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INTRODUCTION The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long-term post-alloHCT survivors. METHODS Three-hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels. RESULTS Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty-five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6-13.1); P

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

BACKGROUND Patient decision aids (P‐DAs) inform medical decision making, but longer term effects are unknown. This article describes extended follow‐up from a thyroid cancer treatment P‐DA trial. METHODS In this single‐center, parallel‐design randomized controlled trial conducted at a Canadian tertiary/quaternary care center, early‐stage thyroid cancer patients from a P‐DA trial were contacted 15 to 23 months after randomization/radioactive iodine (RAI) decision making to evaluate longer term outcomes. It was previously reported that the use of the computerized P‐DA in thyroid cancer patients considering postsurgical RAI treatment significantly improved medical knowledge in comparison with usual care alone. The P‐DA and control groups were compared for the following outcomes: feeling informed about the RAI treatment choice, decision satisfaction, decision regret, cancer‐related worry, and physician trust. In a subgroup of 20 participants, in‐depth interviews were conducted for a qualitative analysis. RESULTS Ninety‐five percent (70 of 74) of the original population enrolled in follow‐up at a mean of 17.1 months after randomization. P‐DA users perceived themselves to be significantly more 1) informed about the treatment choice (P = .008), 2) aware of options (P = .009), 3) knowledgeable about treatment benefits (P = .020), and 4) knowledgeable about treatment risks/side effects (P = .001) in comparison with controls. There were no significant group differences in decision satisfaction (P = .142), decision regret (P = .199), cancer‐related worry (P = .645), mood (P = .211), or physician trust (P = .764). In the qualitative analysis, the P‐DA was perceived to have increased patient knowledge and confidence in decision making. CONCLUSIONS The P‐DA improved cancer survivors’ actual and long‐term perceived medical knowledge with no adverse effects. More research on the long‐term outcomes of P‐DA use is needed. Cancer 2015;121:3717–3726. © 2015 American Cancer Society., In this extended follow‐up study of a randomized controlled trial of a thyroid cancer treatment patient decision aid, patient decision aid users perceive themselves to be significantly more informed about the choice of radioactive iodine treatment, although their decision satisfaction and regret are not significantly different from those of controls not exposed to the patient decision aid. Patient decision aid utilization has no significant negative impact on cancer‐related worry, mood, or trust in the treating physician in long‐term follow‐up.

Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel–Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P

Summary Background Acromegaly results from increased growth hormone and its target insulin-like growth factor-1, most commonly due to a pituitary tumour. As it is frequently accompanied by infertility, little is known about the course of this disease in pregnancy. Objective We describe 13 new pregnancies in acromegalic women and compare their outcomes in a systematic review of the literature. Methods We collected clinical, biochemical, imaging, and outcomes data during and following pregnancy and performed a systematic review for a total of 47 pregnancies. An extended analysis of 106 pregnancies was also performed. Results In 13 newly described cases, pregnancy was un-complicated without need for additional surgical intervention. In these pregnancies, adjunctive medical therapy was required in three patients. This was in the form of somatostatin analogs (SA) (3/13) as well as pegvisomant in 1/13 to control symptomatic and biochemical progression. One 37-year-old female succeeded in having two separate pregnancies 2 years apart both without need for any form of medical therapy. Review of an additional 34 published reports allowed for an analysis of outcomes in 47 pregnancies. Adjunctive medical therapy during pregnancy was required in 15 of these cases where 12 received SA and an additional three received dopamine agonists. None of these patients developed endocrine or neurologic complications during pregnancy. In an extended analysis of 106 pregnancies, treatment during pregnancy appears to be associated with good disease control but increased risk of microsomic or macrosomic newborns depending on the medical agent used. Conclusions In 13 newly described pregnancies along with systematic review of an additional 34 cases indicate that pregnancy in treated acromegalic women can proceed without significant complications or teratogenicity. Medical treatment during pregnancy with DA or SA appears to be associated with altered neonatal weight. Nevertheless, gestation may have a beneficial impact on acromegaly control both during and following pregnancy.

