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Purpose: The aim of this study was to generate immortalized human anterior pituitary adenoma cells. Reliable cell models for the study of human pituitary adenomas are as yet lacking and studies performed so far used repeated passaging of freshly excised adenomas, with the attendant limitations due to limited survival in culture, early senescence, and poor reproducibility., Methods & Results: We devised a technique based upon repeated co-transfections of two retroviral vectors, one carrying the catalytic subunit of human telomerase, hTERT, the other SV40 large T antigen. This approach extended the lifespan of cells derived from a human growth hormone-secreting adenoma up to 18 months while retaining morphology of primary cells, growth hormone synthesis and growth hormone secretion., Conclusions: Our attempt represents the first demonstration of successful lifespan extension of human growth hormone-secreting pituitary adenoma cells via co-transfection of hTERT and SV40T and paves the way to future attempts to obtain stable cell lines.

Cytokines' involvement in tumorigenesis has been hypothesized. Interleukin-22 (IL-22) is implicated in proliferative and anti-apoptotic pathways via its receptor IL-22R. Its role in pituitary adenomas has never been investigated. Twenty-seven patients with pituitary macroadenomas (PA, 21 males, mean age 53.8 ± 14.4 years) and 30 healthy controls (19 males, mean age 50.4 ± 8.4 years) were enrolled. Out of 27 PA patients, 17 had a non-functioning tumour (NFPA) and 10 a PRL-secreting adenoma (PRL-oma). Serum IL-22 levels were measured in both patients and controls. Immunohistochemical (IHC) tumoral IL-22R expression was evaluated in 10 patients with NFPA and 4 with PRL-oma. IL-22 levels were significantly higher in PA patients than in controls [32.47 (11.29-70.12) vs. 5.58 (0.19-21.46) pg/mL, p < 0.0001] but did not correlate with tumor maximum diameter and were not associated to pituitary function impairment. PRL-oma patients had significantly higher IL-22 levels than NFPA patients [37.18 (14.82-70.12) vs. 21.29 (11.29-56) pg/mL, p = 0.039]. IHC revealed a strong IL-22R staining in 100 % of PRL-omas and 60 % of NFPAs. We provide the first evidence of increased serum IL-22 levels in patients with pituitary macroadenoma, especially in PRL-omas, regardless of tumor size and/or degree of pituitary function impairment. We also demonstrated the expression of IL22R in all PRL-omas and in 60 % of NFPAs.

The ligand/receptor hepatocyte growth factor (HGF)/c-met signaling system promotes cellular growth and angiogenesis through PI3K/phosphor-Akt and STAT3/phosphor-STAT3 downstream effectors. In this study, we have evaluated the expression of molecules of the HGF/c-met pathway in pituitary adenomas (PA). The expression of HGF, c-met, PI3K (p85αsubunit) pAkt, STAT3, and pSTAT3 was analyzed by immunohistochemistry in an archival series of 30 PA (12 non-functioning and 18 functioning; 25 macroadenomas and 5 microadenomas). PAs expressed all six proteins in tumor epithelial cells. The proportion of c-met(+ve) cells was greater than HGF(+ve) cells (49 ± 19 vs 34 ± 17 %, P < 0.01), the pAkt(+ve) cells greater than PI3K(+ve) cells (39 ± 16.0 vs 1.3 ± 0.5 %, P < 0.001), and the STAT3(+ve) cells greater than active pSTAT3(+ve) cells (14 ± 8 vs 7 ± 6 %, P < 0.01). Furthermore, endothelial Akt immunostaining was detected on the vascular surface area of 17 PAs, in macroadenomas more frequently than in microadenomas (82 vs 18 %). The percentage of immunostained endothelial cells was greater in macro than in microadenomas (19 ± 7 and 7 ± 3 %; P < 0.05). In conclusion, HGF and c-met are widely expressed in PA, and correlate with pAkt expression. These data, together with the finding of pAkt immunostaining on microvascular areas related to tumor size, suggest a major role of the pAKT signaling in tumor growth and angiogenesis. There might be practical implications for the targeted therapy of PA.

