ACTH Levels After Surgery Help Predict Remission, Recurrence in Cushing’s

Levels of adrenocorticotropic hormone (ACTH) in circulation after pituitary surgery may help predict which Cushing’s disease patients will achieve early remission and which will eventually see the disease return, a study shows.

Also, the earlier that patients reached their lowest peak of ACTH levels, the better their long-term outcomes.

The study, “Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease,” was published in the journal Endocrine Connections.

Removing the pituitary tumor through a minimally invasive surgery called transsphenoidal surgery is still the treatment of choice for Cushing’s disease patients. But not all patients enter remission, and even among those who do, a small proportion will experience disease recurrence.

While cortisol levels have been suggested as a main predictor of remission and recurrence, there is no consensus as to which cutoff point should be used after surgery, or the best time for measuring this hormone.

Because Cushing’s disease is caused by an ACTH-producing tumor in the pituitary gland, and ACTH has a short half-life (approximately 10 minutes), it is expected that ACTH levels drop markedly within a few hours after surgery.

Thus, a group of researchers in Spain aimed to determine whether blood levels of ACTH could be useful for predicting remission of Cushing’s disease both immediately after surgery (defined as less than 72 hours) and in the long term.

Researchers analyzed 65 patients with Cushing’s disease who had undergone transsphenoidal surgery (seven required a second intervention) between 2005 and 2016. Remission within three months was seen in 56 of 65 cases; late disease recurrence was seen in 18 of 58 cases.

Investigators measured the ACTH nadir concentration (defined as the lowest concentration) and the time taken to reach nadir levels after surgery, as well as the plasma ACTH concentration before hospital discharge.

While ACTH levels had no predictive value, the team found that people who went into remission had significantly lower ACTH nadir levels and ACTH levels at discharge. On the other hand, levels of ACHT nadir and at discharge were significantly higher for people who experienced a relapse, compared to those who remained in remission.

Using artificial intelligence algorithms, the researchers further found that ACTH nadir, ACTH at discharge, and cortisol nadir values were all of great relevance to predict remission within three months.

Analysis indicated that using a cutoff point of 3.3 pmol/L of ACTH after surgery and before discharge gave the best sensitivity and specificity for predicting a patient’s prognosis.

Researchers further found that the time patients took to reach their ACTH nadir, regardless of nadir levels, also influenced their outcomes. In fact, patients reaching this nadir in less than than 46 hours more likely achieved early remission.

And taking longer than 39 hours to reach the ACTH nadir was significantly more frequent in patients who experienced recurrence. This indicates that the time to ACTH nadir is an important measure for prognosis.

“In the immediate postoperative period of patients with [Cushing’s disease], the ACTH concentration is of prognostic utility in relation to late disease remission,” the researchers said.

Overall, “we propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate,” the study concluded.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.

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/

3D-Printing Technology Improves Outcomes In Pituitary Adenoma Surgery

Huang X, et al. Pituitary. 2019;doi:10.1007/s11102-018-0927-x.

March 3, 2019

The use of 3D-printed models could lead to less operation time and blood loss and fewer postoperative complications in adults who undergo endoscopic endonasal transsphenoidal surgery for pituitary adenomas and other conditions, according to findings published in Pituitary.

“Several factors influence the outcome of endoscopic endonasal surgery, including the tumor volume, patient age, lesion location and sphenoid pneumatolysis,” Xiaobing Jiang, of the department of neurosurgery at Union Hospital of Tongji Medical College of Huazhong University of Science and Technology in Wuhan, Hubei, China, and colleagues wrote. “An accurate model of the target tumor structure is a major prerequisite for a successful [pituitary adenoma] resection, especially for macroadenomas, as this may avoid disastrous complications due to suboptimal treatment.”

