Day 30, Cushing’s Awareness Challenge 2016

Today is the final day of the Cushing’s Awareness Challenge and I wanted to leave you with this word of advice…

To that end, I’m saving some of what I know for future blog posts, maybe even another Cushing’s Awareness Challenge next year.  Possibly this will become a tradition.

I am amazed at how well this Challenge went this year, giving that we’re all Cushies who are dealing with so much.   I hope that some folks outside the Cushing’s community read these posts and learned a little more about us and what we go through.

So, tomorrow, I’ll  go back to posting the regular Cushing’s stuff on this blog – after all, it does have Cushing’s in its name!

I am trying to get away from always reading, writing, breathing Cushing’s and trying to celebrate the good things in my life, not just the testing, the surgery, the endless doctors.

If you’re interested, I have other blogs about traveling, friends, fun stuff and trying to live a good life, finally.  Those are listed in the right sidebar of this blog, past the Categories and before the Tags.

Meanwhile…

Time-for-me

Choose wisely…

A Single-Center 10-Year Experience with Pasireotide in Cushing’s Disease: Patients’ Characteristics and Outcome

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing’s disease (CD). Our 10-year experience with pasireotide in CD is reported here.

Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor®; Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months).

Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients.

Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

From http://www.ncbi.nlm.nih.gov/pubmed/27127913

Endocrine Society experts call for expanded screening for primary aldosteronism

Washington, DC–The Endocrine Society today issued a Clinical Practice Guideline calling on physicians to ramp up screening for primary aldosteronism, a common cause of high blood pressure.

People with primary aldosteronism face a higher risk of developing cardiovascular disease and dying from it than other people with high blood pressure. As many as one in ten people with high blood pressure may have primary aldosteronism. Uncontrolled high blood pressure can put these individuals at risk for stroke, heart attack, heart failure or kidney failure.

The guideline, entitled “The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline,” was published online and will appear in the May 2016 print issue of The Journal of Clinical Endocrinology & Metabolism (JCEM), a publication of the Endocrine Society. The guideline updates recommendations from the Society’s 2008 guideline on primary aldosteronism.

“In the past eight years, we have come to recognize that primary aldosteronism, despite being quite common, frequently goes undiagnosed and untreated,” said John W. Funder, MD, PhD, of the Hudson Institute of Medical Research in Clayton, Australia, and chair of the task force that authored the guideline. “This is a major public health issue. Many people with primary aldosteronism are never screened due to the associated costs. Better screening processes are needed to ensure no person suffering from primary aldosteronism and the resulting risks of uncontrolled high blood pressure goes untreated.”

Primary aldosteronism occurs when the adrenal glands — the small glands located on the top of each kidney – produce too much of the hormone aldosterone. This causes aldosterone, which helps balance levels of sodium and potassium, to build up in the body. The resulting excess sodium can lead to a rise in blood pressure.

The Endocrine Society recommends primary aldosterone screening for people who meet one of the following criteria:

  • Those who have sustained blood pressure above 150/100 in three separate measurements taken on different days;
  • People who have hypertension resistant to three conventional antihypertensive drugs;
  • People whose hypertension is controlled with four or more medications;
  • People with hypertension and low levels of potassium in the blood;
  • Those who have hypertension and a mass on the adrenal gland called an adrenal incidentaloma;
  • People with both hypertension and sleep apnea;
  • People with hypertension and a family history of early-onset hypertension or stroke before age 40; and
  • All hypertensive first-degree relatives of patients with primary aldosteronism.

Other recommendations from the guideline include:

  • The plasma aldosterone-to-renin ratio (ARR) test should be used to screen for primary aldosteronism.
  • All patients diagnosed with primary aldosteronism should undergo a CT scan of the adrenal glands to screen for a rare cancer called adrenocortical carcinoma.
  • When patients choose to treat the condition by having one adrenal gland surgically removed, an experienced radiologist should take blood samples from each adrenal vein and have them analyzed. This procedure, called adrenal vein sampling, is the gold standard for determining whether one or both adrenal glands is producing excess aldosterone.
  • For people with primary aldosteronism caused by overactivity in one adrenal gland, the recommended course of treatment is minimally invasive surgery to remove that adrenal gland.
  • For patients who are unable or unwilling to have surgery, medical treatment including a mineralocorticoid receptor (MR) agonist is the preferred treatment option.

