Resolution of the physical features of Cushing’s syndrome in a patient with a cortisol secreting adrenocortical adenoma after unilateral adrenalectomy

Posted on May 1, 2016 by MaryO

A 37-year-old woman developed clinical manifestations of Cushing’s syndrome over a span of 2 years. Physical examination revealed features that best describe Cushing’s syndrome, such as wide purple striae (>1 cm) over the abdomen, facial plethora and easy bruisability.1  Other features observed were hypertension, moon facies, acne, a dorsocervical fat pad, central obesity and dyslipidaemia.

The diagnosis of hypercortisolism was confirmed using a 1 mg overnight dexamethasone suppression test (19.7 ng/dL, N: <1.8) and 24 h urine free cortisol (185.9 μg/24 h, N: 3.5–45). A suppressed adrenocorticotropic hormone (ACTH) level (4 pg/mL, N: 5–20) and a lack of hyperpigmentation suggested ACTH-independent Cushing’s syndrome. Further work up using CT with contrast of the adrenals showed a 2.4×2.3×2.4 cm right adrenal mass. The patient then underwent laparoscopic adrenalectomy of the right adrenal gland. Steroids was started postoperatively and tapered over time. Histopathology results were consistent with an adrenocortical adenoma (2.5 cm widest dimension). Six months after surgery, there was resolution of the physical features, weight loss and improvement in blood pressure.

Figure 1 is a serial photograph of the physical features seen in Cushing’s syndrome, such as moon facies, a dorsocervical fat pad and wide purple striae, taken preoperatively, and at 3 and 6 months after surgery. With treatment, physical and biochemical changes of Cushing’s syndrome both resolve through time.2 The time course of the resolution of these changes, however, is varied.2 ,3 We observed that the physical features were ameliorated at 3 months and resolved at 6 months.

Learning points

  • Physicians as well as patients should be aware that improvement of the features of Cushing’s syndrome after treatment does not occur immediately.

  • Dramatic resolution of the physical features of Cushing’s syndrome, however, can be observed as early as 6 months after surgery.

Figure 1

View larger version:

Figure 1

Physical features of Cushing’s syndrome (top to bottom: moon facies, a dorsocervical fat pad and wide purple striae (>1 cm) over the abdomen) documented before surgery, and at 3 and 6 months after surgery.

Footnotes

  • Twitter Follow John Paul Quisumbing at @jpquisumbingmd

  • Contributors JPMQ worked up the case and wrote the case report. MASS reviewed the case report and critically appraised it. JPMQ incorporated his suggestions.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

References

  1. ↵
    1. Ross EJ,
    2. Linch DC

    . Cushing’s syndrome-killing disease: discriminatory value of signs and symptoms aiding early diagnosis.Lancet 1982;2:646–9. doi:10.1016/S0140-6736(82)92749-0

    [CrossRef][Medline][Web of Science]
  2. ↵
    1. Sippel RS,
    2. Elaraj DM,
    3. Kebebew E, et al

    . Waiting for change: symptom resolution after adrenalectomy for Cushing’s syndrome. Surgery2008;144:1054–61. doi:10.1016/j.surg.2008.08.024

    [CrossRef][Medline][Web of Science]
  3. ↵
    1. Mishra AK,
    2. Agarwal A,
    3. Gupta S, et al

    . Outcome of adrenalectomy for Cushing’s syndrome: experience from a tertiary care center. World J Surg2007;31:1425–32. doi:10.1007/s00268-007-9067-6

    [CrossRef][Medline]

From http://casereports.bmj.com/content/2016/bcr-2016-215693.short?rss=1

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Day 30, Cushing’s Awareness Challenge 2016

Posted on April 30, 2016 by MaryO

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…

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

Posted on April 30, 2016 by MaryO

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

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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

Posted on April 30, 2016 by MaryO

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

 

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Day 29, Cushing’s Awareness Challenge 2016

Posted on April 29, 2016 by MaryO

People sometimes ask me how I found out I had Cushing’s Disease.  Theoretically, it was easy.  In practice, it was very difficult.

Ladies Home Journal, 1983In 1983 I came across a little article in the Ladies Home Journal which said “If you have these symptoms…”

I found the row with my symptoms and the answer read “…ask your doctor about Cushing’s”.

After that article, I started reading everything I could on Cushing’s, I bought books that mentioned Cushing’s. I asked and asked my doctors for many years and all of them said that I couldn’t have it.  It was too rare.  I was rejected each time.

Due to all my reading at the library, I was sure I had Cushing’s but no one would believe me. My doctors would say that Cushing’s Disease is too rare, that I was making this up and that I couldn’t have it.

In med school, student doctors are told “When you hear hoofbeats, think horses, not zebras“.

According to Wikipedia: “Zebra is a medical slang term for a surprising diagnosis. Although rare diseases are, in general, surprising when they are encountered, other diseases can be surprising in a particular person and time, and so “zebra” is the broader concept.

The term derives from the aphorism “When you hear hoofbeats behind you, don’t expect to see a zebra”, which was coined in a slightly modified form in the late 1940s by Dr. Theodore Woodward, a former professor at the University of Maryland School of Medicine in Baltimore.  Since horses are the most commonly encountered hoofed animal and zebras are very rare, logically you could confidently guess that the animal making the hoofbeats is probably a horse. By 1960, the aphorism was widely known in medical circles.”

So, doctors typically go for the easily diagnosed, common diseases.  Just because something is rare doesn’t mean that no one gets it.  We shouldn’t be dismissed because we’re too hard to diagnose.

When I was finally diagnosed in 1987, 4 years later, it was only because I started bleeding under the skin. My husband made circles around the outside perimeter each hour with a marker so my leg looked like a cut log with rings.

When I went to my Internist the next day he was shocked at the size of the rings. He now thought I had a blood disorder so he sent me to a Hematologist/Oncologist.

Fortunately, that new doctor ran a twenty-four hour urine test and really looked at me and listened to me.  Both he and his partner recognized that I had Cushing’s but, of course, couldn’t do anything further with me.  They packed me off to an endo where the process started again.

My final diagnosis was in October, 1987.  Quite a long time to simply  “…ask your doctor about Cushing’s”.

Looking back, I can see Cushing’s symptoms much earlier than 1983.  But, that ‘s for a different post.

 

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