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Lucile Parlant-Pinet, Catherine Harthé, Florence Roucher, Yves Morel, Françoise Borson-Chazot, Gérald Raverot, and Véronique Raverot

Objectives

Gel filtration chromatography (GFC), the gold standard for macroprolactinaemia (MPRL) diagnosis, is a slow, costly and labour-intensive method. To limit the number of GFC required, we evaluated two screening tests for MPRL: prolactin (PRL) recovery after polyethylene glycol (PEG) precipitation and PRL concentration ratio, derived from two assays, each having different big-big-PRL cross-reactivities.

In some patients, MPRL is characterised by clinical symptoms which can be associated with an excess of monomeric PRL. We compared the monomeric PRL concentration obtained from GFC with the PRL concentration i) on a cobas e 601 analyser and ii) in the supernatant after PEG precipitation.

Design and methods

We studied hyperprolactinaemic sera subjected to physician-ordered GFC, between February 2013 and July 2014. We performed PEG precipitation (to evaluate the PRL concentration and rate of recovery in the supernatant) and two PRL assays: RIA and electrochemiluminescent assay (ECLIA), on a Roche cobas e 601 analyser, and calculated the RIA/ECLIA ratio.

Results

Among the 222 sera, we were able to diagnose or exclude MPRL in 72.1% of cases, based solely on the ratio and/or recovery. In the remaining cases, GFC was necessary for making a diagnosis. Elevated monomeric PRL was present in 10.9% of macroprolactinaemic sera. In the case of MPRL, both PRL measurements on the cobas analyser and in the supernatant weakly correlated with monomeric PRL values obtained from GFC.

Conclusions

The combination of PEG and RIA/ECLIA ratio analysis reduced the number of necessary GFC. However, GFC is essential in MPRL cases to evaluate the monomeric PRL concentration.

Free access

Lori Képénékian, Thomas Mognetti, Jean-Christophe Lifante, Anne-Laure Giraudet, Claire Houzard, Stéphane Pinson, Françoise Borson-Chazot, and Patrick Combemale

Objective

Pheochromocytoma (PHEO) may occur in 0.1–5.7% of patients presenting with a neurofibromatosis type 1 (NF1). Current recommendations are to explore only symptomatic patients. The objective of the study is to evaluate the prevalence and the interest of a systematic PHEO screening in this population.

Design

A prospective study in a French tertiary center including consecutive NF1 patients older than 18 years.

Methods

A systematic screening combining abdominal imaging and urinary fractionated metanephrines was proposed. In case of positivity of one or both exams, 123I-metaiodobenzylguanidine scintigraphy or [18F]-fluoro-dihydroxyphenylalanine PET imaging was performed. The diagnosis of secreting PHEO was retained in case of elevated urinary metanephrines associated with positive scintigraphy and non-secreting PHEO when urinary metanephrines were normal with a positive scintigraphy.

Results

Between January 2014 and August 2015, 234 patients were included and 156 patients (66.7%) completed both exams. In these 156 patients, 12 PHEOs were diagnosed, representing a prevalence of 7.7%. Of these, six PHEOs were secreting, with only two symptomatic patients. The tumor size of these PHEOs were bigger than that of non-secreting PHEO (25.2 ± 6.6 vs 14 ± 6.9 mm, P = 0.0165). One lesion was bilateral. Mean metanephrine and normetanephrine levels were 3.2 ± 2.6N and 2.8 ± 1N respectively. Three patients underwent surgery. The six patients with non-secreting PHEO were asymptomatic. One of them had bilateral lesion and one underwent surgery.

Conclusions

PHEO in NF1, whether or not secreting, are mostly asymptomatic. The current strategy to explore only symptomatic patients leads to an underestimation of prevalence with the risks inherent to the existence of an unrecognized PHEO.

Free access

Cécile Nozières, Laurence Chardon, Bernard Goichot, Françoise Borson-Chazot, Valérie Hervieu, Karim Chikh, Catherine Lombard-Bohas, and Thomas Walter

Objectives

Inappropriate calcitonin (CT) release, a major feature of medullary thyroid cancer (MTC), may occur in neuroendocrine tumors (NETs). The aims of this retrospective study were to assess i) the characteristics and prognosis of CT-producing NETs, and ii) the value of CT monitoring during follow-up.

Methods

All patients with NETs in whom serum CT was assayed between 2010 and 2012 were included. MTCs were excluded. Clinical, biological, and histological characteristics were studied.

