Rare neuroendocrine tumours may be misdiagnosed as Cushing’s disease

Posted on October 31, 2014 by MaryO

By Eleanor McDermid, Senior medwireNews Reporter

Ectopic tumours secreting corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) are very rare in children and can result in a misdiagnosis of Cushing’s disease (CD), say researchers.

Three of the patients in the reported case series had pituitary hyperplasia and underwent transsphenoidal surgery for apparent CD before the tumour that was actually causing their symptoms was located. The hyperplasia was probably caused by release of CRH from the ectopic tumour, which stimulated the pituitary gland, giving the impression of an ACTH-secreting pituitary adenoma, explain Maya Lodish (National Institutes of Health, Bethesda, Maryland, USA) and study co-authors.

These three patients were part of a series of seven, which Lodish et al describe as “a relatively large number of patients, considering the infrequency of this disease.”

The patients were aged between 1.8 and 21.3 years. Three had neuroendocrine tumours located in the pancreas ranging in size from 1.4 to 7.0 cm, two had thymic carcinoids ranging from 6.0 mm to 11.5 cm, one patient had a 12.0 cm tumour in the liver and one had a 1.3 cm bronchogenic carcinoid tumour of the right pulmonary lobe.

Four of the patients had metastatic disease and, during up to 57 months of follow-up, three died of metastatic disease or associated complications and two patients had recurrent disease.

“Our series demonstrates that these are aggressive tumors with a high mortality rate,” write the researchers in the Journal of Clinical Endocrinology & Metabolism. “It is important to follow the appropriate work up, regarding both biochemical and imaging tests, which can lead to the correct diagnosis and to the most beneficial therapeutic approach.”

The team found the CRH stimulation test to be helpful, noting, for example, that none of the patients had a rise in cortisol that was consistent with CD, with all patients showing smaller responses ranging from 2% to 15%. Likewise, just one patient had an ACTH rise higher than 35% on CRH administration, and four patients had a “flat” response, which has previously been associated with ectopic neuroendocrine tumours.

Of note, six patients had normal or high plasma CRH levels, despite all having high cortisol levels, which would be expected to result in undetectable plasma CRH due to negative feedback, implying another source of CRH production. Five patients had blunted diurnal variation of both cortisol and ACTH levels consistent with Cushing’s syndrome.

The patients also underwent a variety of imaging procedures to identify the source of ACTH/CRH production, some of which, such as octreotide scans, are specialist and not available in most hospitals, the researchers note, potentially contributing to inappropriate diagnosis and management.

From http://www.news-medical.net/news/20141030/Rare-neuroendocrine-tumours-may-be-misdiagnosed-as-Cushinge28099s-disease.aspx

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Cushing Syndrome in Children: Growth after Surgical Cure

Posted on October 22, 2014 by MaryO

Cushing syndrome (CS) occurs only rarely in children, but when it does, it causes weight gain and stunting. In young children, adrenal tumors are usually the cause while in adolescents, pituitary tumors are more likely.

The September 2014 issue of Endocrine-Related Cancer examines growth patterns in 19 pediatric patients with ACTH-dependent CS (CD) and 18 patients with a form of ACTH-independent CS, micronodular adrenal hyperplasia (MAH). The researchers gathered data at the time of surgery and also followed up one year later.

Patients in the CD and the MAH groups had similar demographic characteristics, baseline heights and BMI scores before surgery. All patients experienced significant improvements in height and BMI after surgery. Patients with MAH, however, fared significantly better than those with CD and had better post-operative growth.

The researchers propose several reasons:

  • When ACTH-secreting pituitary adenoma requires extensive surgical exploration, remaining pituitary cells often lose some of their function.
  • CD patients tend to be older and have consistent and increased glucocorticoid exposure; they develop vertebral fractures more often leading to compromised skeletal and overall growth potential. MAH patients often have cyclical CS, with intermittent hypercortisolism and an overall milder CS.
  • CD patients often need a longer-than-expected course of therapy with steroids after surgery, which alters metabolism and growth.
  • CD patients have been shown to have advance bone age because of ACTH-induced metabolic changes.

The authors indicate that CS patients are often considered for growth hormone therapy once the underlying problem is corrected. They remind clinicians that MAH patients are less likely to need growth hormone. They recommend close monitoring for CD patients, and early intervention with growth hormone if growth does not meet expectation. –

See more at: http://www.hcplive.com/articles/Cushing-Syndrome-in-Children-Growth-after-Surgical-Cure

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Utility of measurement of dexamethasone levels in the diagnostic testing for Cushing’s syndrome

Posted on June 21, 2014 by MaryO

From Day 1 of the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting and Expo »

Chicago, IL – June 21, 2014

ST Sharma, JA Yanovski, SB Abraham, LK Nieman

Summary: Dexamethasone (dex) suppression tests (DST) are used for screening and differential diagnosis of Cushing’s syndrome (CS). The 1 mg overnight (LD) DST is used to diagnose CS, the dex-suppressed CRH stimulation (Dex-CRH) test to differentiate CS from pseudocushings (PCS) while the 8 mg overnight (HD) DST is used to differentiate Cushing’s disease (CD) from ectopic ACTH syndrome (EAS). Researchers assessed the utility of dex levels in improving the diagnostic accuracy of these tests and they found that low dex and high CBG levels can account for false positive (FP) DST and Dex-CRH test results. Use of a higher dex dose in pts with low dex levels can help decrease FP results.