Background: Pituitary adenomas are usually well-differentiated tumors but may show locally aggressive behavior., Aim: To investigate the relationship between proliferation and apoptosis parameters and tumor recurrence in a series of 20 radically resected pituitary macroadenomas (11 functioning, 9 non-functioning)., Materials and Methods: Proliferative activity and DNA ploidy were analyzed by flow cytometry (FCM) on fresh surgical specimens. Immunohistochemistry for Ki-67/MIB-1 and for the anti-apoptotic protein Bcl-2 was performed on paraffin-embedded specimens from the same tumors. Tumor regrowth was evaluated by magnetic resonance imaging (MRI)., Results: Six adenomas recurred after surgery, regardless of hormonal hypersecretion. Pre-surgical tumor size was significantly higher in recurrent than in non-recurrent adenomas (p=0.003). Pre-surgical MRI demonstrated cavernous sinus (CS) invasiveness in all recurrent tumors, while none of the non-invasive adenomas recurred (p=0.042, by Fisher's exact test). The DNA content was aneuploid in 5/20 adenomas, one of which recurred. Cell percentages in the S (%SPF) and G2+M (%G2-M) phases and proliferative index (PI) (PI=%SPF+%G2-M) were significantly higher in aneuploid than in diploid adenomas (p<0.05), but no significant differences concerning all FCM parameters were observed between recurrent and non-recurrent adenomas. Similarly, MIB-1 did not show a significant difference of expression between recurrent and non-recurrent adenomas (p=0.33). Bcl-2 immunoreactivity was detected in 12/15 pituitary adenomas, involving 63±35% of tumor cells, regardless of tumor recurrence., Conclusions: In this group of radically resected pituitary macroadenomas, neuroradiological finding of CS invasiveness--but not FCM parameters nor MIB-1 and Bcl-2 expression--is useful for predicting tumor recurrence.

Objective: Upon binding with HGF, the thyrosine-kinase receptor c-met induces cell growth, scattering and morphogenic effects via the trasducers STAT3 and phosphorylated-STAT3, PI3K/Akt, Rho. HGF, c-met and STAT3 are expressed with very high frequency in papillary thyroid carcinomas (PTC), suggesting a role in PTC. Herein we first investigate the simultaneous expression of HGF, c-met, STAT3, phosphor-STAT3, PI3K, Akt and Rho in thyroid nodules., Design and Methods: Using immunohistochemistry, we studied: 30 colloid nodules (CN), 18 hyperplastic nodules (HN), 20 follicular adenomas (FA), 15 oncocytic adenomas (OA), 20 PTC, 16 follicular carcinomas (FTC) and 6 anaplastic carcinomas (ATC)., Results: All 7 proteins were expressed in 15% of FA (with HGF, PI3K and Rho stromal reactivity) and 25% of PTC, and the combination HGF/c-met/STAT3/ pSTAT3/PI3K was expressed by all PTC, each protein being expressed by tumor cells. In contrast, 13/16 FTC (81%) exhibited immunoreactivity for PI3K (both epithelial and stromal), and 100% of ATC was PI3K+ (both epithelial and stromal) and Rho+ (epithelial). Epithelial expression of PI3K correlated with the clinical behavior of histotypes and, within FTC, the proportion of PI3K+ cells correlated with both the clinical and pathological stage (r=0.95; p<0.001). As for the shared epithelial expression of PI3K, this concerned approximately one-fourth of tumor cells in FTC and ATC vs one-thirtieth in PTC., Conclusions: Our data may have practical implications for the targeted medical therapy of thyroid cancer arising from the follicular epithelium.

Temozolomide (TMZ) is an alkylating chemotherapeutic agent that has recently been used in some cases as a new therapeutic tool for pituitary carcinomas and aggressive pituitary adenomas. In this report, we present the case of effective TMZ treatment in a 42-year-old man with ACTH-secreting carcinoma. The tumor grew progressively over 4 years, from 2.2 to 31.1 cm³, despite three surgical approaches and γ-knife treatment. Ki-67 increased from 2 to 18%. An intradural metastasis at the foramen magnum was detected by MRI after the third operation. Thereafter, four cycles of 5-day TMZ administration (200 mg/m²/day during the first, and 150 mg/m²/day during the following cycles) induced dramatic tumor size reduction (>90%). Clinical conditions improved progressively and, after 17 months from the beginning of TMZ administration, the patient is still alive. The treatment was well tolerated except for a transient thrombocytopenia (grade 4 WHO).