Jiang and colleagues conducted a retrospective analysis of 20 adults who underwent endoscopic endonasal transsphenoidal surgery at Union Hospital in Wuhan. Participants were included based on similar tumor sizes, the presence of no other diseases and nonintuitive tumor identification. All surgeries in the cohort occurred between January and August 2017, with 10 participants (mean age, 44.4 years; 50% women) receiving CT and MRI before surgery; the remaining 10 also received an operation with 3D printing (mean age, 41.2 years; 50% women).

To create the 3D models, images from CT and MRIs were combined. The 3D printer then used this information to create the model, which took between 2 hours, 10 minutes, and 4 hours, 32 minutes, to design and 10 hours, 12 minutes, and 22 hours, 34 minutes, to print.

After surgery, the researchers found that mean operation time was lower in participants who had 3D models compared with participants who did not (127 minutes vs. 143.4 minutes; P = .007). In addition, there was less blood loss in participants with 3D printing compared with participants without (159.9 mL vs. 170 mL; P = .009). The researchers noted that there were postoperative complications in 20% of the 3D-printing group and 40% of the CT and MRI alone group.

“As it is highly precise and allows personalization, 3D-printing technology has started to be applied in medicine in recent years. In neurosurgery, 3D-printing technology can provide models for the patients’ disease characteristics, such as skull defects, brain tumors, intracranial aneurysms and intracranial vascular malformations,” the researchers wrote. “We believe that with its continuous development, 3D-printing technology will be applied in clinical practice in the near future.” – by Phil Neuffer

DisclosuresThe authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B582c6512-708a-4900-ad20-f0adb5a79390%7D/3d-printing-technology-improves-outcomes-in-pituitary-adenoma-surgery

Faster Adrenal Recovery May Predict Cushing’s Disease Recurrence

A shorter duration of adrenal insufficiency — when the adrenal gland is not working properly — after surgical removal of a pituitary tumor may predict recurrence in Cushing’s disease patients, a new study suggests.

The study, “Recovery of the adrenal function after pituitary surgery in patients with Cushing Disease: persistent remission or recurrence?,” was published in the journal Neuroendocrinology.

Cushing’s disease is a condition characterized by excess cortisol in circulation due to a tumor in the pituitary gland that produces too much of the adrenocorticotropic hormone (ACTH). This hormone acts on the adrenal glands, telling them to produce cortisol.

The first-line treatment for these patients is pituitary surgery to remove the tumor, but while success rates are high, most patients experience adrenal insufficiency and some will see their disease return.

Adrenal insufficiency happens when the adrenal glands cannot make enough cortisol — because the source of ACTH was suddenly removed — and may last from months to years. In these cases, patients require replacement hormone therapy until normal ACTH and cortisol production resumes.

However, the recovery of adrenal gland function may mean one of two things: either patients have their hypothalamus-pituitary-adrenal axis — a feedback loop that regulates ACTH and cortisol production — functioning normally, or their disease returned.

So, a team of researchers in Italy sought to compare the recovery of adrenal gland function in patients with a lasting remission to those whose disease recurred.

The study included 61 patients treated and followed at the Ospedale Maggiore Policlinico of Milan between 1990 and 2017. Patients had been followed for a median of six years (minimum three years) and 10 (16.3%) saw their disease return during follow-up.

Overall, the median time to recovery of adrenal function was 19 months, but while most patients in remission (67%) had not yet recovered their adrenal function after a median of six years, all patients whose disease recurred experienced adrenal recovery within 22 months.

Among those with disease recurrence, the interval from adrenal recovery to recurrence lasted a median of 1.1 years, but in one patient, signs of disease recurrence were not seen for 15.5 years.

Statistical analysis revealed that the time needed for adrenal recovery was negatively associated with disease recurrence, suggesting that patients with sorter adrenal insufficiency intervals were at an increased risk for recurrence.

“In conclusion, our study shows that the duration of adrenal insufficiency after pituitary surgery in patients with CD is significantly shorter in recurrent CD than in the persistent remission group,” researchers wrote.

“The duration of AI may be a useful predictor for CD [Cushing’s disease] recurrence and those patients who show a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored being more at risk of disease relapse,” they concluded.