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The Hormone Health Network offers resources on primary aldosteronism athttp://www.hormone.org/questions-and-answers/2012/primary-aldosteronism.

Other members of the Endocrine Society task force that developed this guideline include: Robert M. Carey, of the University of Virginia Health System in Charlottesville, VA; Franco Mantero of the University of Padova in Padua, Italy; M. Hassan Murad of the Mayo Clinic in Rochester, MN; Martin Reincke of the Klinikum of the Ludwig-Maximilians-University of Munich in MĂĽnchen, Bavaria, Germany; Hirotaka Shibata of Oita University in Oita, Japan; Michael Stowasser of the University of Queensland in Brisbane, Australia; and William F. Young, Jr. of the Mayo Clinic in Rochester, MN.

The Society established the Clinical Practice Guideline Program to provide endocrinologists and other clinicians with evidence-based recommendations in the diagnosis and treatment of endocrine-related conditions. Each guideline is created by a task force of topic-related experts in the field. Task forces rely on evidence-based reviews of the literature in the development of guideline recommendations. The Endocrine Society does not solicit or accept corporate support for its guidelines. All Clinical Practice Guidelines are supported entirely by Society funds.

The Clinical Practice Guideline was co-sponsored by the American Heart Association, the American Association of Endocrine Surgeons, the European Society of Endocrinology, the European Society of Hypertension, the International Association of Endocrine Surgeons, the International Society of Hypertension, the Japan Endocrine Society and The Japanese Society of Hypertension.

The guideline was published online at http://press.endocrine.org/doi/10.1210/jc.2015-4061, ahead of print.

Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world’s oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.

The Society, which is celebrating its centennial in 2016, has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

From http://www.eurekalert.org/pub_releases/2016-04/tes-ese042616.php

Promising Pre-Clinical and Phase 1 Data Support Advance of Selective Cortisol Modulator CORT125134 as Potential Treatment for Cushing’s Syndrome and Solid-Tumor Cancers

MENLO PARK, CA–(Marketwired – Apr 28, 2016) –  Corcept Therapeutics Incorporated (NASDAQ: CORT), a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol, today released data supporting the clinical advancement of its proprietary, selective cortisol modulator, CORT125134. The company has begun recruiting patients for a Phase 1/2 trial of the compound to treat patients with solid-tumor cancers. It also expects to begin recruiting patients for a Phase 2 study of CORT125134 to treat patients with Cushing’s syndrome this quarter.

“Advancing CORT125134 is an important step in protecting and extending our growing Cushing’s syndrome franchise and in developing cortisol modulation for a wide range of other serious diseases,” said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. “This selective cortisol modulator has shown great promise. We are optimistic that, for some patients with Cushing’s syndrome, CORT125134 may be even better than our approved product, Korlym® — just as effective, but without the side effects associated with Korlym’s affinity for the progesterone receptor. Equally important, we look forward to investigating its potential as a treatment for solid-tumor cancers.”

CORT125134 is the lead compound in Corcept’s proprietary portfolio of selective cortisol modulators. It is a non-steroidal competitive antagonist of the glucocorticoid receptor (GR) that does not bind to the body’s other hormone receptors, including the progesterone receptor (PR). Korlym’s interaction with PR results in termination of pregnancy and can cause endometrial thickening and irregular vaginal bleeding in some women. CORT125134 is proprietary to Corcept and is protected by composition of matter and method of use patents extending to 2033.

Advancement to Phase 2 Trials Supported by Positive Pre-Clinical and Phase 1 Data
“The data generated so far make this compound a promising candidate to treat both Cushing’s syndrome and, potentially, a number of solid-tumor cancers,” said Hazel Hunt, Ph.D., Corcept’s Vice President of Research. “Its Phase 1 data showed that it shares Korlym’s potent affinity for GR, one of the receptors to which cortisol binds. Our clinical testing showed that it can prevent the effects of the steroid prednisone, a commonly-used synthetic GR agonist. Preventing the effects of prednisone is a very important finding, as it mirrors the essential quality of an effective medical treatment for patients with Cushing’s syndrome.”