Human galectin-3 (hgal-3) is a beta-galactoside binding protein involved in a number of physiological and pathological processes. Increasing hgal-3 immunoexpression has been reported in several human tumors, including thyroid carcinomas, but not in benign thyroid lesions. We analyzed the immunolocalization of hgal-3 in cell compartments of benign and malignant thyroid lesions. Hgal-3 immunoperoxidase reaction was carried out on 133 thyroid tissue samples obtained from 113 patients; 20 of these were normal (NT), 85 were benign thyroid lesions [20 colloid nodules (CN), 21 nodular hyperplasias (NH), 7 focal lymphocytic thyroiditis (FLT), 15 Hashimoto's thyroiditis (HT), 22 follicular adenomas (FA)], 25 differentiated carcinomas [15 papillary carcinomas (PC), 6 follicular carcinomas (FC) and 4 Hürthle cell carcinomas (HC)] and 3 anaplastic carcinomas (AC). Among the malignant thyroid lesions, hgal-3 was detected in 12/15 (80%) PC, 3/4 (75%) HC and in 4/6 (66.6%) FC, but in none of the 3 AC. Conversely, hgal-3 immunoexpression was absent in NT and in all benign thyroid lesions, but 1/15 HT and 10/22 (45.4%) FA. In the latter, hgal-3 was mostly expressed in microfollicular areas and in five of the six atypical FA. Hgal-3 cytoplasmic-perinuclear immunolocalization was observed in the majority of thyroid carcinomas and in more than half of the FA, theoretically suggesting an involvement of this protein in thyroid tumorigenesis throughout an antiapoptotic activity. Moreover, hgal-3 expression in FA might anticipate the likelihood of evolution of these benign lesions towards malignancy.

By immunohistochemistry, we have investigated the expression of hepatocyte growth factor (HGF), HGF-R or c-met and the transcritor factor STAT3 in a series of 80 colorectal tumours (40 adenomas and 40 adenocarcinomas). The expression of HGF, c-met and STAT3 was revealed in 40/40 (100%) of adenomas and in 26/40 (65%) of adenocarcinomas; the remaining 14/40 (35%) carcinomas expressed c-met but failed to express HGF and STAT3. Positive immunoreaction score was defined through the number of stained cells: low (1-10%), moderate (11-50%) and high (>51%). In adenomas, the HGF immunoreaction was high in 33 (82.5%) and moderate in 7 (17.5%); the c-met staining was high in 3 (7.5%) and moderate in 37 (92.5%); and the STAT3 reactivity was high in 25 (62.5%) and moderate in 15(37.5%). In carcinomas, the HGF immunoreaction was moderate in 21 (80.7%) and low in 5 (19.2%); the c-met staining was high in 14 (35%), moderate in 25 (62.5) and low in 1 (2.5%); and the STAT3 reactivity was moderate in 17 (65.3%) and low in 9 (34.6%). In both type of lesions, HGF and c-met showed a membranous and cytoplasmic location. In adenomas, STAT3 was detected in cytoplasm and nucleus and in carcinomas it was limited to cytoplasm. While the HGF/c-met/STAT3 expression in adenomas was significantly different from carcinomas (c2 = 17, p < 0.0001), no correlation was found among HGF, c-met, or STAT3 immunostaining with histotype or degree of dysplasia in adenomas and the same for histotype, grading or staging in carcinomas. These features, suggesting a role of the HGF/c-met/STAT3 signal in colon tumorigenesis, indicate that a reduced expression of HGF and c-met is associated to progression of adenoma into carcinoma.

