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Objectives: 68 Ga‐DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR‐expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68 Ga‐DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68 Ga‐DOTATOC PET in the most common PitNET, ie non‐functioning (NF)‐PitNET. Design/Patients: NF‐PitNET patients (n = 9) and controls (n = 13) were examined preoperatively with 68 Ga‐DOTATOC PET for 45 min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co‐registered using PMOD software. The maximum standard uptake value (SUVmax) was analyzed in manually outlined regions of interest (ROI) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression. Results: Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4‐8.5] vs 14.1 [12.5‐15.9]; P <.01]. In ROC analysis, the area under the curve was 0.87 (P <.01) for SUVmax, with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF‐PitNETs were of gonadotroph (n = 7) and corticotroph (n = 2) origin. SSTR expression was high for SSTR3, low‐to‐moderate for SSTR2, and low for SSTR1 and SSTR5. Conclusions: This proof‐of‐concept study shows that 68Ga‐DOTATOC PET can be used to differentiate between normal pituitary tissue and NF‐PitNET. [ABSTRACT FROM AUTHOR]

Summary: Background: Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin‐releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushing's disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin. Methods: We retrospectively analysed 91 patients with Cushing's syndrome who had either negative findings on pituitary dynamic enhanced magnetic resonance imaging (MRI) or nonsuppressed high‐dose dexamethasone suppression tests (HDDST). Thin‐slice thoracoabdominal computed tomography (CT) and octreotide receptor imaging of whole body were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through IPSS with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients. Results: Diagnosis of CD. Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery. Conclusions: IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH. [ABSTRACT FROM AUTHOR]

Familial Isolated Pituitary Adenomas (FIPA), an autosomal dominant disease with low penetrance is being increasingly recognized. FIPA families can be divided into two distinct groups based on genetic and phenotypic features. Patients with mutations in the aryl hydrocarbon receptor-interacting protein ( AIP) gene are characterized by young-onset somatotroph or lactotroph macroadenomas, while in the other, larger group of FIPA patients with typically adult-onset disease and more varied adenoma types, no causative gene(s) has been identified. Young-onset macroadenoma patients can also be identified with germline AIP mutation without an apparent family history. Further data and longer follow-up are necessary to establish formal guidelines, but the current data suggest genetic screening of the AIP gene in patients with a pituitary adenoma and no other associated features who have (i) a family history of pituitary adenoma, (ii) childhood-onset pituitary adenoma or (iii) a pituitary somatotroph or lactotroph macroadenoma diagnosed before the age of 30 years. [ABSTRACT FROM AUTHOR]

Objective Craniopharyngioma (CP) is a benign tumour of the suprasellar region that is associated with increased morbidity and mortality in comparison with other causes of hypopituitarism. We aimed to establish the rate and causes of mortality and morbidity in patients with CP who attended our centre. Design We performed a retrospective case note audit of patients with CP who were managed by our service. We established the standardized mortality ratio (SMR) for patients with CP. We compared obesity prevalence with two other hypopituitary groups who are managed by our service. Patients We identified 70 patients with CP, 97% of whom had undergone surgery and 42% radiotherapy. We compared the prevalence of obesity with that of 89 patients with hypopituitarism secondary to surgery for nonfunctioning pituitary adenoma and 29 patients with post-traumatic hypopituitarism (PTHP). Measurements Standardized mortality ratio for patients with CP was 8·75 (95% CI of 5·4-13·3); SMR for women was 10·51 (95% CI 5·04-19·3) and 7·55 (95% CI 3·77-13·52) for men. The rates of growth hormone (GH), gonadotrophin, adrenocorticotrophic hormone (ACTH) and TSH deficiencies were 91%, 93·5%, 92% and 86%, respectively. The rate of diabetes insipidus (DI) was 81%; 7·1% had adipsic DI. Dyslipidaemia was present in 46·9% and diabetes mellitus in 11·5%. Obesity affected 66% of patients with CP, 47% of patients with nonfunctioning adenoma and 31% of those with PTHP ( P < 0·001). Conclusions Patients with CP suffer from high rates of mortality and morbidity. The underlying causes for mortality and for obesity in this population remain poorly understood. [ABSTRACT FROM AUTHOR]