Corcept’s Phase 1 trial of CORT125134 enrolled 124 healthy volunteers. GR antagonism was tested by measuring CORT125134’s ability to modulate prednisone’s effects on serum osteocalcin, white blood cell counts, glucose metabolism and expression of the FKBP5 gene — a marker of GR activation. With respect to all parameters, CORT125134 was as potent a modulator of prednisone’s activity as Korlym (see Figure 1; p value < 0.0003).

Pharmacokinetic data indicate that CORT125134 is suitable for once-daily dosing.

“Positive Phase 1 data, together with encouraging pre-clinical results, prompted us to advance CORT125134 as a treatment for Cushing’s syndrome as well as a treatment for cancer,” continued Dr. Hunt. “Substantial pre-clinical and clinical research suggests that cortisol modulation increases the effectiveness of chemotherapy in some solid-tumor cancers. Pre-clinical data suggest that CORT125134 may be even more potent than Korlym in treating some tumor types.”

Corcept and investigators at the University of Chicago have studied the effectiveness of CORT125134 in transgenic mouse models of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer. Mice implanted with TNBC tumor cells were treated with a combination of paclitaxel and CORT125134. Mifepristone (the active ingredient in Korlym) in combination with paclitaxel served as a positive control. As expected, the combination of mifepristone and paclitaxel significantly slowed tumor progression. However, the combination of CORT125134 and paclitaxel slowed it even more (see Figure 2; p value = 0.0004). In a similar experiment, castrated mice seeded with prostate cancer tumor cells were treated with either mifepristone or CORT125134. The outcome was comparable to the TNBC study: When combined with castration (which in humans would be achieved pharmacologically by the administration of an androgen receptor antagonist such as enzalutamide), mifepristone retarded tumor progression, but CORT125134 had an even more pronounced effect (see Figure 3; p value = 0.037).

CORT125134 may also enhance the efficacy of immune-modulation therapy. In an animal model of colon cancer, the addition of CORT125134 to PD-1 monotherapy significantly slowed tumor progression (see Figure 4; p value = 0.013):

Oncology Trial Design
This trial’s initial phase will investigate nab-paclitaxel in combination with CORT125134 to treat any solid-tumor cancer susceptible to treatment with nab-paclitaxel. (“Nab-paclitaxel” is the generic name for Celgene’s drug, Abraxane®.) Once a maximum tolerated dose is identified, Corcept plans to open one or more expansion cohorts, each containing 20 patients, to test the combination’s efficacy in one or more of the solid-tumor cancers studied in the dose-finding phase. Possible target indications include TNBC, castration-resistant prostate cancer, ovarian cancer, pancreatic cancer and sarcoma. Other dose-finding cohorts may be enrolled to study CORT125134 in combination with different companion therapeutic agents, including PD-1 inhibitors.

The trial is open-label and will be conducted at sites in the United States, the first of which is open and has begun screening patients.

“That we are advancing the same selective cortisol modulator as a treatment for both a metabolic disease and one or more oncologic indications is a testament to the broad therapeutic potential of cortisol modulation,” said Robert S. Fishman, MD, Corcept’s Chief Medical Officer. “We are excited to start these trials.”

Cushing’s Syndrome Trial Design
This Phase 2 trial of CORT125134 will enroll 30 patients with endogenous Cushing’s syndrome. Patients will be assigned to a low- or high-dose group and will receive CORT125134 for 12 weeks, with up-titration possible in each group at weeks four and eight. The trial will be open label. Study centers will be located in both the European Union and the United States.

About Korlym®
Korlym modulates the effect of cortisol at GR, one of the two receptors to which cortisol binds, thereby inhibiting the effects of excess cortisol in patients with Cushing’s syndrome. Since 2012, Corcept has made Korlym available as a once-daily oral treatment of hyperglycemia secondary to endogenous Cushing’s syndrome in adult patients with glucose intolerance or diabetes mellitus type 2 who have failed surgery or are not candidates for surgery. Korlym was the first FDA-approved treatment for that illness and the FDA has designated it as an Orphan Drug for that indication.

