Inflammation-based scores in a large cohort of adrenocortical carcinoma and adrenocortical adenoma: role of the hormonal secretion pattern.

BACKGROUND: Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. METHODS: We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n = 429) and ACC (n = 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. RESULTS: All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA (all p values < 0.001). NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test (1 mg-DST), both in ACC and ACA (p < 0.01). The ROC curve analysis determined NLR > 2.6 as the best cut-off to discriminate ACC from ACA [AUC = 0.846, p < 0.01]. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess (p = 0.002, p = 0.007, and p = 0.044 respectively). Finally, LMR and NLR differed between inactive-ACC (n = 10) and inactive-ACA (n = 215) (p = 0.040 and p = 0.031, respectively). CONCLUSION: Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.

Thiamethoxam in soybean seed treatment: Plant bioactivation and hormesis, besides whitefly control?

Amid concerns on the myriad of existing chemical stressors in agroecosystems, pesticides and particularly neonicotinoid insecticides are in the forefront. Despite that, these neurotoxic compounds remain the dominant group of insecticides in worldwide use with the added versatility of use in seed coatings. Such use sparks environmental concerns counterbalanced by their reported insecticidal efficacy and potential plant bioactivation. Nonetheless, this alleged double benefit and interconnection expected with neonicotinoids has been little explored particularly when the whole plant phenology is considered. Regardless of the expected efficacy against targeted insect pest species, like whiteflies, neonicotinoids may spark dual effect on plants - negative at higher concentrations, positive at low concentrations, which is consistent with the hormesis phenomenon that may be expressed as a plant bioactivation. This effect may also cascade to the targeted insect species, what deserves attention. Therefore, soybean seeds treated with increasing concentrations of the neonicotinoid thiamethoxam were followed throughout their development in greenhouse, recording the plant response and yield, besides their effect in whiteflies (Bemisia tabaci MEAM1). Thiamethoxam application was correlated to leaf contents of thiamethoxam and its metabolite clothianidin. Plant hormesis was found for leaf area and root growth, but not for other plant morphological or physiological parameters, nor plant yield. The insecticide concentration-dependency compromised whitefly population growth without evidence of cascading any plant-mediated hormesis to the insects. Thus, although plant hormesis was recognized with thiamethoxam in treated soybean seeds in relevant parameters, no evidence of plant bioactivation was observed to justify its use with such a secondary objective, nor did this hormesis impair whitefly control.

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).

Long-term remission of acromegaly after somatostatin analogues withdrawal: a single-centre experience.

PURPOSE: A long-lasting remission of acromegaly after somatostatin analogues (SAs) withdrawal has been described in some series. Our aim was to update the disease evolution after SAs withdrawal in a cohort of acromegalic patients. METHODS: We retrospectively evaluated 21 acromegalic patients previously included in a multicentre study (Ronchi et al. 2008), updating data at the last follow-up. We added further 8 patients selected for SAs withdrawal between 2008-2018. Pituitary irradiation represented an exclusion criterion. The withdrawal was suggested after at least 9 months of clinical and hormonal disease control. Clinical and biochemical data prior and after SAs withdrawal were analysed. RESULTS: In the whole cohort (29 patients) mean age was 50 ± 14.9 years and 72.4% were females. In 69% pituitary surgery was previously performed. Overall, the median time of treatment before SAs withdrawal was 53 months (IQR = 24-84). At the last follow up in 2019, 23/29 patients (79.3%) had a disease relapse after a median time of 6 months (interquartile range or IQR = 3-12) from the drug suspension, while 6/29 (20.7%) were still on remission after 120 months (IQR = 66-150). IGF-1 levels were significantly lower before withdrawal in patients with persistent remission compared to relapsing ones (IGF-1 SDS: -1.5 ± 0.6 vs -0.11 ± 1, p = 0.01). We did not observe any other difference between patients with and without relapse, including SAs formulation, dosage and treatment duration. CONCLUSION: A successful withdrawal of SAs is possible in a subset of well-controlled acromegalic patients and it challenges the concept that medical therapy is a lifelong requirement.