Objective: Since Cushing's disease due to large pituitary tumors is rare, we evaluated biochemical characteristics at entry and the results of first surgical approach and of adjuvant therapeutic strategies during a long-term follow-up period., Design: We studied 26 patients (nine male, 17 female; 42.5+/-12.7 years, mean+/-s.e.) with ACTH-secreting pituitary macroadenoma (tumor diameter: 11-40 mm)., Methods: At entry, plasma ACTH, serum cortisol and 24-h urinary free cortisol (UFC) levels were measured in all patients, a high-dose dexamethasone (dexa) suppression test was evaluated in 22 cases and a corticotrophin releasing hormone (CRH) test in 20 cases. Patients were re-evaluated after operation and, when not cured, they underwent second surgery, radiotherapy and/or ketoconazole treatment. The follow-up period was 78+/-10 months., Results: Before surgery, dexa decreased ACTH (>50% of baseline) in only 14/22 patients. The CRH-stimulated ACTH/cortisol response was normal in six patients, impaired in six patients and exaggerated in eight patients. After operation eight patients were cured, nine had normalized cortisol levels and nine were not cured. Pre-surgery, mean ACTH values were significantly higher in the not cured patients than in those normalized (P<0.05) and cured (P<0.01); the ACTH response to CRH was impaired in only six patients of the not cured group. The tumour diameter was significantly less in cured patients (P<0.02) and in normalized patients (P<0.05) than in the not cured ones. Magnetic resonance imaging (MRI) showed invasion of the cavernous sinus in 2/9 normalized, and in 6/9 not cured patients. After surgery, ACTH, cortisol and UFC were significantly lower than at entry in cured and in normalized patients, but not in not cured patients. In the cured group, the disease recurred in one patient who was unsuccessfully treated with ketoconazole. In the normalized group, a relapse occurred in eight patients: radiotherapy and ketoconazole induced cortisol normalization in one case, hypoadrenalism in one case and were ineffective in another one, while five patients were lost at follow-up. In the not cured group, eight patients underwent second surgery, radiotherapy and/or ketoconazole, while one patient was lost at follow-up. These therapies induced cortisol normalization in two patients and hypoadrenalism in one., Conclusions: (i) A sub-set of patients with ACTH-secreting pituitary macroadenoma showed low sensitivity to high doses of dexamethasone and to CRH, (ii) pituitary surgery cured Cushing's disease in a minority of patients, (iii) high baseline ACTH levels, impaired ACTH response to CRH, increased tumor size or invasion of the cavernous sinus were unfavourable prognostic factors for surgical therapy, and (iv) second surgery, radiotherapy and/or ketaconazole cured or normalized hypercortisolism in half of the patients with recurrence or not cured.

Objective: Pituitary adenomas rarely occur in childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. In this study we evaluated the symptoms at onset and the long-term consequences induced in teenagers by functioning or nonfunctioning pituitary adenomas., Design and Patients: Clinical, biochemical and neuroradiological data of 44 young patients (12 males and 32 females, aged 16.3 +/- 1.9 years at diagnosis) with pituitary adenomas were evaluated retrospectively at baseline and after therapy. Patients underwent surgery, radiotherapy and/or medical treatment depending on clinical history and endocrine secretion of the tumour. Follow-up ranged from 8 to 252 months (median 55 months)., Measurements: Baseline and dynamic pituitary function were evaluated in all cases at diagnosis and after treatments. Magnetic resonance imaging (MRI) or computed tomography (CT) scan were performed before therapy and during follow-up. Hormone levels were measured using commercial radioimmunologic or immunoradiometric methods., Results: Pituitary macroadenomas (group 1) or microadenomas (group 2) were found in 61% and 39% of cases, respectively. Overall, 68% were PRL-secreting, 7% GH-secreting, 5% ACTH-secreting and 20% nonfunctioning. The most frequent symptoms at onset were oligoamenorrhoea (62%) and galactorrhoea (59%) in the girls, and headache (58%) in the boys. Pubertal development was delayed in 12/27 (44%) cases with macroadenoma. Growth failure was observed in 4/44 (9%) patients (3 in group 1 and 1 in group 2). At diagnosis, hypopituitarism was detected in 10/27 (37%) patients with macroadenoma. Surgery alone cured 4/18 (22%) and 4/9 (44%) patients in group 1 and group 2, respectively. Adjuvant therapies (second surgery and/or radiotherapy and/or medical treatment) cured the disease in 2/13 (15%) patients with macroadenoma and allowed a persistent normalization in other 4/13 (31%) and 2/4 (50%) cases in group 1 and group 2, respectively. Medical treatment alone cured 2/9 (22%) patients with PRL-secreting macroadenoma and normalized PRL levels in another six (66%) with macroprolactinoma and in 2/7 (28%) patients with microprolactinoma., Conclusion: Delay of growth was rarely observed in teenagers with pituitary adenomas. At the onset of the disease, many girls complained of oligoamenorrhoea and galactorrhoea, while headache and delay of pubertal development were the symptoms more frequently referred by boys. Surgery alone was effective in a minority of patients and adjuvant therapies were helpful to obtain the remission of the disease in many cases. In patients with PRL-secreting pituitary adenoma, medical treatment, both as first choice or as adjuvant therapy, normalizes serum PRL levels in 14/27 (52%) cases.

