Impact of Remission Status in Endogenous Cushing’s Syndrome on Cancer Incidence

Posted on March 4, 2025 by MaryO

Abstract

Objective
Endogenous Cushing’s syndrome (CS) has been linked with an increased risk of cancer. We aimed to evaluate the association between cancer risk and disease remission post-surgery in adrenal CS and Cushing’s disease (CD).
Design
A nationwide retrospective matched-cohort study of patients with CS diagnosed between 2000-2023 in Israel, using Clalit Health Services’ database. Methods Patients with CS were matched 1:5 with controls by age, sex, socioeconomic status, and BMI. Remission status post-surgery was assessed within two years after the diagnosis of CS. The outcome measured was time to first diagnosis of malignancy, at least three years post-CS diagnosis, excluding those who died or developed cancer earlier. Malignancy risk, stratified by remission status, was evaluated using Cox proportional hazards with death as a competing event.
Results
The cohort comprised 388 cases and 1,862 controls [mean age at diagnosis, 47.4±16.8 years; 1,534 (68.2%) women]. Among patients with CD, those who did not achieve remission within 2 years post diagnosis (n=69) had a higher risk of malignancy compared to those who achieved remission (n=99) (HR 3.89, 95% CI 1.41-10.75). Cancer risk in patients with CD who achieved remission was similar to that of the controls (HR 0.58, 95% CI 0.23-1.47). In patients with adrenal CS, the risk of cancer was comparable between those who did not achieve early remission (n=39) and those who did (n=113) (HR 1.68, 95% CI 0.83-3.40).
Conclusion
Though cancer risk is higher in both CD and adrenal CS, we have shown that achieving surgical remission within 2 years may attenuate cancer risk in patients with CD, but not in those with adrenal CS.

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

Oncocytic Pituicytoma in a Patient with Cushing’s Disease

Posted on February 20, 2025 by MaryO

The final, formatted version of the article will be published soon.

1) Background: Posterior pituitary tumors (PPTs) are extremely rare, with fewer than 400 cases reported to date. In 2022, the WHO classified four types of tumors originating from the posterior pituitary: traditional pituicytoma, oncocytic pituicytoma, granular pituicytoma, and ependymal pituicytoma. To our knowledge, only one subject with coexistence of Cushing’s disease and oncocytic pituicytoma (spindle cell oncocytoma) has been reported, but the clinical features of this patient were not described in detail.

2) Case presentation: We presented a case of a patient with Cushing’s syndrome and a pituitary mass. Transsphenoidal surgery was performed, and pathologic examination revealed two distinct tumors: a corticotroph adenoma with a diameter of less than 2mm and a larger oncocytic pituicytoma. Post-surgery serum cortisol was 51 nmol/L, indicating complete remission. Corticotroph adenoma or corticotroph hyperplasia were identified after surgery in less than half of the subjects with Cushing’s disease and PPT. (3)

Conclusions: Our study indicates that Cushing’s disease in patients with PPT may be caused by the existence of collision lesions, with corticotroph adenoma or hyperplasia being difficult to detect due to their small dimensions.

Keywords: Cushing’s disease, oncocytic pituicytoma, Spindle cell oncocytoma, pituitary adenoma, Posterior pituitary tumors

Received: 27 Aug 2024; Accepted: 17 Feb 2025.

Copyright: © 2025 Li, Chen, Tan, Yu, Tang, Cai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Huiwen Tan, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Ying Tang, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Bowen Cai, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jianwei Li, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

 

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1487120/abstract

 

Filed under: Clinical trials, Cushing's, pituitary, Rare Diseases, Treatments | Tagged: , , , | Leave a comment »

Corcept’s relacorilant GRADIENT trial misses primary endpoint

Posted on November 6, 2024 by MaryO

Corcept Therapeutics has shared some results from its Phase III GRADIENT trial for relacorilant – its experimental treatment for Cushing’s syndrome caused by adrenal gland pathology.

The trial will be used alongside data from the earlier GRACE trial to support the company’s new drug application (NDA) submission this quarter. However, it missed its primary endpoint.

The complete results of the company’s GRADIENT trial will be presented at a medical conference next year, but current results – released on 30 October – demonstrate that there was no statistically significant difference in hypertension in relacorilant and placebo patients.

The randomised double-blind trial included 137 patients across sites in the US, Europe and Israel. Over 22 weeks, half of the patients received relacorilant while the other half received a placebo.

The trial’s primary endpoint was the improvement in systolic blood pressure (SBP) compared to placebo. Its secondary endpoints were concerned with hyperglycemia, weight and body composition.

Mean SBP saw a reduction of 6.6 mm Hg in relacorilant patients compared to baseline. This is in contrast to a reduction of 2.1 mm Hg in placebo patients. The difference between these results was not statistically significant.

However, Corcept’s GRADIENT trial did meet some secondary endpoints and was well-tolerated. Patients taking relacorilant exhibited clinically meaningful and statistically significant improvements in hypertension, hyperglycemia, weight and body composition compared to baseline. In contrast, placebo patients did not.

