A consensus on the diagnosis and treatment of acromegaly complications

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed

Aspects of Black Hole Quantum Mechanics and Thermodynamics in 2+1 Dimensions

We discuss the quantum mechanics and thermodynamics of the (2+1)-dimensional black hole, using both minisuperspace methods and exact results from Chern-Simons theory. In particular, we evaluate the first quantum correction to the black hole entropy. We show that the dynamical variables of the black hole arise from the possibility of a deficit angle at the (Euclidean) horizon, and briefly speculate as to how they may provide a basis for a statistical picture of black hole thermodynamics.Comment: 20 pages and 2 figures, LaTeX, IASSNS-HEP-94/34 and UCD-94-1

Hamiltonian thermodynamics of two-dimensional vacuum dilatonic black holes

We consider the Hamiltonian dynamics and thermodynamics of the two-dimensional vacuum dilatonic black hole in the presence of a timelike boundary with a fixed value of the dilaton field. A~canonical transformation, previously developed by Varadarajan and Lau, allows a reduction of the classical dynamics into an unconstrained Hamiltonian system with one canonical pair of degrees of freedom. The reduced theory is quantized, and a partition function of a canonical ensemble is obtained as the trace of the analytically continued time evolution operator. The partition function exists for any values of the dilaton field and the temperature at the boundary, and the heat capacity is always positive. For temperatures higher than $\beta_c^{-1} = \hbar\lambda/(2\pi)$, the partition function is dominated by a classical black hole solution, and the dominant contribution to the entropy is the two-dimensional Bekenstein-Hawking entropy. For temperatures lower than~$\beta_c^{-1}$, the partition function remains well-behaved and the heat capacity is positive in the asymptotically flat space limit, in contrast to the corresponding limit in four-dimensional spherically symmetric Einstein gravity; however, in this limit, the partition function is not dominated by a classical black hole solution.Comment: 20 pages, REVTEX. Added a discussion on the boundary action and boundary terms in Sec. IIIA. Minor changes in Acknowledgements and Reference

Reduced phase space formalism for spherically symmetric geometry with a massive dust shell

We perform a Hamiltonian reduction of spherically symmetric Einstein gravity with a thin dust shell of positive rest mass. Three spatial topologies are considered: Euclidean (R^3), Kruskal (S^2 x R), and the spatial topology of a diametrically identified Kruskal (RP^3 - {a point at infinity}). For the Kruskal and RP^3 topologies the reduced phase space is four-dimensional, with one canonical pair associated with the shell and the other with the geometry; the latter pair disappears if one prescribes the value of the Schwarzschild mass at an asymptopia or at a throat. For the Euclidean topology the reduced phase space is necessarily two-dimensional, with only the canonical pair associated with the shell surviving. A time-reparametrization on a two-dimensional phase space is introduced and used to bring the shell Hamiltonians to a simpler (and known) form associated with the proper time of the shell. An alternative reparametrization yields a square-root Hamiltonian that generalizes the Hamiltonian of a test shell in Minkowski space with respect to Minkowski time. Quantization is briefly discussed. The discrete mass spectrum that characterizes natural minisuperspace quantizations of vacuum wormholes and RP^3-geons appears to persist as the geometrical part of the mass spectrum when the additional matter degree of freedom is added.Comment: 36 pages, REVTeX v3.1 with amsfonts. (References updated; minor typos corrected.

Consensus on criteria for acromegaly diagnosis and remission

Purpose: The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy. Methods: Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes. Results: In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I &gt; 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches. Conclusion: Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease.</p

Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1).