Hepatocyte growth factor (HGF), HGF receptor (c-met) and the interleukin 6 (IL-6) are expressed in thyroid nodules. In extra-thyroidal tissues, the HGF/c-met and IL-6/IL-6 receptor (IL-6R) systems activate STAT3, a member of the signal transducers and activators of transcription (STATs) family. To evaluate whether either system utilizes STAT3 in thyroid nodules, we examined the immunohistochemical expression of HGF, c-met, IL-6, IL-6R, STAT3 in 6 normal thyroids and in 68 thyroid nodules. STAT3 expression was observed in 12/12 (100%) papillary thyroid carcinomas (PTC) but in none of the follicular tumors. Among benign thyroid nodules, only 2/10 (20%) follicular adenomas (FA) were STAT3+. All these 14 STAT3+ cases expressed both HGF and c-met, but only 5 PTC co-expressed IL-6 and IL-6R and the 2 FA were IL-6+ but IL-6R-. The remaining 8 FA were all HGF/c-met-, but IL-6+; of these 8, only 2 were also IL-6R+. In conclusion, in thyroid nodules STAT3 is expressed only in PTC and a number of FA. Since these cases are consistently HGF+/c-met+ and only one-third of them co-express IL-6/IL-6R, STAT3 expression correlates with the HGF/c-met expression, not with the IL-6/IL-6R expression. The 100% rate of expression of the HGF/c-met/STAT3 signaling in PTC could be relevant for the establishment of the papillary phenotype. Because of the communeness of a HGF/c-met/STAT3 pattern between all PTC and a subset of FA, we speculate that a fraction of FA may progress to PTC.

The aim of this study was to verify whether treatment with slow-release lanreotide (SRL) before surgery is useful in the management of patients with GH-secreting pituitary macroadenoma. Twenty untreated acromegalics were enrolled randomly in two groups. Ten patients (group 1: 2 males and 8 females aged 44.5 +/- 4.3 years) underwent surgery via transsphenoidal access. Only one of them was cured by surgery, whereas the other nine were treated with SRL. In the other ten patients (group 2: 3 males and 7 females aged 43.2 +/- 12.3 years), transsphenoidal surgery followed SRL treatment. Surgery induced the normalization of GH and IGF-1 levels in four group 2 patients - three of them had shown an evident shrinkage of the tumor after SRL treatment. After surgery, group 1 showed a significant decrease of mean IGF-1 (580 +/- 63 vs. 789 +/- 64 ng/ml, p < 0.02), but not of GH values (26.1 +/- 9.8 vs. 44.8 +/- 19.3 ng/ml, NS); the cured patient was excluded from the following evaluations. Group 2 showed an evident, but not significant, decrease of both GH and IGF-1 values compared to values measured at the end of medical treatment (GH: 22.4 +/- 9.7 vs. 7.7 +/- 4.7 ng/ml, NS. IGF-1: 570 +/- 69 vs. 402 +/- 58 ng/ml, NS). Gonadal, thyroid and adrenal impairment was evident in six, four and no patients in group 1 and in three, two and one patients in group 2, respectively. SRL 30 mg was administered every 14 days for three months and then every 10 days until the 6th month. Before SRL treatment, mean GH and IGF-1 levels did not differ significantly in group 1 vs. group 2 (GH: 29.3 +/- 10.5 vs. 43.4 +/- 22.0 ng/ml; IGF-1: 633 +/- 38 vs. 778 +/- 83 ng/ml). In group 1, a significant decrease of serum GH, but not of IGF-1 levels, was achieved at the end of 1st trimester of SRL (GH: 17.6 +/- 5.4 ng/ml, p < 0.05. IGF-1: 540 +/- 48 ng/ml, NS), whereas a significant decrease in both GH and IGF-1 values was evident during the 2nd trimester (GH: 6.1 +/- 3.0 ng/ml, p < 0.05. IGF-1: 433 +/- 74 ng/ml, p < 0.02). Serum GH levels, measured during the 2nd trimester of SRL therapy, were also significantly lower than levels measured at the end of the 1st trimester (p < 0.05). Group 2 serum GH and IGF-1 levels were not significantly decreased at the end of the 1st trimester (GH: 27.2 +/- 12.1 ng/ml, NS. IGF-1: 698 +/- 74 ng/ml, NS), whereas only serum IGF-1 (570 +/- 69 ng/ml, p < 0.05) was significantly reduced during the 2nd trimester of SRL (GH: 22.4 +/- 9.7 ng/ml, NS). Serum GH and IGF-I fell in the normal range in 4 patients in group 1 and one in group 2 at the end of the second trimester of SRL therapy. Independently of the trial applied, the mean clinical score level ameliorated significantly in both groups (group 1: p < 0.0005; group 2: p < 0.0001). In both groups, the proportion of patients complaining of headache and tissue swelling and the score level of headache, tissue swelling and excessive sweating decreased significantly. In group 1 the score level of fatigue and arthralgia also decreased significantly. In conclusion, this study proves that in patients with GH-secreting pituitary macroadenoma: (i) surgery followed by SRL induces a better clinical and biochemical status than SRL alone; (ii) SRL treatment before surgery ameliorates the clinical and biochemical outcome and reduces the prevalence of hypopituitarism due to surgery.

