BackgroundPituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause.Objectivesi) To compare ...subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS.Study designWe analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes.ResultsPSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS.ConclusionPSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases.
Although growth hormone (GH)‐ and prolactin (PRL)‐secreting pituitary adenomas are considered benign, in many patients, tumour growth and/or invasion constitute a particular challenge. In other ...tumours, progression relies in part on dysfunction of intercellular adhesion mediated by the large family of cadherins. In the present study, we have explored the contribution of cadherins in GH and PRL adenoma pathogenesis, and evaluated whether this class of adherence molecules was related to tumour invasiveness. We have first established, by quantitative polymerase chain reaction and immunohistochemistry, the expression profile of classical cadherins in the normal human pituitary gland. We show that the cadherin repertoire is restricted and cell‐type specific. Somatotrophs and lactotrophs express mainly E‐cadherin and cadherin 18, whereas N‐cadherin is present in the other endocrine cell types. This repertoire undergoes major differential modification in GH and PRL tumours: E‐cadherin is significantly reduced in invasive GH adenomas, and this loss is associated with a cytoplasmic relocalisation of cadherin 18 and catenins. In invasive prolactinomas, E‐cadherin distribution is altered and is accompanied by a mislocalisation of cadherin 18, β‐catenin and p120 catenin. Strikingly, de novo expression of N‐cadherin is present in a subset of adenomas and cells exhibit a mesenchymal phenotype exclusively in invasive tumours. Binary tree analysis, performed by combining the cadherin repertoire with the expression of a subset of known molecular markers, shows that cadherin/catenin complexes play a significant role in discrimination of tumour invasion.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the ...prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case–control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (
p
< 0.001;
p
< 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL ...adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency.
Innovative treatments for meningiomas Graillon, T.; Tabouret, E.; Salgues, B. ...
Revue neurologique,
06/2023, Volume:
179, Issue:
5
Journal Article
Peer reviewed
Open access
Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last ...10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Over the last two decades, the understanding of the mechanisms involved in pituitary ontogenesis has largely increased. Since the first description of
POU1F1
human mutations responsible for a ...well-defined phenotype without extra-pituitary malformation, several other genetic defects of transcription factors have been reported with variable degrees of phenotype–genotype correlations. However, to date, despite the identification of an increased number of genetic causes of isolated or multiple pituitary deficiencies, the etiology of most (80–90 %) congenital cases of hypopituitarism remains unsolved. Identifying new etiologies is of importance as a post-natal diagnosis to better diagnose and treat the patients (delayed pituitary deficiencies, differential diagnosis of a pituitary mass on MRI, etc.), and as a prenatal diagnosis to decrease the risk of early death (undiagnosed corticotroph deficiency for instance). The aim of this review is to summarize the main etiologies and phenotypes of combined pituitary hormone deficiencies, associated or not with extra-pituitary anomalies, and to suggest how the identification of such etiologies could be improved in the near future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists has been shown to enhance suppression of GH secretion. In the present study, a new chimeric molecule, BIM-23A387, which ...selectively binds to the SS subtype 2 receptor (sst2; Ki = 0.10 nm) and to the DA D2 receptor (D2DR; Ki = 22.1 nm) was tested in cultures prepared from 11 human GH-secreting tumors for its ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was compared with individual sst2 and D2DR agonists of comparable activity at the individual receptors. All tumors expressed both sst2 and D2DR mRNAs (0.8 ± 0.2 and 4.7 ± 0.7 copy/copy β-glucuronidase mRNA, respectively). In cell cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH release induced by the individual sst2 and D2DR analogs and by BIM-23A387 was similar. However, the mean EC50 for GH suppression by BIM-23A387 (0.2 pm) was 50 times lower than that of the individual sst2 and D2DR analogs, either used individually or combined. Similar data were obtained in four tumors that were only partially responsive to octreotide. The inhibition of GH release by BIM-23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the sst2 antagonist, BIM-23454. Only when both antagonists were combined was the GH suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a mean 73 ± 6% inhibition of PRL in six mixed GH plus PRL tumors. These data demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in suppressing GH and PRL secretion from acromegalic tumors, which cannot be explained merely on the basis of binding affinity for SS and/or DA receptors.
Les phéochromocytomes et les paragangliomes sont des tumeurs rares responsables d’une surmorbidité et d’une surmortalité. Au cours de ces 20 dernières années, de nombreuses avancées ont permis de ...mieux les caractériser sur le plan phénotypique (via l’imagerie métabolique) et génotypique (avec la mise en évidence de nombreux gènes de prédisposition). La prise en charge d’un phéochromocytome ou d’un paragangliome nécessite désormais le recours à un centre expert dès la phase diagnostique. L’objectif de cette revue est de souligner les principales caractéristiques de ces tumeurs, et ce, afin de sensibiliser le clinicien aux différentes étapes permettant d’aboutir à une prise en charge optimale.
