Publications by authors named "Gérald Raverot"

123 Publications

Letter to the editor from Helene Lasolle: "USP8 and TP53 drivers are associated with CNV in a corticotroph adenoma cohort enriched for aggressive tumors".

J Clin Endocrinol Metab 2021 Apr 5. Epub 2021 Apr 5.

Fédération d'Endocrinologie, Hospices Civils de Lyon, Groupement Hospitalier Est, Bron, France.

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http://dx.doi.org/10.1210/clinem/dgab217DOI Listing
April 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Eur J Endocrinol 2020 Dec 1. Epub 2020 Dec 1.

R Verkauskiene, Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciencies, Kaunas, Lithuania.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform.

Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD.

Design: On-line survey in endocrine centres throughout Europe.

Patients And Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018.

Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved.

Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.
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http://dx.doi.org/10.1530/EJE-20-1180DOI Listing
December 2020

Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis.

Acta Neuropathol Commun 2020 11 10;8(1):190. Epub 2020 Nov 10.

Fédération d'endocrinologie, Centre de Référence des Maladies Rares Hypophysaires, Groupement Hospitalier Est, Hospices Civils de Lyon, 8 av Doyen Lepine, 69677, Bron Cedex, France.

The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min-max) = 38% (0-97) of probes) compared to corticotroph (11% (0-77)), somatotroph (5% (0-99)), gonadotroph (0% (0-10)) and immunonegative tumors (0% (0-17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn't show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same 'quiet' profile, leaving the mechanism underlying tumorigenesis open to question.
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http://dx.doi.org/10.1186/s40478-020-01067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653703PMC
November 2020

Somatostatin receptor ligands induce TSH deficiency in thyrotropin-secreting pituitary adenoma.

Eur J Endocrinol 2021 Jan;184(1):1-8

Centre de Référence des Maladies Rares de la Thyroïde et des Récepteurs Hormonaux TRH Centre de Référence des Maladies Rares de l'Hypophyse HYPO Service d'Endocrinologie, Diabétologie et Nutrition, CHU d'Angers, Institut MITOVASC, Université d'Angers, Angers, France.

Objective: Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL.

Design: Retrospective study.

Methods: Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency.

Results: Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency.

Conclusions: SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.
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http://dx.doi.org/10.1530/EJE-20-0484DOI Listing
January 2021

Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up.

J Clin Med 2020 Oct 13;9(10). Epub 2020 Oct 13.

Service d'Endocrinologie, Diabète, Nutrition, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France.

Hypophysitis, secondary to programmed cell death 1 protein (PD1) and programmed cell death 1 ligand 1 (PDL1) inhibitors, were thought to be rare, with only a few studies describing more than one case with long-term follow-up. The aim of the present study was to describe the clinical, laboratory, and morphological characteristics of PD1/PDL1 inhibitor-induced hypophysitis, and its long-term course. This cohort study was conducted at the University Hospital of Lyon, France, with longitudinal follow-up of patients. Seventeen cases of PD1/PDL1 inhibitor-induced hypophysitis were included. The median time to onset of hypophysitis was 28 weeks (range: 10-46). At diagnosis, 16 patients complained of fatigue, 12 of nausea or loss of appetite, while headache was rare. We found no imaging pituitary abnormality. All patients presented adrenocorticotropic hormone (ACTH) deficiency; other pituitary deficiencies were less common ( = 7). At last follow-up (median: 13 months), ACTH deficiency persisted in all but one patient and one patient recovered from gonadotropic deficiency. PD1/PDL1 inhibitor-induced hypophysitis is a clinical entity different from those associated to cytotoxic T-lymphocyte antigen-4 (CTLA4) inhibitors, with less obvious clinical and radiological signs, and probably a different mechanism. The paucity of symptoms demonstrates the need for systematic hormonal follow-up for patients receiving PD1/PDL1 inhibitors.
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http://dx.doi.org/10.3390/jcm9103280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601962PMC
October 2020

Pegvisomant in combination or pegvisomant alone after failure of somatostatin analogs in acromegaly patients: an observational French ACROSTUDY cohort study.

Endocrine 2021 Jan 28;71(1):158-167. Epub 2020 Sep 28.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, 94275, Le Kremlin-Bicêtre, France.

Objective: After surgery, when somatostatin analogs (SAs) do not normalise IGF-I, pegvisomant (PEG) is indicated. Our aim was to define the medical reasons for the treatment of patients with PEG as monotherapy (M) or combined with SA, either as primary bitherapy, PB (PEG is secondarily introduced after SA) or as secondary bitherapy, SB (SAs secondarily introduced after PEG).

