Background Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability ...in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection. Methods Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events. Results A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41–0.63) nmol/L and 68.7 (27.9–150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P =0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P =0.013 and OR: 1.54, P =0.017, respectively). Conclusions plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.
IntroductionAt present, there is no approved medical treatment option for patients with non-functioning pituitary adenoma. A number of open-label studies suggest that treatment with somatostatin ...analogues may prevent tumour progression. In vivo somatostatin receptor imaging using 68Ga-DOTATATE PET (PET, positron emission tomography) could help in preselecting patients potentially responsive to treatment. Our aim is to investigate the effect of the somatostatin analogue lanreotide as compared with placebo on tumour size in patients with a 68Ga-DOTATATE PET-positive non-functioning pituitary macroadenoma (NFMA).Methods and analysisThe GALANT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients with a suprasellar extending NFMA. Included patients undergo a 68Ga-DOTATATE PET/CT of the head and tracer uptake is assessed after coregistration with pituitary MRI. Forty-four patients with a 68Ga-DOTATATE PET-positive NFMA are randomised in a 1:1 ratio between lanreotide 120 mg or placebo, both administered as subcutaneous injections every 28 days for 72 weeks. The primary outcome is the change in cranio-caudal tumour diameter on pituitary MRI after treatment. Secondary outcomes are change in tumour volume, time to tumour progression, change in quality of life and number of adverse events. Final results are expected in the second half of 2021.Ethics and disseminationThe study protocol has been approved by the Medical Research Ethics Committee of the Academic Medical Centre (AMC) of the Amsterdam University Medical Centres and by the Dutch competent authority. It is an investigator-initiated study with financial support by Ipsen Farmaceutica BV. The AMC, as sponsor, remains owner of all data. Results will be submitted for publication in a peer-reviewed journal.Trial registration numberNL5136 (Netherlands Trial Register); pre-recruitment.
Purpose
Clinically non-functioning pituitary macroadenomas (NFMA) have been reported to express somatostatin receptors (SSTR), but results are inconsistent across different studies. This may be ...related to limited sensitivity and specificity of techniques used to date, i.e. immunohistochemistry in surgical specimens and
111
In-DTPA-octreotide scintigraphy in vivo. The aim of this study was to assess SSTR expression in NFMA in vivo using
68
Ga-DOTATATE PET, which offers superior sensitivity and spatial resolution as compared with planar scintigraphy or SPECT.
Methods
Thirty-seven patients diagnosed with NFMA underwent
68
Ga-DOTATATE PET/CT of the head in the framework of a randomised controlled trial assessing the effect of the somatostatin analogue lanreotide on NFMA size. Individual co-registered T1-weighted pituitary MRIs were used to assess
68
Ga-DOTATATE uptake (SUV
mean
) in the adenoma. An SUV
mean
of > 2 was considered positive.
Results
68
Ga-DOTATATE uptake was positive in 34/37 patients (92%), with SUV
mean
of positive adenomas ranging from 2.1 to 12.4 (mean ± SD 5.8 ± 2.6).
Conclusions
This is the first report of
68
Ga-DOTATATE PET performed in NFMA patients, demonstrating in vivo SSTR expression in the vast majority of cases. The high positivity rate when compared with results obtained with
111
In-DTPA-octreotide scintigraphy probably reflects the superior sensitivity of PET imaging.
Trial registration
Netherlands Trial Register,
NL5136
, registered on 18 August 2015; EudraCT, 2015-001234-22, registered on 10 March 2015,
https://eudract.ema.europa.eu/
Abstract
Context
Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).
...Objective
To determine which type of α-adrenergic receptor blocker provides the best efficacy.
Design
Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898)
Setting
Multicenter study including 9 centers in The Netherlands.
Patients
134 patients with nonmetastatic PPGL.
Intervention
Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized.
Main Outcome Measures
Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.
Results
Median cumulative time outside blood pressure targets was 11.1% (interquartile range IQR: 4.3–20.6 in the phenoxybenzamine group compared to 12.2% (5.3–20.2) in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8–58.0) and 50.0 (35.3–63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.
Conclusions
The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.
Context: Pretreatment with alpha-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). Objective: ...To determine which type of alpha-adrenergic receptor blocker provides the best efficacy. Design: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898) Setting: Multicenter study including 9 centers in The Netherlands. Patients: 134 patients with nonmetastatic PPGL. Intervention: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. Main Outcome Measures: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. Results: Median cumulative time outside blood pressure targets was 11.1% (interquartile range IQR: 4.3-20.6 in the phenoxybenzamine group compared to 12.2% (5.3-20.2) in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. Conclusions: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome. (J Clin Endocrinol Metab 105: 1-11, 2020) Key Words: pheochromocytoma, sympathetic paraganglioma, alpha-adrenergic receptor blocker, hemodynamic instability
No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled ...trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA.
