Purpose: Multiple endocrine neoplasia type 1 (MEN1) is thought to increase the risk of meningioma and ependymoma. Thus, we aimed to describe the frequency, incidence, and specific clinical and histological features of central nervous system (CNS) tumors in the MEN1 population (except pituitary tumors).
Experimental Design: The study population included patients harboring CNS tumors diagnosed with MEN1 syndrome after 1990 and followed up in the French MEN1 national cohort.
Recurrent or high-grade meningiomas are an unmet medical need. Recently, we demonstrated that targeting mTOR by everolimus was relevant both in vitro and in humans. However, everolimus induces an AKT activation that may impact the anti-proliferative effect of the drug.
View Article and Find Full Text PDFForty percent of somatotroph tumors harbor recurrent activating mutations, historically called the oncogene. In -negative somatotroph tumors, expression itself is highly variable; those with overexpression most resemble phenotypically those carrying the oncogene. is monoallelically expressed in the normal pituitary due to methylation-based imprinting.
View Article and Find Full Text PDFPurpose: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect .
View Article and Find Full Text PDFDihydropryimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with severe or lethal toxicities with oral capecitabine. Usually, patients with history of 5-FU-based therapy with no signs for life-threatening toxicities are considered as not DPD-deficient individuals who can be safely treated next with capecitabine if required. Here we describe the case of a woman originally treated with standard FEC100 protocol for metastatic breast cancer with little severe toxicities but grade-3 mucosities that were quickly resolved by symptomatic treatment.
View Article and Find Full Text PDFCytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic.
View Article and Find Full Text PDFTherapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory.
View Article and Find Full Text PDFPegvisomant (PEG), an antagonist of growth hormone (GH)-receptor (GHR), normalizes insulin-like growth factor 1 (IGF1) oversecretion in most acromegalic patients unresponsive to somatostatin analogs (SSAs) and/or uncontrolled by transsphenoidal surgery. The residual GH-secreting tumor is therefore exposed to the action of circulating PEG. However, the biological effect of PEG at the pituitary level remains unknown.
View Article and Find Full Text PDFTo test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients. Blocking expression of endogenous PIT-1 induced a marked decrease of cell proliferation. Overexpressing PITWT twofold led also to a dose-dependent decrease of cell proliferation that was accompanied by cell death.
View Article and Find Full Text PDFBackground & Aims: The KRAS gene is mutated in most pancreatic ductal adenocarcinomas (PDAC). Expression of this KRAS oncoprotein in mice is sufficient to initiate carcinogenesis but not progression to cancer. Activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is required for KRAS for induction and maintenance of PDAC in mice.
View Article and Find Full Text PDFObjective: As prolactinomas fail to respond to dopamine agonist (DA) in 10-20% of cases, we hypothesized that somatostatin subtype 2 receptor (sst2) overexpression in DA-resistant prolactinomas may enhance suppression of prolactine (PRL) using chimeric agonist (dopastatin) that simultaneously binds sst2 and the dopamine subtype 2 receptor (D2DR).
Design And Methods: PRL suppression by octreotide, sst5 agonist, sst2-D2DR agonist (BIM-23A760 dopastatin) and cabergoline was assessed in primary cultures of seven DA-resistant prolactinomas overexpressing sst2.
Results: sst2 was effectively overexpressed via adenoviral expression in prolactinomas (38.
The treatment of growth hormone (GH)- and prolactin (PRL)-secreting tumors resistant to current therapeutic molecules (somatostatin and dopamine analogues) remains challenging. To target these tumors specifically, we chose to inactivate a gene coding for a crucial factor in cell proliferation and hormonal regulation, specifically expressed in pituitary, by using a dominant-negative form of this gene involved in human pituitary deficiencies: transcription factor Pit-1 (POU1F1) mutated on arginine 271 to tryptophan (R271W). After lentiviral transfer, the effect of R271W was studied in vitro on human tumoral somatotroph and lactotroph cells and on the murine mammosomatotroph cell line GH4C1 and in vivo on GH4C1 subcutaneous xenografts in nude mice.
View Article and Find Full Text PDFNonfunctioning pituitary adenomas (NFPA; gonadotroph derived), even not inducing hormonal hypersecretion, cause significant morbidity by compression neighboring structures. No effective and specific medical methods are available so far for treating these tumors. The pituitary homeobox 2 (PITX2) gene is a member of the bicoid-like homeobox transcription factor family, which is involved in the Wnt/Dvl/β-catenin pathway.
View Article and Find Full Text PDFBackground: Germline RET gene mutations are well known to be the genetic causes of multiple endocrine neoplasia type 2 (MEN2) and may be identified by genetic screening.
Aim: The purpose of the present study was to screen nine MTC patients for RET sequence changes.
Materials And Methods: In this study, our sample was composed of 30 individuals: 9 index patients with medullary thyroid carcinoma (MTC) corresponding either to 3 subjects with clinical evidence of MEN2, 6 with apparently sporadic MTC (sMTC), and 21 relatives have been investigated for RET mutations.
In human somatotroph adenomas, growth hormone (GH) hypersecretion can be inhibited by somatostatin analogues such as octreotide. Unfortunately, serum GH levels reach normal values in only 60% of treated patients. The decreased sensitivity to octreotide is strongly related to a lower expression of somatostatin receptor sst2.
View Article and Find Full Text PDFAim And Background: To show results of the first year of an infection surveillance network for haemodialysis patients (Dialin). In order to improve the security and quality of care, six haemodialysis centers have organized an infection watching network. The purpose of the network is to compare of the watching results between centers.
View Article and Find Full Text PDFBackground And Objectives: Imatinib mesylate induces a complete cytogenetic response (CCR) in many patients with chronic myeloid leukemia (CML). However, the ultimate goal of therapy for CML is complete elimination of Philadelphia chromosome positive cells or BCR-ABL rearrangements. We studied molecular responses in CML patients in CCR after imatinib treatment.
View Article and Find Full Text PDFDespite important advances in human therapeutics, no specific treatment for both non-functioning gonadotroph and resistant somatotroph adenomas is available. Gene transfer by viral vectors can be considered as a promising way to achieve a specific and efficient treatment. Here we show the possibility of efficient gene transfer in human pituitary adenoma cells in vitro using a human immunodeficiency virus (HIV)-type 1-derived vector.
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