The IGF2 methylation score for adrenocortical cancer: an ENSAT validation study.

Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224-6.343; OR 1.467 95% CI 1.202-1.792, respectively; Hosmer-Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930-0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866-0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285-2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.

Cofilin is a cAMP effector in mediating actin cytoskeleton reorganization and steroidogenesis in mouse and human adrenocortical tumor cells.

cAMP pathway plays a major role in the pathogenesis of cortisol-producing adrenocortical adenomas (CPA). cAMP-induced steroidogenesis is preceded by actin cytoskeleton reorganization, a process regulated by cofilin activity. In this study we investigated cofilin role in mediating cAMP effects on cell morphology and steroidogenesis in adrenocortical tumor cells. We demonstrated that forskolin induced cell rounding and strongly reduced phosphorylated (P)-cofilin/total cofilin ratio in Y1 (-52 ± 16%, p < 0.001) and human CPA cells (-53 ± 18%, p < 0.05). Cofilin silencing significantly reduced both forskolin-induced morphological changes and progesterone production (1.3-fold vs 1.8-fold in controls, p < 0.05), whereas transfection of wild-type or S3A (active), but not S3D (inactive) cofilin, potentiated forskolin effects on cell rounding and increased 3-fold progesterone synthesis with respect to control (p < 0.05). Furthermore, cofilin dephosphorylation by a ROCK inhibitor potentiated forskolin-induced cell rounding and steroidogenesis (2-fold increase vs forskolin alone). Finally, we found a reduced P-cofilin/total cofilin ratio and increased cofilin expression in CPA vs endocrine inactive adenomas by western blot and immunohistochemistry. Overall, these results identified cofilin as a mediator of cAMP effects on both morphological changes and steroidogenesis in mouse and human adrenocortical tumor cells.

Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

Epicardial fat thickness significantly decreases after short-term growth hormone (GH) replacement therapy in adults with GH deficiency.

BACKGROUND AND AIM: Growth Hormone Deficiency (GHD) is characterized by increased visceral fat accumulation. Echocardiographic epicardial fat thickness is a new marker of visceral adiposity. Aim of the present study was to evaluate whether epicardial fat thickness can significantly change and therefore serve as a marker of visceral fat reduction after short-term rhGH replacement therapy in patients with adult-onset GHD. METHODS AND RESULTS: Echocardiographic epicardial fat thickness was measured in 18 patients (10 M, 8 F, age 48 ± 11.8 yrs, BMI 29 ± 5.9 kg/m(2)) with adult-onset GHD, at baseline and after 6 and 12 months of rhGH therapy and in 18 healthy matched controls, at baseline. Echocardiographic epicardial fat thickness, conventional anthropometric and metabolic parameters, body fat percentage and quality of life were also evaluated. Epicardial fat thickness in adult GHD patients was higher than in controls (9.8 ± 2.8 vs 8 ± 3 mm, p < 0.05). Epicardial fat thickness significantly decreased after 6-months of rhGH replacement therapy (from 9.8 ± 2.8 to 7.0 ± 2.3 mm, P < 0.01, i.e. -29% from baseline). After 12 months of rhGH replacement therapy, epicardial fat thickness showed a further significant decrease (from 7.0 ± 2.3 to 5.9 ± 3.1 mm, P < 0.01, i.e. -40% from baseline). No significant changes in BMI or waist circumference after 6 or 12 months of rhGH therapy were observed. CONCLUSIONS: Echocardiographic epicardial fat thickness may represent a valuable and easy marker of visceral fat and visceral fat changes during rhGH replacement treatment in patients with adult-onset growth hormone deficiency.

Survivin in adrenocortical tumors - pathophysiological implications and therapeutic potential.