Cushing’s syndrome is caused by an excess of cortisol and primarily affects those using steroid medications, which contain a synthetic version of the hormone. The condition is characterised by an increase of fat (particularly on the neck and shoulders), a change in face shape, stretch marks and skin which bruises easily. Cushing’s syndrome can also cause hypertension.

Corcept Therapeutics also shared that relacorilant was well-tolerated in the GRADIENT trial. It reported that there were no cases of relacorilant-induced hypokalemia, endometrial hypertrophy or related vaginal bleeding, adrenal insufficiency or QT prolongation.

The NDA submission for relacorilant for Cushing’s syndrome is expected this quarter. The GRADIENT trial will support results from the company’s GRACE trial, which were shared in June. The GRACE trial included 152 patients and met its primary endpoint of loss of hypertension control in the randomised-withdrawal phase.

Considering the results of the GRADIENT trial, Corcept Therapeutics’ chief development officer Bill Guyer said: “GRADIENT’s positive results in patients with Cushing’s syndrome confirm relacorilant’s promise as a significant medical advancement for the treatment of this deadly disease. As was true in the GRACE study, patients in GRADIENT who received relacorilant experienced clinically meaningful improvements in a broad range of hypercortisolism signs and symptoms, without suffering some of the serious adverse effects that can arise in patients taking currently approved treatments.

“These data will be a powerful addition to relacorilant’s NDA, which we plan to submit by year-end.”

https://www.clinicaltrialsarena.com/news/corcepts-relacorilant-gradient-trial-misses-primary-endpoint/?cf-view

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Sparrow Pharmaceuticals Announces Completion of Phase 2 Trial and FDA Orphan Drug Designation of Clofutriben for Endogenous Cushing’s Syndrome

Posted on November 1, 2024 by MaryO

Sparrow Pharmaceuticals, a clinical-stage biopharmaceutical company developing novel, targeted therapies to address unmet needs in both endocrinology and immunology, today announced that the Phase 2 RESCUE trial of clofutriben, a potent and selective HSD-1 inhibitor, for the treatment of endogenous Cushing’s syndrome is complete. All eligible patients who completed the trial elected to continue treatment with clofutriben in an open label extension (OLE) protocol. The promising results observed to date have catalyzed planning for the next phase of development to begin next year. In addition, Sparrow announced that clofutriben has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA) for the treatment of endogenous Cushing’s syndrome.

The RESCUE trial was a randomized, placebo-controlled trial of clofutriben for ACTH-dependent endogenous Cushing’s syndrome, a rare disease caused by a tumor that leads to hypersecretion of cortisol. HSD-1 inhibition with clofutriben lowers intracellular cortisol in key tissues where excess cortisol causes toxicity, thereby potentially reducing morbidity from cortisol excess. “HSD-1 inhibition with clofutriben is a completely novel approach to the treatment of endogenous Cushing’s syndrome that may overcome many of the serious problems with current therapies, including major safety, tolerability, and complexity issues such as the risk of adrenal insufficiency and adrenal crisis,” commented Sparrow Chief Medical Officer Frank Czerwiec, MD, PhD. “One of the most encouraging observations is that, given the option to continue clofutriben or switch to another treatment at the end of the trial, patients chose to continue clofutriben in the OLE. We are working closely with our medical, scientific, and patient advisors on plans to present these data and on designs for our next phase of clinical trials to startup next year.”

Sparrow also announced that clofutriben has been granted Orphan Drug Designation (ODD) by the FDA for the treatment of endogenous Cushing’s syndrome. “ODD qualifies sponsors for incentives including tax credits for qualified clinical trials, exemption from user fees, and a potential seven years of market exclusivity after NDA approval,” added Jamie MacPherson, PharmD, Sparrow’s SVP of Regulatory Affairs and Quality. “We are pleased that the FDA has recognized the potential for clofutriben to treat this devastating disease.”

Clofutriben is a potent and selective HSD-1 inhibitor that is in clinical testing for endogenous Cushing’s syndrome (EnCS) and autonomous cortisol secretion (ACS), a milder and more prevalent, yet still serious, form of hypercortisolism than EnCS. HSD-1 is an intracellular enzyme that activates glucocorticoids in target tissues in which glucocorticoids such as cortisol are associated with morbidity including liver, adipose, brain, bone, muscle, and skin. Additionally, clofutriben in combination with the glucocorticoid medicine prednisolone is in Phase 2 clinical trials for the treatment of immunological disorders, beginning with polymyalgia rheumatica (PMR), a prevalent autoimmune disease that mainly affects people over 50. Clofutriben co-administration is intended to reduce the side effects of prednisolone while maintaining its immune suppressive and anti-inflammatory benefits, thereby unlocking the potential of a class of medicines that has been limited in utility for more than 75 years by severe toxicity.

To learn more about Sparrow Pharmaceuticals and clofutriben, visit www.sparrowpharma.com.