The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22.
Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 50%) or placebo (22 50%). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo −0·1 mm (95% CI −1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events.
Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA.
Ipsen Farmaceutica BV.
OBJECTIVE
To investigate whether the spontaneous secretion of growth hormone and prolactin in adult patients with pituitary‐dependent Cushing's disease is decreased.
PATIENTS
Fourteen adult patients ...(9 women, 5 men; age: 34 ± 3.4 years, mean ± SEM) with pituitary‐dependent Cushing's disease and 14 controls matched for age, gender and body mass index were studied.
METHODS
Blood samples were withdrawn at 10 minutes intervals starting at 0900 h for 24 h. GH and PRL release were quantified with deconvolution methods. The regularity of GH and PRL release was measured with approximate entropy statistics.
RESULTS
The number of GH secretory events per 24 h was higher in patients than in controls: 19 ± 1.3 vs. 14 ± 1.5 peaks per 24 h, respectively (P = 0.020). GH secretion rate was about one quarter lower in patients (ns), and the 24 h secretion of PRL was unchanged. Total GH production correlated negatively with the urinary excretion of free cortisol (R = 0.729, P = 0.005) and with the plasma cortisol production rate (R = 0.613; P = 0.026).
The orderliness of GH and PRL secretion was appraised with the approximate entropy statistic (ApEn). For GH secretion ApEn(1,20%) in patients was 0.952 ± 0.084 vs. 0.404 ± 0.047 in controls, P = 1.17 × 10−4, pointing to a markedly disordered secretion in patients. Similar results were obtained for PRL secretion: patients: 1.586 ± 0.063 vs. 1.003 ± 0.068 in controls, P = 3.67 × 10−5. No statistically significant differences in secretory dynamics were demonstrated between the 10 patients with a microadenoma and the four with a macroadenoma.
CONCLUSION
The amount of GH released spontaneously into the circulation in adult patients with pituitary‐dependent Cushing's disease is inversely related to the degree of cortisol hypersecretion. However, except for severe hypercortisolism, GH secretion is relatively preserved. In addition, secretion of GH and PRL is remarkably disordered in patients with Cushing's disease. Since we could not detect differences in GH and/or PRL secretory dynamics between patients with a microadenoma and those harboring a macroadenoma, we speculate that an intrapituitary paracrine mechanism and/or elevated cortisol feedback effects may be responsible for the evident disruption of GH and PRL secretion patterns.
At present, there is no approved medical treatment option for patients with non-functioning pituitary adenoma. A number of open-label studies suggest that treatment with somatostatin analogues may ...prevent tumour progression. In vivo somatostatin receptor imaging using
Ga-DOTATATE PET (PET, positron emission tomography) could help in preselecting patients potentially responsive to treatment. Our aim is to investigate the effect of the somatostatin analogue lanreotide as compared with placebo on tumour size in patients with a
Ga-DOTATATE PET-positive non-functioning pituitary macroadenoma (NFMA).
The GALANT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients with a suprasellar extending NFMA. Included patients undergo a
Ga-DOTATATE PET/CT of the head and tracer uptake is assessed after coregistration with pituitary MRI. Forty-four patients with a
Ga-DOTATATE PET-positive NFMA are randomised in a 1:1 ratio between lanreotide 120 mg or placebo, both administered as subcutaneous injections every 28 days for 72 weeks. The primary outcome is the change in cranio-caudal tumour diameter on pituitary MRI after treatment. Secondary outcomes are change in tumour volume, time to tumour progression, change in quality of life and number of adverse events. Final results are expected in the second half of 2021.
The study protocol has been approved by the Medical Research Ethics Committee of the Academic Medical Centre (AMC) of the Amsterdam University Medical Centres and by the Dutch competent authority. It is an investigator-initiated study with financial support by Ipsen Farmaceutica BV. The AMC, as sponsor, remains owner of all data. Results will be submitted for publication in a peer-reviewed journal.
NL5136 (Netherlands Trial Register); pre-recruitment.
GH secretion is regulated by the interaction of GHRH and
somatostatin and is released in 10–20 pulses in each 24-h cycle. The
exact roles in pulse generation played by somatostatin, GHRH, and the
...recently isolated GH-releasing peptide, Ghrelin, are not fully
elucidated. To investigate the GHRH-mediated GH secretion in human, we
investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two
young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a
novel inactivating defect of the GHRH receptor gene. Data were compared
with values in age- and gender-matched controls. Plasma GH
concentration were measured by a sensitive immunofluorometric assay,
with a detection limit of 0.01 mU/L. All plasma GH concentrations in
the female patient were measurable; in the male patient 30 of 145
samples were at or below the detection limit. GH secretion was
pulsatile, with 21 and 23 secretory episodes/24 h in the male and
female patients, respectively. The fraction of basal to total GH
secretion was raised in both patients by 0.18 and 0.15, respectively.