Treatment options for adrenocortical carcinoma (ACC) are very limited. In other solid tumors, small vaccination trials targeting the anti-apoptotic molecule survivin suggested immunological and clinical benefit in selected patients. Therefore, we investigated whether survivin might be a suitable target for immunotherapy in ACC. Survivin mRNA and protein expression was assessed in adrenal tissue specimens [by real-time-PCR in 29 ACC, 24 adrenocortical adenomas (ACA) and 12 normal adrenal glands; by immunohistochemistry in 167 ACCs, 15 ACA, and 5 normal adrenal glands]. Expression was correlated with clinical outcome using Kaplan-Meier and Cox regression analyses. The anti-apoptotic role of survivin was investigated in the SW13 ACC cell line using survivin siRNA. The presence of spontaneous survivin specific T-cells in peripheral blood was assessed by FACS dextramere staining in 29 ACC patients in comparison to healthy controls. Survivin mRNA in ACC was significantly overexpressed when compared with ACA or normal adrenal glands. Immunohistochemistry confirmed survivin protein expression in 97% of the ACCs. In 83% of samples, staining was moderate or high and clinical outcome in this subgroup showed a trend towards poorer prognosis [hazard ratio for death 2.28 (95% CI 0.99-5.28); p=0.053]. Survivin knockdown in SW-13 cell significantly increased the rate of apoptosis. Finally, spontaneous survivin-reactive T cells were detectable in 3 of 29 ACC patients. In conclusion, our data suggest that survivin could play an important role in the anti-apoptotic mechanisms in ACC and provide first hints that targeting survivin might be an interesting new therapeutic approach in this rare disease.

GH response to oral glucose tolerance test: a comparison between patients with acromegaly and other pituitary disorders.

CONTEXT: The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments. OBJECTIVE: The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT. DESIGN, SUBJECTS, AND METHODS: Thirty-three patients (24 females and nine males, aged 50.1 ± 12.3 yr, 13 operated and two irradiated) with various hypothalamic-pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT. RESULTS: In HPD patients mean postglucose nadir GH levels were 0.11 ± 0.08 µg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 ± 0.08 vs. 0.08 ± 0.08 µg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 ± 0.13 µg/liter, P = 0.02), although there was an overlapping in about half of patients. CONCLUSIONS: Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function.

Oxidative stress status of highly prolific sows during gestation and lactation.

Elevated oxidative stress is reported to be associated with pregnancy complications in highly prolific sows. Oxidative DNA damage and the antioxidant status were determined in blood samples collected during the course of gestation and lactation in multiparous sows. Blood samples were drawn from sows (n = 5) on days 30, 60, 90 and 110 of gestation (G30, G60, G90 and G110, respectively), on day 3, 10 and 18 of lactation (L3, L10 and L18, respectively) and on day 5 of postweaning (W5). Lymphocytes were isolated from the fresh blood and cryopreserved in each time point. Lymphocyte DNA damage was analyzed by alkaline single-cell gel electrophoresis (comet assay) to determine the single- and double-strand brakes and endogenous antioxidant concentrations using an HPLC system with UV detection. The comet assay showed elevated (P < 0.05) DNA damage (between 38% and 47%) throughout the gestational and lactational periods than during early gestation (G30; 21%). Plasma retinol concentration was reduced (P < 0.05) at the end of gestation (G110) compared with G30. Plasma α-tocopherol concentrations also showed a similar trend as to retinol. This study indicates that there is an increased systemic oxidative stress during late gestation and lactation, which are not fully recovered until the weaning compared with the G30, and that antioxidant nutrients in circulation substantially reduced in the mother pig at G110.

Eight-year follow-up of a child with a GH/prolactin-secreting adenoma: efficacy of pegvisomant therapy.