From https://cushingsdiseasenews.com/2019/01/29/faster-adrenal-recovery-may-predict-recurrence-cushings-disease/

Korlym: How an abortion pill turned out to be a treatment for a rare disease

Even though the $550 yellow pills sold as Korlym have a controversial origin as the abortion pill, Leslie Edwin said they “gave me life.”

The 40-year-old Georgia resident lives with Cushing’s syndrome, a potentially deadly condition that causes high levels of the hormone cortisol to wreak havoc on a body. When first diagnosed, she said, she gained about 100 pounds, her blood sugars were “out of control,” and she suffered acne, the inability to sleep and constant anxiety.

“I wouldn’t leave the house,” Edwin said of her first bout with the condition. “I quit my job after a certain point. I just couldn’t keep being in front of people.”

That’s when Edwin endured surgeries, including one to remove her pituitary gland. She went into remission, but then, in 2016, her weight shot up 30 pounds and the anxious feelings returned. Her doctors prescribed Korlym.

The drug’s active ingredient is mifepristone, once called RU-486 and better known as the abortion pill because it causes a miscarriage when taken early in a pregnancy. Nearly two decades ago, Danco Laboratories won approval to market Mifeprex in the United States as the abortion drug, with tight restrictions on use. Corcept Therapeutics, a Silicon Valley-based drug company, began marketing Korlym six years ago as a specialty drug for about 10,000 rare-disease patients such as Edwin.

The difference in price between Korlym and Mifeprex is striking, even though the ingredients are the same: One 200-milligram pill to prompt an abortion costs about $80. In contrast, a 300-milligram pill prescribed for Cushing’s runs about $550 before discounts. (Patients wanting an abortion take only one pill. People with Cushing’s often take up to three pills a day for months or years.)

Joseph Belanoff, chief executive of the drug’s maker, Corcept, said Korlym’s average cost per patient is $180,000 annually and concedes that “we have an expensive drug. There’s no getting around that.” But, he said, he believes Corcept has a “social contract” to take care of patients and pledged that any patient who is prescribed Korlym will get it regardless of insurance coverage or costs.

The story of Korlym highlights how America’s drug development system can turn an old drug into a new one that treats relatively few — but often very desperate — patients.

When the Food and Drug Administration approved Korlym in 2012, it was designated as an orphan drug, giving Corcept seven years of market exclusivity as well as other economic incentives. Congress approved orphan drug incentives to encourage the development of medicines for rare diseases that affect fewer than 200,000 patients. Since the drug’s approval, Korlym’s price has risen about 150 percent, and last year the company’s revenue nearly doubled to $159.2 million and it reported a net income of $129.1 million. (Korlym is the company’s only product, and it treats about 1,000 patients in the United States.)

Belanoff said the profits from Korlym pay for the company’s past spending on the drug’s research and development as well as its effort to create new drugs. The company recently reported an encouraging Phase 2 trial update on Korlym’s successor, relacorilant, a drug that could treat Cushing’s without the side effects for some women of endometrial thickening and vaginal bleeding that can occur with Korlym.

The company’s pipeline is also full of potential oncology drugs that hold the promise of using molecules to influence the cortisol receptors, with wide-ranging effects in the body. Korlym in combination with another drug is being tested for the treatment of metastatic triple-negative breast cancer, which tends to be more aggressive than other types of breast cancer. And relacorilant is in the very early stages of testing to treat castration-resistant prostate cancer.

While many of the second-generation drugs are not related to Korlym structurally, Korlym did “provide the funding. . . . If there had not been orphan-drug pricing and the [Orphan Drug] Act, you would have to look for a different way to develop those drugs,” Belanoff said.

Korlym came to market in 2012 with an average wholesale price of $223.20 per pill before discounts, according to the health-care technology firm Connecture. By December 2017, each pill had an average wholesale price of $549.60 before any discounts or rebates were negotiated for patients.

Teva Pharmaceutical Industries recently announced it had filed an application to produce a generic version of the drug. Teva declined to comment for this report.

A ‘pioneering substance’

Cushing’s syndrome happens when the body produces too much cortisol, which normally helps keep the cardiovascular system functioning well and allows the body to turn proteins, carbohydrates and fats into energy. But too much cortisol can be destructive. It can cause cognitive difficulties, depression, fatigue, high blood pressure, bone loss and, in some cases, Type 2 diabetes. Those affected by the syndrome can develop a fatty hump between their shoulders and a rounded face. Without treatment, patients can die of a variety of complications, including sepsis after the hormone compromises the immune system.

Mifepristone, the active ingredient in Korlym, helps Cushing’s patients by blocking the body’s ability to process cortisol. It induces an abortion by blocking another of the body’s receptors, for progesterone, which causes the uterine wall to break down and the pregnancy to end.

When the FDA approved Korlym for a specific set of Cushing’s patients, the agency required a “TERMINATION OF PREGNANCY” warning box at the top of the label.

Endocrinologist Constantine Stratakis, scientific director at the National Institute of Child Health and Human Development, who specializes in treating people with Cushing’s syndrome, calls mifepristone a “pioneering substance” because it “has a lot of crossover” to other receptors in the body.

That means the drug has a lot of potential uses. Belanoff and Alan Schatzberg, a Stanford University psychiatrist and scientist, co-founded Corcept in 1998 to explore whether mifepristone could help treat major depression. In 2002, Schatzberg said the drug “may be the equivalent of shock treatments in a pill.” But clinical trials were not successful.

Social contract

By 2007, Corcept had found another possibility and filed an application to see whether mifepristone might work for Cushing’s patients.

Developing the drug cost about $300 million, according to Belanoff, and involved long-term toxicology tests to ensure that patients could safely take high doses for months or years. Korlym is approved to treat Cushing’s patients who have failed to relieve their symptoms through surgery or do not qualify for surgery, so some patients expect to take it for the rest of their lives while others just a few months.

Most patients are covered by private insurance, Belanoff said, but Medicare and Medicaid pay for the drug as well. According to Medicare Part D data, 52 Korlym patients cost Medicare $2.6 million in 2013. Two years later, 115 beneficiaries filed claims of $11.4 million.

Edwin is on private insurance and describes herself as being in “a really high tax bracket,” yet she never paid more than $25 a month through Corcept’s patient assistance program . She stopped taking the drug last year after her Cushing’s symptoms retreated.

“Across the board, it would be very difficult to find any patient that pays the full price,” said Edwin, who volunteers as president of the nonprofit patient advocacy group Cushing’s Support and Research Foundation.

The small organization, which reported $50,000 in contributions and grants in 2015, notes on its website that Corcept as well as Novartis Oncology provide financial support to the organization. The group’s federal tax filing details that the majority of its expenses go to distributing a quarterly newsletter, contacting members and patients “to promote mission,” and referring patients to doctors.

Specialty drugs such as Korlym often have sky-high price tags and are often distributed through special pharmacy programs. Drug companies commonly work with insurers and patient assistance programs to lower the patient’s out-of-pocket costs.

But for Corcept, the effort to brand the drug as a Cushing’s medication was also important, Belanoff said: “We were starting with a notorious drug.”

“There is a real infrastructure in caring for these patients,” he said. “It is not just like getting your medicine at [a drug store] and figuring out what to do with it.”

Sherwin D’Souza, an internal medicine doctor at St. Luke’s Boise Medical Center in Idaho, prescribed Korlym for the first time last year to Vonda Huddleston, who was uninsured. D’Souza said he knew Corcept would provide financial assistance until Huddleston could get insurance to help pay for surgery to remove a tumor in her adrenal gland that is suspected of causing her high cortisol levels.

Huddleston, though, did not feel well on the drug and gained weight. D’Souza took her off Korlym and scheduled surgery. “I was sort of trying to buy time and treat her conditions,” D’Souza said. “It’s very expensive . . . but they do have a very good program for patients in need of the drug.”

Kaiser Health News

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

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