The total 24-h GH production rate was greatly diminished; in the male
patient it was 6.9 mU/L (normal values for his age, 26–63 mU/L), and
in the female patient it was 4.2 mU/L (normal values for her age,
96–390 mU/L). The nyctohemeral plasma GH rhythm was preserved
(P < 0.001), with normal acrophases (0430 and
0218 h in the male and female, respectively). Approximate entropy
was greatly elevated in both subjects (0.82 in the male and 1.17 in the
female; upper normal values for age and gender, 0.24 and 0.59,
respectively). Intravenous injection of 50 μg GHRH failed to increase
the plasma GH concentration in both patients, but 100 μg GH-releasing
peptide-2 elicited a definite increase (male patient, 0.13 to 1.74
mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial
empty sella on magnetic resonance imaging scanning.
In summary, the present studies in two patients with a profound
loss of function mutation of the GHRH receptor favor the view that in
the human the timing of GH pulses is primarily supervised by
intermittent somatostatin withdrawal, and the amplitude of GH
pulses is driven by GHRH. In addition, we infer that effectual
GHRH input controls the GH cell mass and the orderliness of the
secretory process.
To quantify prolactin (PRL) secretion patterns, ten untreated (female) microprolactinoma patients and six (male) macroprolactinoma patients underwent repetitive blood sampling every 10 min over 24 h. ...PRL release activity was analyzed from plasma PRL concentration (immunofluorimetric assay) profiles via a model-independent discrete peak detection program (Cluster) and a waveform-independent deconvolution technique (Pulse). Diurnal variations were analyzed by cosinor analysis. The number of distinct PRL pulses (mean +/- S.E.M.) was increased in patients: microprolactinoma 18.6 +/- 0.6/24 h versus female controls 12.4 +/- 0.6 (P = 6.7 x 10-s), and macroprolactinoma 18.0 +/- 0.9 versus male controls 13.5 +/- 0.8/24 h (P = 0.003). In patients, PRL pulse height, amplitude, pulse area and interpeak nadir concentrations were each greatly elevated compared with gender-matched controls. By 2-component deconvolution analysis, the mean nadir PRL secretion rate in microprolactinoma patients was augmented 20-fold at 0.408 +/- 0.089 microgram/l per min versus in female controls 0.019 +/- 0.009 microgram/l per min (P < 0.001); and in macroprolactinoma by 130-fold at 2.067 +/- 0.693 micrograms/l per min versus male controls 0.016 +/- 0.001 microgram/l per min (P = 0.001). Corresponding 24 h mean PRL secretion rates were in women, 0.658 +/- 0.147 and 0.044 +/- 0.018 (P < 0.001), and in men, 3.309 +/- 1.156 and 0.035 +/- 0.010 micrograms/l per min (P = 0.001), being respectively 15- and 94-fold increased in tumors. The estimated PRL production per day was 160 +/- 15 and 187 +/- 20 micrograms in male and female controls respectively. PRL production was 2860 +/- 640 micrograms in female patients with microadenomas (P < 0.001), and 37,800 +/- 5900 micrograms in male macroadenoma patients (P = 0.001). Cosinor analysis of the plasma concentrations revealed a significant rhythm in nine of ten, patients with a microadenoma, and in five of six with a macroadenoma. The same method applied to pulse height and amplitude disclosed a significant rhythm for PRL pulse height, but not for pulse amplitude, suggesting preserved rhythmicity of baseline interpulse nadir PRL concentrations. Approximate entropy (ApEn), a scale- and model-independent regularity statistic, averaged 1.6559 +/- 0.028 in microprolactinoma patients versus 0.8128 +/- 0.079 in female controls (P = 1.7 x 10(-8)); ApEn in macroadenomas was 1.5674 +/- 0.054 versus male controls 0.8773 +/- 0.076 (P = 1.7 x 10(-5), signifying greater secretory irregularity in the patients. Compared with microadenomas, macroadenomas exhibited a higher mean plasma concentration, overall mean PRL secretion rate, nadir secretion rate and pulse area, but similar peak frequency. We conclude that PRL secretion by prolactinomas is characterized by increased plasma PRL episodicity of release, increased total (15- to 100-fold) and basal (20- to 130-fold) secretion rates, and increased disorderlines of minute-to-minute secretion. These abnormalities of secretory control are very similar to those for GH and ACTH identified earlier in acromegaly and Cushing's disease respectively, thus suggesting mechanistic generality of pituitary tumor secretory derangements, independent of the particular hormone.
PDF
![Efficacy of [alpha]-Blocker...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0021-972X/small "Efficacy of [alpha]-Blockers on Hemodynamic Control during Pheochromocytoma Resection: A Randomized Controlled Trial")