Methods:

  • This is a retrospective study of patients (pts) with CS, PCS and normal volunteers (NV) who had a dex level measured as part of LDDST, HDDST or Dex-CRH test.
  • A post-dex cortisol (F) level ≥1.8 mcg/dl in the LDDST and a 15 min post-CRH F level ≥1.4 mcg/dl in the Dex-CRH test suggested CS.
  • A ≥69% suppression of F levels in HDDST indicated CD.
  • Dex levels

Results:

  • LDDST (n=77): Post-dex F was abnormal in 44 pts, 37 of these did not have CS on follow-up.
  • Proportion of pts with low dex levels was similar in those with incorrect or correct LDDST results (P=0.7).
  • Three of 5 pts with an abnormal result and low dex levels (44-117 ng/dl) had suppressed post-dex F levels after a 2 mg overnight DST. HDDST (N=56): Results were not consistent with the final diagnosis (CD or EAS) in 13 (23%) pts.
  • Of these, 5 had low dex levels (400-1220 ng/dl).
  • Proportion of pts with low dex levels was similar between those with correct and incorrect HDDST results (P=0.5).
  • HDDST in 1 pt with ACTH-dependent CS suggested EAS (28% suppression) with low dex level.
  • IPSS indicated CD.
  • After a doubled dex dose (16 mg), F levels suppressed by 76%, changing the HDDST result to CD.
  • Dex-CRH (n=139): Results were consistent with the final diagnosis in 133 pts (74 CS, 20 NV, 39 PCS).
  • Six pts with an abnormal result had dex levels
  • Of these, repeat testing with doubled dex dose (1 mg every 6 hours) in 2 pts led to higher dex levels (610, 757 ng/dl) and normal F level in one.
  • Two pts with abnormal result were on OCPs, 1 with a known high cortisol binding globulin (CBG) level.
  • None had CS on follow-up.
  • There was no correlation between dex and post-dex F levels in LDDST, 15 min post-CRH F levels in Dex-CRH test and % suppression of F post-dex in HDDST (P=NS).

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Global Pituitary ACTH Hypersecretion (Cushing’s Disease) Therapeutics Pipeline Review 2014

Posted on June 3, 2014 by MaryO

DUBLIN–(BUSINESS WIRE)–Research and Markets (http://www.researchandmarkets.com/research/zp4qhh/pituitary_acth) has announced the addition of the “Pituitary ACTH Hypersecretion (Cushing’s Disease) – Pipeline Review, H1 2014” report to their offering.

“Pituitary ACTH Hypersecretion (Cushing’s Disease) – Pipeline Review, H1 2014”

This report provides comprehensive information on the therapeutic development for Pituitary ACTH Hypersecretion (Cushing’s Disease), complete with comparative analysis at various stages, therapeutics assessment by drug target, mechanism of action (MoA), route of administration (RoA) and molecule type, along with latest updates, and featured news and press releases. It also reviews key players involved in the therapeutic development for Pituitary ACTH Hypersecretion (Cushing’s Disease) and special features on late-stage and discontinued projects.

The report enhances decision making capabilities and help to create effective counter-strategies to gain competitive advantage. It strengthens R&D pipelines by identifying new targets and MOAs to produce first-in-class and best-in-class products.

Scope

  • The report provides a snapshot of the global therapeutic landscape of Pituitary ACTH Hypersecretion (Cushing’s Disease)
  • The report reviews key pipeline products under drug profile section which includes product description, MoA and R&D brief, licensing and collaboration details & other developmental activities
  • The report reviews key players involved in the therapeutics development for Pituitary ACTH Hypersecretion (Cushing’s Disease) and enlists all their major and minor projects
  • The report summarizes all the dormant and discontinued pipeline projects
  • A review of the Pituitary ACTH Hypersecretion (Cushing’s Disease) products under development by companies and universities/research institutes based on information derived from company and industry-specific sources
  • Pipeline products coverage based on various stages of development ranging from pre-registration till discovery and undisclosed stages
  • A detailed assessment of monotherapy and combination therapy pipeline projects
  • Coverage of the Pituitary ACTH Hypersecretion (Cushing’s Disease) pipeline on the basis of target, MoA, route of administration and molecule type
  • Latest news and deals relating related to pipeline products

Companies Involved in Therapeutics Development

  • Isis Pharmaceuticals, Inc.
  • Ipsen S.A.
  • Novartis AG
  • Corcept Therapeutics Incorporated
  • HRA Pharma, SA
  • Cortendo Invest AB
  • Orphagen Pharmaceuticals, Inc.
  • ElexoPharm GmbH

