New discoveries offer possible Cushing’s disease cure

LOS ANGELES — More than a century has passed since the neurosurgeon and pathologist Harvey Cushing first discovered the disease that would eventually bear his name, but only recently have several key discoveries offered patients with the condition real hope for a cure, according to a speaker here.

There are several challenges clinicians confront in the diagnosis and treatment of Cushing’s disease, Shlomo Melmed, MB, ChB, FRCP, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, said during a plenary presentation. Patients who present with Cushing’s disease typically have depression, impaired mental function and hypertension and are at high risk for stroke, myocardial infarction, thrombosis, dyslipidemia and other metabolic disorders, Melmed said. Available therapies, which range from surgery and radiation to the somatostatin analogue pasireotide (Signifor LAR, Novartis), are often followed by disease recurrence. Cushing’s disease is fatal without treatment; the median survival if uncontrolled is about 4.5 years, Melmed said.

“This truly is a metabolic, malignant disorder,” Melmed said. “The life expectancy today in patients who are not controlled is apparently no different from 1930.”

The outlook for Cushing’s disease is now beginning to change, Melmed said. New targets are emerging for treatment, and newly discovered molecules show promise in reducing the secretion of adrenocorticotropic hormone (ACTH) and pituitary tumor size.

“Now, we are seeing the glimmers of opportunity and optimism, that we can identify specific tumor drivers — SST5, [epidermal growth factor] receptor, cyclin inhibitors — and we can start thinking about personalized, precision treatment for these patients with a higher degree of efficacy and optimism than we could have even a year or 2 ago,” Melmed said. “This will be an opportunity for us to broaden the horizons of our investigations into this debilitating disorder.”

Challenges in diagnosis, treatment

Overall, about 10% of the U.S. population harbors a pituitary adenoma, the most common type of pituitary disorder, although the average size is only about 6 mm and 40% of them are not visible, Melmed said. In patients with Cushing’s disease, surgery is effective in only about 60% to 70% of patients for initial remission, and overall, there is about a 60% chance of recurrence depending on the surgery center, Melmed said. Radiation typically leads to hypopituitarism, whereas surgical or biochemical adrenalectomy is associated with adverse effects and morbidity. Additionally, the clinical features of hypercortisolemia overlap with many common illnesses, such as obesity, hypertension and type 2 diabetes.

“There are thousands of those patients for every patient with Cushing’s disease who we will encounter,” Melmed said.

The challenge for the treating clinician, Melmed said, is to normalize cortisol and ACTH with minimal morbidity, to resect the tumor mass or control tumor growth, preserve pituitary function, improve quality of life and achieve long-term control without recurrence.

“This is a difficult challenge to meet for all of us,” Melmed said.

Available options

Pituitary surgery is typically the first-line option offered to patients with Cushing’s disease, Melmed said, and there are several advantages, including rapid initial remission, a one-time cost and potentially curing the disease. However, there are several disadvantages with surgery; patients undergoing surgery are at risk for postoperative venous thromboembolism, persistent hypersecretion of ACTH, adenoma persistence or recurrence, and surgical complications.

Second-line options are repeat surgery, radiation, adrenalectomy or medical therapy, each with its own sets of pros and cons, Melmed said.

“The reality of Cushing’s disease — these patients undergo first surgery and then recur, second surgery and then recur, then maybe radiation and then recur, and then they develop a chronic illness, and this chronic illness is what leads to their demise,” Melmed said. “Medical therapy is appropriate at every step of the spectrum.”

Zebrafish clues

Searching for new options, Melmed and colleagues introduced a pituitary tumor transforming gene discovered in his lab into zebrafish, which caused the fish to develop the hallmark features of Cushing’s disease: high cortisol levels, diabetes and cardiovascular disease. In the fish models, researchers observed that cyclin E activity, which drives the production of ACTH, was high.

Melmed and colleagues then screened zebrafish larvae in a search for cyclin E inhibitors to derive a therapeutic molecule and discovered R-roscovitine, shown to repress the expression of proopiomelanocortin (POMC), the pituitary precursor of ACTH.

In fish, mouse and in vitro human cell models, treatment with R-roscovitine was associated with suppressed corticotroph tumor signaling and blocked ACTH production, Melmed said.

“Furthermore, we asked whether or not roscovitine would actually block transcription of the POMC gene,” Melmed said. “It does. We had this molecule (that) suppressed cyclin E and also blocks transcription of POMC leading to blocked production of ACTH.”

