Cushing’s Patients at Risk of Life-threatening Pulmonary Fungal Infection

Cushing’s disease patients who exhibit nodules or masses in their lungs should be thoroughly investigated to exclude fungal infection with Cryptococcus neoformans, a study from China suggests.

While rare, the infection can be life-threatening, showing a particularly worse prognosis in patients with fluid infiltration in their lungs or with low white blood cell counts in their blood.

The study, “Cushing’s disease with pulmonary Cryptococcus neoformans infection in a single center in Beijing, China: A retrospective study and literature review,” was published in the Journal of the Formosan Medical Association.

Cortisol, a hormone that is produced in excess in Cushing’s disease patients, is a kind of glucocorticoid that suppresses inflammation and immunity. Consequently, subjects exposed to cortisol for long periods, much like immuno-compromised patients, are at high risk for infections.

In Cushing’s patients, the most common infections include Pneumocystis jiroveciAspergillus fumigatus, and Cryptococcosis — 95 percent of which are caused by C. neoformans.

But while “Cushing’s disease patients are susceptible to C. neoformans, the association between pulmonary C.neoformans and [Cushing’s disease] is poorly explored,” researchers said.

In an attempt to understand the clinical characteristics of Cushing’s patients who develop C.neoformans infections, researchers in Beijing, China, reviewed the clinical records of six patients at their clinical center.

Their analysis also included six other patients whose cases had been reported in previous publications.

Patients had a mean age of 44 and 10 were diagnosed initially with high blood pressure. Seven also had diabetes mellitus.

All patients had elevated cortisol levels in their urine and high levels of the adrenocorticotropic hormone (ACTH). Ultimately, all patients were found to have masses in their pituitary glands, causing the high cortisol and ACTH levels.

Patients complained of lung symptoms, including shortness of breath after physical activity, cough, and expectoration. But they had no fever or signs of blood in the lungs, which could suggest lung infection.

A CT scan of the chest then revealed lung nodules in four patients, and lung masses in five patients. Four patients, including one with a lung mass, also had lung air spaces filled with some material (pulmonary consolidation), which was consistent with pulmonary infection.

After analyzing lung nodule/mass biopsies, lung fluids, or blood samples, all patients were diagnosed with C. neoformans pulmonary cryptococcosis.

For their infection, patients received anti-fungal drugs, including amphotericin-B, fluconazole, flucytosine, and liposomal amphotericin. Cushing’s disease, however, was treated with surgery in 10 patients and ketoconazole in two patients.

Despite the treatments, five patients died during follow-up, including four who experienced co-infections or spreading of the cryptococcal infection and one patient with extensive bleeding after surgical removal of the gallbladder.

Among them, two patients had significantly low white blood cell levels and elevated cortisol levels, and four had infiltration in their lungs, suggesting these are markers of poor prognoses.

Researchers also noted that the patients who received ketoconazole died during in the reviewed studies. They attribute this to ketoconazole’s anti-fungal properties, which may interfere with its ability to manage Cushing’s symptoms.

Given the high susceptibility of Cushing’s disease patients to C. neoformans infections, “pulmonary nodules or masses should be aggressively investigated to exclude” this potentially fatal opportunistic infection, the researchers suggested.

“The infiltration lesions in chest CT scan and lymphopenia seem to be potential to reflect the poor prognosis,” they said.

From https://cushingsdiseasenews.com/2018/06/15/pulmonary-fungal-infection-threatens-cushings-disease-patients-study/

Radiation to the Whole Pituitary Compartment Effective at Controlling Cushing’s

Radiation therapy targeting the entire sella — the compartment where the pituitary gland resides at the base of the brain — is effective at controlling Cushing’s disease and should be considered for patients with suspected invasive adenoma tumors, a new study shows.

The study, “Technique of Whole-Sellar Stereotactic Radiosurgery for Cushing’s Disease: Results from a Multicenter, International Cohort Study,” was published in the journal World Neurosurgery.

In patients with Cushing’s disease, excess cortisol levels are caused by a kind of pituitary tumor (adenoma)  that secretes too much adrenocorticotropic hormone (ACTH).

Removing the adenoma using the transsphenoidal approach — a minimally invasive procedure performed through the nose to remove pituitary tumors — remains the first-line treatment for patients with newly diagnosed Cushing’s syndrome. For patients who fail surgery and medical management, stereotactic radiosurgery (SRS) may be used.