Methods: We retrospectively analysed French data from ACROSTUDY.

Results: 167, 88 and 57 patients were treated with M, PB or SB, respectively, during a median time of 80, 42 and 70 months. The median PEG dose was respectively 15, 10 and 20 mg. Before PEG, the mean IGF-I level did not differ between M and PB but the proportion of patients with suprasellar tumour extension was higher in PB group (67.5% vs. 44.4%, P = 0.022). SB regimen was used preferentially in patients with tumour increase and IGF-I level difficult to normalise under PEG. In both secondary regimens, the decrease of the frequency of PEG's injections, compared to monotherapy was confirmed. However, the mean weekly dose of PEG between M and PB remained the same.

Conclusions: The medical rationale for continuing SAs rather than switching to PEG alone in patients who do not normalise IGF-I under SAs was a tumour concern with suprasellar extension and tumour shrinkage under SA. A potential explanation for introducing SA in association with PEG appears to be a tumour enlargement and difficulties to normalise IGF-I levels under PEG given alone. In both regimens, the prospect of lowering PEG injection frequency favoured the choice.
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http://dx.doi.org/10.1007/s12020-020-02501-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835180PMC
January 2021

A key role for conservative treatment in the management of pituitary apoplexy.

Endocrine 2021 Jan 21;71(1):168-177. Epub 2020 Sep 21.

Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677, Bron, France.

Purpose: The management of pituitary apoplexy, a rare emergency neuroendocrine condition, is controversial. The aim of the present study is to compare the outcomes of patients with pituitary apoplexy managed either by a conservative or surgical approach.

Methods: A retrospective cohort study including patients diagnosed between 2007 and 2018 in a tertiary French university hospital. Pituitary Apoplexy Score (PAS) was retrospectively applied in the perspective of therapeutic decision support.

Results: Forty-six patients were treated for pituitary apoplexy either with conservative management (n = 27) or surgery (n = 19). At initial evaluation, visual field defects (VFD) and visual acuity impairment were more frequent in patients from the surgery group. At 1 year there were no statistical differences in the rates of complete/near-complete resolution of VFD (100 vs. 91.7%), visual acuity impairment (100 vs. 87.5%), and cranial nerve palsies (83.3 vs. 100%), between conservative and surgical treatment groups. There were more endocrine deficits at 1 year in the surgical group (p = 0.029). PAS (n = 41) was 3.4 on average in the early surgery group and 1.3 in the conservative treatment/delayed surgery group. Among patients with a score < 4, 31.3% were operated at first line and did not present better outcomes than patients managed conservatively. In all, 88.9% of patients with a score ≥ 4 underwent surgery.

Conclusions: PAS may be a reliable parameter for defining therapeutic strategy. Patients with non-severe and nonprogressive neuro-ophthalmological deficits can be managed conservatively without negative impact on outcomes, thus surgery should be reserved only for those patients with a PAS ≥ 4.
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http://dx.doi.org/10.1007/s12020-020-02499-8DOI Listing
January 2021

Immunotherapy in Corticotroph and Lactotroph Aggressive Tumors and Carcinomas: Two Case Reports and a Review of the Literature.

J Pers Med 2020 Aug 13;10(3). Epub 2020 Aug 13.

Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, 69677 Bron, France.

Once temozolomide has failed, no other treatment is recommended for pituitary carcinomas and aggressive pituitary tumors. Recently, the use of immune checkpoint inhibitors (ICIs) has raised hope, but so far, only one corticotroph carcinoma and one aggressive corticotroph tumor treated with immunotherapies have been reported in the literature. Here, we present two cases, one corticotroph carcinoma and one aggressive prolactinoma (the first one reported in the literature) treated with ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) every three weeks, followed by maintenance treatment with nivolumab (3 mg/kg every 2 weeks) in the case of the corticotroph carcinoma, and we compare them with the two previously reported cases. Patient #1 presented a biochemical partial response (plasma ACTH decreased from 13,813 to 841 pg/mL) and dissociated radiological response to the combined ipilimumab and nivolumab-the pituitary mass decreased from 37 × 32 × 41 to 29 × 23 × 42 mm, and the pre-existing liver metastases decreased in size (the largest one from 45 to 14 mm) or disappeared, while a new 11-mm liver metastasis appeared. The maintenance nivolumab (21 cycles) resulted in a stable disease for the initial liver metastases, and in progressive disease for the newly appeared metastasis (effectively treated with radiofrequency ablation) and the pituitary mass. Patient #2 presented radiological and biochemical progressive disease after two cycles of ICIs-the pituitary mass increased from 38 × 42 × 26 to 53 × 57 × 44 mm, and the prolactin levels increased from 4410 to 9840 ng/mL. In conclusion, ICIs represent a promising therapeutic option for aggressive pituitary tumors and carcinomas. The identification of subgroups of responders will be key.
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http://dx.doi.org/10.3390/jpm10030088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563495PMC
August 2020