In patients with early stage papillary thyroid carcinoma (PTC) who have had a thyroidectomy, the decision must be made to accept or reject radioactive iodine remnant ablation (RRA). Counselling patients about this decision can be challenging, given the medical evidence uncertainties and the complexity of related information. Although physicians are the primary source of medical information for patients considering RRA, some patients have a desire for supplemental information from sources such as the internet. Yet, thyroid cancer resources on the internet are of variable quality, and some may not be applicable to the individual case. We have developed a computerized educational tool [called a decision aid (DA)], directed to patients with early stage papillary thyroid cancer, and intended as an adjunct to physician counselling, to relay evidence-based medical information on disease prognosis and the choice to accept or reject RRA. DAs are tools used to inform patients about available treatment options and have been utilized in oncologic decision-making. We tested our web-based DA in fifty patients with early stage PTC and found that it improved medical knowledge. Furthermore, participants found the technical usability of the tool acceptable. We are currently conducting a randomized controlled trial comparing the use of the DA plus usual care to usual care alone to confirm the educational benefit of the website and examine its impact on the decision-making process. In the future, DAs may play an expanded role as an adjunct to physician counselling in the care of patients with thyroid cancer.

Summary Objective For patients with acromegaly who are suboptimally controlled on long-acting octreotide (LAR), treatment options are to switch to pegvisomant monotherapy (PM) or add pegvisomant to LAR (P-LAR). Our objective was to evaluate if the safety and efficacy of these regimens differ. Design This was an open-label, multicentre, randomized, 40-week outpatient study. The control arm consisted of patients controlled on LAR (n = 28). Patients A total of 27 patients with suboptimally controlled acromegaly [as indicated by a serum IGF-I level ≥ 1·3 × upper limit of normal (ULN) of the age-related reference range] were randomized to PM (10 mg once daily initially, then adjusted in 5-mg increments every 8 weeks based on IGF-I levels) and 29 to P-LAR (LAR dosing remained fixed). Measurements The primary end-point was adverse events (AEs). The secondary end-point was biochemical IGF-I-based efficacy. The RIA for IGF-I was discontinued by the manufacturer during the study and a chemiluminescent assay was subsequently used. Previously obtained IGF-I levels were re-analysed. Results PM and P-LAR were well tolerated and there were no differences in the number of AEs. Patients receiving P-LAR tended to be more likely to have clinically significant increases in hepatic transaminase levels, especially those receiving high-dose LAR. Normalization of IGF-I was similar with both regimens (56% and 62% of patients for PM and P-LAR respectively). The change in IGF-I assay resulted in lower rates of IGF-I normalization than expected. Reductions in fasting glucose levels were greater with PM than with P-LAR (−0·8 mmol/l; 95% confidence interval −1·16, −0·53 mmol/l). Conclusions In patients suboptimally controlled on LAR, PM and P-LAR were equally well tolerated and effective in normalizing IGF-I, and overall clinical improvement was observed with both regimens. Thus, pegvisomant monotherapy and adjunctive therapy are equally viable options for the treatment of LAR-resistant acromegaly.