SRS is not a surgery in the traditional sense, as it does not require an incision. Instead, SRS uses many focused radiation beams to treat tumors and other problems in the brain, neck and other parts of the body.

While surgery may achieve very good remission rates in patients with an identifiable adenoma, as many as 50 percent of Cushing’s disease patients have no identifiable adenoma on magnetic resonance imaging (MRI) scans. In such cases, surgeons can opt for SRS targeting the entire sella, a procedure called whole-sellar SRS. However, the outcomes of whole-sellar SRS are not fully known.

Researchers conducted an international, retrospective study to analyze the outcomes of Cushing’s disease patients who received whole-sellar SRS.

The study enrolled 68 patients, including 52 who received the procedure for persistent disease, nine whose disease returned after surgery, and seven as their initial treatment.

Patients underwent a type of SRS known as gamma knife radiosurgery (GKRS), which uses small beams of gamma rays to target and treat brain tumors. They were then followed for a mean of 5.3 years.

Whole-sellar SRS was effective at controlling the disease, researchers found. In the five years after receiving the treatment, 75.9 percent of patients achieved a remission. Of those, 86% remained recurrence-free for five or more years.

The mean volume of area targeted using whole-sellar SRS was 2.6 cm3. Researchers discovered that treatment volumes greater than 1.6 cm3 were associated with a shorter time to remission, indicating that targeting a larger portion is more beneficial.

Also, statistical analysis revealed that a reduced dose of radiation was linked to recurrence, suggesting that a higher dose is more advantageous.

Regarding adverse events, 22.7% of patients who underwent whole-sellar SRS developed loss of one or more pituitary hormones.

Researchers also compared outcomes of patients who underwent whole-sellar SRS to those who received adenoma-targeted SRS, of which the latter involves irradiating only the tumor.

Interestingly, there were no differences in remission rate, time to remission, recurrence-free survival, or new endocrine disease development between both groups.

“Whole-sellar GKRS is effective at controlling [Cushing’s disease] when an adenoma is not clearly defined on imaging or when an invasive adenoma is suspected at the time of initial surgery,” the researchers concluded.

From https://cushingsdiseasenews.com/2018/05/25/precise-radiation-pituitary-sella-effective-control-cushings-study/

Endoscopic Surgery Should Be Standard for Cushing’s Patients with Large Tumors

Cushing’s disease patients with macroadenomas — pituitary tumors larger than 10 mm — should undergo transsphenoidal pituitary surgery using the endoscopic technique, according to a new systematic review.

The study, “Endoscopic vs. microscopic transsphenoidal surgery for Cushing’s disease: a systematic review and meta-analysis,” was published in the journal Pituitary.

Cushing’s disease develops due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The first-choice treatment for Cushing’s disease is transsphenoidal pituitary surgery, which is performed through the nose to remove pituitary tumors.

There are two main methods to conduct this kind of surgery: microscopic, which is done using a magnifying tool, and endoscopic surgery, which uses a thin, lighted tube with a tiny camera. The microscopic technique was the established method for transsphenoidal surgery, until physicians started doing endoscopic pituitary surgery in 1992.

Most surgical centers choose to perform either the microscopic or endoscopic technique but do not offer both. As a result, only a few small studies have compared the outcomes of microscopic and endoscopic surgical techniques in Cushing’s disease performed at the same center. These studies showed no clear differences in remission rates or surgical morbidity.

To date, no systematic review comparing the microscopic and the endoscopic surgical techniques in Cushing’s disease has been conducted and, therefore, convincing evidence to support either technique is lacking.

To address this, researchers set out to conduct a systematic review and meta-analysis that compares the endoscopic and microscopic transsphenoidal surgery techniques for Cushing’s disease with regards to surgical outcomes and complication rates.

Researchers searched through nine electronic databases to identify potentially relevant articles. In total, 97 cohort studies with 6,695 patients were included in the study. Among the total patient population, 5,711 received microscopical surgery and 984 were endoscopically operated.

Overall remission was achieved in 80 percent of patients, with no clear differences between the techniques. The recurrence rate was around 10 percent, and short-term mortality was less than 0.5 percent.

