Brown J.K.,Harvard University |
Miller K.K.,Neuroendocrine Unit
Radiology | Year: 2015
Purpose: To test the performance of dual-energy computed tomography (CT) in the assessment of marrow adipose tissue (MAT) content of the lumbar spine by using proton (hydrogen 1 [1H]) magnetic resonance (MR) spectroscopy as a reference standard and to determine the influence of MAT on the assessment of bone mineral density (BMD). Materials and Methods: This study was institutional review board approved and complied with HIPAA guidelines. Written informed consent was obtained. Twelve obese osteopenic but otherwise healthy subjects (mean age 6 standard deviation, 43 years 6 13) underwent 3-T 1H MR spectroscopy of the L2 vertebra by using a point-resolved spatially localized spectroscopy sequence without water suppression. The L2 vertebra was scanned with dual-energy CT (80 and 140 kV) by using a dual-source multi-detector row CT scanner with a calibration phantom. Mean basis material composition relative to the phantom was estimated in the L2 vertebra. Volumetric BMD was measured with and without correction for MAT. Bland-Altman 95% limits of agreement and Pearson correlation coefficients were calculated. Results: There was excellent agreement between 1H MR spectroscopy and dual-energy CT, with a mean difference in fat fraction of 20.02 between the techniques, with a 95% confidence interval of 20.24, 0.20. There was a strong correlation between marrow fat fraction obtained with 1H MR spectroscopy and that obtained with dual-energy CT (r = 0.91, P , .001). The presence of MAT led to underestimation of BMD, and this bias increased with increasing MAT content (P , .001). Conclusion: Dual-energy CT can be used to assess MAT content and BMD of the lumbar spine in a single examination and provides data that closely agree and correlate with 1H MR spectroscopy data. © RSNA, 2015.
PubMed | OPKO BiologicsKiryat Gat, Charité - Medical University of Berlin, Internal Clinic in University Hospital St AnnaBrno, Ludwig Maximilians University of Munich and 2 more.
Type: Journal Article | Journal: European journal of endocrinology | Year: 2016
Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This studys objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults.54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.
News Article | November 10, 2016
SAN DIEGO, Nov. 10, 2016 (GLOBE NEWSWIRE) -- Crinetics Pharmaceuticals ("Crinetics"), an innovative therapeutics company focused on specialty endocrine disorders and endocrine-related cancers, announced today the addition of Anne Klibanski, M.D. as a member of the company's scientific advisory board. "I am excited to be a part of this growing team that is working to study and develop effective oral therapies for acromegaly and other neuroendocrine tumors," said Dr. Klibanski. "The ultimate goal is to find treatments and cures for the wide range of neuroendocrine diseases and improve the lives of patients suffering from these serious conditions." "We continue to assemble a world-class team with expertise in creating and developing innovative therapeutics for specialty endocrine disorders," said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. "We are excited to welcome Dr. Klibanski to the scientific advisory board of Crinetics Pharmaceuticals. She is an internationally-recognized leader in neuroendocrinology and complements our team as we grow Crinetics into a clinical-stage therapeutics company." Dr. Klibanski is the director of the Neuroendocrine and Pituitary Tumor Clinical Center and chief of the Neuroendocrine Unit at Massachusetts General Hospital, and the Laurie Carrol Guthart Professor of Medicine at Harvard Medical School. She is a clinical researcher who studies pituitary tumor pathogenesis and the impact that pituitary and hypothalamic disorders have on body composition, including low bone mass. Awards in recognition of her work have included The Endocrine Society Clinical Investigator Award and the British Trust Medal. She is the author of more than 350 peer-reviewed publications and has served on the NIH NIDDK Board of Counselors and on the Editorial Board of the Journal of Clinical Endocrinology and Metabolism. She is past-president of the Pituitary Society and serves on its board. She has been involved in leadership positions of many educational programs sponsored by the Endocrine Society, the Pituitary Society, and many patient advocacy groups to teach physicians and patients about pituitary tumors and neuroendocrine disorders. She has a B.A. from Barnard College and an M.D. from New York University School of Medicine. About Crinetics Pharmaceuticals Crinetics Pharmaceuticals discovers and develops novel therapeutics targeting peptide hormone receptors for the treatment of specialty endocrine disorders and endocrine-related cancers. Its pioneering small molecule somatostatin agonist program for the treatment of acromegaly and neuroendocrine tumors aims to provide a convenient, more effective oral therapy for patients whose only current options are painful injected depot drugs. Crinetics was founded by a team of scientists with a proven track record of endocrine drug discovery and development to create important new therapeutic options for endocrinologists and their patients. The company is backed by top life sciences investors, 5AM Ventures, Versant Ventures, and Vivo Capital and is headquartered in San Diego. For more information, please visit www.crinetics.com.
Tritos N.A.,Neuroendocrine Unit |
Eppakayala S.,Neuroendocrine Unit |
Swearingen B.,Massachusetts General Hospital |
Swearingen B.,Harvard University |
And 7 more authors.
