α(v)ß(3) integrin expressed by melanoma cells. Images clearly show that the (125)I-compound has the capacity to monitor the growth of a melanoma xenograft. Indeed, retention of the labeled ligand in the tumor mass has a good tumor/background ratio, and a significant reduction of its uptake was observed after injection of unlabeled ligand. These results suggest that the use of (125)I-labeled morpholine-based RGD-cyclopentapeptides targeting α(v)ß(3) positive tumors may play a role in future therapeutic strategies.

Click-chemistry-derived triazole ligands of arginine-glycine-aspartate (RGD) integrins with a broad capacity to inhibit adhesion of melanoma cells and both in vitro and in vivo angiogenesis.

A click chemistry approach was applied for the discovery of triazole-based arginine-glycine-aspartate (RGD) mimetics by Cu(I)-catalyzed 1,3-dipolar alkyne-azide coupling reaction, which showed binding affinity properties toward α(v)ß(3)/α(v)ß(5) integrins. Biological assays showed compound 18 capable of binding α(v)ß(3) integrin with nanomolar affinity according to a two-sites model, and molecular modeling studies revealed a peculiar π-stacking interaction between the triazole ring and Tyr178 side chain. Accordingly, compound 18 inhibited the adhesion of integrin-expressing human melanoma cells to RGD-containing proteins of the extracellular matrix, such as vitronectin, fibronectin, and osteopontin, and also angiogenesis in in vitro and in vivo experimental models. The relevant biological effects exerted by compound 18 suggest its potential application as an antiangiogenic agent in the diagnosis and therapy of tumors where α(v)ß(3) integrin expression is up-regulated.

Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation.

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntington's disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.

Relationship of sustained brain natriuretic peptide release after reperfused acute myocardial infarction with gated SPECT infarct measurements and its connection with collagen turnover and left ventricular remodeling.

BACKGROUND: The relationship among plasma brain natriuretic peptide (BNP), markers of extracellular matrix (ECM) remodeling, and left ventricular (LV) dilation after reperfused acute myocardial infarction is poorly known. METHODS AND RESULTS: Echocardiogram, plasma BNP, and ECM degradation markers (serum amino-terminal telopeptide of type I procollagen and type III procollagen and carboxy-terminal telopeptide of type I procollagen [ICTP]) were evaluated in 34 patients at days 1, 3, and 30 after first reperfused acute myocardial infarction. At 1 month, infarct size and severity and LV volume were measured by sestamibi gated single photon emission computed tomography. Patients were stratified according to day 3 BNP levels into 2 groups: group 1 (n = 17) had BNP values over the median value, and group 2 (n = 17) had BNP values under the median value. Infarct size and severity were similar in the 2 groups. LV volumes increased in group 1 but decreased in group 2 (P < .01). BNP values, LV volume/mass index, and infarct size were independent predictors of 1-month LV dilation (beta = .58 [P = .001], beta = .41 [P = .01], and beta = .32 [P = .03], respectively). Levels of serum amino-terminal propeptide of type I procollagen and type III procollagen were similar in both groups. The level of ICTP increased significantly in group 1 only, and after 3 days, it was higher (P < .01) than in group 2. In group 1 ICTP significantly interacted with the relationship between BNP release and serial changes in LV volumes (F = 4.87, P = .03). CONCLUSIONS: ICTP is related to elevated BNP level independently of infarct size and severity and interacts with the relationship between BNP and LV dilation. BNP levels could play a role in LV remodeling by favoring ECM degradation.

Critical update and emerging trends in imatinib treatment for gastrointestinal stromal tumor.

The extraordinary success of imatinib in gastrointestinal stromal tumor (GIST) represents a model for molecularly targeted therapy of solid tumors. Research is currently going to identify the molecular basis of mechanisms of action and drug resistance. For the optimal management of the patients treated, a multidisciplinary approach, including medical oncologists, surgeons, pathologists, and radiologists is needed. In this article, we reviewed recent advances in the clinical management of GIST patients treated with imatinib, and in the knowledge of the molecular mechanisms that are basic to imatinib effects.

Multiple effects of somatostatin analogs verified in three cases of metastasized neuroendocrine tumors of the gastroenteropancreatic system.