About Cushing’s Syndrome
Endogenous Cushing’s syndrome is caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing’s syndrome is an orphan indication that most commonly affects adults aged 20-50. An estimated 10-15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients annually in the United States. An estimated 20,000 patients in the United States have Cushing’s syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About Triple-Negative Breast Cancer
Triple-negative breast cancer is a form of the disease in which the three receptors that fuel most breast cancer growth — estrogen, progesterone and the HER-2/neu gene — are not present. Because the tumor cells lack the necessary receptors, treatments that target estrogen, progesterone and HER-2 receptors are ineffective. In 2013, approximately 40,000 women were diagnosed with TNBC. It is estimated that more than 75 percent of these women’s tumor cells expressed the GR receptor to which cortisol binds. There is no FDA-approved treatment and neither a targeted treatment nor an approved standard chemotherapy regimen for relapsed TNBC patients exists.

About Corcept Therapeutics Incorporated
Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol. Korlym, a first-generation cortisol modulator, is the company’s first FDA-approved medication. The company is conducting a Phase 1/2 trial of mifepristone for the treatment of TNBC, a Phase 1/2 trial of CORT125134 to treat a variety of solid-tumor cancers and has a proprietary portfolio of other selective GR antagonists that modulate the effects of cortisol but not progesterone. Corcept owns extensive intellectual property covering the use of cortisol modulators, including mifepristone and CORT125134, in the treatment of a wide variety of metabolic, oncologic and psychiatric disorders. It also holds composition of matter patents for CORT125134 and its other selective cortisol modulators.

Forward-Looking Statements
Statements made in this news release, other than statements of historical fact, are forward-looking statements. These forward-looking statements, including statements regarding the initiation and advancement of clinical trials and the development of Corcept’s pre-clinical and clinical pipeline, are subject to known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements, including the pace of enrollment in or the outcome of the company’s Phase 1/2 study of CORT125134 to treat solid-tumor cancers and planned Phase 2 trial of CORT125134 to treat patients with Cushing’s syndrome, the effects of rapid technological change and competition, the protections afforded by Corcept’s intellectual property rights, or the cost, pace and success of Corcept’s other product development efforts. These and other risks are set forth in the company’s SEC filings, all of which are available from the company’s website (www.corcept.com) or from the SEC’s website (www.sec.gov). Corcept disclaims any intention or duty to update any forward-looking statement made in this news release.

Abraxane® is a registered trademark of Celgene Corporation.

From http://www.marketwired.com/press-release/promising-pre-clinical-phase-1-data-support-advance-selective-cortisol-modulator-cort125134-nasdaq-cort-2119635.htm

 

Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine tumors of the thymus

Background and purpose: Thymic neuroendocrine carcinomas (TNECs) are extremely uncommon. Certain cases of TNECs can produce the adrenocorticotropic hormone (ACTH) and cause ectopic ACTH syndrome (EAS). The current literature on this topic consists mainly of case reports, and therapeutic guidelines are lacking. The aim of this study was to discuss the diagnosis, surgical management, and prognosis of EAS caused by TNECs to improve clinical experience with this rare disease.

Methods: From June 1984 to June 2014, at the Peking Union Medical College Hospital, the surgical interventions and follow-up outcomes of 16 consecutive patients (eight men and eight women) with EAS caused by TNECs were retrospectively analyzed.

Results: The median age was 32.5 years (range: 13–47 years), and the median disease duration was 8.5 months (range: 1–150 months). All patients presented with clinical and biochemical evidence indicating a diagnosis of Cushing’s syndrome.

Contrast-enhanced thoracic computed tomography scans were critical to locating the ACTH-producing tumor and evaluating the feasibility of resection. All patients underwent surgery. One patient died of septicemia in the intensive care unit 2 weeks after surgery. No other morbidity or mortality occurred during the perioperative period. The median overall survival (OS) was 41 months (95% CI: 30.3–51.7 months), and the progression-free survival was 28 months (95% CI: 21.6–34.3 months). Both overall survival (P=0.002) and progression-free survival (P=0.030) improved significantly after complete resection.

Conclusion: TNEC is an extremely aggressive disease that should be considered when treating patients with Cushing’s syndrome due to ectopic ACTH secretion. In particular, all suspected patients should undergo contrast-enhanced thoracic computed tomography scans to facilitate early diagnosis. The current first-line treatment is surgical resection, and complete resection is a favorable prognostic factor. However, additional patients and a longer follow-up will be needed to determine the variables that are predictive of survival and to improve patient prognosis.

Download this article at https://www.dovepress.com/ectopic-adrenocorticotropic-hormone-syndrome-caused-by-neuroendocrine–peer-reviewed-article-OTT

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