About Sparrow Pharmaceuticals

Sparrow Pharmaceuticals was founded to spare patients the ravages of steroids. Leveraging underappreciated scientific insights into glucocorticoid biology, the company is working to provide better treatment options for serious disorders of hypercortisolism, and to revolutionize the treatment of autoimmune and inflammatory conditions. Its lead product, clofutriben (previously SPI-62), is an oral, small molecule, novel therapeutic treatment designed to target a source of active intracellular glucocorticoids in key tissues.

From https://www.morningstar.com/news/business-wire/20241028067997/sparrow-pharmaceuticals-announces-completion-of-phase-2-trial-and-fda-orphan-drug-designation-of-clofutriben-for-endogenous-cushings-syndrome

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Day 12, Cushing’s Awareness Challenge

Posted on April 12, 2024 by MaryO

In March of 1987, after the endo finally  confirmed that I had Cushing’s, I was sent to a local hospital where they repeated all those same tests for another week and decided that it was not my adrenal gland (Cushing’s Syndrome) creating the problem. The doctors and nurses had no idea what to do with me, so they put me on the brain cancer ward.

When I left this hospital after a week, we didn’t know any more than we had before.

As luck would have it, NIH (National Institutes of Health, Bethesda, Maryland) was doing a clinical trial of Cushing’s. I live in the same area as NIH so it was not too inconvenient but very scary at first to think of being tested there. At that time I only had a choice of NIH, Mayo Clinic and a place in Quebec to do this then-rare pituitary surgery called a Transsphenoidal Resection.

My husband asked my endo if it were his wife, if he would recommend this surgery.  The endo responded that he was divorcing his wife – he didn’t care what happened to her.  Oh, my!

I chose NIH – closest and free. After I was interviewed by the doctors there, I got a letter that I had been accepted into the clinical trial.

The night before I was admitted, I signed my will.  I was sure I was going to die there.  If not during testing, as a result of surgery.

The first time I was there was for 6 weeks as an inpatient. More of the same tests.

There were about 12 of us there and it was nice not to be alone with this mystery disease. Many of these Cushies (mostly women) were getting bald, couldn’t walk, having strokes, had diabetes. One was blind, one had a heart attack while I was there. Several were from Greece.

My first roommate was a nurse.  She spent the entire first night screaming in pain.  I was very glad when they moved me to a new room!

Towards the end of my testing period, I was looking forward to the surgery just to get this whole mess over with – either a cure or dying. While I was at NIH, I was gaining about a pound a day!

During the time I was home the weekend  before surgery, a college classmate of mine (I didn’t know her) DID die at NIH of a Cushing’s-related problem. I’m so glad I didn’t find out until reading the alumnae magazine a couple months later!  She was the same class, same major, same home-town, same disease…

We have a Scottish doctor named James Lind to thank for the clinical trial.  He  conducted the first ever clinical trial in 1747 and developed the theory that citrus fruits cured scurvy.  Lind  compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

I’d like to think that I advanced the knowledge of Cushing’s at least a little bit by being a guinea  pig in 1987-1989.

From the NIH: http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx

Hope through Research

Several components of the National Institutes of Health (NIH) conduct and support research on Cushing’s syndrome and other disorders of the endocrine system, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, and the National Center for Research Resources.

NIH-supported scientists are conducting intensive research into the normal and abnormal function of the major endocrine glands and the many hormones of the endocrine system. Researchers continue to study the effects of excess cortisol, including its effect on brain structure and function. To refine the diagnostic process, studies are under way to assess the accuracy of existing screening tests and the effectiveness of new imaging techniques to evaluate patients with ectopic ACTH syndrome. Researchers are also investigating jugular vein sampling as a less invasive alternative to petrosal sinus sampling. Research into treatment options includes study of a new drug to treat the symptoms of Cushing’s syndrome caused by ectopic ACTH secretion.

Studies are under way to understand the causes of benign endocrine tumor formation, such as those that cause most cases of Cushing’s syndrome. In a few pituitary adenomas, specific gene defects have been identified and may provide important clues to understanding tumor formation. Endocrine factors may also play a role. Increasing evidence suggests that tumor formation is a multistep process. Understanding the basis of Cushing’s syndrome will yield new approaches to therapy.

The NIH supports research related to Cushing’s syndrome at medical centers throughout the United States. Scientists are also treating patients with Cushing’s syndrome at the NIH Clinical Center in Bethesda, MD. Physicians who are interested in referring an adult patient may contact Lynnette Nieman, M.D., at NICHD, 10 Center Drive, Room 1-3140, Bethesda, MD 20892-1109, or by phone at 301-496-8935. Physicians interested in referring a child or adolescent may contact Constantine Stratakis, M.D., D.Sc., at NICHD, 10 Center Drive, Room 1-3330, Bethesda, MD 20892-1103, or by phone at 301-402-1998.

Filed under: Clinical trials, Cushing's | Tagged: , , , , , , , , , , , , , | 1 Comment »

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