Immune Landscape of Pituitary Tumors Reveals Association Between Macrophages and Gonadotroph Tumor Invasion.

J Clin Endocrinol Metab 2020 11;105(11)

Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, Lyon, France.

Purpose: Pituitary neuroendocrine tumors (PitNETs) are frequent intracranial neoplasms that present heterogenic characteristics. Little is known about the immune cell network that exists in PitNETs and its contribution to their aggressive behavior.

Methods: Here we combined flow cytometry, t-SNE analysis, and histological approaches to define the immune landscape of surgically resected PitNETs. Xenografts of rodent pituitary tumor cells and resected PitNETs were performed in Rag2KO mice, in combination with in vitro analysis aimed at dissecting the role of pituitary tumor-cells in monocyte recruitment.

Results: We report that gonadotroph PitNETs present an increased CD68+ macrophage signature compared to somatotroph, lactotroph, and corticotroph PitNETs. Transcriptomic and histological characterizations confirmed gonadotroph infiltrating macrophages expressed CD163, MRC-1, ARG1, and CSF1R M2 macrophage markers. Use of growth hormone (GH)3/GH4 somatotroph and LβT2/αT3.1 gonadotroph cells drove THP1 macrophage migration through respective expression of CCL5 or CSF1. Although both LβT2 and GH3 cells recruited F4/80 macrophages following their engraftment in mice, only LβT2 gonadotroph cells showed a capacity for M2-like polarization. Similar observations were performed on patient-derived xenografts from somatotroph and gonadotroph tumors. Analysis of clinical data further demonstrated a significant correlation between the percentage of CD68+ and CD163+ infiltrating macrophages and the invasive character of gonadotroph tumors.

Conclusions: Gonadotroph tumor drive the recruitment of macrophages and their subsequent polarization to an M2-like phenotype. More importantly, the association between infiltrating CD68+/CD163+ macrophages and the invasiveness of gonadotroph tumors points to macrophage-targeted immunotherapies being a potent strategy to limit the progression of gonadotroph PitNETs.
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http://dx.doi.org/10.1210/clinem/dgaa520DOI Listing
November 2020

Aggressive Pituitary Adenomas and Carcinomas.

Endocrinol Metab Clin North Am 2020 09 8;49(3):505-515. Epub 2020 Jul 8.

Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, "Claude Bernard" Lyon 1 University, Hôpital Louis Pradel, 59 Pinel Boulevard, Lyon, Bron 69677, France. Electronic address:

A subset of pituitary tumors present an aggressive behavior that remains difficult to predict, and in rare cases they metastasize. The current European Society for Endocrinology (ESE) guidelines for the management of aggressive pituitary tumors and carcinomas provide valuable guidance, but several issues remain unaddressed because of the scarcity of data in the literature. This article presents key clinical aspects regarding aggressive pituitary tumors and carcinomas, and also discusses some of the unanswered questions of the ESE guidelines, focusing on both diagnosis and treatment.
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http://dx.doi.org/10.1016/j.ecl.2020.05.008DOI Listing
September 2020

Treatment Options for Gonadotroph Tumors: Current State and Perspectives.

J Clin Endocrinol Metab 2020 10;105(10)

Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, Auvergne-Rhône-Alpes, France.

Context: Gonadotroph tumors represent approximatively one-third of anterior pituitary tumors, but despite their frequency, no medical treatment is currently recommended for them. This would be greatly needed because following surgery, which is the first-line treatment, a significant percentage of gonadotroph tumors regrow.

Evidence Acquisition: We performed PubMed searches in March 2020 using the term "gonadotroph" in combination with 36 different keywords related to dopamine type 2 receptor agonists, somatostatin receptor (SST) ligands, temozolomide, peptide receptor radionuclide therapy (PRRT), immunotherapy, vascular endothelial growth factor receptor (VEGFR)-targeted therapy, mammalian target of rapamycin (mTOR) inhibitors, and tyrosine kinase inhibitors. Articles resulting from these searches, as well as relevant references cited by these articles were reviewed.