Cerebrospinal fluid leak (due to a hole or a tear) occurred more often in patients who underwent endoscopic surgery. On the other hand, transient diabetes insipidus — short-term diabetes — occurred more often in patients who received endoscopic surgery.

When classifying patients by tumor size, however, researchers found that patients with macroadenomas — tumors larger than 10 mm — had higher rates of remission and lower recurrence rates after endoscopic surgery. Patients with microadenomas (tumors smaller than 10 mm) had comparable outcomes with either technique.

“Endoscopic surgery for patients with Cushing’s disease reaches comparable results for microadenomas, and probably better results for macroadenomas than microscopic surgery,” the investigators wrote.

Taking these results into account, the researchers suggest that endoscopic surgery may be considered the current standard of care, though microscopic surgery can be used based on the neurosurgeon’s preference.

They also emphasize that centers that solely perform the microscopic technique should consider at least referring Cushing’s disease patients with macroadenomas to a center that performs the endoscopic technique.

From https://cushingsdiseasenews.com/2018/05/24/endoscopic-surgery-more-effective-macroadenomas-cushings-study/

Gene test for growth hormone deficiency developed

A new test developed by University of Manchester and NHS scientists could revolutionise the way children with growth hormone deficiency are diagnosed.

Children suspected of having GHD – which cause growth to slow down or stop and other serious physical problems—currently require a test involving fasting for up to 12 hours.

The fasting is followed by an intravenous infusion in hospital and up to 10 blood tests over half a day to measure growth hormone production.

Because the current test is unreliable, it often has to be done twice before growth hormone injections can be prescribed.

Now the discovery—which the team think could be available within 2 to 5 years -could reduce the process to a single blood test, freeing up valuable time and space for the NHS.

Dr. Adam Stevens from The University of Manchester and Dr. Philip Murray from Manchester University NHS Foundation Trust, were part of the team whose results are published in JCI Insight today.

Dr. Stevens said: “We think this is an important development in the way doctors will be able to diagnose growth hormone deficiency – a condition which causes distress to many thousands of children in the UK

“This sort of diagnostic would not be available even a few years ago but thanks to the enormous computing power we have, and advances in genetics, it is now possible for this aspect of care to be made so much easier for patients – and the NHS.

“These volume of data involved is so huge and complicated that traditional data-processing application software is inadequate to deal with it.”

Comparing data from 72 patients with GHD and 26 healthy children, they used high powered computers to examine 30,000 genes—the full gene expression- of each child.

A sophisticated mathematical technique called Random Forest Analysis analysed around three million separate data points to compare different gene patterns between the children with and without GHD.

The research identified 347 genes which when analysed with the computer algorithm can determine whether a child has GHD or not and thus whether they will benefit from treatment.

Growth hormone deficiency (GHD) occurs when the pituitary gland—which is size of a pea- fails to produce enough growth hormone. It more commonly affects children than adults.

Many teenagers with GHD have poor bone strength, fatigue and lack stamina as well as depression, lack of concentration, poor memory and anxiety problems.

GHD occurs in roughly 1 in 5,000 people. Since the mid-1980s, synthetic growth hormones have been successfully used to treat children—and adults—with the deficiency.

Dr. Murray added: “This study provides strong proof of concept, but before it is in a position to be adopted by the NHS, we must carry out a further validation exercise which will involve comparing our new diagnostic with the existing test.

“Once we have crossed that hurdle, we hope to be in a position for this to be adopted within 2 to 5 years – and that can’t come soon enough for these children.”

Child Growth Foundation manager Jenny Child’s daughter has Growth Hormone Deficiency.

She said: Growth Hormone Deficiency isn’t just about growth, as lack of growth hormone impacts the child in many ways, such as lack of strength and they can find it difficult to keep up physically with their peers. It impacts the child’s self-esteem as they are often treated as being much younger, because of their size. Growth hormone treatment allows the child to grow to their genetic potential.

“A growth hormone stimulation test can be very daunting for both child and parents. The test can make the child feel quite unwell and they can experience headaches, nausea and unconsciousness through hypoglycaemia.”

 Explore further: Northern climes make a difference with growth hormone treatment

More information: Philip G. Murray et al. Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency, JCI Insight (2018). DOI: 10.1172/jci.insight.93247

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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