Pituitary | Year: 2013
Patients with thyrotropin-secreting pituitary adenomas may present with mass effect, hypopituitarism, and/or hyperthyroidism. The spectrum of pathologic and clinical features of patients whose tumors demonstrate β-thyrotropin immunoreactivity (β-TSH IR) has not been characterized. To characterize the phenotype of patients with pituitary adenomas with positive β-TSH IR, we conducted a retrospective analysis of patient records of all adult patients (n = 1,223) undergoing pituitary surgery in our institution over one decade (1999-2009). The search identified 166 adults with tumors which had β-TSH IR. These patients were individually matched to 166 patients whose tumors revealed no β-TSH IR. Clinical, pathological, imaging and biochemical data were extracted. 332 patients, aged 51.4 ± 15.1 years [150 women (45 %) and 182 men (55 %)], with pituitary adenomas (mean tumor diameter ± SD: 22.7 ± 9.0 mm) were studied. The degree of β-TSH IR was associated with the presence of central hyperthyroidism (p < 0.0001) or goiter (p = 0.0217). Patients whose tumors expressed more extensive β-TSH IR were less likely to develop pituitary apoplexy than those without β-TSH IR (p = 0.0428). In addition, the degree of β-TSH IR correlated with the presence of immunoreactivity for β-FSH (p < 0.0001), β-LH (p < 0.0001), alpha subunit (p < 0.0001), and GH (p = 0.0036). Conclusions: Pituitary adenomas expressing β-TSH IR were more likely to demonstrate immunoreactivity for β-FSH, β-LH, GH or alpha subunit. Patients with such tumors were more likely to exhibit hyperthyroidism and goiter, but less likely to develop pituitary apoplexy than patients without β-TSH IR. These findings suggest that β-TSH IR is associated with specific phenotypic features in patients with pituitary adenomas. © 2012 Springer Science+Business Media, LLC.
Perello M.,Neuroendocrine Unit |
Giovambattista A.,Neuroendocrine Unit |
Castrogiovanni D.,Neuroendocrine Unit |
Gaillard R.C.,University of Lausanne |
Spinedi E.,Neuroendocrine Unit
NeuroImmunoModulation | Year: 2011
The aim of this study was to evaluate the effect of ovariectomy on the acute-phase response of inflammatory stress. Ex vivo adrenocortical, peripheral mononuclear cell (PMNC) and adipocyte activities were studied in intact and ovariectomized mice. Endotoxemia was mimicked by intraperitoneal administration of bacterial lipopolysaccharide (LPS; 25 mg per mouse) to sham-operated and 21-day ovariectomized mice. Circulating corticosterone, tumor necrosis factor-α (TNFα) and leptin concentrations were monitored before and 30-120 min after the administration of LPS. Additionally, in vitro experiments were performed with isolated corticoadrenal cells, PMNCs and omental adipocytes from sham-operated and ovariectomized mice incubated with specific secretagogues. The results indicate that while ovariectomy enhanced TNFα secretion after in vivo administration of LPS, it reduced corticoadrenal response and abrogated LPS-elicited leptin secretion into the circulation. While the corticoadrenal sensitivity to ACTH stimulation was reduced by ovariectomy, the LPS-induced PMNC response was not affected. Exogenous leptin enhanced baseline PMNC function regardless of surgery. Finally, ovariectomy drastically reduced in vitro adipocyte functionality. Our data support the notion that ovariectomy modified neuroendocrine-immune-adipocyte axis function and strongly suggest that ovarian activity could play a pivotal role in the development of an adequate immune defense mechanism after injury. Copyright © 2010 S. Karger AG, Basel.
Zacharia B.E.,Pancreas Center at Columbia |
Gulati A.P.,Pancreas Center at Columbia |
Bruce J.N.,Pancreas Center at Columbia |
Carminucci A.S.,Pancreas Center at Columbia |
And 6 more authors.
Neurosurgery | Year: 2014
Background and importance: Rarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors. Clinical presentation: We present a case series of 4 patients with aggressive, adrenocorticotrophic hormone-producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for > 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM. Conclusion: This is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.
Doknic M.,Neuroendocrine Unit |
Stojanovic M.,Neuroendocrine Unit |
Popovic V.,Neuroendocrine Unit
Pediatric Endocrinology Reviews | Year: 2014
Background: Growth hormone (GH) treatment currently requires years of treatment. Maintaining full compliance with daily injections has been difficult. Teens have the highest rate of non-concordance (missing injections 1-2 per week). In adults the rate of low concordance (low IGF1) rises with each year of treatment. Improving compliance to GH therapy by less burdensome means of GH replacement can be achieved either by changing GH delivery frequency (weekly, monthly) or by changing injection device characteristics (minimal preparation, easy setting, minimal pain, automatic needle insertion, needle free devices).Long acting formulations: Long-acting forms of GH have been developed either as sustained-release preparations of GH (Nutropin-depot, which has been withdrawn in 2004 and LB 03002 once weekly GH, which has received a positive opinion by CHMP of EMA in early 2013) or as the conjugated analogues which prolong the half life of GH. Currently a variety of modified GH molecules which delay GH clearance (CTP modified GH, recombinant polypeptide XTEN, GH conjugated with albumin, GH linked to immunoglobulin) are studied and the ongoing studies are in different phases (from I-III). Each of these preparations has been tested in experimental animal models.Efficacy and safety: Although different types of formulations have been studied, all are pharmacokinetically and pharmacodynamically effective in extending GH action and result in prolonged increase in IGF-I concentrations. Clinical data are available for once-weekly sustained-release GH treatment and the data show beneficial effects in adults with GH deficiency over a 12 month period and adequate growth rate in pre-pubertal children with GH deficiency over the period of three-years.Conclusions: Clinical data are still very limited. Available short term studies show that treatment with long-acting GH preparation is effective and safe in GH deficient children and adults. A different physiology underlies the long-acting GH and we still need to improve our knowledge about these formulations of GH. Long-term studies are needed to confirm the value and safety (greater exposure to GH) of these agents.