Day 1: Cushing’s Awareness Challenge

Posted on April 1, 2024 by MaryO

April is always Cushing’s Awareness Challenge month because Dr. Harvey Cushing was born on April 8th, 1869.

30-posts

Thanks to Robin for this wonderful past logo!  I’ve participated in these 30 days for Cushing’s Awareness several times so I’m not quite sure what is left to say this year but I always want to get the word out when I can.

As I see it, there have been some strides the diagnosis or treatment of Cushing’s since last year.  More drug companies are getting involved, more doctors seem to be willing to test, a bit more awareness, maybe.

April Fool's Day

How fitting that this challenge should begin on April Fool’s Day.  So much of Cushing’s  Syndrome/Disease makes us Cushies seem like we’re the April Fool.  Maybe, just maybe, it’s the doctors who are the April Fools…

Doctors tell us Cushing’s is too rare – you couldn’t possibly have it.  April Fools!

All you have to do is exercise and diet.  You’ll feel better.  April Fools!

Those bruises on your legs?  You’re just clumsy. April Fools!

Sorry you’re growing all that hair on your chin.  That happens as you age, you know.  April Fools!

Did you say you sleep all day?  You’re just lazy.  If you exercised more, you’d have more energy. April Fools!

You don’t have stretch marks.  April Fools!

You have stretch marks but they are the wrong [color/length/direction] April Fools!

The hump on the back of your neck is from your poor posture. April Fools!

Your MRI didn’t show a tumor.  You couldn’t have Cushing’s. April Fools!

This is all in your mind.  Take this prescription for antidepressants and go home.  April Fools!

If you have this one surgery, your life will get back to normal within a few months. April Fools!

What?  You had transsphenoidal surgery for Cushing’s?  You wasted your time and money. April Fools!

I am the doctor.  I know everything.  Do not try to find out any information online. You could not have Cushing’s.  It’s too rare…  April FOOL!

All this reminds me of a wonderful video a message board member posted a while ago:

So now – who is the April Fool?  It wasn’t me.  Don’t let it be you, either!

Filed under: Cushing's, Cushing's Awareness Challenge 2016, Diagnostic Testing, Rare Diseases, symptoms, Treatments | Tagged: , , , , , , , , , , , , , , , , , , , , , , | 2 Comments »

Sparrow Pharmaceuticals Hopes To Change The Future Of Endocrinology

Posted on November 5, 2021 by MaryO

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

Go ahead and continuously improvement iStock-1295289697

Sparrow Pharmaceuticals is an emerging biopharma company on a mission to help patients suffering from an excess of corticosteroids, with a focus on Cushing’s syndrome, autonomous cortisol secretion (ACS), and polymyalgia rheumatica (PMR).

Cushing’s and ACS are both caused by an excess of cortisol produced by tumors. Patients with Cushing’s can present physically with a fatty hump between their shoulders, a rounded face, and pink or purple stretch marks on their skin. Cushing’s syndrome and ACS can both result in high blood pressure, bone loss, type 2 diabetes, weight gain, and mood, cognition, and sleep disorders. Any of those symptoms may be side effects for patients with conditions such as PMR who rely on long-term treatment with corticosteroid medications such as prednisone.

“Cushing’s syndrome impacts around 20,000 patients in the U.S. alone,” says David Katz, Chief Scientific Officer for Sparrow. “Approximately 50% of those patients can be cured by surgery, but some will develop another tumor years later. ACS is an under-recognized condition, but it may affect up to 3 million patients in the U.S. There are also around 2 million people in the U.S. who rely on long-term use of corticosteroid medications to control autoimmune diseases and other conditions.”

The treatments being developed by Sparrow are based on recognition that cortisol and corticosteroid medications are activated in certain tissues such as the liver, bone, fat, and brain, where in excess they act to cause toxicity. The company’s investigational drugs inhibit HSD-1, the enzyme responsible for that activation.

Sparrow is about to launch a Phase 2 trial for Cushing’s syndrome. In early 2022 the company will also begin two additional Phase 2 trials for ACS and PMR, a common autoimmune disease in elderly patients. PMR is an arthritic syndrome characterized by a phenomenon known as claudication, which means the more you use a limb, the more it hurts and the harder it is to use. “For example, the more a PMR patient walks, the more painful and stiff their legs will become,” says Katz. “If they’re trying to do anything with their arms, the arms will get stiffer and more painful. The disease is pretty debilitating in terms of physical function. The only approved treatment for PMR is steroids, which have side effects such as diabetes, hypertension, osteoporosis, and fractures.”