Gene array studies indicated that osteopontin (OPN) mRNA is highly expressed in adrenocortical carcinomas (ACCs). OPN enhances invasiveness, proliferation, and metastasis formation, and is associated with poor survival in some malignant diseases. Integrin alphavbeta3 has been shown to mediate OPN effects on invasion. In this study, we demonstrated OPN and integrin alphavbeta3 expression in normal adrenal glands and benign adenomas, with staining seen exclusively in adrenocortical cells as well as even stronger staining in ACC. Western blot analysis confirmed overexpression of OPN in ACC (p0.01). With Matrigel invasion assays, we have shown that OPN greatly stimulates the invasiveness of NCI-h295 cells (six-fold increase, p0.001). Transfection with integrin alphavbeta3 further increased invasiveness after OPN stimulation (p0.001). This increase was reversed by the addition of an anti-integrin beta3 antibody, indicating a functional relationship of OPN and integrin alphavbeta3 in ACC. With tissue arrays, we confirmed high OPN expression in 147 ACC samples. However, no association with survival was seen in Kaplan-Meier analysis including 111 patients with primary tumours graded for OPN staining and follow-up data available. In conclusion, our in vitro data indicate that OPN and integrin alphavbeta3 may act as a functional complex facilitating the invasiveness of adrenocortical tumours. This relationship remains of relevance to our understanding of carcinogenesis, but further studies are needed to address the physiological and pathological function of OPN in adrenal tissue.

Background For women with differentiated thyroid carcinoma (DTC), the effect of radioactive iodine (RAI) therapy on gonadal and reproductive function is an important consideration. Objective and methods We systematically reviewed controlled studies examining the gonadal and reproductive effects of RAI therapy in women and adolescents surviving DTC. We searched nine electronic databases. All abstracts and papers were independently reviewed by two reviewers. Results After reviewing 349 unique citations and 61 full-text papers, 16 papers including data from 3023 women or adolescents with DTC were included. All studies were observational, with no long-term randomized control trial data. The age at first RAI treatment varied from 8 to 50 years and the cumulative activities of RAI administered for treatment varied from 30 to 1099 mCi. Transient absence of menstrual periods occurred in 8-27% of women within the first year after RAI, particularly in older women. In addition, RAI-treated women experienced menopause at a slightly younger age than women not treated with RAI. In the first year after RAI therapy, several studies reported increased rates of spontaneous and induced abortions. However, RAI treatment for DTC was generally not associated with a significantly increased risk of long-term infertility, miscarriage, induced abortions, stillbirths, or offspring neonatal mortality or congenital defects. Conclusions In female survivors of DTC, there is little observational evidence to suggest important adverse effects of RAI treatment on gonadal function, fertility or pregnancy outcomes beyond 12 months, with the exception of a possible slightly earlier age of menopause.

Numerous factors have been shown to govern adenohypophysial cell proliferation. Human and animal models have documented that the hypothalamic trophic hormone growth hormone-releasing hormone stimulates cell proliferation, and prolonged stimulation leads to tumor formation. Similarly, lack of dopaminergic inhibition of lactotrophs and lack of feedback suppression by adrenal, gonadal or thyroid hormones are implicated, perhaps through hypothalamic stimulatory mechanisms, in pituitary adenoma formation superimposed on hyperplasia. However, most pituitary tumors are not associated with underlying hyperplasia. Overexpression of growth factors and their receptors, such as EGF, TGFalpha, EGF-R and VEGF has been identified in pituitary adenomas, and reduction of follistatin expression has been implicated in gonadotroph adenomas. Aberrant expression of members of the FGF family, an FGF antisense gene and FGF receptors have all been described in pituitary adenomas. The clonal composition of pituitary adenomas attests to the molecular basis of pituitary tumorigenesis, however, the evidence suggests that these various hypophysiotropic hormones and growth factors likely play a role as promoters of tumor cell growth in genetically transformed cells.