Results

Twenty-one (12%) of 176 patients in whom serum CT was systematically assayed had concentrations >100 ng/l, with tumours predominantly of bronchial or pancreatic origin (P<0.0001), and of high grade (P=0.0006). Poor prognosis was linked to high CT levels, poor differentiation, and grade 3. In a total group of 24 patients with serum CT >100 ng/l, symptoms potentially attributable to CT were recorded in eight, with occasional overlap with the carcinoid syndrome among other secretory syndromes. Immunohistochemistry could be performed in six tumor specimens, CT being detected in five. In 11 patients with five or more successive CT assays, hormone levels were fairly well correlated with clinical courses.

Conclusion

Serum CT levels may be raised in some patients with NETs, especially from foregut origin, and of high grade. The suggested value of CT monitoring during follow-up must be confirmed in further studies.

Free access

Gérald Raverot, Anne Wierinckx, Emmanuel Jouanneau, Carole Auger, Françoise Borson-Chazot, Joël Lachuer, Michel Pugeat, and Jacqueline Trouillas

Objective

Silent corticotroph adenomas (SCAs) are rare pituitary tumours immunoreactive for ACTH, but without clinical evidence of Cushing's disease. We characterized SCAs based on clinical, hormonal and molecular data, and compared the characteristics of these tumours with those of macro (MCA)- and micro (mCA)-ACTH adenomas with Cushing's disease.

Methods

Fifty ACTH adenomas (14 SCAs, 15 MCAs and 21 mCAs) with complete corresponding clinical, radiological and biochemical data were selected. Histological corticotroph differentiation; immunostaining for ACTH, β-endorphin and β-LPH; and mRNA expression levels of TPIT, POMC, GR α, prohormone convertase 1/3 (PC1/3) and galectin-3 were compared in 21 representative tumours.

Results

Despite the absence of clinical hypercortisolism in patients with SCA, elevated plasma ACTH levels that were similar to those associated with mCA were observed. The cortisol/ACTH ratio was similar between SCA and MCA groups and lower than that found with mCA (P<0.05). This dissociation could be explained by lower expression of PC1/3 in SCA and MCA than in mCA (P<0.05). After an i.v. dexamethasone suppression test, ACTH levels were significantly higher in patients with MCA than in those with mCA (P<0.05). Cytological and immunocytochemical analyses as well as mRNA expression levels of TPIT, POMC and GR α confirmed corticotroph differentiation in both mCAs and MCAs and in half of the SCAs, with a strong correlation between TPIT and POMC mRNA expression levels in SCAs (R 2=0.72; P<0.01) and in MCAs (R 2=0.65; P<0.05).

Conclusions

Despite the absence of hypercortisolism, SCAs exhibit histological, biochemical and molecular corticotroph differentiation. SCA and MCA show hormonal and molecular similarities differentiating them from mCA.

Free access

Juliette Abeillon-du Payrat, Karim Chikh, Nadine Bossard, Patricia Bretones, Pascal Gaucherand, Olivier Claris, Anne Charrié, Véronique Raverot, Jacques Orgiazzi, Françoise Borson-Chazot, and Claire Bournaud

Context

Hyperthyroidism occurs in 1% of neonates born to mothers with active or past Graves' disease (GD). Current guidelines for the management of GD during pregnancy were based on studies conducted with first-generation thyroid-binding inhibitory immunoglobulin (TBII) assays.

Objective

This retrospective study was conducted in order to specify the second-generation TBII threshold predictive of fetal and neonatal hyperthyroidism, and to identify other factors that may be helpful in predicting neonatal hyperthyroidism.

Methods

We included 47 neonates born in the Lyon area to 42 mothers harboring measurable levels of TBII during pregnancy. TBII measurements were carried out in all mothers; bioassays were carried out in 20 cases.

Results

Nine neonates were born with hyperthyroidism, including five with severe hyperthyroidism requiring treatment. Three neonates were born with hypothyroidism. All hyperthyroid neonates were born to mothers with TBII levels >5 IU/l in the second trimester (sensitivity, 100% and specificity, 43%). No mother with TSH receptor-stimulating antibodies (TSAb measured by bioassay) below 400% gave birth to a hyperthyroid neonate. Among mothers of hyperthyroid neonates, who required antithyroid drugs during pregnancy, none could stop treatment before delivery. Analysis of TBII evolution showed six unexpected cases of increasing TBII values during pregnancy.

Conclusion

Maternal TBII value over 5 IU/l indicates a risk of neonatal hyperthyroidism. Among these mothers, a TSAb measurement contributes to identify more specifically those who require a close fetal thyroid ultrasound follow-up. These results should be confirmed in a larger series.

Free access

Mirela Diana Ilie, Véronique Raverot, François Tronc, Alexandre Vasiljevic, Françoise Borson-Chazot, and Gérald Raverot

Context

Cabergoline has been shown to have some effect in the treatment of moderate Cushing’s disease, but its effectiveness in Cushing’s syndrome of ectopic or occult origin remains to be investigated.