Unknown Clinical Challenges

Katz is excited about the clinical trials for ACS and PMR because no sizable interventional trials have been reported in either of those conditions.

“We’re going into a completely new area, and we don’t know what we’re going to encounter in terms of patient recruitment and retention,” says Katz. “There is also no strong precedent for how to get approval for a drug in these conditions. The only treatment indicated for PMR is steroids, and that came without any efficacy clinical trials. There are no drugs approved for ACS. It’s hard to anticipate the challenges we will face when we are in an area that is very new.”

Patient centricity is a topic that is very important to Katz, and he spends a lot of time thinking about how to make trials a more pleasant experience for patients by limiting the burden placed on them. He notes that can sometimes be a difficult trade-off because of the procedures that must be performed to meet regulatory standards.

“In Cushing’s syndrome clinical care and clinical trials, the standard way for someone’s cortisol level to be measured is a 24-hour urine collection,” states Katz. “That involves looking at the amount of cortisol in the urine over a 24-hour period. That collection is inconvenient and burdensome, and the patient must then carry it somewhere to be analyzed.”

Sparrow hopes to shift that collection to a spot urine sample, like what patients would experience during a physical. The patient would urinate into a cup and hand it off to a clinic employee for analysis. The process would be much simpler and less burdensome for the patient. Sparrow will first need to prove that in a clinical trial the spot sample will work as well or better than the 24-hour collection. Subjects in the initial clinical trials will have to contribute the 24-hour collections so that Sparrow can demonstrate that future patients will not need to do so.

The Future of Endocrinology

Katz has a positive outlook on the future of endocrinology. Sparrow’s leading drug candidate, SPI-62, is an oral, small-molecule HSD-1 inhibitor. In four clinical trials, it demonstrated potent targeting of HSD-1 in both the brain and liver, and significantly lowered cortisol levels in the liver. The studies also showed a favorable safety and tolerability profile.

“If we are successful at developing SPI-62, I believe it will change the field of endocrinology,” says Katz. “We aim to shift the focus in Cushing’s syndrome to intracellular cortisol as the main driver of symptoms. What I mean by that is if we find that SPI-62 substantially reduces symptoms and that the degree of inhibition of our target HSD-1 correlates well with clinical improvement, then we can get to a new standard of care. We can potentially get rid of the 24-hour urine collections, which will be a big relief to patients. Additionally, many of today’s drugs have a side effect called adrenal insufficiency, which results when the drugs either reduce cortisol too much or completely block activity. Many of today’s drugs also require frequent monitoring and dose titration to prevent adrenal insufficiency. We believe that with HSD-1 inhibition we might avoid adrenal insufficiency as well.”

Katz is hopeful patients treated with SPI-62 will not require monitoring and dose titration. That proof will take years and lots of clinical trials. Sparrow may also produce the first targeted therapy for ACS. That could improve the recognition of ACS as a prevalent form of hypercortisolism and a substantial cause of morbidity and mortality.

“ACS is probably the most under-recognized condition in endocrinology based on recent epidemiological studies,” adds Katz. “It’s possible that as few as 3% of patients who have ACS actually have a diagnosis.  That is shocking for a condition that is associated with a lot of cardiometabolic and bone morbidity, negative effects on mood and cognition, sleep, and muscle strength, and is associated with excess mortality. We want to bring attention to this condition by bringing out a targeted therapy to treat a spectrum of symptoms by getting to the root cause of them.”

From https://www.clinicalleader.com/doc/sparrow-pharmaceuticals-hopes-to-change-the-future-of-endocrinology-0001

Filed under: Clinical trials, Cushing, Cushing's, Diagnostic Testing | Tagged: , , , , , , , | Leave a comment »

Cushing Death Rate ‘Unacceptable,’ Triple That of General Population

Posted on April 15, 2021 by MaryO

Excess mortality among people with endogenous Cushing syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality ― defined as the ratio of the number of deaths from CS divided by the total number of CS patients ― was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS compared to those with Cushing disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population…. The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told Medscape Medical News that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet…. This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing was unexpectedly high despite patients with adrenal cancer being excluded.”

Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, Oregon, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications…. We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest Study in Scale and Scope of Cushing Syndrome Mortality

Endogenous Cushing syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing syndrome). Surgery is the mainstay of initial treatment of Cushing syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing syndrome,” Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both CS types (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15 – 7.84).