A 3.4-year-old girl was admitted to the Pediatric Department because of tall stature (116.0 cm, +5.1 SDS) and increased height velocity (16.3 cm/year, +6.1 SDS). Basal hormonal evaluation revealed elevated insulin-like growth factor I (IGF-I) levels (938 ng/ml, nv 40-190), prolactin (PRL) (98.0 ng/ml, nv 1.7-24.0) and mean growth hormone (GH) nocturnal concentration (147 ng/ml). Basal adrenal, gonadal and thyroid functions were normal. Hand-wrist bone age was 3.6 years. Magnetic resonance imaging revealed a macroadenoma with moderate suprasellar invasion. The adenoma was surgically removed and histological characterization confirmed the diagnosis of GH/PRL-secreting adenoma. The patient was admitted to our Endocrine Unit when 7.9 years old, because of the persistence of elevated GH, IGF-I and PRL levels, although there was a slight height velocity reduction and absence of tumor recurrence. Treatment with cabergoline was initiated, but only PRL levels normalized. Afterwards, octreotide long-acting release (LAR) was added without reaching the normalization of GH and IGF-I levels. Thus, treatment with octreotide LAR was discontinued and pegvisomant was added to cabergoline, leading to the normalization of IGF-I levels and height velocity without side effects. Other anterior pituitary functions were always normal. To conclude, treatment of pituitary gigantism with pegvisomant was effective and well tolerated in a young giant unresponsive to combined cabergoline and octreotide treatment.

Evaluation of GH-IGF-I axis in adult patients with coeliac disease.

The aim of this study was to evaluate GH/IGF-I axis and other pituitary functions in adult patients with coeliac disease. For this purpose, twenty-eight adult coeliac patients [20M, 8F:19-74 years; body mass index (BMI): 18.5-28 kg/m (2)] were recruited. Basal thyroid, adrenal and gonadal function, serum IGF-I and PRL, and routine parameters were evaluated. Dynamic GH secretion was carried out by GHRH plus arginine test. In 20 patients, antipituitary antibodies (APA) were also evaluated. Seven out of 28 patients, independently from disease onset and the gluten-free diet (GFD), showed an impaired GH secretion (25%). All were males, 2 with severe growth hormone deficiency (GHD) and 5 with partial GHD. In patients with GHD, as compared to coeliac patients with normal GH secretion, HOMA (2.1+/-1.2 vs. 0.9+/-0.4) and QUICKI (0.35+/-0.03 vs. 0.39+/-0.02) levels were significantly higher and lower, respectively, while IGF-I levels were slightly lower (17.7+/-3.7 vs. 24.7+/-6.3, p=NS). APA were negative in all 20 patients studied. In conclusion, a significant number of adult coeliac patients show an impaired GH secretion, this alteration being predominant in males and independent from disease onset and diet regimen. Given the absence of APAs, the cause of this pituitary dysfunction remains unclear even if a previous autoimmune involvement in some cases cannot be excluded.

An unusual case of recurrent autoimmune hypophysitis.

Autoimmune hypophysitis (AH) is an inflammatory disease that can present either as empty sella or as pituitary mass. A 16-years-old girl was admitted at our Unit for primary amenorrhea. A pituitary MRI performed 2 years before for severe headache demonstrated a large sellar and suprasellar lesion. As a craniopharyngioma was suspected, the consultant neurosurgeon suggested the removal of the lesion. Two months later, a preoperative MRI showed the disappearance of the lesion and a residual empty sella, figure consistent with AH. When the patient came at our observation, basal and dynamic testing documented a state of hypopituitarism, high titers of antipituitary antibodies and a partial empty sella at MRI. Hormonal replacement therapy was started, obtaining a good clinical and biochemical control. Four years later, severe headache and a MRI suggestive of pituitary adenoma recurred. A relapse of the autoimmune phenomenon seemed the most feasible hypothesis. A MRI performed 3 months later did not show any pituitary lesion and empty sella was again described. This patient represents one of the few reported cases of recurrent hypophysitis and demonstrates that both pituitary enlargement and empty-sella can be seen in the same patient at different times of his history.

Acromegaly secondary to an incidentally discovered growth-hormone-releasing hormone secreting bronchial carcinoid tumour associated to a pituitary incidentaloma.

In this report we emphasize the opportunity of considering the uncommon causes of chronic GH-excess in the initial diagnostic process, such as GHRH hypersecretion, especially in the presence of ambiguous pituitary neuroimaging. This topic may have an important clinical significance in order to plan the most cost-effective diagnostic procedures and management and to avoid unnecessary pituitary neurosurgery.

Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients.

OBJECTIVES: Aberrant cAMP signaling is involved in the pathogenesis of somatotropinomas. The aim of the study was to screen acromegalic patients for the presence of variants of phosphodiesterase type 11A (PDE11A) gene, which have been recently identified in adrenocortical and testicular tumors. SUBJECTS AND METHODS: We sequenced the PDE11A gene-coding region in 78 acromegalic patients and 110 controls. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and normal pituitary samples. RESULTS: We found 15 nonsynonymous germline substitutions in 13 acromegalic patients (17%), i.e. 14 missense variants (Y727C in six, R804H in one, R867G in four, and M878V in three) and one truncating mutation (FS41X), with a prevalence only slightly higher than that observed in controls (14%). Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants, with the exception of two tumors (one with loss of heterozygosity (LOH) at the PDE11A locus and one with FS41X mutation) showing markedly reduced PDE11A staining. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A changes showed a tendency to have a more aggressive tumor compared with patients with wild-type sequence (extrasellar extension in 69 vs 45%). CONCLUSIONS: This study first demonstrated the presence of PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls. The normal expression of the enzyme in the majority of tumor tissues together with the lack of significant clinical phenotype suggests that these variants might only marginally contribute to the development of somatotropinomas.

Detection of small bowel tumors by videocapsule endoscopy in patients with acromegaly.

The prevalence of colon polyposis andmalignancies is increased in acromegalic patients as compared to the general population. An epidemiological study suggests a high prevalence also of small bowel (SB) tumors that nowadays may be detected by videocapsule endoscopy (VCE). The aim of the study was to assess the prevalence of SB neoplasms using VCE in acromegalic patients in comparison to control subjects and to correlate it with cancer risk factors and acromegaly-related parameters. Eighteen acromegalic patients (6 males and 12 females, age+/-SD: 54+/-10 yr), 5 cured after surgery (followed by radiotherapy in 3 cases) and 13 on pharmacological treatment were enrolled, and 36 sex- and age-matched non-acromegalic subjects served as a control group. Cancer risk factors, duration of acromegaly, GH and IGF-I levels, IGF binding protein 3 and IGF-II concentrations, metabolic parameters, tumor markers, colonic lesions by total colonoscopy, and SB lesions by VCE were investigated. VCE images suggestive of SB lesions were detected in 5/36 controls [14%, 4 described as gastrointestinal stromal nodular tumors (GIST), and 1 as polyp] and in 5/18 acromegalic patients [28%, 2 GIST and 3 polyps]. In acromegaly, the calculated relative risk for all SB lesions was 1.69 [95%confidence interval (CI): 0.78-3.65], while the relative risk for SB polyps was 2.50 (95% CI: 1.23-5.07). The effective duration of active disease was longer in patients with positive than in those with negative VCE (112+/-89 vs 49+/-40 months, p=0.06). In conclusion, these preliminary results suggest that acromegalic patients might have a high risk of SB polyp development. VCE might be a useful adjunctive diagnostic tool in acromegaly.

Prevalence of GH deficiency in cured acromegalic patients: impact of different previous treatments.