OBJECTIVE: The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple endocrine neoplasia type 1 (MEN1). PARTICIPANTS: The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. PROCESS: Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. CONCLUSIONS: MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develop carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, and lipomas. Patients with MEN1 have a decreased life expectancy, and the outcomes of current treatments, which are generally similar to those for the respective tumors occurring in non-MEN1 patients, are not as successful because of multiple tumors, which may be larger, more aggressive, and resistant to treatment, and the concurrence of metastases. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection and undertaking treatment specific for MEN1 tumors. Thus, it is recommended that MEN1 patients and their families should be cared for by multidisciplinary teams comprising relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors

Hamiltonian thermodynamics of the Reissner-Nordstr\"om-anti-de Sitter black hole

We consider the Hamiltonian dynamics and thermodynamics of spherically symmetric Einstein-Maxwell spacetimes with a negative cosmological constant. We impose boundary conditions that enforce every classical solution to be an exterior region of a Reissner-Nordstr\"om-anti-de Sitter black hole with a nondegenerate Killing horizon, with the spacelike hypersurfaces extending from the horizon bifurcation two-sphere to the asymptotically anti-de Sitter infinity. The constraints are simplified by a canonical transformation, which generalizes that given by Kucha\v{r} in the spherically symmetric vacuum Einstein theory, and the theory is reduced to its true dynamical degrees of freedom. After quantization, the grand partition function of a thermodynamical grand canonical ensemble is obtained by analytically continuing the Lorentzian time evolution operator to imaginary time and taking the trace. A~similar analysis under slightly modified boundary conditions leads to the partition function of a thermodynamical canonical ensemble. The thermodynamics in each ensemble is analyzed, and the conditions that the (grand) partition function be dominated by a classical Euclidean black hole solution are found. When these conditions are satisfied, we recover in particular the Bekenstein-Hawking entropy. The limit of a vanishing cosmological constant is briefly discussed. (This paper is dedicated to Karel Kucha\v{r} on the occasion of his sixtieth birthday.)Comment: 34 pages, REVTeX v3.0. (Minor corrections and presentational revisions; added references.

Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients.

Context:In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown.Objective:The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement.Design and Setting:This was a prospective observational study in the setting of US clinical practices.Patients and Outcome Measures:AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates.Results:After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects.Conclusions:In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation

Background: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. Methods: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. Results: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. Conclusion: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money

Meta-Analysis on the Effects of Octreotide on Tumor Mass in Acromegaly

<div><h3>Background</h3><p>The long-acting somatostatin analogue octreotide is used either as an adjuvant or primary therapy to lower growth hormone (GH) levels in patients with acromegaly and may also induce pituitary tumor shrinkage.</p> <h3>Objective</h3><p>We performed a meta-analysis to accurately assess the effect of octreotide on pituitary tumor shrinkage.</p> <h3>Data Sources</h3><p>A computerized Medline and Embase search was undertaken to identify potentially eligible studies.</p> <h3>Study Eligibility Criteria</h3><p>Eligibility criteria included treatment with octreotide, availability of numerical metrics on tumor shrinkage and clear definition of a clinically relevant reduction in tumor size. Primary endpoints included the proportion of patients with tumor shrinkage and mean percentage reduction in tumor volume.</p> <h3>Data Extraction and Analysis</h3><p>The electronic search identified 2202 articles. Of these, 41 studies fulfilling the eligibility criteria were selected for data extraction and analysis. In total, 1685 patients were included, ranging from 6 to 189 patients per trial. For the analysis of the effect of octreotide on pituitary tumor shrinkage a random effect model was used to account for differences in both effect size and sampling error.</p> <h3>Results</h3><p>Octreotide was shown to induce tumor shrinkage in 53.0% [95% CI: 45.0%–61.0%] of treated patients. In patients treated with the LAR formulation of octreotide, this increased to 66.0%, [95% CI: 57.0%–74.0%). In the nine studies in which tumor shrinkage was quantified, the overall weighted mean percentage reduction in tumor size was 37.4% [95% CI: 22.4%–52.4%], rising to 50.6% [95% CI: 42.7%–58.4%] with octreotide LAR.</p> <h3>Limitations</h3><p>Most trials examined were open-label and had no control group.</p> <h3>Conclusions</h3><p>Octreotide LAR induces clinically relevant tumor shrinkage in more than half of patients with acromegaly.</p> </div