Thomas Cuny

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

CONTEXT Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age ≤30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. OBJECTIVE We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. DESIGN The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. PATIENTS AND SETTINGS One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. RESULTS Twenty-one out of 174 (12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. CONCLUSION Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

Somatostatin receptor sst2 gene transfer in human prolactinomas in vitro: impact on sensitivity to dopamine, somatostatin and dopastatin, in the control of prolactin secretion.

OBJECTIVE 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 (38.1±7.4 vs. 0.1±0.1 copy/copy β-Gus) and induced octreotide sst2-mediated PRL suppression that remained lower than that induced by DA. BIM-23A760 inhibited PRL similarly to cabergoline both in the control and sst2-expressing cells. Antagonist experiments confirmed predominant dopaminergic effect in dopastatin activity. CONCLUSION sst2 was successfully overexpressed in prolactinomas. However BIM-23A760 was unable to enhance PRL suppression underlining a predominant dopaminergic contribution in its action.

Robot-assisted adrenalectomy.

Currently laparoscopic adrenalectomy (LA) is regarded as the preferred surgical approach for the management of most adrenal surgical disorders. Despite the benefits of LA, the procedure has shortcomings that are shared by other laparoscopic techniques. Commonly noted problems include the absence of 3-dimensional perception, reduced dexterity, and poor ergonomics for the surgeon. Recently, robotic technology has been introduced into laparoscopic clinical practice. The requirement for precise surgery in adrenalectomy is important, and the introduction of robotically assisted LA offers new possibilities. This review summarizes current available data regarding robotic adrenalectomy, including its indications, advantages, limitations, and comparison with conventional laparoscopic adrenalectomy. See the videos, Supplemental Digital Content 1, http://links.lww.com/SLE/A33, Supplemental Digital Content 2, http://links.lww.com/SLE/A34 and Supplemental Digital Content 3, http://links.lww.com/SLE/A35.

Physiopathology of somatolactotroph cells: from transduction mechanisms to cotargeting therapy

In pituitary somatolactotroph cells, G protein–coupled receptors and receptor tyrosine kinases binding their specific ligands trigger an enzymatic cascade that converges to MAP kinase activation in the subcellular compartment. Different signaling pathways, such as AC/cAMP/PKA and PI3K/Akt pathways, interact with MAP kinase to regulate key physiological functions, such as hormonal secretion and cell proliferation. Abnormalities affecting these signaling pathways have been identified as preponderant factors of pituitary tumorigenesis. In addition to trans‐sphenoidal surgery, somatostatin analogs are used to control hormonal hypersecretion in GH‐secreting adenomas. However, a subset of these tumors remains uncontrolled with these treatFments, calling for new therapeutic approaches. In these cases, novel multivalent somatostatin analogs or new somatostatin–dopamine chimeric molecules could be of interest. Another attractive therapeutic approach may be to use one or several inhibitors acting downstream in the signaling pathway, such as mammalian target of rapamycin inhibitor. Cotargeting therapy and gene therapy are promising tools for these problematic pituitary tumors.

Efficacy and safety of denosumab for the treatment of osteoporosis: A systematic review

Denosumab is an anti-RANK ligand (RANKL) monoclonal antibody approved for the treatment of postmenopausal osteoporosis and prevention of skeletal metastasis complications. Administered subcutaneously every 6 months, it reduces the risk of vertebral fracture by 70% and of hip fracture by 40%. Its safety profile is acceptable. Denosumab may be used to treat patients with moderate to severe renal insufficiency. It has anti-fracture activity equivalent to that of zoledronic acid, but no residual effect, and no action at all beyond 6 months. In France, denosumab is reimbursed as a second-line treatment after a first attempt with bisphosphonate.

Endoscopic and robotic parathyroidectomy in patients with primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is one of the most common endocrine disorders for which parathyroidectomy is the most effective therapy. Until late 1970s, the standard approach to parathyroidectomy was a four-gland exploration using a large skin incision. However, 80 to 85 percent of cases of PHPT are caused by a single adenoma. As such, the concept of performing a bilateral exploration in order to visualize all four glands has been argued to be excessive since in the majority of cases, there is only one abnormal gland. Focused exploration (one gland) is currently the standard technique for parathyroidectomy worldwide. Despite a rapid acceptance of minimally invasive approaches in most endocrine surgery centers, the use of an endoscope with or without the use of a robotic system to perform parathyroidectomy remains controversial. The goal of this study was to review current available data about surgical approaches using an endoscope with or without the use of a robotic system in the management of patients with PHPT. For conventional endoscopic and video assisted parathyroidectomy, several comparative studies have demonstrated some advantages in terms of reduced postoperative pain, better cosmetic results and higher patient satisfaction compared to open non-endoscopic minimally invasive parathyroidectomy. Robot-assisted transaxillary parathyroidectomy has the advantage of leaving no scar in the neck but its role has not yet been delineated clearly given the limited number of published series. Subjective postoperative cosmetic evaluation is good by concealing the scar in the axilla or infraclavicular area. However, this approach is associated with more extensive dissection than during conventional open or endoscopic neck access surgical procedures. Patients with true ectopic mediastinal parathyroid glands are good candidates for conventional or robot-assisted thoracoscopic approaches because these glands are in remote and narrow anatomical locations.

Medical therapies in pituitary adenomas: Current rationale for the use and future perspectives

Pituitary adenomas (PA) represent in the majority of cases, benign tumors whose treatment currently associate surgery, medical therapies and radiotherapy in a multidisciplinary approach. While trans-sphenoidal surgery remains, except for prolactin-secreting adenomas, the first-line treatment of PA, it can considerably be hampered by the existence of an invasive and/or aggressive tumor for which medical therapies are often requested. In this review, we extensively discuss, both at molecular and clinical levels, the medical therapies currently used and in development in the different phenotypes of pituitary adenomas.

New avenues for the pharmacological management of type 2 diabetes: An update

Type 2 diabetes mellitus (T2DM) is one of the most troubling chronic disease regarding the huge number of new cases diagnosed annually worldwide. Currently available oral antidiabetic drugs (OADs) attempt to correct the underlying pathophysiological dysfunctions leading to T2DM: insulin resistance for the insulin sensitizers (metformin and thiazolidinediones), and impaired insulin secretion for the insulin secretagogues (sulfonylureas, glinides and more recently incretin mimetics). Incretin-based therapies include GLP-1 receptor agonists that provide pharmacologic levels of GLP-1 receptor stimulation beyond those that would occur from the action of the native hormone alone, and dipeptidyl-peptidase-4 (DPP-4) inhibitors that preserve endogenous GLP-1 by decreasing its degradation by the DPP-4 enzyme. In 2012, the development of new OADs aims to target untapped pathophysiological aspects of the disease (kidney homeostasis, glucagon signalling, chronic low-grade inflammation) for tailoring glycaemic control in T2DM. SGLT-2 inhibitors are the most advanced new OADs that lower HbA1C by increasing glycosuria and lead to a moderate weight loss. Although there is genuine hope that the range of OADs can be extended, a long-term evaluation of side effects and true clinical benefits is necessary.

Robotic lateral transabdominal adrenalectomy.

Laparoscopic transabdominal adrenalectomy is considered to be the standard of care for adrnalectomy. Widespread adoption of robotic technology has positioned robotic adrenalectomy as an option in some medical centers. Many studies have compared laparoscopic versus robotic approaches to perform adrenalectomy and evaluated potential advantages to balance higher costs. This review summarizes current available data regarding the use of the robotic system to perform adrenalectomy (RA) and its comparison with laparoscopic adrenalectomy (LA). J. Surg. Oncol. 2015; 112:305–309.