Call for Papers: Cushing’s Syndrome: New Evidence and Future Challenges

Posted on November 13, 2014 by MaryO

Call for Papers

Cushing’s syndrome is a rare and potentially lethal disease which still represents a challenge for the endocrinologists, being characterized by elevated morbidity even long-term after the remission of hypercortisolism. Several diagnostic issues prevent an early recognition of the disease and rate of recurrence is significantly high after surgical, medical, or radiotherapy management.

Recent advances of biology and medicine are improving our knowledge on genetics and pathophysiology of this disease, both at the pituitary and adrenal level. New therapeutic agents are currently under investigation and an impelling need for efficacy and safety studies is rising in the endocrinology community. At the same time, the role of the “old” agents in the clinical practice is under debate and deserves a thorough analysis on larger series than those currently available. Likewise, the need for specific treatment of comorbidities is a clinical question which still remains unsolved.

We invite authors to submit original research and review articles that will stimulate the continuing efforts to understand the molecular pathology underlying Cushing’s syndrome, the development of strategies to diagnose and treat this condition in adults and children, and the evaluation of outcomes.

Potential topics include, but are not limited to:

  • Advances in genetics of Cushing’s syndrome
  • Diagnostic issues in Cushing’s syndrome
  • Novel paradigms for treatment of Cushing’s syndrome
  • Role of the “old” pharmacological agents in the treatment of Cushing’s syndrome
  • Persistent increased mortality and morbidity after “cure” of Cushing’s syndrome
  • Role of inflammation in the pathogenesis of Cushing’s syndrome
  • Cushing’s syndrome as model of metabolic derangements
  • Challenges in the diagnosis and treatment of paediatric Cushing’s syndrome
Manuscript Due Friday, 8 May 2015
First Round of Reviews Friday, 31 July 2015
Publication Date Friday, 25 September 2015

Lead Guest Editor

  • Elena Valassi, Autonomous University of Barcelona, Barcelona, Spain

Guest Editors

From http://www.hindawi.com/journals/ije/si/156126/cfp/

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Cortendo gains $11M for late-stage Cushing’s study

Posted on October 31, 2014 by MaryO

Cortendo is coming to America. Founded in Sweden, the little biotech has a new CEO who’s building the executive team in the Philadelphia area. And he’s dropping plans for a listing on the Oslo exchange in favor of a U.S. IPO after raising $11 million in bridge financing.

Cortendo CEO Matthew Pauls

The big idea at Cortendo is to take an existing drug–ketoconazole, which is used off-label for Cushing’s disease–and tinker with it to make it safer and more effective. HealthCap, the Third Swedish National Pension Fund (“AP3”), Storebrand and Arctic Fund Management are putting up the venture round. And their money is funding an on-going Phase III study designed to make their case with the FDA.

“It is a nice bridge to the U.S. which also allows us from funding perspective to drive that critically important Phase III to closure,” says CEO Matthew Pauls, an ex-Shire ($SHPG) and Insmed exec from the commercial side of the industry who joined the company a couple of months ago.

Cushing’s is characterized by elevated levels of cortisol, which trigger a host of serious and potentially lethal side effects. The new drug–dubbed COR-003–is designed to hit key enzymes in the cortisol synthesis pathway, using a more targeted segment of ketoconazole.

“We took basically the better half of the molecule and are using it explicitly for Cushing’s syndrome,” says the CEO. Now Cortendo–which is run by a core team of 6, which Pauls plans to expand–will drive for final late-stage data in 2017, setting up a prospective application with the FDA that could allow the company to proceed with plans to create its own commercial operations.

There are about 20,000 to 25,000 Cushing’s patients in the U.S., adds Pauls, with maybe 30,000 to 40,000 in Europe. About half of those patients can expect surgery to address the disease, with the rest candidates for medicinal therapies.

The U.S. represents the company’s largest market opportunity, says Pauls. So it makes sense to drop the Oslo listing in favor of a U.S. exchange. Exactly when that filing could come and where, he adds, hasn’t been determined yet.

– here’s the release

From http://www.fiercebiotech.com/story/little-cortendo-gains-11m-late-stage-cushings-study-hatches-us-ipo-plans/2014-10-30

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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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EU Looks to Okay Ketoconazole for Use in Cushing’s Syndrome

Posted on September 27, 2014 by MaryO

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended granting a marketing authorization for ketoconazole (Ketoconazole HRA; Laboratoire HRA Pharma) for the treatment of Cushing’s syndrome, a rare hormonal disorder sometimes called hypercortisolism.

Cushing’s syndrome is characterized by an excess of the hormone cortisol in the blood, which may be caused by a tumor. Treatment options currently available in the European Union include surgery to remove the tumor responsible for the high cortisol levels and radiotherapy, as well as several medicines that reduce the production of cortisol.

But pharmacological options remain very limited, and there is an unmet medical need for additional treatments, especially when surgery fails or for patients who cannot undergo surgery or take other medications. For this reason, the EMA’s CHMP evaluated the medicine under expedited review.

The opinion adopted by the CHMP at its September 2014 meeting is an intermediary step on Ketoconazole HRA’s path to patient access.

The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. Once a marketing authorization has been granted, decisions about price and reimbursement will then take place at the level of each member state considering the potential role/use of this medicine in the context of the national health system of that country.

The recommendation is that Ketoconazole HRA is to be prescribed only by physicians specialized in treating Cushing’s syndrome, as the dosing needs to be individualized for each patient.

This is because oral ketoconazole was previously suspended in the European Union for the indication it was first approved for, fungal infections, due to risk for liver injury. The US Food and Drug Administration (FDA) also decreed, at the same time, that doctors should no longer prescribe ketoconazole tablets as a first-line therapy for any fungal infection, for the same reason.

Information will be sent to healthcare professionals to allow them to advise patients and prescribe the medicine safely and effectively.

A Medicine Used Off-Label for More than 30 Years

Doctors have used ketoconazole to treat Cushing’s syndrome for more than 30 years, although it has never been authorized for this indication in the European Union. The drug is also frequently used off-label in the United States and elsewhere for this purpose.

The CHMP’s recommendation builds on information from published literature and documented off-label use in clinical practice.

At the time of the suspension of ketoconazole for fungal infections, healthcare professionals and patients were concerned that ketoconazole would no longer be available for patients with Cushing’s syndrome.

The CHMP therefore reviewed Ketoconazole HRA through accelerated assessment to facilitate patients’ access to a fully authorized medicine as soon as possible with evidence-based information for patients and doctors.

When assessing Ketoconazole HRA for the treatment of Cushing’s syndrome, the CHMP considered that “in this rare and potentially life-threatening condition, the medicine’s benefits are greater than its risks, which can be manageable in clinical practice by specific measures mitigating the risk of liver toxicity, including close monitoring of the patients’ liver function.”

In 2012, it was estimated that the disease affected approximately 46,000 people in the European Union. Cushing’s syndrome is a long-lasting condition that can be life-threatening because of its complications, including diabetes, high blood pressure, and depression.

From http://www.medscape.com/viewarticle/832399?src=rss

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