Evidence Synthesis: SST2 analogs have demonstrated only very limited antitumor effect, while high-dose cabergoline has been more effective in preventing tumor regrowth, but still in only a minority of cases. In the setting of an aggressive gonadotroph tumor, temozolomide is the recommended medical treatment, but has demonstrated also only limited efficacy. Still, its efficacy has been so far better than that of PRRT. No case of a gonadotroph tumor treated with pasireotide, VEGFR-targeted therapy, mTOR inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors is reported in literature.

Conclusions: Gonadotroph tumors need better phenotyping in terms of both tumor cells and associated tumor microenvironment to improve their treatment. Until formal recommendations will be available, we provide the readers with our suggested approach for the management of gonadotroph tumors, management that should be discussed within multidisciplinary teams.
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http://dx.doi.org/10.1210/clinem/dgaa497DOI Listing
October 2020

Evaluation of Nurses' and Patients' Overall Satisfaction with New and Previous Formulations of Octreotide Long-acting Release (Sandostatin LAR): A French Observational Study.

Adv Ther 2020 09 18;37(9):3901-3915. Epub 2020 Jul 18.

Hepatogastroenterology and Digestive Oncology Unit, University Hospital of Reims, Reims, France.

Introduction: The first long-acting release (LAR) formulation of octreotide was marketed in France in the late 1990s. An injectable formulation of Sandostatin LAR (Novartis SAS) with a new diluent has been developed to facilitate its preparation and administration and to improve its use in practice.

Methods: We conducted an observational, cross-sectional and multicenter study in France whose main outcome was to compare nurses' satisfaction with the preparation and administration of both previous and new formulations of octreotide LAR. Secondary outcomes included assessment of patient satisfaction (quality of life and pain felt during the injection) and product tolerance. Data were collected at two time points (one for the first formulation group and one for the second formulation group) through paper questionnaires administered to physicians, patients and nurses including a visual analog scale (VAS) from 0 (unsatisfied) to 10 (very satisfied).

Results: Results showed that overall nurse satisfaction improved from 5.3 (95% CI 4.9-5.8) with the previous formulation to 7.5 (95% CI 7-7.9) with the new formulation (p < 0.0001). Regarding secondary outcomes, the simplicity of the injection increased (84% for the previous formulation and 94% for the new formulation) and the purge problem disappeared (36% for the previous formulation and 4% for the new formulation).

Conclusion: The improvement due to the new formulation of Sandostatin LAR was reported in terms of handling, ease of use and overall nurse satisfaction. The new formulation greatly reduced treatment administration problems associated with the previous formulation, while maintaining low injection site pain and an equivalent safety profile in both indications.
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http://dx.doi.org/10.1007/s12325-020-01429-4DOI Listing
September 2020

Efficacy and safety of dopamine agonists in patients treated with antipsychotics and presenting a macroprolactinoma.

Eur J Endocrinol 2020 Aug;183(2):221-231

Assistance Publique Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Context: In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge.

Objective: Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics.

Design: This was a multicenter (France and Belgium) retrospective study.

Patients: Eighteen patients treated with antipsychotics were included.

Results: Under DA, median PRL levels decreased from 1247 (117-81 132) to 42 (4-573) ng/mL (P = 0.008), from 3850 (449-38 000) to 141 (60-6000) ng/mL (P = 0.037) and from 1664 (94-9400) to 1215 (48-5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0-57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions.

Conclusions: Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.
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http://dx.doi.org/10.1530/EJE-20-0125DOI Listing
August 2020

Are aggressive pituitary tumors and carcinomas two sides of the same coin? Pathologists reply to clinician's questions.

Rev Endocr Metab Disord 2020 Jun;21(2):243-251

Pathology Department, Foch Hospital, 40 rue Worth, 92151, Suresnes, France.