In this open sequential study we evaluated the long-term effectiveness and tolerability of the i.m. administration of slow release lanreotide 30 mg (SRL) in 18 acromegalics (7 M/11 F, age 50.9+/-12.7 yr). Baseline mean GH and IGF-1 levels were 15.8+/-6.6 ng/ml and 702+/-74 ng/ml, respectively. Four hours, 1, 7, and 14 days after SRL, mean GH levels were 8.9+/-5.9 (p < 0.005), 11.4+/-6.9 (p < 0.05), 9.1+/-4.5 (p < 0.05), and 9.1+/-4.1 ng/ml (p < 0.05), respectively; and the IGF-1 values at 1, 7, and 14 days were 624+/-77 (p < 0.05), 555+/-83 (p < 0.001), and 467+/-58 ng/ml (p < 0.0001), respectively. Four hours after SRL administration GH was < 2.5 ng/ml in 11 patients and decreased 85% of the basal value, without normalizing, in another case. In the following 2 weeks, 7 and 2 patients maintained GH < 2.5 ng/ ml or < 50% of baseline; 3 and 2 of them attained IGF-1 values in the normal range or < 50% of basal levels. A patient developed acute pancreatitis after the injection of the drug and therefore stopped the treatment. Another patient did not continue SRL, and she was turned on octreotide, s.c. administered (OCT), because only the latter treatment ameliorated significantly the headache. In 16/18 patients the treatment was continued until the 24th month. SRL was administered every 14 days until the 24th month in 3 cases, whereas in 13 patients the dose schedule was increased every 10 days since the 7th month because they did not normalize serum GH and IGF-1 levels. In these 16 patients baseline GH and IGF-1 levels were 10.0+/-2.5 ng/ml and 671+/-75 ng/ml, respectively. At the 1st, 3rd, and 6th month of treatment mean GH levels fell to 5.4+/-1.4 (p < 0.05), 5.3+/-1.8 (p < 0.05), and 5.0+/-1.6 (p < 0.05) ng/ml, respectively; and IGF-1 declined to 511+/-87 (p < 0.005), 565+/-85 (p < 0.05), and 525+/-94 (p < 0.01) ng/ml, respectively. Throughout the first semester GH was < 2.5 ng/ml in 5 patients and decreased > 50% in another three. IGF-1 levels normalized in 3/5. Throughout the following 18 months of treatment, mean GH (3.4+/-1.0 ng/ml) and IGF-1 (413+/-75 ng/ml) values decreased significantly in comparison with both the baseline concentrations (GH p < 0.01, IGF-1 p < 0.001) and the levels measured during the 1st semester of treatment (GH p < 0.05, IGF-1 p < 0.001). GH remained < 2.5 ng/ml in 11 patients, and in 8/11 cases IGF-1 fell in the normal range. Serum GH and IGF-1 levels decreased by more than 50% of baseline levels in 2 other cases. At MRI, pituitary adenoma was no longer evident in one patient previously treated with OCT and significantly decreased in another patient previously treated with surgery plus radiotherapy, as well as in a patient previously untreated. During treatment the percentage of patients complaining of headache and fatigue decreased significantly (chi2, p < 0.05 and p < 0.0005, respectively). Overall, the headache (p < 0.005), arthralgia (p < 0.05), and paresthesia (p < 0.01) ameliorated significantly. Ultrasound scan showed gallbladder sludge or sand-like stones in 5/11 patients. This study, which is one of the longest surveys on a relatively large series of acromegalics treated with SRL, confirms the long-term effectiveness of this drug for the treatment of patients with active acromegaly. SRL decreases significantly GH and IGF-1 in most cases and induces the shrinkage of the pituitary tumor in some patients previously either untreated or both treated for acromegaly. SRL improves significantly clinical symptoms and it is well tolerated.