OBJECTIVE: Radiotherapy (RT) for pituitary adenomas, including GH-secreting ones, frequently leads to GH deficiency (GHD). Data on the effects of surgery alone (S) on dynamic GH secretion are limited. The aim of the study was to investigate the occurrence of GHD in acromegalic patients treated with different therapeutic options. DESIGN AND METHODS: Fifty-six patients in remission from acromegaly, (33 F & 23 M, age: 54+/-13 years, body mass index (BMI): 28.4+/-4.1 kg/m(2), 21 with adequately substituted pituitary deficiencies) treated by S alone (n=33, group 1) or followed by RT (n=23, group 2), were investigated for GHD by GHRH plus arginine testing, using BMI-adjusted cut-offs. Several metabolic and cardiovascular parameters (waist circumference, body fat percentage, blood pressure, fasting and post-oral glucose tolerance test glucose, HbA1c, insulin resistance and lipid profile) were evaluated in all the patients and 28 control subjects with known diagnosis of GHD. RESULTS: Serum GH peak after challenge was 8.0+/-9.7 microg/l, without any correlation with post-glucose GH nadir and IGF-1 levels. The GH response indicated severe GHD in 34 patients (61%) and partial GHD in 15 patients (27%). IGF-1 were below the normal range in 14 patients (25%). The frequency of GHD was similar in the two treatment groups (54% in group 1 and 70% in group 2). No significant differences in metabolic parameters were observed between acromegalic patients and controls with GHD. CONCLUSIONS: Severe GHD may occur in about 60% of patients treated for acromegaly, even when cured after S alone. Thus, a stimulation test (i.e. GHRH plus arginine) is recommended in all cured acromegalic patients, independently from previous treatment.

New techniques for high-temperature melting measurements in volatile refractory materials via laser surface heating.

An original technique for the measurement of high-temperature phase transitions was implemented based on a laser-heating method, enabling chemically unstable, refractory materials to be melted under controlled conditions. This technique includes two independent but correlated methods: In the first, fast multichannel pyrometry is employed to measure thermograms and spectral emissivity; in the second, a low-power probe laser beam is used for the detection of reflectivity changes induced by phase transitions on the sample surface. The experiments are carried out under medium ( approximately 10(2) kPa) or high ( approximately 10(2) MPa) inert-gas pressures in order to kinetically suppress evaporation in volatile or chemically instable samples. Two models for the simulation of the laser-heating pulses are as well introduced. Some results are presented about the successful application of this technique to the study of the melting behavior of oxides such as UO(2+x), ZrO(2), and their mixed oxides. The method can be extended to a broad class of refractory materials.

Adrenal morpho-functional alterations in patients with acromegaly.

Acromegaly is associated with a greater morbidity and higher incidence of tumors, possibly due to the permissive role of elevated GH and IGF-I levels. In the general population, adrenal masses are frequently discovered (prevalence 1-5%) at computed tomography (CT). We evaluated the prevalence of adrenal lesions in patients with acromegaly. We studied 94 acromegalic patients, 54 females (mean age 55.0+/-16.0 yr) and 40 males (mean age 50+/-14 yr) referred to 5 Endocrinology Units between 2001-2003; 49 had active disease and 45 had been treated with surgery and/or were controlled with medical therapy. Abdominal CT showed adrenal lesions in 27 patients; 9 of them had unilateral masses (10%) with benign features (diameter 0.5-3 cm) and 18 had hyperplasia (14 monolateral and 4 bilateral), with no significant differences between patients with active vs controlled disease, and with no correlation between prevalence of masses and duration of disease, GH and IGF-I levels. Hormone study (urinary free cortisol, catecholamines/metanephrines, upright plasma renin activity and aldosterone, morning plasma ACTH and low-dose dexamethasone suppression test) disclosed no major endocrine alterations. During a 1-yr follow-up, the adrenal masses increased in size in 3 cases and 1 patient also developed subclinical Cushing's syndrome. Adrenal lesions seem more frequent in acromegaly than in the general population, but no single factor (GH/IGF-I levels or disease duration) predicts them. The masses appear to be benign and nonhypersecreting, but a longer follow-up is recommended to disclose any changes in their morphofunctional state.