Context Recent case reports detail the successful use of temozolomide in the management of aggressive pituitary tumours. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that counteracts the effect of temozolomide. Objective To study MGMT expression in pituitary tumours and consider whether MGMT expression is associated with response to temozolomide therapy in aggressive pituitary tumours. Patients We report two patients with aggressive pituitary tumours treated with temozolomide, one who responded to temozolomide and the other who did not. MGMT expression was assessed in a further 88 archived pituitary tumour samples. Design MGMT expression was assessed by immunohistochemistry. MGMT promoter methylation was studied by methylation-specific polymerase chain reaction (MSP), sequencing of MGMT was performed and loss of heterozygosity (LOH) analysis undertaken. Results Low MGMT expression and MGMT promoter methylation were found in the pituitary tumour of the patient who responded to temozolomide. Conversely, high MGMT expression was seen in the patient demonstrating a poor response to temozolomide. Eleven out of 88 archived tumour samples (13%) had low MGMT expression. Prolactinomas were more likely to have low MGMT expression compared with other pituitary tumour subtypes ( P < 0·001). There was no significant difference in MGMT expression between invasive and noninvasive tumours, or between recurrent and nonrecurrent tumours. A significant inverse correlation was found between MGMT expression and promoter methylation ( P = 0·012). Conclusion MGMT expression as assessed by immunohistochemistry may predict response to temozolomide therapy in patients with aggressive pituitary tumours. MGMT promoter methylation is likely to explain low MGMT expression in some, but not all, pituitary tumours. [ABSTRACT FROM AUTHOR]

Objective BRAF is an oncogene that is commonly mutated in both melanomas and papillary thyroid carcinomas, usually at position V600E that leads to constitutive activity in the Ras–mitogen-activated protein kinase (MAPK) pathway. We speculated that this same gene may be either mutated at this site, or overexpressed, in pituitary adenomas. Design and measurements We sequenced 37 pituitary adenomas for a mutation at the V600E position. In addition, we investigated B-Raf mRNA expression in normal pituitary ( n = 5) and nonfunctioning pituitary adenomas (NFPA) ( n = 6) by semiquantitative PCR, and in a further 27 pituitary adenomas of various types and 10 normal pituitaries using real-time quantitative PCR. Finally, we explored B-Raf protein expression in 10 normal pituitaries and 12 NFPAs. Results No sequence mutations for the substitution V600E were identified. B-Raf mRNA was overexpressed in pituitary adenomas compared to normal pituitary, and this was entirely due to overexpression in NFPAs. NFPAs also showed very variable expression of B-Raf protein, but those tumours showing highest levels of B-Raf mRNA expressed the most B-Raf protein. Conclusions Mutations previously seen in the majority of melanomas and a substantial minority of papillary thyroid carcinomas are not a frequent finding in pituitary adenomas. However, overexpression of B-Raf mRNA and protein may be a feature of NFPAs, highlighting overactivity of the Ras-B-Raf-MAP kinase pathway in these tumours. [ABSTRACT FROM AUTHOR]

Objective Most studies on the diagnostic value of serum thyroglobulin (Tg) concentrations in differentiated thyroid carcinoma (DTC) use fixed cut-off levels in heterogeneous groups of patients with respect to initial therapy and do not provide prognostic data. The objective was to investigate the prognostic values of serum Tg for disease-free remission and death, measured at fixed time-points after initial therapy using receiver operator characteristic (ROC) curve analyses. Design Single-centre observational study with 366 consecutive patients with DTC, who had all been treated according to the same protocol for initial therapy and follow-up. Methods Tg concentrations were measured at five fixed time-points after initial surgery. Tg cut-off values with the highest accuracy were calculated with ROC analyses. Results During the 8·3 ± 4·6 years of follow-up, 84% of the patients were cured. Pre-ablative Tg levels were an independent prognostic indicator for disease-free remission (Tg cut-off value 27·5 µg/l, positive predictive value 98%). The highest diagnostic accuracies of serum Tg for tumour presence were found during TSH-stimulated Tg measurements, 6 months after initial therapy (Tg cut-off value 10 µg/l; sensitivity 100%, specificity 93%). DTC-related mortality was 14%. TSH-stimulated Tg levels before ablation and 6 months after initial therapy were independent prognostic indicators for death. Conclusion Optimal institutional Tg cut-off levels for diagnosis and prognosis should be defined using ROC analyses for each condition and time-point. Tg measurements 6 months after initial therapy during TSH stimulation had an excellent diagnostic value. Tg levels are independent prognostic indicators for disease-free remission and death. Using this strategy, high-risk patient groups can be selected based on Tg levels, in addition to conventionally used prognostic indicators. [ABSTRACT FROM AUTHOR]

