Clinical trial NCT01022515: Specificity of Elevated Plasma EM66 Levels in Pheochromocytoma
Official title: Clinical Application of New Pheochromocytoma Markers: INSERM Pilot Study of the Specificity of Elevated Plasma EM66 Concentrations in Patients With Pheochromocytoma or Paraganglioma Compared to Patients With Essential Hypertension
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pheochromocytoma
Paraganglioma
Essential Hypertension
Keywords: pheochromocytoma
paraganglioma
hypertension
Lead sponsor: University Hospital, Rouen
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2009-12-01
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: two distint population will be involved :

* patients with pheochromocytoma or paraganglioma
* patients with essential hypertension

Brief summary: Pheochromocytoma or paraganglioma are tumors generating hypertension as a symptom. Different biological tests are currently available to diagnose these tumors. However, they all lack specificity since they do not distinguish cases of hypertension without pheochromocytoma or paraganglioma. To improve the diagnostic specificity of these tumors, the investigators are testing a new marker called EM66.

Detailed description: Neuroendocrine tumors (NT) correspond to neoplasms that develop from endocrine and neuroendocrine cells scattered throughout the body. They are characterized by the occurrence, in their cytoplasm, of dense-core secretory vesicles containing hormones, neuropeptides and acidic proteins such as granins. The diversity of NT (from hypophysis, pancreas, adrenal, gastrointestinal tract) makes very difficult the identification and evaluation of the different types of tumors by the diagnostic and prognostic tools currently available. We have thus established a research program aimed at identifying new biological markers for the detection, the prognosis and the follow-up of NT by seeking in tumor and plasma samples of patients, granin-derived peptides. Our program was initiated on one type of NT : pheochromocytoma. These neoplasms correspond to tumoral chromaffin cells mainly originating from the adrenal medulla. It is considered that 10 % of pheochromocytoma patients will develop metastases and, currently, except in the presence of metastases, there are no means to predict malignancy of the tumor. We setup a radioimmunoassay of EM66 (a secretogranin II-derived peptide) that allowed us to demonstrate that (i) plasma concentrations of the peptide are significantly elevated in pheochromocytoma patients, (ii) combined with other biological tests EM66 measurement increase the diagnostic sensitivity for these neoplasms, (iii) after surgical removal of the tumor, plasma EM66 concentrations rapidly return to basal level and, (iv) intra-tumoral EM66 concentrations are higher in benign than in malignant pheochromocytomas (Yon et al., 2003, Guillemot et al., 2006). These results reveal that EM66 constitutes a novel tool for the diagnosis, prognosis and follow-up of pheochromocytoma. In the frame of a clinical use of an EM66 measurement test, it is necessary to evaluate the specificity of this marker. For instance, renal deficiency, hypergastrinemia, reduction of renal clearance, type A gastritis, Crohns disease, or proton-pump inhibitory treatment, lead to increase plasma chromogranin A (CgA) concentrations (false-positive cases). In addition, while hypertension account for one of the symptoms of pheochromocytoma patients, in essential hypertensive patients, CgA levels are higher than in normotensive individuals. The main objective of our clinical transfer research project consists to study the specificity of the measurement of EM66 as a diagnostic and prognostic marker of pheochromocytoma. This multicentric study will allow us to compare plasma EM66 levels in pheochromocytoma patients with a cohort of essential hypertensive patients. At the same time, in a long-range prospect, due to the lack of malignancy markers for these tumors, we will investigate if plasma or tumor EM66 levels are correlated to the differentiation status of pheochromocytomas, and if the expression level of a set of genes that we identified by a transcriptomic approach developed in the laboratory, is associated with the malignant status of the tumors. The stakes of this transfer research, involving our laboratory and the Center for Clinical Investigations (CIC) of Rouen and Lille, are to provide an easy and simple novel tool to practitioners and anatomo-pathologists for the screening, the evaluation and the follow-up of patients with neuroendocrine tumors.

Eligibility criteria: Patients with pheochromocytoma/paraganglioma

Inclusion criteria :

* men \& women, age \> 18 years old
* Newly diagnosed patient : suspicion of pheochromocytoma or paraganglioma with elevation of urinary metanephrines and/or normetanephrines along with evidence of tumor which surgical removal is considered (histological findings following surgery will be the gold standard for final diagnosis and inclusion in the study)
* During follow-up of a patient with known genetic predisposition to pheochromocytoma/paraganglioma : suspicion of pheochromocytoma or paraganglioma with or without elevation of urinary metanephrines and/or normetanephrines along with evidence of a tumor which surgical removal is considered (histological findings following surgery will be the gold standard for final diagnosis and inclusion in the study) ,
* Patients with known pheochromocytoma/paraganglioma, whether malignant or not, whether with metanephrine secretion or not, With tumor sites at inclusion in the study
* Patients informed and willing to participate in the study
* Patients with medical insurance (French social security) Non inclusion criteria
* Patients newly diagnosed, recently operated and the histological findings disprove pheochromocytoma or paraganglioma.
* patient imprisoned or under legal protection.

Patients with essential hypertension Inclusion criteria

* men \& women, age \> 18 years old
* paired with a patient with pheochromocytoma/paraganglioma for : gender, age (± 5 years) and centre
* patient with hypertension. No aetiology was found after initial check up.
* Normal 24 hours urinary excretion of metanephrines \& normetanephrines
* For women of childbearing potential : effective contraceptive method and negative urinary pregnancy test
* Patients informed and willing to participate in the study
* Patients with medical insurance (French social security) Non inclusion criteria
* Treatment with proton-pump inhibitors in the 8 days before inclusion in the study
* Treatment with beta-blockers, antidepressants, Benzodiazepins, dopa, alphamethyl dopa, if this treatment cannot be interrupted during the study (i.e. for approximately 10 days)
* patient imprisoned or under legal protection.

Primary outcomes:
measure: Plasma EM66
timeFrame: two years
Secondary outcomes:
measure: Plasma Chromogranin A levels
timeFrame: before treatement
Other outcomes:
Locations:
city: Lille
country: France
facility: CIC 9301
city: Lille
country: France
facility: Endocrinology Department
city: Mont Saint Aignan
country: France
facility: Inserm U982/EA 4310; Rouen University (DC2N)
city: Paris
country: France
facility: Cardiology Department
city: Paris
country: France
facility: CIC 9304
city: Rouen
country: France
facility: Cic-Crb 0204
city: Rouen
country: France
facility: Endocrinology Department
city: Villejuif
country: France
facility: Endocrinology Department, Gustave-Roussy Institute
Study officials:
affiliation: University Hospital, Rouen
name: Anne F Cailleux, MD
role: PRINCIPAL_INVESTIGATOR
References: