Postsurgical treatment often necessary in persistent, recurrent Cushing’s disease

Nearly half of adults with Cushing’s disease that persists or recurs after surgical treatment require second and sometimes third therapeutic interventions, including pituitary surgical reintervention, radiotherapy, pharmacotherapy or bilateral adrenalectomy, study data from Mexico show.

Moisés Mercado, MD, FRCPC, of the ABC Hospital Neurological and Cancer Centers in Mexico City, and colleagues evaluated 84 adults (median age, 34 years; 77 women) with Cushing’s disease to determine the long-term efficacy of secondary interventions for persistent and recurrent Cushing’s disease. Median follow-up was 6.3 years.

Overall, 81 participants were primarily treated with transsphenoidal surgery. More than half experienced long-lasting remission (61.7%); disease remained active in 16%, who were diagnosed with persistent Cushing’s disease; and 22% experienced relapse after remission and were diagnosed with recurrent Cushing’s disease.

After the initial procedure, 18 participants required pituitary surgical reintervention, including 10 with recurrent and eight with persistent disease. Radiation therapy was administered to 14 participants, including two as primary therapy and 12 after failed pituitary surgery. Pharmacologic treatment with ketoconazole was prescribed for 15 participants at one point during the course of disease. Bilateral adrenalectomy was performed in 12 participants.

Pituitary surgical reintervention was the most commonly used secondary treatment (22.2%), followed by pharmacologic therapy with ketoconazole (16%), radiotherapy (14.8%) and bilateral adrenalectomy (14.8%). More than half of participants experienced early remissions after a second operation (66.6%) and radiotherapy (58.3%), whereas long-lasting remission was reached in only 33.3% of participants who underwent a second surgery and 41.6% of participants who underwent radiotherapy. Half of participants who underwent bilateral adrenalectomy were diagnosed with Nelson’s syndrome.

Overall, 88% of participants achieved remission, and disease was biochemically controlled with pharmacologic treatment in 9.5% of participants after their initial, secondary and third-line treatments.

“The efficacy of treatment alternatives for recurrent or persistent [Cushing’s disease] vary among patients, and often, more than one of these interventions is required in order to achieve a long-lasting remission,” the researchers wrote. – by Amber Cox

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B5519b312-5912-4c65-b2ed-2ece3f68e83f%7D/postsurgical-treatment-often-necessary-in-persistent-recurrent-cushings-disease

Postoperative ACTH, cortisol levels may predict Cushing’s disease remission rate

Early and midterm nonremission after transsphenoidal surgery in people with Cushing’s disease may be predicted by normalized early postoperative values for adrenocorticotropic hormone and cortisol, study data show.

Prashant Chittiboina, MD, MPH, assistant clinical investigator in the neurosurgery unit for pituitary and inheritable diseases at the National Institute of Neurological Diseases and Stroke at the NIH, and colleagues evaluated 250 patients with Cushing’s disease who received 291 transsphenoidal surgery procedures during the study period to determine remission after the procedure. Patients were treated between December 2003 and July 2016. Early remission was assessed at 10 days and medium-term remission was assessed at 11 months.

Early nonremission was predicted by normalized early postoperative values for cortisol (P = .016) and by normalized early postoperative values for adrenocorticotropic hormone (ACTH; P = .048). Early nonremission was further predicted with 100% sensitivity, 39% specificity, 100% negative predictive value and 18% positive predictive value for a cutoff of –12 µg/mL in normalized early postoperative values for cortisol and with 88% sensitivity, 41% specificity, 96% negative predictive value and 16% positive predictive value for a cutoff of –40 pg/mL in normalized early postoperative values for ACTH.

Medium-term nonremission was also predicted by normalized early postoperative values for cortisol (P = .023) and ACTH (P = .025).

“We evaluated the utility of early postoperative cortisol and ACTH levels for predicting nonremission after transsphenoidal adenomectomy for Cushing’s disease,” the researchers wrote. “Postoperative operative day 1 values at 6 a.m. performed best at predicting early nonremission, albeit with a lower [area under the receiver operating characteristic curve]. Normalizing early cortisol and ACTH values to post-[corticotropin-releasing hormone] values improved their prognostic value. Further prospective studies will explore the utility of normalized very early postoperative day 0 cortisol and ACTH levels in identifying patients at risk for nonremission following [transsphenoidal surgery] in patients with [Cushing’s disease].” – by Amber Cox

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B7de200ed-c667-4b48-ab19-256d90a7bbc5%7D/postoperative-acth-cortisol-levels-may-predict-cushings-disease-remission-rate

Surgery Preferred Option in Cushing’s Disease for Best Survival

Patients with Cushing’s disease who have been in remission for more than 10 years still have an increased mortality risk compared with the general population, says an international team of researchers, who found the risk of early death was particularly increased in those with Cushing’s and accompanying circulatory disease.

Richard N Clayton, MD, department of medicine, Keele University, Stoke-on-Trent, United Kingdom, showed that Cushing’s disease, which is characterized by increased secretion of adrenocorticotropic hormone by the anterior pituitary gland, is associated with an increased mortality risk of more than 60% and a median survival of around 40 years.

In patients who also had circulatory disease, the mortality risk was even higher, say Dr Clayton and colleagues.

However, patients who had undergone curative pituitary surgery had a long-term risk of death no different from that of the general population. US Endocrine Society guidelines published last August recommend that optimal treatment of Cushing’s syndrome involves direct surgical removal of the causal tumor.

But Dr Clayton and colleagues point out that even patients who undergo pituitary surgery will nevertheless “require lifelong follow-up at a center experienced in dealing with this condition, having regular checks for diabetes, hypertension, and other cardiovascular risk factors.”

The study was published online June 2 in Lancet Diabetes & Endocrinology.

In an accompanying editorial, Rosario Pivonello, MD, PhD, department of clinical medicine and surgery, section of endocrinology, University of Naples Federico II, Italy, and colleagues write that, although surgery is not suitable for all patients, “Prompt pituitary surgery might be the preferred treatment for Cushing’s disease to guarantee the best mortality outcome.”

Calling for further research to better understand why one treatment “has a better effect on mortality than another,” they state: “The results from this study might also motivate rapid interventions, cure, and long-term follow-up in patients with Cushing’s disease — even for a long time after hypercortisolism resolution.”

Studying Those Who Have Survived More Than 10 Years

Dr Clayton and colleagues explain that previous studies have explored mortality in patients with Cushing’s disease during either active disease or remission. But the outcome of patients in remission, especially long-term remission, is still a matter of debate, and assessing long-term survival has been limited by various methodological differences. To overcome some of these issues, they performed a retrospective analysis of case records from specialist referral centers in the United Kingdom, Denmark, the Netherlands, and New Zealand.

They identified 320 patients diagnosed with Cushing’s disease and cured for a minimum of 10 years at enrollment and had no relapses during the study period. The ratio of women to men was 3:1.

Median patient follow-up was 11.8 years, yielding a total of 3790 person-years of follow-up 10 years after cure. There was no difference in follow-up between countries. And as there were no significant demographic and clinical differences between men and women, the data were pooled.

During the study 16% of patients died. Median survival was 31 years for women and 28 years for men, at approximately 40 years following remission. The overall standardized mortality ratio (SMR) for all-cause mortality compared with the general population was 1.61 (P = .0001).

Patients with Cushing’s and circulatory disease had an SMR vs the general population of 2.72 (P < .0001), but deaths from cancer among those who had survived Cushing’s disease were not higher than the general population, at an SMR of 0.79 (P = .41).

Patients with Cushing’s and diabetes also had an increased mortality risk, at a hazard ratio (HR) of 2.82 (P < .0096) compared with the general population, while hypertension was not significantly associated with increased mortality, at an HR of 1.59 (P = .08).

There was also an association between mortality and number of treatments, at an HR of 1.77 for two vs one treatment (P = .08) and an HR of 2.6 for three vs one treatment (P = .02).

Pituitary Surgery Alone Associated With No Increased Risk of Death

Pituitary surgery performed as the first and only treatment was associated with an SMR vs the general population of 0.94 compared with an SMR of 2.58 for other patients (P < .0005).

Patients who had pituitary surgery only had a median survival of 31 years compared with 24 years if surgery had been required at any time (P = 0.03).

The research team states: “For patients who have been cured of Cushing’s disease for 10 years or more, treatment complexity and an increased number of treatments, reflecting disease that is more difficult to control, appears to negatively affect survival.”

“Pituitary surgery alone achieves a mortality outcome that is not different from the normal population and should be performed in a center of excellence,” they conclude.

However, in the editorial, Dr Pivonello and colleagues point out that the surgical approach “is not a treatment option for some patients, either because of contraindications (eg, severe clinical complications) or because of an absence of clear indication for surgery (eg, tumor is not completely removable by surgery).”

The authors and editorialist have reported no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online June 2, 2016. Abstract, Editorial

From http://www.medscape.com/viewarticle/865073#vp_2

Day 19, Cushing’s Awareness Challenge 2016

In case you haven’t guessed it, my cause seems to be Cushing’s Awareness.  I never really decided to devote a good portion of my life to Cushing’s, it just fell into my lap, so to speak – or my laptop.

I had been going along, raising my son, keeping the home-fires burning,  trying to forget all about Cushing’s.  My surgery had been a success, I was in remission, some of the symptoms were still with me but they were more of an annoyance than anything.