Objective It has been reported that both normal pituitary and pituitary tumours express PPAR-γ, a nuclear hormone receptor, the expression being more abundant in pituitary tumours, and that this is the basis for the reported antiproliferative effects of the thiazolidinedione, rosiglitazone, in animal models. However, the mechanisms for the responsivity to rosiglitazone have remained unclear. Design and measurements To investigate this further, 'real-time' PCR was used to assess PPAR-γ mRNA expression, and Western blotting and immunohistochemistry to study its protein expression, in 46 human pituitary tumours and normal pituitary tissue. Cell proliferation of the GH3 pituitary cell line was assessed by [³H]-thymidine-incorporation after 48 h rosiglitazone and pioglitazone (10-4M-10-10 M) treatment alone, or rosiglitazone in combination with the PPAR-γ antagonist GW9662. Results PPAR-γ mRNA and protein was found to be expressed in normal pituitary and was variably expressed in pituitary tumours, but were increased specifically in nonfunctioning pituitary adenomas. However, very little staining was observed with immunohistochemistry, with only occasional cell nuclei stained, and no difference was detectable between controls and tumours. Rosiglitazone at 10-4M and 10-5 M concentrations inhibited cell proliferation (10-4 M 14.0%±1.5% and 10-5 M 67%±4% [mean ± SEM] vs Control 100±3%, P < 0.0001) while lower concentrations showed no significant effect. Following withdrawal of rosiglitazone 10-5 M, the cells fully recovered at a further 48 h, while lower doses showed a 'rebound' of stimulation. Pioglitazone was of similar potency to rosiglitazone in inhibiting proliferation. The PPAR-γ antagonist did not show a significant reversal of the antiproliferative effect of rosiglitazone, and indeed suppressed proliferation on its own. Conclusions Our data suggest that the antiproliferative action of rosiglitazone is probably not via PPAR-γ. [ABSTRACT FROM AUTHOR]

Double pituitary adenomas are extremely rare. They can be divided into contiguous and clearly separated types. Most contiguous tumours are surgically removed as one tumour and the co-existence of different adenoma types can be confirmed by histological methods. In contrast, detailed preoperative neuroimaging studies can suggest the co-existence of separated multiple adenomas. In patients with multiple adenomas, surgical failure may result when one adenoma is missed during surgery. Among 600 surgical cases we encountered four patients with clearly separated double pituitary adenomas; all were highly suspect on preoperative MRI studies. All four patients manifested acromegalic symptoms; one patient also exhibited hyperprolactinemia and two had familial pituitary adenomas unrelated to multiple endocrine neoplasia type I (MEN-1). All underwent transsphenoidal surgery and histology confirmed the diagnosis of GH-producing plus gonadotroph adenoma in two cases and of two GH-producing adenomas each in the other two patients. Although the pathogenesis of our double adenomas remains unknown, genetic abnormalities may be involved because two patients had familial pituitary adenomas unrelated to MEN-1. When preoperative MRI is suggestive of double adenomas, careful surgical exploration is necessary to avoid missing the other adenoma because the risk of surgical failure is high, especially in patients with functioning adenomas. [ABSTRACT FROM AUTHOR]

The pathogenetic mechanisms underlying pituitary tumorigenesis are largely unknown. Previous reports have suggested that aggressive pituitary adenomas and/or carcinomas may be associated with genetic alterations that are distinct from those responsible for the more common and less aggressive pituitary adenomas. Here, we describe the clonal composition of a pituitary carcinoma, its recurrence and its metastasis. The samples studied were from a 48-year-old woman who presented with recurrent Cushing's syndrome. During the 8-year course of her disease, she had an ACTH-producing pituitary carcinoma requiring two transsphenoidal procedures and resection of a metastatic cervical lymph node. Her disease remained active despite surgical resection, external beam irradiation and medical treatment with ketoconazole. Ultimately, bilateral adrenalectomy was performed to control the hypercortisolism. Morphological and immunohistochemical studies revealed that the primary and recurrent pituitary tumours and the metastatic lesion were an endocrine tumour with ACTH and growth hormone immunoreactivity. Primary, recurrent and metastatic tumour DNAs were analysed for X-chromosome inactivation and loss of heterozygosity (LOH) at several microsatellite loci on chromosomes 9,10, 11, 13 and 22. All three lesions were monoclonal in composition as suggested by the pattern of X chromosome inactivation of the PGK-1 allele. Moreover, the primary, recurrent and metastatic lesions demonstrated LOH at the microsatellite allelic markers PYGM and D10S217. In contrast, however, the metastatic lesion showed a loss-to-retention pattern at two distinct loci (IFNA and D22S156) compared to the primary and recurrent pituitary tumours. These findings, while consistent with a clonal composition of the primary and metastatic pituitary lesions, show each clone to be distinct. This is the first description of a metastatic pituitary carcinoma with a distinct clonal composition from its primary source. [ABSTRACT FROM AUTHOR]