AIMS AND BACKGROUND: In neuroendocrine tumors of the gastroenteropancreatic (GEP) system, radiolabeled analogs of somatostatin (SST) are useful to the surgeon in different phases of treatment: preoperatively, to identify the lesion with somato-statin receptor scintigraphy (SRS), intraoperatively for localization using a hand-held gamma probe, and postoperatively acting directly to eliminate any residual tumor cells. Additional features of these analogs that are of value in treating such GEP tumors include their antiproliferative potential, which is in the process of being verified, and, above all, their anti-secretory action, so effective in symptom control. In this study the authors, based on their own experience, evaluate the effectiveness of SST analogs in treating GEP endocrine tumors. METHODS: Three patients with malignant GEP apudomas were studied. In case 1, an insulinoma, the patient underwent four surgical procedures for ablation of the pancreatic tumor and of hepatic and lymph node metastases in addition to local radiofrequency treatment and radiometabolic therapy. Case 2 was a carcinoid tumor of the small intestine with hepatic metastases, managed by ileal resection, local radiofrequency treatment and receptor-mediated radionuclide therapy. In case 3, a non-functioning pancreatic carcinoma with liver and lymph node metastases, the patient underwent four surgical procedures, hepatic chemoembolization, antiproliferative treatment using octreotide (OCT) and metabolic radionuclide therapy. RESULTS: In all three cases SRS proved highly sensitive in the early detection of even the smallest recurrences. There was uncertainty, however, regarding the effectiveness of therapy with radiolabeled SST analogs. Hepatic metastases from the carcinoid were completely unresponsive, but in the case of the insulinoma, the hepatic metastases showed necrosis following treatment, while lymph node metastases were unaffected. In the case of the non-functioning carcinoma, there was a correlation between treatment and a marked improvement in the patient's clinical condition, although the appearance of the lesions themselves remained unchanged. The antiproliferative effect of OCT in this case was nil. CONCLUSIONS: SRS proved highly accurate in detecting recurrences during follow-up. The merits of radiometabolic therapy, on the other hand, were unclear, a finding reported elsewhere in the literature, and in the only case treated by prolonged OCT treatment, no antiproliferative action was observed. The diagnostic usefulness of SRS was thus confirmed and it appears likely that radiolabeled analogs used intraoperatively for tumor localization will prove equally of value. The effectiveness of receptor-mediated radionuclide therapy is still in the process of being verified. Based on the expectation of analogs with an universal affinity for SST receptors (sst), it is reasonable to look forward to a significant increase in the efficacy of this type of therapy.

Brain networks underlying the clinical effects of long-term subthalamic stimulation for Parkinson's disease: a 4-year follow-up study with rCBF SPECT.

UNLABELLED: The motor improvement derived from high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) is maintained over time after surgery. The aim of the present prospective follow-up study was to assess regional cerebral blood flow (rCBF) changes related to such improvement in the long term. METHODS: Ten PD patients with STN-DBS underwent 3 rCBF SPECT studies at rest-once preoperatively in the off-drug condition and the other 2 postoperatively in the off-drug/on-stimulation conditions at 5 +/- 2 and 42 +/- 7 mo. Patients were administered with Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) scale, and Schwab and England (S&E) scale. Statistical parametric mapping was used to investigate rCBF changes during long-term STN stimulation in comparison with preoperative rCBF and the relationship between rCBF and UPDRS scores was used as a covariate of interest. RESULTS: All patients showed a maximum clinical improvement during the first months after surgery and remained rather stable during further follow-up. The effect of STN-DBS from the pre- to the postoperative condition at 5 mo was to produce rCBF increases in the presupplementary motor area (pre-SMA), premotor (PMC), and dorsolateral prefrontal cortices. From the postoperative condition at 5 mo to that at 42 mo, the STN stimulation produced further rCBF increases in these frontal areas, and also in the primary motor/sensory cortices, globus pallidi, ventral lateral thalamic nuclei, cerebellum, pons, and midbrain entailing the substantia nigra (P < 0.0001). A correlation was detected between the improvement in motor scores and the rCBF increase in the pre-SMA and PMC (P < 0.0001). No correlation was present between the daily consumption of levodopa and the rCBF. CONCLUSION: Our study suggests that the long-term STN stimulation leads to improvement in neural activity in the frontal motor/associative areas. After an rCBF increase during the first months of stimulation, these regions showed a further increment in the later phase, which was accompanied by an increased activity in subcortical structures. The correlation between motor improvement and rCBF increase in higher order motor cortical areas suggests that even in the long term, as well as in the short term, the STN-DBS achieves its therapeutic benefit by restoring the activity within these cortical regions.