In a small, open-label, proof-of-principal study, four patients with Cushing’s disease who received roscovitine for 4 weeks developed normalized urinary free cortisol, Melmed said.

Currently, the FDA Office of Orphan Products Development is funding a multicenter, phase 2, open-label clinical trial that will evaluate the safety and efficacy of two of three potential doses of oral roscovitine (seliciclib) in patients with newly diagnosed, persistent or recurrent Cushing disease. Up to 29 participants will be treated with up to 800 mg per day of oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes.

“Given the rarity of the disorder, it will probably take us 2 to 3 years to recruit patients to give us a robust answer,” Melmed said. “This zebrafish model was published in 2011, and we are now in 2019. It has taken us 8 years from publication of the data to, today, going into humans with Cushing’s. Hopefully, this will light the pathway for a phase 2 trial.”

 Offering optimism’

Practitioners face a unique paradigm when treating patients with Cushing’s disease, Melmed said. Available first- and second-line therapy options often are not a cure for many patients, who develop multimorbidity and report a low quality of life.

“Then, we are kept in this difficult cycle of what to do next and, eventually, running out of options,” Melmed said. “Now, we can look at novel, targeted molecules and add those to our armamentarium and at least offer our patients the opportunity to participate in trials, or at least offer the optimism that, over the coming years, there will be a light at the end of the tunnel for their disorder.”

Melmed compared the work to Lucas Cranach’s Fons Juventutis (The Fountain of Youth). The painting, completed in 1446, shows sick people brought by horse-drawn ambulance to a pool of water, only to emerge happy and healthy.

“He was imagining this ‘elixir of youth’ (that) we could offer patients who are very ill and, in fact, that is what we as endocrinologists do,” Melmed said. “We offer our patients these elixirs. These Cushing’s patients are extremely ill. We are trying with all of our molecular work and our understanding of pathogenesis and signaling to create this pool of water for them, where they can emerge with at least an improved quality of life and, hopefully, a normalized mortality. That is our challenge.” – by Regina Schaffer

Reference:

Melmed S. From zebrafish to humans: translating discoveries for the treatment of Cushing’s disease. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.

Disclosure: Melmed reports no relevant financial disclosures.

 

From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B585002ad-640f-49e5-8d62-d1853154d7e2%7D/new-discoveries-offer-possible-cushings-disease-cure

Even in Remission, Cushing’s Patients Have Excess Mortality

Cushing’s disease patients in Sweden have a higher risk of death than the general Swedish population, particularly of cardiovascular complications, and that increased risk persists even in patients in remission, a large nationwide study shows.

The study, “Overall and disease-specific mortality in patients with Cushing’s disease: a Swedish nationwide study,” was published in the Journal of Clinical Endocrinology and Metabolism.

The outcomes of Cushing’s disease patients have improved with the introduction of several therapeutic approaches, such as minimally invasive surgery and cortisol-lowering therapies. However, mortality is still high, especially among those who do not achieve remission.

While currently patients in remission are thought to have a better prognosis, it is still unclear whether these patients still have a higher mortality than the general population. Understanding whether these patients are more likely to die and what risk factors are associated with increased mortality is critical to reduce death rates among Cushing’s patients.

A team of Swedish researchers thus performed a retrospective study that included patients diagnosed with Cushing’s disease who were part of the Swedish National Patient Registry between 1987 and 2013.

A total of 502 patients with Cushing’s disease were included in the study, 419 of whom were confirmed to be in remission. Most patients (77%) were women; the mean age at diagnosis was 43 years, and the median follow-up time was 13 years.

During the follow-up, 133 Cushing’s patients died, compared to 54 expected deaths in the general population — a mortality rate 2.5 times higher, researchers said.

The most common causes of death among Cushing’s patients were cardiovascular diseases, particularly ischemic heart disease and cerebral infarctions. However, infectious and respiratory diseases (including pneumonia), as well as diseases of the digestive system, also contributed to the increased mortality among Cushing’s patients.

Of those in remission, 21% died, compared to 55% among those not in remission. While these patients had a lower risk of death, their mortality rate was still 90% higher than that of the general population. For patients who did not achieve remission, the mortality rate was 6.9 times higher.

The mortality associated with cardiovascular diseases was increased for both patients in remission and not in remission. Also, older age at the start of the study and time in remission were associated with mortality risk.