Pituitary adenohypophyseal tumors are considered as benign and termed "adenomas". However, many tumors are invasive and a proportion of these exhibit an "aggressive behavior" with premature death due to progressive growth. Only very rare (0.2%) tumors with metastases are considered malignant and termed "carcinomas". Taking into account this variability in behavior and the oncological definition, pathologists have proposed changing the term adenoma to tumor. Here we explain why use the term tumor instead of adenoma and identify tumor characteristics, associated with a high risk for poor prognosis. In a cohort of 125 tumors with aggressive behavior (APT) and 40 carcinomas with metastases (PC), clinical and pathological features were very similar. The comparison of this cohort (APT+PC) with a reference surgical cohort of 374 unselected patients clearly shows that the two cohorts differ greatly, especially the percentage of tumors with Ki67 ≥ 10% (35%vs3%; p < 0.001). A five-tiered prognostic classification, associating invasion and proliferation, identified grade 2b tumors (invasive and proliferative), with a high risk of recurrence/progression. Because half of the APT+ PC tumors have a Ki67 index ≥10%, and 80% of them show 2 or 3 positive markers of proliferation, we suggest that tumors that are clinically aggressive, invasive and highly proliferative with a Ki67 ≥ 10%, represent tumors with malignant potential. The percentage of grade 2b tumors, suspected of malignancy, which will become aggressive tumors or carcinomas is unknown. It is probably very low, but higher than 0.2% in surgical series. Early identification and active treatment of these aggressive tumors is needed to decrease morbidity and prolong survival.
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http://dx.doi.org/10.1007/s11154-020-09562-9DOI Listing
June 2020

Gonadotroph Tumors Show Subtype Differences That Might Have Implications for Therapy.

Cancers (Basel) 2020 Apr 20;12(4). Epub 2020 Apr 20.

Endocrinology Department, "Groupement Hospitalier Est" Hospices Civils de Lyon, 69677 Bron, France.

Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed a retrospective study and analyzed the clinicopathological characteristics of 98 gonadotroph tumors operated in a single large pituitary center. Although being larger in men ( = 0.01), the aggressiveness of gonadotroph tumors did not appear to be sex-related. LH tumors were rare (4/98) and exclusively encountered in men. Somatostatin receptor type 5 (SST5) was absent in all analyzed tumors. The immunoreactive score (IRS) of somatostatin receptor type 2 (SST2) and of estrogen receptor alpha (ERα) was associated with the histological subtype ( = 0.01 and = 0.02). IRS ERα correlated moderately with IRS SST2 in all (rho = 0.44, adjusted -value = 0.0001) and in male (rho = 0.51, adjusted -value = 0.0002) patients, and with follicle-stimulating hormone (FSH) percentage in all (rho = 0.40, adjusted -value = 0.0005) and in female (rho = 0.58, adjusted -value = 0.004) patients. In conclusion, gonadotroph tumors exhibit histological characteristics pinpointing the existence of several subtypes. Their heterogeneity warrants further investigations and may have to be taken into account when studying these tumors and investigating treatment options.
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http://dx.doi.org/10.3390/cancers12041012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226008PMC
April 2020

Pasireotide for acromegaly: long-term outcomes from an extension to the Phase III PAOLA study.

Eur J Endocrinol 2020 Jun;182(6):583

Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Objective: In the Phase III PAOLA study (clinicaltrials.gov: NCT01137682), enrolled patients had uncontrolled acromegaly despite ≥6 months of octreotide/lanreotide treatment before study start. More patients achieved biochemical control with long-acting pasireotide versus continued treatment with octreotide/lanreotide (active control) at month 6. The current work assessed the extent of comorbidities at baseline and outcomes during a long-term extension.

Design/methods: Patients receiving pasireotide 40 or 60 mg at core study end could continue on the same dose in an extension phase if biochemically controlled or receive pasireotide 60 mg if uncontrolled. Uncontrolled patients on active control were switched to pasireotide 40 mg, with the dose increased at week 16 of the extension if still uncontrolled (crossover group). Efficacy and safety are reported to 304 weeks (~5.8 years) for patients randomized to pasireotide (core + extension), and 268 weeks for patients in the crossover group (extension only).

Results: Almost half (49.5%; 98/198) of patients had ≥3 comorbidities at core baseline. During the extension, 173 patients received pasireotide. Pasireotide effectively and consistently reduced GH and IGF-I levels for up to 5.8 years' treatment; 37.0% of patients achieved GH <1.0 µg/L and normal IGF-I at some point during the core or extension. Improvements were observed in key symptoms. The long-term safety profile was similar to that in the core study; 23/173 patients discontinued treatment because of adverse events.

Conclusions: In this patient population with a high burden of comorbid illness, pasireotide was well tolerated and efficacious, providing prolonged maintenance of biochemical control and improving symptoms.
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http://dx.doi.org/10.1530/EJE-19-0762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222286PMC
June 2020

[Checkpoint inhibitors-induced hypophysitis].

Bull Cancer 2020 Apr 19;107(4):490-498. Epub 2020 Mar 19.