The simultaneous occurrence of multiple adenomas in the pituitary gland is a rare event. We report the coexistence of three non functioning pituitary microadenomas in a 37-year-old woman, referred to us for oligomenorrhea and headache. Biochemical evaluation revealed prolactin (131 U/liters), follicle-stimulating hormone (4.1 U/liters), luteinizing hormone (3.9 U/liters), 17beta-estradiol (74 pg/mL), free (2.0 pg/mL) and total testosterone (0.5 ng/mL), dehydroepiandrosterone-sulfate (3.5 microg/mL), 17OH-progesterone (0.8 ng/mL), cortisol (13.1 microg/dL), free triiodothyronine (4.8 pmol/L), free thyroxine (18.5 pmol/liters), thyrotropin (1.6 mU/L), and growth hormone (0.2 ng/mL) levels in the normal range, as for as the response to dynamic endocrine tests. MRI showed an enlarged sella turcica, occupied by three distinct hypointense areas that measured less than 5 mm in diameter in the left, medium and right side of the pituitary, respectively. This finding was confirmed 6 months later by a second MRI that revealed also a light increase in microadenomas dimensions. The patient, therefore, underwent neurosurgery by transfenoidal approach. Histologic examination showed no morphologic differences between the specimens obtained from the different microadenomas. Immunohistochemistry evaluation revealed a positive staining for the common alpha-subunit of glycoproteic hormones and negative for the other pituitary hormones tested, while electron microscopy showed cells with a poor secretory apparatus and a variable grade of cell differentiation. In conclusion, we report the fifth case described with multiple pituitary adenomas diagnosed in vivo and the first with three coexisting tumors revealed by MRI before neurosurgery. The occurrence of multiple pituitary tumors emphasizes the role of pituitary and extrahypophiseal factors in the clonal expansion of genetically altered cells.

Cabergoline decreases both serum PRL levels and size of prolactinomas, including some tumors resistant to other dopamine-agonists. It is common observation that the shrinkage of the adenoma is preceded by suppression of PRL levels. A minority of patients, who do not show a significant decrease of PRL after a short trial with dopamine-agonists, undergoes neurosurgery or radiotherapy. We report on the case of a 14-year-old girl with a huge prolactinoma who showed, during cabergoline treatment (0.5 mg twice a week), a significant shrinkage of the pituitary mass but no decrease of the very high PRL values. She was referred to us after partial removal of the suprasellar extension of the pituitary tumor. The post-surgical evaluation showed very high PRL levels (9352 microg/l; 20941 microg/l before surgery), which did not decrease during the 2-year treatment with cabergoline (nadir value: 8735 microg/l). However, one month after the beginning of therapy, MRI showed a significant shrinkage of the tumor (tumor volume 5.7 ml, compared with 45.1 ml prior to surgery and 24.4 ml after surgery). Subsequently MRIs demonstrated a progressive reduction of the size with a complete disappearance of the suprasellar and parasellar tissue (tumor volume 1.8, 0.9 and 0.2 ml, at 3, 6 and 12 months, respectively). The MRI performed at the 24th month showed a secondary empty sella, with residual tumor tissue in the right sphenoidal sinus. Increasing cabergoline, up to 3 mg a week, failed to induce any decrease of PRL levels. In conclusion, in such macroprolactinomas the shrinkage of tumor is not strictly correlated with (or it is partially dissociated from) the inhibition of PRL hypersecretion. The choice of other therapeutic options in cabergoline-resistant macroprolactinomas needs careful neuroradiological evaluation after a short trial of pharmacological treatment.

The simultaneous occurrence of a pituitary adenoma and an intracranial meningioma is a rare event. We report the coexistence of an eosinophilic pituitary adenoma and a endotheliomatous meningioma, in the sellar region, and evaluate their endocrine, neuro-radiological and immunohistochemical pattern. A 47-year-old woman affected by acromegaly was referred to us. Serum GH level was 82 ng/ml and remained unresponsive to both OGTT (75 g per os) and iv. GHRH 1-29 (100 micrograms); IGF-1 was 807 ng/ml. Eight hours after acute sc administration of octreotide (100 micrograms) GH returned to normal levels (2.3 ng/ml). CT scan showed a large intra- and suprasellar mass involving the right cavernous sinus, with a retrosellar extension along the tentorium. A slight and inhomogeneous enhancement, with a periferal rim of bright signal was apparent at MRI. Conversely, the retrosellar component showed a bright homogeneous enhancement. The patient, therefore, underwent neurosurgery. Histological examination revealed the coexistence of 2 types of tissue: areas of endotheliomatous meningioma were interspersed among sheets of acidophilic adenoma tissue. Immunohistochemical analysis was performed in order to determine the relationship between the two masses: a positive staining for GH was shown in the areas of adenoma, as against for GHRH, neither in the adenomatous tissue nor in the slices of meningioma. Although MRI showed a latero-sellar post-surgical residual of meningioma, serum GH value was < 1 ng/ml. In conclusion, the relationship between the GH-secreting adenoma and the meningioma is unclear; however the GH-hypersecretion is not induced by a hypothetic GHRH-activity from the meningioma.