“A more aggressive treatment of hypertension, dyslipidemia [abnormal amount of fat in the blood], and other cardiovascular risk factors might be warranted in patients with CS in remission,” researchers said.

Of the 419 patients in remission, 315 had undergone pituitary surgery, 102 had had their adrenal glands removed, and 116 had received radiation therapy.

Surgical removal of the adrenal glands and chronic glucocorticoid replacement therapy were associated with a worse prognosis. In fact, glucocorticoid replacement therapy more than twice increased the mortality risk. Growth hormone replacement was linked with better outcomes.

In remission patients, a diagnosis of diabetes mellitus or high blood pressure had no impact on mortality risk.

Overall, “this large nationwide study shows that patients with [Cushing’s disease] continue to have excess mortality even after remission,” researchers stated. The highest mortality rates, however, were seen in “patients with persistent disease, those who were treated with bilateral adrenalectomy and those who required glucocorticoid replacement.”

“Further studies need to focus on identifying best approaches to obtaining remission, active surveillance, adequate hormone replacement and long-term management of cardiovascular and mental health in these patients,” the study concluded.

From https://cushingsdiseasenews.com/2019/02/28/even-in-remission-cushings-patients-have-excess-mortality-swedish-study-says/

High Cortisol Levels, as Seen in Cushing’s, Can Lead to Greater Risk of Heart Disease, Study Finds

People with high cortisol levels have lower muscle mass and higher visceral fat deposits, putting them at a greater risk for cardiovascular disease, new research shows.

High levels of cortisol can result from a variety of reasons, including Cushing’s disease and adrenal tumors. Most adrenal tumors are found to be non-functioning, meaning they do not produce excess hormones. However, up to 47 percent of patients have mild autonomous cortisol excess (MACE).

The study, “Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas,” was published in the journal Clinical Endocrinology.

Long-term studies have shown that as a group, patients with MACE tend to have increased cardiovascular risk factors, such as hypertension, type 2 diabetes mellitus (DM2), obesity, and high lipid levels, which are associated with higher cardiovascular death rates.

Abdominal adiposity, which refers to fat deposits around the abdomen and stomach, and central sarcopenia, referring to loss of skeletal muscle mass, are both known to be linked to higher cardiovascular risk and increased mortality.

Overt hypercortisolism is known to lead to increased visceral adiposity (body fat stored within the abdominal cavity) and muscle loss. However, little is known about the body composition of patients with adrenal adenomas and MACE.

Therefore, researchers set out to determine whether central sarcopenia and adiposity are present in patients with MACE, and whether they can be markers of disease severity in patients with adrenal adenomas. To determine this, researchers used body composition measurements of 25 patients with Cushing’s disease, 48 patients with MACE, and 32 patients with non-functioning adrenal tumors (NFAT) using abdominal CTs.

Specifically, researchers looked at visceral fat, subcutaneous fat, and total abdominal muscle mass. Visceral fat refers to fat around organs, and it is “deeper” than subcutaneous fat, which is closer to the skin.

Results showed that, compared to patients with non-functional tumors, those with Cushing’s disease had a higher visceral to total (V/T) fat ratio but a lower visceral to subcutaneous (V/S) fat ratio. In MACE patients, however, both ratios were decreased compared to patients with non-functional tumors.

Cushing’s disease patients also had 10 cm2  less total muscle mass, compared to patients with non-functional tumors.

An overnight dexamethasone suppression test was conducted in these patients to determine levels of cortisol in the blood. The next morning, cortisol levels were checked. High levels of cortisol indicate the presence of a disease, such as MACE or Cushing’s disease.

After administering the test, researchers determined that for an increase in cortisol in the morning, there was a correlating increase in the V/T ratio and the V/S fat ratio, and a decrease in the mean total muscle mass.

Therefore, the higher the degree of hypercortisolism, the lower the muscle mass and the higher the visceral adiposity.

These results could prove to be clinically useful as both visceral adiposity and low muscle mass are risk factors of a number of diseases, including cardiovascular disease.

“Body composition measurement may provide an additive value in making a diagnosis of clinically important MACE and aid in individualizing management of patients with ACAs and MACE,” the researchers concluded.

From https://cushingsdiseasenews.com/2017/11/30/cushings-disease-high-cortisol-levels-leads-to-greater-risk-heart-disease/

A retrospective analysis of postoperative hypokalemia in pituitary adenomas after transsphenoidal surgery

Abstract.