Disruption of the gene for the cyclin dependent kinase inhibitor (CDKI) p27/kip1 results in pituitary corticotroph hyperplasia while diminished expression of this protein has been described in aggressive human pituitary tumors. We have previously shown that 1,25‐vitamin D(3) (VD) hypophosphorylates p27 and interferes with the degradation of this CDKI in thyroid carcinoma cells. In this study we investigated whether VD/EB1089 can induce p27 accumulation and cause growth arrest of pituitary corticotroph cells. VD and EB1089 exhibited a significant reduction in AtT20 corticotroph but not PRL235 Iactotroph cell growth. These changes were accompanied by selective accumulation of p27 in AtT20 but not in PRL235 cells. As p27 levels are highly dependent on protein degradation, we examined the effect of VD/EB1089 on p27 association with factors that target this CDKI to the proteasome. VD/EB1089 significantly restricted the association of p27 with Skp2 as well as with cyclin dependent kinase 2 (CDK2). As the tumor suppressor and phosphatase PTEN has been implicated in p27 regulation, we tested whether the effects of VD/EB1089 on p27 accumulation in corticotrophs could be mediated through this pathway. VD/EB1089 did not appreciably alter PTEN expression. Moreover, transfection of PTEN did not influence the effect of VD on p27 accumulation in corticotrophs. We conclude that VD/EB1089 can selectively arrest pituitary corticotroph growth and induce p27 accumulation. This effect is mediated at least partially through diminished p27 association with Skp2 and with CDK2. In contrast to other cell systems, PTEN does not participate in the regulation of corticotroph p27 and is not involved in mediating the effect of VD on p27 in these cells. Our findings highlight p27 and VD analogs as targets for manipulation and drug development respectively in the treatment of inoperable corticotroph adenomas.

Summary objective Age-related decline in IGF-I and gonadal hormones have been postulated to play an important role in the pathogenesis of age-related bone loss in men. In this cross-sectional study, the relation between serum IGF-I and gonadal hormones with bone mineral density (BMD) was examined in community-dwelling men. design and subjects Serum IGF-I, testosterone and BMD were examined in 61 community-dwelling men over the age of 27, who were randomly selected from the Calgary cohort of 1000 subjects in the Canadian Multicentre Osteoporosis Study. In the present study, IGF-I, serum testosterone, SHBG, free androgen index (FAI), parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D] and other markers of bone turnover were measured. BMD was measured at the spine and hip (HOLOGIC 4500). Simple linear regression was used to assess the linear relation between IGF-I, testosterone, BMD and other biochemical markers of bone metabolism and potential confounding variables and subsequent multivariate regression models were constructed separately for each BMD measurement to assess the importance of IGF-I and testosterone in the presence of potential confounding variables. results Serum IGF-I, FAI and SHBG significantly decreased as a function of age, whereas serum levels of PTH increased. Only 25(OH)D, total testosterone and FAI were positively associated with serum IGF-I after adjusting for age and BMI. Multiple linear regression models revealed that IGF-I was a significant predictor of BMD at the total hip, femoral neck and femoral trochanter neck (P ≤ 0·001). In contrast, the FAI was a significant predictor of BMD at the lumbar spine and wards area (P ≤ 0·011), and SHBG was a significant predictor at the total hip and femoral trochanter (P ≤ 0·045). conclusion These data support the hypothesis that the age-related decline in bone mass in men is associated with declining levels of IGF-I and testosterone.