Hospices civils de Lyon, fédération d'endocrinologie, 28, avenue Doyen-Lépine, 69677 Bron cedex, France; ImmuCare, institut de cancérologie des hospices civils de Lyon (IDCRC-HCL), Lyon, France; Université de Lyon, université Claude-Bernard-Lyon-1, Lyon, France.

Checkpoint inhibitors immunotherapy is more and more prescribed in oncology, causing new immune related endocrine adverse events. Hypophysitis occurs in approximately 10 % of patients treated with anti-CTLA4. It occurs two to three months after initiation of the immunotherapy. The initial presentation is characterized, in typical forms, by the association of headache, asthenia and hyponatremia. Hormonal exploration usually shows ACTH, gonadotropic and thyrotropic deficiencies. ACTH deficiency may be life-threatening and requires urgent supplementation, without awaiting for biological results. MRI is warranted in order to exclude differential diagnoses, such as pituitary metastases. Hypophysitis induced by anti-PD1/PDL1 seems to be a different nosologic entity characterized by a later onset and a less symptomatic presentation. Biologically ACTH deficiency seems to be constant and permanent, and often isolated. Treatment requires high-dose steroids only in case of severe tumor syndrome (resistant headache, visual disturbance) or acute decompensation of ACTH deficiency. Patients always need lifelong hormonal supplementation of pituitary deficits and must be followed and educated specifically. Immunotherapy can be delayed during the acute phase, but can be secondarily continued if there is an oncological benefit. As it is a pauci-symptomatic but potentially life-threatening complication, biological screening must be systematic in patients treated with checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.bulcan.2020.01.012DOI Listing
April 2020

Metformin and everolimus in neuroendocrine tumours: A synergic effect?

Clin Res Hepatol Gastroenterol 2020 11 4;44(6):954-960. Epub 2020 Mar 4.

Service d'oncologie médicale, hôpital Edouard-Herriot, hospices civils de Lyon, Pavillon E, UJOMM, 69437 Lyon, France; University of Lyon, Univsersité de Lyon 1, Lyon, France. Electronic address:

Objective: To explore potential synergy in effectiveness between metformin and everolimus, 2 inhibitors of the mTOR pathway, for neuroendocrine tumours (NET).

Design And Methods: A cohort of patients with advanced gastroenteropancreatic or lung NETs treated by everolimus were stratified in to those without diabetes, those with diabetes and without metformin, and those with diabetes with metformin. The primary endpoint was the median progression-free survival (PFS).

Results: A total of 213 patients were included, 165 of which were non-diabetic; among diabetic patients, 19 were treated with metformin and 29 with others anti-diabetic drugs. No significant difference in median PFS [95%CI] was found between the three groups: 10.05 months [8.27;11.83] for non-diabetic patients, 15.24 [19.88;49.43] for diabetic w/metformin, and 9.03 months [4.01;14.06] for diabetic w/o metformin group. In univariate analysis, factors significantly associated with longer PFS was a functioning NET, a number of metastatic sites<3, the absence of lung metastasis, and an uptake on Octreoscan®, but not the absence of metformin use; only uptake on Octreoscan® remained significant in multivariate analysis.

Conclusions: In contrast with the literature, we did not find a synergy between everolimus and metformin in NET. Prospective studies are underway to improve the comprehension of the potential synergy regarding population and tumour type.
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http://dx.doi.org/10.1016/j.clinre.2020.02.011DOI Listing
November 2020

Evaluation of the Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Inadequately Controlled With First-Generation Somatostatin Analogs.

Front Endocrinol (Lausanne) 2019 3;10:931. Epub 2020 Feb 3.

Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.

Acromegaly is a rare, serious endocrine disorder characterized by excess growth hormone (GH) secretion by a pituitary adenoma and overproduction of insulin-like growth factor I (IGF-I). Transsphenoidal surgery is the treatment of choice, although many patients require additional interventions. First-generation somatostatin analogs (SSAs) are the current standard of medical therapy; however, not all patients achieve control of GH and IGF-I. Outcomes from a Phase IIIb open-label study of patients with uncontrolled acromegaly on first-generation SSAs switching to pasireotide are reported. Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 μg/L from a five-point profile over 2 h, and IGF-I >1.3× upper limit of normal [ULN]) despite ≥3 months' treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be increased (maximum: 60 mg/28 days) after week 12 if biochemical control was not achieved, or decreased (minimum: 10 mg/28 days) for tolerability. Patients who completed 36 weeks' treatment could continue receiving pasireotide during an extension (weeks 36-72) when concomitant medication for acromegaly was permitted. Primary endpoint was proportion of patients with mGH <1 μg/L IGF-I 2.5 μg/L. For patients who entered the extension, 14.8% (95% CI: 8.1-23.9), 12.5% (95% CI: 6.4-21.3), 14.8% (95% CI: 8.1-23.9) and 11.4% (95% CI: 5.6-19.9) had mGH <1 μg/L and IGF-I
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http://dx.doi.org/10.3389/fendo.2019.00931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008501PMC
February 2020

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors.