A 35-year-old woman with an otherwise normal heart had been suffering from recurrent paroxysmal supraventricular tachycardia during the past 3 years. Serum thyroid function tests were repeatedly normal. When a thyroid nodule became evident, a toxic adenoma was diagnosed. Serum total hormone values were normal, but a few hours after the last recurrence of paroxysmal supraventricular tachycardia, total T3, free T3 and free T4 became clearly elevated. At that time hemorrhagic necrosis of the adenoma, though localized only at the periphery of the tumor, heavily impaired nodule overactivity, as judged by the disappearance of paroxysmal supraventricular tachycardia, by normal free thyroid hormone levels and by the return of a normal TSH response to TRH.

Computer-assisted perimetry (CP) is a new method which quantifies the differential light sensitivity threshold and allows the statistical analysis of the data. It offers advantages as compared with manual methods. This study has been carried out in 27 patients with pituitary adenomas (four males and 23 females; 13 with prolactinomas; six with acromegaly, four with Cushing's disease and four with non-secreting adenomas). A skull X-ray and a computed tomodensitometry (CT), a manual Goldman perimeter and a computer assisted visual field examination were performed in all cases. The presence of a pituitary tumour was suggested by the X-ray and by the CT in 12 and 23 patients respectively out of the 27: the CT scan revealed a suprasellar extension in seven cases. Visual field defects were detected by means of the Goldman perimeter in six patients and by means of the computer-assisted technique in 25/27. The effectiveness of this new technique was proved by the concordance with the CT scan results in 21 cases and by the histological examination of the four adenomas which were not apparent at CT scan. A significant difference was found for both eyes (right eye, chi squared = 258, P less than 0.001; left eye, chi squared = 295.0, P less than 0.001) between patients and controls. No correlation existed between visual defects and the pituitary size apparent at CT scan. Six patients were evaluated with the CT and CP after 1 year of bromocriptine treatment; a slight reduction of size was documented with the CT in four cases, whereas a significant positive change in visual acuity was observed in five patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Context Aryl hydrocarbon receptor ( AHR) pathway has a key role in cellular detoxification mechanisms and seems implicated in tumorigenesis. Moreover, polymorphisms and mutations of AHR gene have been associated with several human and animal tumours. Although AHR has been found differently expressed in pituitary adenomas, AHR gene mutation status has never been investigated in acromegalic patients. Design In this study, we evaluated patients with apparently sporadic GH-secreting pituitary adenoma for AHR gene variants. Patients and Methods Seventy patients with sporadic GH-secreting pituitary adenoma (M = 27, age 59·1 ± 1·6 years) and 157 sex- and age-matched controls were enrolled in the study. In all patients and controls, the exons 1, 2, 3, 5 and 10 of AHR gene were evaluated for nucleotide variants by sequencing analysis. Results The rs2066853 polymorphism was identified in the exon 10 of 18/70 acromegalic patients and 9/157 healthy subjects (25·7 vs. 5·7%, χ2 = 18·98 P < 0·0001), in homozygosis in one patient and in heterozygosis in the other 17 and in the 9 healthy subjects. Moreover, a heterozygous rs4986826 variant in exon 10 was identified in a patient with heterozygous rs2066853 polymorphism, and in the patient with homozygous rs2066853 variant. This second polymorphism was not detected in the control group. Patients with rs2066853 polymorphism showed increased IGF-1 ULN ( P < 0·05) and prevalence of cavernous sinus invasion ( P = 0·05), thyroid ( P = 0·02), bladder ( P = 0·0001) or lymphohematopoietic ( P < 0·05) tumours. Conclusions AHR gene rs2066853 polymorphism is significantly more frequent in acromegalic patients than in healthy subjects and is associated with increased disease aggressivity. Moreover, the rs4986826 variant was detected in few patients with rs2066853 polymorphism, but its role is to be cleared. [ABSTRACT FROM AUTHOR]