Case series

In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing’s syndrome of ectopic or occult origin. Cabergoline’s effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases.

Review of the literature

In the literature, we found only 11 cases of ectopic or occult Cushing’s syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded.

Conclusions

Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing’s syndrome.

Free access

Sandrine Fieffe, Isabelle Morange, Patrick Petrossians, Philippe Chanson, Vincent Rohmer, Christine Cortet, Françoise Borson-Chazot, Thierry Brue, Brigitte Delemer, and The French Acromegaly Registry

Objectives

The French Acromegaly Registry records data of acromegalic patients' since 1992 in French, Belgian (Liège), and Swiss (Lausanne) centers. We studied the prevalence of diabetes in this population looking for risk factors. Patients from one of the centers (Reims) were then analyzed more thoroughly.

Methods

This study has been conducted on all the patients recorded from 1999 until 2004 (519 patients). Evolution of cohorts' was reassessed in 2009. Of the different variables recorded in the registry: age, sex, body mass index (BMI), duration of acromegaly, GH, IGF1 and prolactin levels, pituitary tumor size, hormonal deficiencies, presence, duration and treatment of diabetes, hypertension, and rheumatological disease were analyzed.

Results

The prevalence of diabetes in the registry was 22.3%. Diabetic patients were older and had a higher BMI. Compared with the data of the French Social Security, acromegalic patients showed a more precocious apparition of diabetes and prevalence was higher in each age group.

Compared with non-diabetic acromegalic subjects, diabetic patients had a more prolonged evolution of acromegaly before diagnosis. The levels of GH and IGF1 were not significantly different between the two groups. Only hypertension was significantly more frequent in diabetic patients.

Conclusions

In our population, the prevalence of diabetes was estimated to be 22.3%. The GH and IGF1 levels did not appear as predictive factors for the presence of diabetes. On the contrary, age, BMI, and hypertension were significant risk factors as in the general population of type 2 diabetics.

Free access

Cécile Nozières, Thomas Walter, Marie-Odile Joly, Sophie Giraud, Jean-Yves Scoazec, Françoise Borson-Chazot, Chantal Simon, Jean-Paul Riou, and Catherine Lombard-Bohas

Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.

Free access

Geneviève Sassolas, Zakia Hafdi-Nejjari, Anne Marie Schott, Claire Bournaud, Jean Louis Peix, Jacques Orgiazzi, Nicole Dutrieux-Berger, Françoise Borson-Chazot, and The Group of Pathologists of the Rhône-Alpes Région

Objective

To analyze, at a population level, the relation between the incidences of benign thyroid diseases in patients submitted to surgery and that of thyroid cancers based on their respective geographical distributions.

Methods

The study included 3169 cases (691 cancers and 2478 benign diseases) operated on in 2002 in the Rhône-Alpes région, which is subdivided into eight départements and 311 cantons.

Results

The total thyroid intervention rate was 54.6/100 000 (23.4 and 86.4), and the annual cancer incidence was 11.9/100 000 (4.7 and 13.8) for men and women respectively. The prevalence of cancer among thyroid surgery was 21.8% and that of cancer discovered in goiters increased with age (44% at 60 years). Intervention rates varied from départment to département. In women, the incidence of microcancers was correlated to the thyroid intervention for benign pathologies rate. In men, the incidence of supracentimetric cancers was related to the TIBR. At the canton level, the relative risk of benign diseases was correlated to that of cancers. TIBR and incidence of cancers were higher in urban cantons than in nonurban ones. The density of endocrinologists influenced the prevalence of cancers among all the cases submitted to surgery.

Conclusion

In the Rhône-Alpes population with high rates of thyroid cancer incidence and of thyroid surgery, a number of correlations were found according to gender and tumor size. However, the general incidence of cancer was not directly related to surgical activity. Geographical variability may be related to the heterogeneous medical and pathological practices.

Free access

Valérie Bernard, Catherine Lombard-Bohas, Marie-Caroline Taquet, François-Xavier Caroli-Bosc, Philippe Ruszniewski, Patricia Niccoli, Rosine Guimbaud, Cécile N Chougnet, Bernard Goichot, Vincent Rohmer, Françoise Borson-Chazot, Eric Baudin, and for the French Group of Endocrine Tumors

Background

Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option.

Methods

Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to the first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded.

Results

Twelve patients with metastatic insulinoma and refractory hypoglycemia who were treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/day, except in one patient, 5 mg/day) was given after a median of four previous therapeutic lines. Medication aimed at normalizing blood glucose levels in 11 patients. After a median duration of 6.5 months (range 1–35+ months), median time to the first recurrence of symptomatic hypoglycemia was 6.5 months (range 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to two deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia.

Conclusion

Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.