Endocr Connect 2020 Feb 1. Epub 2020 Feb 1.

H Lasolle, Service d'Endocrinologie, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Objective: Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas having ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in 5 patients.

Design: Retrospective cohort study.

Methods: Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB-4, Abcam, IRS>1 being considered positive) and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations.

Results: SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P=0.04) and had a lower grade (P=0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P=0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P=0.007). Among treated patients, normal urinary free cortisol levels were obtained in 3 patients (IRS 0, 2, 6) while a 4-fold decrease was observed in one patient (IRS 4).

Conclusion: SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.
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http://dx.doi.org/10.1530/EC-20-0035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077525PMC
February 2020

How to Classify the Pituitary Neuroendocrine Tumors (PitNET)s in 2020.

Cancers (Basel) 2020 02 22;12(2). Epub 2020 Feb 22.

Pathological Department, Foch Hospital, 40 rue Worth Suresnes 92151, France.

Adenohypophyseal tumors, which were recently renamed pituitary neuroendocrine tumors (PitNET), are mostly benign, but may present various behaviors: invasive, "aggressive" and malignant with metastases. They are classified into seven morphofunctional types and three lineages: lactotroph, somatotroph and thyrotroph (PIT1 lineage), corticotroph (TPIT lineage) or gonadotroph (SF1 lineage), null cell or immunonegative tumor and plurihormonal tumors. The WHO 2017 classification suggested that subtypes, such as male lactotroph, silent corticotroph and Crooke cell, sparsely granulated somatotroph, and silent plurihormonal PIT1 positive tumors, should be considered as "high risk" tumors. However, the prognostic impact of these subtypes and of each morphologic type remains controversial. In contrast, the French five-tiered classification, taking into account the invasion, the immuno-histochemical (IHC) type, and the proliferative markers (Ki-67 index, mitotic count, p53 positivity), has a prognostic value validated by statistical analysis in 4 independent cohorts. A standardized report for the diagnosis of pituitary tumors, integrating all these parameters, has been proposed by the European Pituitary Pathology Group (EPPG). In 2020, the pituitary pathologist must be considered as a member of the multidisciplinary pituitary team. The pathological diagnosis may help the clinician to adapt the post-operative management, including appropriate follow-up and early recognition and treatment of potentially aggressive forms.
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http://dx.doi.org/10.3390/cancers12020514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072139PMC
February 2020

Evolution of macroprolactinomas during pregnancy: A cohort study of 85 pregnancies.

Clin Endocrinol (Oxf) 2020 05 4;92(5):421-427. Epub 2020 Feb 4.

Service d'Endocrinologie - Diabète - Nutrition, Centre Hospitalier Universitaire de Reims, Reims, France.

Objective: Pregnancy in patients with macroprolactinomas has been associated with a higher risk of pituitary tumour growth. However, the incidence and risk factors remain unclear. We aimed to evaluate the evolution of macroprolactinomas during pregnancy and to identify potential risk factors.

Design, Patients And Measurements: This is a two-centre, retrospective, observational study. All patients with macroprolactinomas, treated with a dopamine receptor agonist (DA), and who had at least one pregnancy were included.

Results: There were a total of 85 viable pregnancies in 46 patients with macroprolactinomas. At diagnosis, mean size of pituitary adenomas was 17.9 ± 8.2 mm (10-43 mm) and mean plasma prolactin level was 1012.2 ± 1606.1 µg/L (60-7804 µg/L). Tumour growth-related symptoms were identified 12 times in 9 patients (19.6%) including 3 cases of apoplexy. Restarting, changing and/or increasing DA treatment was effective in 10 cases. Emergency surgery had to be performed twice (due to pituitary apoplexy). Patients with tumour progression tended to present with larger tumours after initial treatment and before pregnancy (9.9 vs 5.9 mm; P = .0504 and 11.5 vs 7.3 mm; P = .0671, respectively), whereas adenoma size at diagnosis did not seem to be a significant factor. The obstetrical outcomes were comparable to the general population.