OBJECTIVE Fatigue is a prominent symptom among patients with GH excess and acromegaly. Identifying the physiological basis of such complaints and obtaining objective measures to quantify their severity remains an ongoing challenge. We investigated whether submaximal measures of aerobic performance can be used to assess GH excess-associated fatigue objectively. DESIGN AND PATIENTS To investigate this possibility we examined the relation between physical function and physical capacity in 12 patients with active acromegaly and persistent fatigue before and after 3 and 6 months of treatment with the long-acting somatostatin analogue octreotide (LAR(R)). MEASUREMENTS Heart rate (HR) and rating of perceived exertion (RPE using Borg's 10-point scale) were measured during a 160-metre self-paced walk test (SPW). Maximum oxygen uptake (VO2max) and ventilation threshold (VeT: a measure of work rate when breathlessness develops) were measured during a progressive treadmill test to fatigue or symptom-limited maximum. The Profile Of Mood States questionnaire (POMS) was used to quantify subjective feelings of fatigue and vigour. Morning fasting levels of GH and IGF-I were measured using immunoassay of serum samples. RESULTS SPW speed at a fast pace of 1.69 +/- 0.18 m/s was achieved with higher than normal HR (112 +/- 15/min; normal = 102) and RPE (2.4 +/- 1.2). Similar to GH-deficient adults, VO2max (22.6 +/- 6.4 ml.kg-1.min-1; normal approximately 30 ml.kg-1.min-1) and VeT (13.1 +/- 2.9 ml.kg-1.min-1; predicted normal approximately 16 ml.kg-1(min-1) were low. However, VeT occurred at a normal fraction of VO2max (VeT/VO2max = 0.58). VeT was significantly increased and plasma IGF-I levels reduced following 3 and 6 months of octreotide LAR(R) treatment. Reduction in circulating IGF-I levels was correlated with improvement in reported vigour (r = 0.85) and VeT (r = 0.65) (P < 0.05). CONCLUSIONS Our findings demonstrate impairment in physical function and physical capacity consistent with the perception of increased fatigue among acromegalic patients. These objective measures of compromised physical function are similar to the changes that we have reported previously in adults with GH deficiency. Taken together, these data suggest that a narrow window for GH/IGF-I levels is required to maintain optimal physical function.

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.

Bronchial endocrine neoplasms causing acromegaly due to ectopic production of growth hormone (GH)-releasing hormone (GHRH) have been reported. We describe the case of a 39-year-old man with clinical and biochemical acromegaly. Magnetic resonance imaging revealed an enlarged pituitary, which was confirmed histologically to harbour somatotroph hyperplasia. Further investigations identified a circumscribed central mass in the right lung which was surgically resected and histologically confirmed to be an endocrine tumour with strong immunopositivity for GHRH, synaptophysin and chromogranin; the lesion also exhibited mild positivity for peptide YY, calcitonin gene-related peptide (CGRP), glucagon-like peptide (GLP)-1, corticotrophin-releasing hormone (CRH), tyrosine hydroxylase, vasoactive intestinal peptide (VIP) and enkephalin. S100 protein was identified in stellate cells surrounding nests of epithelial tumour cells. The MIB-1 antibody labelled about 10% of the tumour cells. We established that the tumour not only produced GHRH but the GHRH-receptor (GHRH-R) as well. GHRH and GHRH-R mRNA were identified and the latter was characterized as two variants, a full-length transcript and a truncated splice variant that has been described in human pituitary somatotroph adenomas. We suggest that GHRH expression by this tumour and the presence of its receptor may be responsible for enhanced growth. The expression of a truncated splice variant that is unable to transduce GHRH signalling may be implicated in the less aggressive behaviour of well-differentiated endocrine tumours that produce GHRH compared with small-cell lung carcinomas that are very responsive to GHRH growth stimulation.

OBJECTIVE Amplification and overexpression of the erbB-2 proto-oncogene in human carcinomas may have prognostic significance. Its role in thyroid carcinoma is controversial. We investigated human thyroid tumours for erbB-2 gene amplification, activating mutations in the transmembrane domain, quantitative mRNA expression and protein expression. MATERIALS AND METHODS DNA and mRNA were extracted from 47 morphologically characterized, frozen thyroid tumours including 10 nodular hyperplasias, 3 follicular carcinomas and 34 papillary carcinomas (4 with tall-cell features, 2 with insular and 2 with anaplastic de-differentiation). DNA amplification was analysed by differential PCR. The transmembrane domain of erbB-2 was sequenced in all tumours for activating mutations in position 659. Levels of mRNA expression were determined by competitive mRNA RT–PCR. Immunohistochemistry (IHC) for erbB-2 protein expression in corresponding paraffin-embedded samples was evaluated. RESULTS Our results showed no DNA amplification of erbB-2. Sequencing of the transmembrane domain of erbB-2 revealed no activating mutations. The level of mRNA expression was variable, 11 papillary carcinomas showing statistically significant elevated mRNA levels compared with corresponding normal thyroid tissue; however, this did not correlate with other indicators of poor prognosis. In contrast to elevated mRNA levels in tumours, the level of protein staining correlated with degree of differentiation, normal and hyperplastic tissue being strongly positive and poorly differentiated tumours negative. CONCLUSION There are no mutations or amplifications of the erbB-2 gene in human thyroid tumours. Elevated erbB-2 mRNA expression in some thyroid tumours is not associated with clinical features of poor prognosis; however, the significance of the elevated mRNA levels is unclear, as it did not result in protein overexpression. Instead, cytoplasmic erbB-2 protein detection by IHC correlates with differentiation of human thyroid tumours and may be a feature of good prognosis.

OBJECTIVEThe aetiology of most pituitary tumours remains unknown. We have examined the potential role of the neu receptor proto-oncogene in human pituitary tumorigenesis. MATERIALS AND METHODSTen non-tumorous pituitary glands and 16 morphologically characterized functional and clinically non-functioning pituitary adenomas were studied. Protein expression was examined by immunohistochemistry, mRNA expression by RT-PCR and competitive PCR, gene amplification by differential PCR, and point mutations by DNA sequencing. RESULTSCytoplasmic positivity for neu was identified in a few scattered cells of the non-tumorous adenohypophysis using an antibody to the intracytoplasmic domain of neu, but no membrane staining was found with an antibody to the extracellular domain; the latter is said to reflect gene amplification. mRNA transcript signals of the expected size were identified in the normal adenohypophysis and in all 16 adenomas examined. No increase in the degree of mRNA expression, however, was noted in the different tumour types compared to normal human pituitary tissue as determined by competitive PCR. As neu can be activated to an oncogene by a point mutation in the transmembrane region, nucleotide substitutions in this domain were investigated. Direct sequencing of codon 659 revealed no point mutations in any of the tumours. Furthermore, since amplification of neu has been noted in various human malignancies, DNA from these tumours was examined by differential PCR. No detectable differences were noted between the neu gene and the single-copy reference gene IFN-γ. CONCLUSIONThe neu gene is expressed in adenohypophysial cells and their tumours. In pituitary adenomas, this expression is not associated with gene amplification or activating mutations to suggest a direct role in pituitary tumorigenesis.

Background. Acromegaly is usually the result of a pituitary growth hormone (GH)-cell adenoma or is more rarely due to ectopic secretion of GH-releasing hormone (GHRH). The authors previously described a more unusual form of acromegaly secondary to ectopic GH synthesis by a pancreatic islet cell tumor. Methods. One year after tumor resection and transient disease remission, multiple abdominal metastases were identified with accompanying elevated levels of circulating GH and insulin-like growth factor-1 (IGF-1). Serial 24-hour GH sampling was performed before and after intravenous GHRH or thyrotropin releasing hormone (TRH) administration during treatment with bromocriptine; treatment with the somatostatin (SRIF) analogue octreotide; or no treatment. RNA from abdominal tumor tissue was extracted and subjected to Northern gel electrophoresis and GH hybridization analysis. Results. Neither GHRH nor TRH resulted in stimulation of the elevated GH levels. Bromocriptine and octreotide did not suppress GH secretion but attenuated the thyroid stimulating hormone (TSH) response to TRH administration. Octreotide (as much as 1500 μg/d) was clinically, biochemically, and radiographically ineffective. GH-secreting abdominal tumor tissue expressed a 0.9-kb mRNA transcript consistent with the size of authentic human GH mRNA. Conclusion. The natural history and ectopic nature of a GH-producing pancreatic carcinoma has been documented, with biochemical remission occurring after initial tumor resection, with autonomous GH hypersecretion after tumor recurrence, and with RNA analysis demonstrating ectopic activation of GH gene transcription. Cancer 1993; 71:66-70.