Drug Profiles

  • mifepristone
  • ketoconazole
  • pasireotide LAR
  • LCI-699
  • DG-3173
  • ISIS-GCCRRx
  • Next Generation Cortisol Inhibitor
  • Small Molecule to Inhibit CYP11B1 for Cushing Disease
  • Peptides to Antagonize ACTH Receptor for Cushing Syndrome
  • Steroidogenic Factor-1 Antagonists
  • Drug to Inhibit Melanocortin Receptor 2 for Cushing Disease

For more information visit http://www.researchandmarkets.com/research/zp4qhh/pituitary_acth

Contacts

Research and Markets
Laura Wood, Senior Manager.
press@researchandmarkets.com
U.S. Fax: 646-607-1907
Fax (outside U.S.): +353-1-481-1716
Sector: Pharmaceuticals

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Are you carrying adrenal Cushing’s syndrome without knowing it?

Posted on November 28, 2013 by MaryO

Genetic research that will be published tomorrow in the New England Journal of Medicine suggests to Dr. André Lacroix, professor at the University of Montreal, that clinicians’ understanding and treatment of a form of Cushing’s syndrome affecting both adrenal glands will be fundamentally changed, and that moreover, it might be appropriate to begin screening for the genetic mutations that cause this form of the disease.

“Screening family members of bilateral adrenal Cushing’s syndrome patients with  may identify affected silent carriers,” Lacroix said in an editorial in the Journal. “The development of drugs that interrupt the defective genetic chemical link that causes the syndrome could, if confirmed to be effective in people, provide individualized specific therapies for hypercortisolism, eliminate the current practice of removing both , and possibly prevent disease progression in genetically affected .”

Adrenal glands sit above the kidneys are mainly responsible for releasing cortisol, a stress hormone. Hypercortiolism means a high level of the adrenal hormone cortisol, which causes many symptoms including weight gain, , diabetes, osteoporosis, concentration deficit and increased cardiovascular deaths.

Cushing’s syndrome can be caused by corticosteroid use (such as for asthma or arthritis), a tumor on the adrenal glands, or a  that releases too much ACTH. The pituitary gland sits under the brain and releases various hormones that regulate our bodies’ mechanisms.

Jérôme Bertherat is a researcher at Cochin Hospital in Paris. In the study he published today, he showed that 55% of Cushing’s Syndrome patients with bilaterally very enlarged adrenal glands have mutations in a gene that predisposes to the development of adrenal tumours. This means that bilateral adrenal Cushing’s is much more hereditary than previously thought. The new knowledge will also enable clinicians to undertake genetic screening. Hervé Lefebvre is a researcher at the University Hospital in Rouen, France. His research shows that the adrenal glands from the same type of patients with two large adrenal glands can produce ACTH, which is normally produced by the pituitary gland. Hormone receptors are the chemical link that cause a cell to behave differently when a hormone is present. Several misplaced hormone receptors cause the ACTH to be produced in the enlarged benign adrenal tissue. Knowing this means that researchers might be able to develop drugs that interrupt the receptors for these hormones and possibly even prevent the benign tissue from developing in the first place.

 Explore further: Scientists discover a curable cause for some cases of high blood pressure

More information: André Lacroix, M.D., Heredity and Cortisol Regulation in Bilateral Macronodular Adrenal Hyperplasia, New England Journal of Medicine 369;22, November 28, 2013

Estelle Louiset, Ph.D., Céline Duparc, Ph.D., Jacques Young, M.D., Ph.D., Sylvie Renouf, Ph.D., Milène Tetsi Nomigni, M.Sc., Isabelle Boutelet, Ph.D., Rossella Libé, M.D., Zakariae Bram, M.Sc., Lionel Groussin, M.D., Ph.D., Philippe Caron, M.D., Antoine Tabarin, M.D., Ph.D., Fabienne Grunenberger, M.D., Sophie Christin-Maitre, M.D., Ph.D., Xavier Bertagna, M.D., Ph.D., Jean-Marc Kuhn, M.D., Youssef Anouar, Ph.D., Jérôme Bertherat, M.D., Ph.D., and Hervé Lefebvre, M.D., Ph.D., Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia, New England Journal of Medicine 369;22, November 28, 2013

Guillaume Assié, M.D., Ph.D., Rossella Libé, M.D., Stéphanie Espiard, M.D., Marthe Rizk-Rabin, Ph.D., Anne Guimier, M.D., Windy Luscap, M.Sc., Olivia Barreau, M.D., Lucile Lefèvre, M.Sc., Mathilde Sibony, M.D., Laurence Guignat, M.D., Stéphanie Rodriguez, M.Sc., Karine Perlemoine, B.S., Fernande René-Corail, B.S., Franck Letourneur, Ph.D., Bilal Trabulsi, M.D., Alix Poussier, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Françoise Borson-Chazot, M.D., Ph.D., Lionel Groussin, M.D., Ph.D., Xavier Bertagna, M.D., Constantine A. Stratakis, M.D., Ph.D., Bruno Ragazzon, Ph.D., and Jérôme Bertherat, M.D., Ph.D., ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing’s Syndrome, New England Journal of Medicine 369;22, November 28, 2013

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