Urinary endothelin-1 excretion according to morpho-functional damage lateralization in reflux nephropathy.

BACKGROUND: Reflux nephropathy (RN) is a pathophysiological human model of reduced nephron reserve, due to loss of renal mass, but little information exists about the role of urinary endothelin-1 (uET-1) in this disease. The aim of this study was to assess the presence of uET-1-like-immunoreactivity (uET-1L) in RN patients, particularly if lateralized renal damage existed. METHODS: Thirty patients with vescico-ureteral reflux (VUR) and consequent RN, were studied. The presence of VUR was established by voiding cysto-urethrography. RN was assessed and graded by 99mTc-dimercapto-succinic acid scan (DMSA). Renal plasma flow (ERPF) was evaluated by (123)I-Hippuran renal sequential scintigraphy, and glomerular filtration rate (GFR) by creatinine clearance. Forty-five healthy subjects were selected as a control group. uET-1L excretion, in both affected and control groups, was assayed. RESULTS: Mann-Whitney U test showed a significant difference between control and patient groups in both GFR and uET-1L. A good correlation between DMSA grading, single kidney clearance and VUR grade was shown. A significant relationship was also shown between uET-1L and both ERPF and GFR. Patients with RN were divided into two subgroups according to functional damage lateralization. Between the two groups, a significant difference was found only for uET-1L when GFR was applied as a covariate in ANCOVA analysis. CONCLUSION: Our preliminary results confirmed the increase of urinary ET-1L excretion in RN, especially when renal functional injury was lateralized.

SPECT semiquantitative analysis of adrenocortical (131)I-6 beta iodomethyl-norcholesterol uptake to discriminate subclinical and preclinical functioning adrenal incidentaloma.

UNLABELLED: The goal of this study was to evaluate the clinical reliability of the (131)I-6 beta-iodomethyl-norcholesterol ((131)I-NP-59) uptake semiquantitative evaluation method we propose for the characterization of adrenocortical masses in a selected population of patients with disease clinically classified as subclinical (SC) and preclinical (PC) Cushing's syndrome (CS) according to Reincke's definition. METHODS: Forty-seven consecutive patients with incidentally discovered unilateral adrenal masses were examined by a triple-head SPECT system after intravenous injection of (131)I-NP-59. Abdominal SPECT was performed at 24, 48, 72, and, in selected cases, 96 h after tracer injection. Connected with adrenals and liver, a standard elliptic region of interest (ROI) was manually drawn, taking care to avoid the gallbladder region. The adrenal ROI integral count, obtained by summing the 24-, 48-, and 72-h counting values, was normalized by the hepatic integral count. Subsequently, the adrenal percentage of relative uptake (UPT%) was computed. RESULTS: Discriminant analysis was performed on the variables UPT%, adrenocorticotropic hormone (ACTH) serum concentration, and CT mass dimension (CTMD) to determine the variable, or combination thereof, best discriminating between the SC-CS and PC-CS groups. Compared with both ACTH and CTMD variables, univariate analysis confirmed the UPT% variable as the most significant to discriminate between these 2 clinical groups. In fact, UPT% alone correctly classified 8 of 9 patients in the SC-CS group and 20 of 22 patients in the PC-CS group with 95% positive and 80% negative predictive values and with overall accuracy, sensitivity, and specificity equal to 90%, 91%, and 89%, respectively. When all 3 variables were submitted to stepwise discriminant analysis, the derived classification matrix, after cross-validation, correctly classified 9 of 9 patients in the SC-CS group and 18 of 22 patients in the PC-CS group with 100% positive and 69% negative predictive values and with overall accuracy, sensitivity, and specificity equal to 87%, 82%, and 100%, respectively. CONCLUSION: According to these initial results, use of the proposed semiquantitative approach associated with both laboratory screening for cortisol production and CTMD measure seems to be able to increase the clinical diagnostic accuracy of PC-CS. This approach could be used in the follow-up of adrenal mass function every time hormonal or clinical features are suggestive of adrenocortical hyperfunction.