This SMR was higher among patients with adrenal Cushing syndrome (3.3) vs Cushing disease (2.8) (P = .003) and among patients who had active disease (5.7) vs those whose disease was in remission (2.3) (P < .001).

The SMR also was worse among patients with Cushing disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing Perioperative Mortality: Consider Thromboprophylaxis

Fleseriu told Medscape Medical News that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing syndrome and balanced with individual bleeding risk,” Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Limumpornpetch has disclosed no relevant financial relationships. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

ENDO 2021: The Endocrine Society Annual Meeting: Presented March 20, 2021

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.

From https://www.medscape.com/viewarticle/949257

Filed under: adrenal, Cushing's, Endo 2021, Meetings and Conferences, pituitary, Rare Diseases, symptoms, Treatments | Tagged: , , , , , , , , , , | 1 Comment »

Treatment for Rare Cancer May Help Cushing’s Patients

Posted on February 5, 2021 by MaryO

The cancer medicine bexarotene may hold promise for treating Cushing’s disease, a study suggests.

The study, “Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT‐20 cells,” was published in the Journal of Cellular and Molecular Medicine.

Cushing’s disease is caused by a tumor on the pituitary gland, leading this gland to produce too much adrenocorticotropic hormone (ACTH). Excess ACTH causes the adrenal glands to release too much of the stress hormone cortisol; abnormally high cortisol levels are primarily responsible for the symptoms of Cushing’s.

Typically, first-line treatment is surgical removal of the pituitary tumor. But surgery, while effective in the majority of cases, does not help all. Additional treatment with medications or radiation therapy (radiotherapy) works for some, but not others, and these treatments often have substantial side effects.

“Thus, the development of new drugs for CD [Cushing’s disease] treatment is extremely urgent especially for patients who have low tolerance for surgery and radiotherapy,” the researchers wrote.

Recent research has shown that a protein called testicular receptor 4 (TR4) helps to drive ACTH production in pituitary cancers. Thus, blocking the activity of TR4 could be therapeutic in Cushing’s disease.

Researchers conducted computer simulations to screen for compounds that could block TR4. This revealed bexarotene as a potential inhibitor. Further biochemical tests confirmed that bexarotene could bind to, and block the activity of, TR4.

Bexarotene is a type of medication called a retinoid. It is approved to treat cutaneous T-cell lymphoma, a rare cancer that affects the skin, and available under the brand name Targretin.

When pituitary cancer cells in dishes were treated with bexarotene, the cells’ growth was impaired, and apoptosis (a type of programmed cell death) was triggered. Bexarotene treatment also reduced the secretion of ACTH from these cells.

In mice with ACTH-secreting pituitary tumors, bexarotene’s use significantly reduced tumor size, and lowered levels of ACTH and cortisol. Cushing’s-like symptoms also eased; for example, bexarotene treatment reduced the accumulation of fat around the abdomen in these mice.

Additional cellular experiments suggested that bexarotene specifically works on TR4 by changing the location of the protein. Normally, TR4 is present in the nucleus — the cellular compartment that houses DNA — where it helps to control the production of ACTH.

But with bexarotene treatment, TR4 tended to go outside of the nucleus, leading to lower ACTH production. The researchers noted that other mechanisms may also be involved in the observed effects of bexarotene.

“In summary, our work demonstrates that bexarotene is a potential inhibitor for TR4. Importantly, bexarotene may represent a new drug candidate to treat CD,” the researchers concluded.

From https://cushingsdiseasenews.com/2021/02/05/bexarotene-cancer-drug-t-cell-lymphoma-acth-production/?preview_id=39289

Filed under: Cancer, Cushing's, Treatments | Tagged: , , , , | Leave a comment »

The Effect Of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome

Posted on May 25, 2020 by MaryO
Braun LT, Fazel J, Zopp S
Journal of Bone and Mineral Research

|
May 22, 2020

This study was attempted to assess bone mineral density and fracture rates in 89 patients with confirmed Cushing’s syndrome at the time of diagnosis and 2 years after successful tumor resection.

Researchers ascertained five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. Via chemiluminescent immunoassays, they assessed bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide, alkaline bone phosphatase, CrossLaps, and TrAcP 5b in plasma or serum. For comparison, they studied 71 gender‐, age‐, and BMI‐matched patients in whom Cushing’s syndrome had been excluded.

The outcomes of this research exhibit that the phase immediately after surgical remission from endogenous CS is defined by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients.

Read the full article on Journal of Bone and Mineral Research.

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