Pheochromocytoma and paraganglioma are tumors leading to increased morbidity and mortality. Over the last 20 years, several major advances allowed a better characterization of these tumors, either from an imaging or from a genetic viewpoint. This is especially the case for the hereditary characteristics of these tumors, as roughly 20 new genes have been identified. This is why the initial steps of the management of a pheochromocytoma and/or a paraganglioma now require a dedicated tertiary referral center. The aim of this review is to depict the diagnostic steps of these tumors, so as to allow the clinician to determine the optimal therapeutic strategy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
9.
Acromegaly in Carney complex Cuny, T.; Mac, T. T.; Romanet, P. ...
Pituitary,
10/2019, Volume:
22, Issue:
5
Journal Article
Peer reviewed
Purpose
Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by mucocutaneous pigmentation, cardiac, cutaneous myxomas and endocrine overactivity. It is generally caused by ...inactivating mutations in the
PRKAR1A
(protein kinase cAMP-dependent type I regulatory subunit alpha) gene. Acromegaly is an infrequent manifestation of CNC, reportedly diagnosed in 10% of patients.
Methods
We here report the case of a patient who was concomitantly diagnosed with Carney complex, due to a new mutation in
PRKAR1A
((NM_002734.3:c.80_83del, p.(Ile27Lysfs*101 in exon 2), and acromegaly. In parallel, we conducted an extensive review of published case reports of acromegaly in the setting of CNC.
Results
The 43-year-old patient was diagnosed with an acromegaly due to a GH-secreting pituitary microadenoma resistant to somatostatin analogs. He underwent transsphenoidal surgery in our tertiary referral center, which found a pure GH-secreting adenoma. In the literature, we identified 57 cases (24 men, 33 women) of acromegaly in CNC patients. The median age at diagnosis was 28.8 ± 12 year and there were 6 cases of gigantism. Acromegaly revealed CNC in only 4 patients. 24 patients had a microadenoma and two carried pituitary hyperplasia and/or multiple adenomas, suggesting that CNC may result in a higher proportion of microadenoma as compared to non-CNC acromegaly.
Conclusions
Although it rarely reveals CNC, acromegaly is diagnosed at a younger age in this setting, with a higher proportion of microadenomas.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In mammals, Hippo signaling pathway is responsible for the growth of organs by regulating cell ...proliferation and apoptosis. The tumor suppressor NF2 protein belongs to the core of the Hippo pathway and a defect of its gene is present in 50% of meningiomas. Absence of NF2 keeps Hippo pathway inactive allowing the translocation of YAP/TAZ to the nucleus and the formation of a complex with TEADs. This complex then promotes the transcription of anti-apoptotic and proliferative genes such as CTGF, CYR61 and AXL. Here we present experimental results on human meningioma fragments and primary cell cultures supporting that Hippo pathway plays a critical role in meningioma tumorigenesis.
Material and Methods
The role of the Hippo pathway was studied on 57 meningiomas, well characterized at clinical, histological and molecular level. The genomic profile, target transcripts of the complex YAP/TAZ-TEADs, cell viability, and cell proliferation were analyzed after siRNA transfection targeting YAP, TAZ, YAP+TAZ and TEADs.
Results
Fifty-seven meningiomas were randomly selected including 27 WHO grade II and III tumors. Thirty (53%) presented a defect on the NF2 gene (NF2def) including 19(65%) grade II/III. NF2def meningiomas presented a significant increase of expression levels of Hippo pathway target transcripts CTGF, CYR61 and AXL in comparison with NF2 wild-type tumors (p<0.0001, p=0.0072 and p=0.0191, respectively). This increase was not correlated with the grade, the sex or with the cerebral localization of the meningiomas. On the other side, IHC analysis suggested this increase was correlated with the nuclear localization of YAP. Disturbing the YAP/TAZ-TEADs complex using siRNA on 10 meningiomas (5 NF2 wild-type and 5 NF2 def) induced a significant decrease on cell proliferation but not on cell viability. This decrease was more important when TAZ was turned off in comparison to turning off of YAP.
Conclusion
Our experimental results strongly support the importance of the Hippo pathway in meningioma tumorigenesis, supporting its relevance as a new target in meningioma therapy. A.Barlier reports receiving research grants from Inventiva Pharma. No potential conflicts of interest were disclosed by the other authors.
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