I started being a little active online, especially on AOL.  At this time, I started going through real-menopause, not the fake one I had gone through with Cushing’s.  Surprisingly, AOL had a group for Cushing’s people but it wasn’t very active.

What was active, though, was a group called Power Surge (as in I’m not having a hot flash, I’m having a Power Surge).  I became more and more active in that group, helping out where I could, posting a few links here and there.

Around this time I decided to go back to college to get a degree in computer programming but I also wanted a basic website for my piano studio.  I filled out a form on Power Surge to request a quote for building one.  I was very surprised when Power Surge founder/webmaster Alice (AKA Dearest) called me.  I was so nervous.  I’m not a good phone person under the best of circumstances and here she was, calling me!

I had to go to my computer class but I said I’d call when I got back.  Alice showed me how to do some basic web stuff and I was off.  As these things go, the O’Connor Music Studio page grew and grew…  And so did the friendship between Alice and me.  Alice turned out to be the sister I never had, most likely better than any sister I could have had.

In July of 2000, Alice and I were wondering why there weren’t many support groups online (OR off!) for Cushing’s. This thought percolated through my mind for a few hours and I realized that maybe this was my calling. Maybe I should be the one to start a network of support for other “Cushies” to help them empower themselves.

I wanted to educate others about the awful disease that took doctors years of my life to diagnose and treat – even after I gave them the information to diagnose me. I didn’t want anyone else to suffer for years like I did. I wanted doctors to pay more attention to Cushing’s disease.

The first website (http://www.cushings-help.com) went “live” July 21, 2000. It was just a single page of information. The message boards began September 30, 2000 with a simple message board which then led to a larger one, and a larger. Today, in 2012, we have over 8 thousand members. Some “rare disease”!

This was on the intro page of Cushing’s Help until 2013…

I would like to give abundant thanks Alice Lotto Stamm, founder of Power Surge, premier site for midlife women, for giving me the idea to start this site, encouraging me to learn HTML and web design, giving us the use of our first spiffy chatroom, as well as giving me the confidence that I could do this. Alice has helped so many women with Power Surge. I hope that I can emulate her to a smaller degree with this site.

Thanks so much for all your help and support, Alice!

In August 2013 my friend died.  In typical fashion, I started another website

I look around the house and see things that remind me of Alice.  Gifts, print outs, silly stuff, memories, the entire AOL message boards on floppy disks…

Alice, I love you and will miss you always…

MaryOOneRose

Decreased prefrontal functional brain response in women with Cushing’s syndrome in remission

endo2016

 

April 03, 2016

Poster Session: Cushing’s Syndrome and Primary Adrenal Disorders

Decreased prefrontal functional brain response in women with Cushing’s syndrome in remission

O Ragnarsson, A Stomby, P Dahlqvist, JA Evang, M Ryberg, T Olsson, J Bollerslev, L Nyberg, G Johannsson

Summary: Neuropsychiatric symptoms including impairment of memory, attention, and executive function are important features of Cushing’s syndrome (CS). Notably, patients with CS in remission commonly demonstrate residual cognitive dysfunction, which has been suggested to be linked to incomplete recovery of neuronal function. Researchers sought to assess whether functional brain responses are altered during cognitive testing in patients with CS in remission. During episodic memory, women with CS in long-term remission have reduced functional brain responses in the prefrontal cortex and in the hippocampus.

Methods:

  • Included in this study were 19 women previously treated for CS (14 Cushing’s disease and 5 cortisol producing adrenal adenomas) and 19 controls, matched for age, gender, and education.
  • The median (interquartile range) remission time was 7 (6-10) years.
  • Researchers studied brain activity with functional magnetic resonance imaging during an episodic-memory face-name task.
  • The primary regions of interest were the prefrontal cortex and the hippocampus.
  • A voxel wise comparison of functional brain responses in patients and controls was performed, and an uncorrected P < 0.001 was considered significant.

Results:

  • During memory encoding, patients displayed lower functional brain responses in the left and right prefrontal gyrus (Brodmann areas [BA] 44, 45, and 46) as well as the right inferior occipital gyrus (BA 18) compared to controls (P < 0.001 for all).
  • Patients displayed lower functional brain responses in several brain areas including the prefrontal, parietal, occipital, and cerebellar cortices bilaterally during memory retrieval.
  • The most predominant difference was found in the right prefrontal cortex (BA 46 and 48; P < 0.001).
  • Reduced functional response in left dorsolateral prefrontal cortex was seen for patients during both encoding and retrieval.
  • Researchers compared the functional brain responses in four hippocampal clusters that were significantly activated during memory encoding among all participants (P < 0.05, FDR).
  • Patients had a trend toward lower functional brain responses in the left anterior hippocampus compared to controls (P=0.05).

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ6AA1CEC190F5428EA690616DAA054518/56991/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2016&nonus=0

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