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.
A Consensus on Criteria for Cure of Acromegaly Giustina, A; Chanson, P; Bronstein, M. D ...
The Journal of clinical endocrinology and metabolism,
2010-July, Letnik:
95, Številka:
7
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Objective: The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000.
Participants: Participants included 74 neurosurgeons and ...endocrinologists with extensive experience of treating acromegaly.
Evidence/Consensus Process: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated.
Conclusions: Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.
The definition for disease control in acromegaly is updated, with improved flexibility and GH cut-off limits to reflect the availability of ultrasensitive GH assays.
Objective: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing’s syndrome, because there is no recent consensus on ...the management of this rare disorder.
Participants: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing’s syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing’s disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing’s disease, and 5) management of ectopic ACTH syndrome, Nelson’s syndrome, and special patient populations.
Evidence: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking.
Consensus Process: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority.
Conclusions: ACTH-dependent Cushing’s syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing’s syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing’s disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing’s syndrome, early diagnosis and prompt therapy are warranted.
Pituitary tumor-transforming gene (PTTG), the index mammalian securin, is abundantly expressed in several tumors and regulates tumor growth and progression. Molecular mechanisms elucidating PTTG ...regulation and actions remain elusive. Here, we provide evidence that PTTG acts as a signal transducer and activator of transcription factor 3 (STAT3) target gene. Total STAT3 and Tyr705 phosphorylated STAT3 were concordantly expressed with PTTG in human colorectal tumors (n=97 and n=95, respectively, P<0.001). STAT3 specifically bound the human PTTG promoter and induced PTTG transcriptional activity (twofold) as assessed by chromatin immunoprecipitation and luciferase reporter assays. STAT3 transfection increased PTTG mRNA and protein abundance twofold in HCT116 human colon cancer cells, and induction was further enhanced (threefold) by constitutively active STAT3 (STAT3-C), whereas strongly abrogated by dominant-negative STAT3 (STAT3-DN). Attenuating PTTG expression by siRNA in STAT3 HCT116 stable transfectants suppressed cell growth and colony formation in vitro, and PTTG cell knockout also constrained activated STAT3-induced explanted murine tumor growth in vivo. STAT3 increased HCT116 cell migration and invasion up to fivefold, whereas cell mobility was abolished by STAT3-DN (>85%). Impairing PTTG expression by siRNA also strongly suppressed STAT3-faciliated cell migration and invasion by up to 90%. Knocking out PTTG in STAT3-C HCT116 stable transfectants strongly decreased tumor metastases in nude mice, indicating the requirement of PTTG for STAT3-promoted metastasis. These results elucidate a mechanism for tumor cell PTTG regulation, whereby STAT3 induces PTTG expression to facilitate tumor growth and metastasis, and further support the rationale for targeting PTTG to abrogate colorectal cancer growth.
Objective: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management.
Participants: The meeting participants comprised 68 pituitary specialists, ...including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly.
Evidence/Consensus Process: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence.
Conclusions: The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.
Guidelines for acromegaly management were developed with critical literature evaluation by a global consensus workshop.
Context:
Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected ...octreotide and maintaining its biological activity.
Objectives:
The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection.
Design:
Four single-dose studies were conducted in 75 healthy volunteers.
Intervention:
Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 μg octreotide were administered.
Main Outcome Measure:
We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion.
Results:
Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h×ng/ml); and median time ≥0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively.
Conclusions:
The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.
Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for ...lifelong management. We performed a comprehensive literature review of the past 12 years (1998–2010) to determine the benefit of disease control (defined as a growth hormone GH concentration <2.5 μg/l and insulin-like growth factor IGF-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease.
Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) ...therapy for preventing growth of postsurgical pituitary tumor remnants.
The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up.
Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment.
Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001.Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (P<0.001). About 42% of patients in the control group required additional surgery or radiotherapy, compared with 38 and 13% subjects in the RT and PT groups, respectively (P=0.002). Outcome measures were not related to NFPA D2R abundance.
Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.
Context: There is currently no medical therapy for Cushing’s disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the ...management of this disorder.
Objective: Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing’s disease.
Design: We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study.
Patients: Thirty-nine patients with either de novo Cushing’s disease who were candidates for pituitary surgery or with persistent or recurrent Cushing’s disease after surgery without having received prior pituitary irradiation.
Intervention: Patients self-administered sc pasireotide 600 μg twice daily for 15 d.
Main Outcome Measure: Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure.
Results: Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders.
Conclusions: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing’s disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.
Results from this phase II study show pasireotide to be a promising pituitary-directed medical therapy for patients with Cushing’s disease.
Pituitary tumor transforming gene (PTTG1) was isolated from rat pituitary tumor cells, and subsequently identified as a securin protein as well as a transcription factor. We show here a global ...transcriptional effect of PTTG1 in human choriocarcinoma JEG-3 cells by simultaneously assessing 20,000 gene promoters using chromatin immunoprecipitation (ChIP)-on-Chip experiments. Seven hundred and forty-six gene promoters (P<0.001) were found enriched, with functions relating to cell cycle, metabolic control and signal transduction. Significant interaction between PTTG1 and Sp1 (P<0.000001) was found by transcriptional pattern analysis of ChIP data and further confirmed by immunoprecipitation and pull-down assays. PTTG1 acts coordinately with Sp1 to induce cyclin D3 expression approximately threefold, and promotes G1/S-phase transition independently of p21. PTTG1 deletion was also protective for anchorage-independent cell colony formation. The results show that PTTG1 exhibits properties of a global transcription factor, and specifically modulates the G1/S-phase transition by interacting with Sp1. This novel signaling pathway may be required for PTTG1 transforming activity.
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