Background

Pituitary adenoma is one of the most common intracranial neoplasms, and its primary treatment is endoscopic endonasal transsphenoidal tumorectomy. Postoperative hypokalemia in these patients is a common complication, and is associated with morbidity and mortality. This study aimed to analyze the etiopathology of postoperative hypokalemia in pituitary adenomas after endoscopic transsphenoidal surgery.

Methods and Materials

This retrospective study included 181 pituitary adenomas confirmed by histopathology. Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Repeated measures ANOVA was used to analyze change in serum potassium levels at different time points.

Results

Multiple Logistic regression analysis revealed that only ACTH-pituitary adenoma (OR = 4.92, 95% CI [1.18–20.48], P = 0.029) had a significant association with postoperative hypokalemia. Moreover, the overall mean serum potassium concentration was significantly lower in the ACTH versus the non-ACTH group (3.34 mmol/L vs. 3.79 mmol/L, P = 0.001). Postoperative hypokalemia was predominantly found in patients with ACTH-pituitary adenoma (P = 0.033).

Conclusions

ACTH-pituitary adenomas may be an independent factor related postoperative hypokalemia in patients despite conventional potassium supplementation in the immediate postoperative period.

Cite this as

You L, Li W, Chen T, Tang D, You J, Zhang X. (2017) A retrospective analysis of postoperative hypokalemia in pituitary adenomas after transsphenoidal surgery. PeerJ5:e3337 https://doi.org/10.7717/peerj.3337

Read the entire article at https://peerj.com/articles/3337/

Hair Test for Cushing Syndrome?

Cortisol levels in hair correlated strongly with standard tests

by Jeff Minerd
Contributing Writer, MedPage Today

Analyzing the levels of cortisol in hair may aid in the diagnosis of Cushing syndrome, perhaps one day replacing invasive blood tests, scientists said.

Cortisol levels in the proximal ends of hair samples taken from patients with the syndrome correlated strongly with blood tests (R=0.4; P=0.03) and urine tests (R=0.5; P=0.005) for cortisol, reported Mihail Zilbermint, MD, of the National Institute of Child Health and Human Development in Bethesda, Md., and colleagues.

“The diagnosis of Cushing syndrome is often challenging and inconclusive, despite numerous tests used for the detection of hypercortisolemia and its origin, and is associated with high morbidity and high risk for mortality, if undiagnosed and untreated,” Zilbermint and colleagues wrote online in Endocrine: International Journal of Basic and Clinical Endocrinology.

“As a potential solution to the limitations of these tests, hair cortisol has been increasingly studied as an additional means to diagnose patients with Cushing Syndrome. Much like hemoglobin A1C is a longitudinal marker of blood glucose levels, hair cortisol can be a measure of the body’s glucocorticoid levels over the previous several weeks to months.”

“Our results are encouraging,” Zilbermint said in a statement. “We are hopeful that hair analysis may ultimately prove useful as a less-invasive screening test for Cushing syndrome or in helping to confirm the diagnosis.”

The study included 30 patients with Cushing syndrome and six control individuals without the disease. The participants’ average age was 26, and 75% were female and 75% were Caucasian.

The investigators took 3 cm-long hair samples from all patients, analyzed the proximal, medial, and distal segments of the samples for cortisol, and compared the results with results of standard blood and urine tests. Cortisol levels were highest in the proximal segments and correlated best with the standard tests, the investigators reported.

“We found that proximal hair cortisol directly correlates with late night serum cortisol and UFC [urinary free cortisol] in patients with and without Cushing syndrome. The most proximal 1 cm of hair was the best section of hair for stratifying the two groups of patients in our cohort.

“These findings support further research on the use of this modality in the workup for Cushing syndrome.”

Regarding the study’s limitations, the team pointed to the small control group of only six patients. Another limitation is that more than half of the participants (58%) were younger than age 18, and pubertal status on cortisol metabolism may be a factor in hair cortisol measurement.

“However, our study’s strengths are that it is the largest sample so far to analyze segmental hair cortisol in Cushing syndrome, and that it is the largest study to compare hair cortisol to any biochemical test for hypercortisolemia in patients with Cushing syndrome,” Zilbermint and colleagues said. “Our study also included a large cohort of Cushing Disease patients, which has been under-represented in prior studies on hair cortisol.”

The study was funded by the National Institutes of Health. Zilbermint and colleagues reported having no relevant financial relationships with industry.

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