Conclusions: Symptomatic growth of macroprolactinoma during pregnancy occurred in 19.6% of medically treated patients. This risk seems higher for patients with poor initial tumour response to the DA treatment. Tumour progression is generally well controlled with medical treatment during pregnancy.
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http://dx.doi.org/10.1111/cen.14162DOI Listing
May 2020

Current status and treatment modalities in metastases to the pituitary: a systematic review.

J Neurooncol 2020 Jan 13;146(2):219-227. Epub 2020 Jan 13.

Department of Skull Base and Pituitary Surgery, Neurological Hospital Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France.

Background: Metastases to the pituitary (MP) are uncommon, accounting for 0.4% of intracranial metastases. Through advances in neuroimaging and oncological therapies, patients with metastatic cancers are living longer and MP may be more frequent. This review aimed to investigate clinical and oncological features, treatment modalities and their effect on survival.

Methods: A systematic review was performed according to PRISMA recommendations. All cases of MP were included, excepted primary pituitary neoplasms and autopsy reports. Descriptive and survival analyses were then conducted.

Results: The search identified 2143 records, of which 157 were included. A total of 657 cases of MP were reported, including 334 females (50.8%). The mean ± standard deviation age was 59.1 ± 11.9 years. Lung cancer was the most frequent primary site (31.0%), followed by breast (26.2%) and kidney cancers (8.1%). Median survival from MP diagnosis was 14 months. Overall survival was significantly different between lung, breast and kidney cancers (P < .0001). Survival was impacted by radiotherapy (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.35-0.67; P < .0001) and chemotherapy (HR 0.58; 95% CI 0.36-0.92; P = .013) but not by surgery. Stereotactic radiotherapy tended to improve survival over conventional radiotherapy (HR 0.66; 95% CI 0.39-1.12; P = .065). Patients from recent studies (≥ 2010) had longer survival than others (HR 1.36; 95% CI 1.05-1.76; P = .0019).

Conclusion: This systematic review based on 657 cases helped to better identify clinical features, oncological characteristics and the effect of current therapies in patients with MP. Survival patterns were conditioned upon primary cancer histologies, the use of local radiotherapy and systemic chemotherapy, but not by surgery.
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http://dx.doi.org/10.1007/s11060-020-03396-wDOI Listing
January 2020

Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.

J Clin Endocrinol Metab 2020 03;105(3)

INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris.

Introduction: Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far.

Methods: This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation.

Results: The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype.

Conclusion: This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.
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http://dx.doi.org/10.1210/clinem/dgaa002DOI Listing
March 2020

Definition and diagnosis of aggressive pituitary tumors.

Rev Endocr Metab Disord 2020 Jun;21(2):203-208

"Groupement Hospitalier Est" Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677, Bron, France.

Pituitary adenomas are considered benign tumors, but approximately 10% of them can have an aggressive behavior and more rarely (0.2%) can present metastasis, being classified as pituitary carcinomas. Aggressive adenomas are generally large and invasive tumors that present unusually rapid growth and/or that grow irrespective of conventional treatment with surgery, medical therapy and radiotherapy. Nevertheless, large tumors, as well as invasive tumors are not always aggressive, with this definition being possible only after clinical follow-up of these tumors, with growth rate and response to therapies being key points to its diagnosis. The correct identification and diagnosis of aggressive adenomas is of great importance as they are associated with great morbidity and increased mortality.
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http://dx.doi.org/10.1007/s11154-019-09531-xDOI Listing
June 2020

The Microenvironment of Pituitary Tumors-Biological and Therapeutic Implications.

Cancers (Basel) 2019 Oct 21;11(10). Epub 2019 Oct 21.

Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, 69008 Lyon, France, (M.D.I.).

The tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics.
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http://dx.doi.org/10.3390/cancers11101605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826349PMC
October 2019

A Somatostatin Receptor Subtype-3 (SST) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors.

Clin Cancer Res 2020 02 17;26(4):957-969. Epub 2019 Oct 17.

Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.

Purpose: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST and SST. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST-agonists and characterize their effects on experimental NFPT models.

Experimental Design: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST-agonist.

Results: We successfully identified the first SST-agonist peptides. SST-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis , and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST-agonist treatments. Concurrently, silencing increased cell viability in a subset of NFPTs.

Conclusions: This study demonstrates that SST-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2154DOI Listing
February 2020