Tumors in Cushing’s Patients Have Distinct Genetic Profiles

Posted on June 23, 2018 by MaryO

A study examining the genes expressed in pituitary tumors of Cushing’s disease patients found that these tumors may be grouped into three distinct subsets.

The finding suggests that different biological processes contribute to the development of each subset, an insight that may aid in developing targeted therapies.

The study, “Gene expression profiling in human corticotrope tumors reveals distinct, neuroendocrine profiles,” was published in the Journal of Neuroendocrinology.

In Cushing disease, a pituitary tumor producing excess amounts of the adenocorticotropic hormone causes the body to produce too much cortisol.

Pituitary tumors respond differently to modulators of ACTH secretion, and patients have different disease manifestations, but what makes them differ from one another is unknown.

To determine if the genetic profile of tumors could explain the clinical diversity reported in these patients, Italian researchers evaluated 40 benign, ACTH-secreting pituitary tumors removed from patients with Cushing’s disease.

Of the 20,815 genes examined in the study, 1,259 were significantly elevated in the pituitary tumors. These were mostly involved in pathways that kept the neuroendocrine cell profile.

Based on their genetic profile, researchers were able to cluster tumors into three distinct subgroups. Samples in group A had four specific genes, associated with tumor-related processes, that were overly active. In group B, there were 313 overly active genes, involved in many of the mechanisms of hormone-secreting adenomas.

Group C had 29 highly active genes, all involved in calcium influx and cell growth – mechanisms that are important for the development of ACTH-secreting adenomas.

“It appears that these tumors present a neuroendocrine cell profile but, at the same time, clearly distinct gene expression patterns [are seen] in individual subgroups,” the researchers wrote.

Looking at clinical characteristics that correlated with each subgroup, the researchers found that most group A patients  had macroadenomas (large tumors) that had invaded the sella – the compartment where the pituitary gland resides at the base of the brain. These patients were also older than those in the other two subgroups.

Some patients in group B also had macroadenomas, but no such tumors were seen in group C. However, researchers found no association between the groups and the hormonal values, clinical findings, or surgical outcomes.

Collectively, the findings add new clues to the molecular mechanisms involved in the progression of benign pituitary tumors. They also provide new ground for developing targeted therapies, the researchers said.

From https://cushingsdiseasenews.com/2018/06/22/tumors-in-cushing-disease-patients-show-distinct-genetic-profiles-study-reports/

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

Posted on June 16, 2018 by MaryO

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 jiroveci, Aspergillus 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/

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

Posted on June 2, 2018 by MaryO

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/

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

Posted on May 26, 2018 by MaryO

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/

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Study Describes 6 Common Surgical Failures in Cushing’s Disease Treatment

Posted on May 16, 2018 by MaryO

To help improve the effectiveness of surgical treatment of Cushing’s disease, researchers conducted a study to determine common failures. They classified these failures into six different categories.

Results were reported in the study, “Root cause analysis of diagnostic and surgical failures in the treatment of suspected Cushing’s disease,” published in the Journal of Clinical Neuroscience.

The surgical removal of lesions that secrete excess adrenocorticotropic hormone (ACTH) is the first line of treatment for patients with Cushing’s disease. But while this approach is effective in reducing cortisol levels, up to 31 percent of patients fail to achieve remission.

When initial surgery is ineffective, additional surgical procedures may help to improve patient outcomes. Medications also are used for those who do not see results from surgery.

Recognizing the factors that contribute to the failure of surgical treatment is crucial to avoiding a deterioration of patient health and to improving long-term outcomes.

Researchers at Harvard Medical School examined the clinical records of 51 patients suspected of having Cushing’s disease. These patients were followed and surgically treated at the Brigham and Women’s Hospital in Boston, from April 2008 to July 2017.

In more than 82 percent of the cases, tissue removed during surgery confirmed that the patients had excess ACTH caused by benign tumors in the adrenal gland. Among the remaining patients, two had additional ACTH-secreting tumors, four had no obvious tumor or abnormal tissue, one had a pituitary mass without ACTH secretion, and one had no evidence of tissue changes despite the detection of a tumor during exploratory surgery.

They were followed for an average of 18.3 months, during which 42 patients achieved remission as confirmed by blood tests. Of these, 34 patients did not require additional treatment; four patients needed additional surgeries to achieve control over cortisol levels; and four patients required additional radiosurgery.

Based on long-term patient outcomes, researchers were able to identify six categories of common diagnostic and surgical failures. They include:

  • persistently high cortisol levels despite the successful removal of lesions
  • the failure of tumor resection
  • recurrence of disease
  • a failure to identify the source of ACTH secretion
  • the absence of identifiable lesions during exploratory surgery
  • concurrent tumors.

While the first three are common among patients with a visible lesion on imaging scans, the latter three are characteristic of patients in whom physicians fail to detect a lesion.

Investigators believe that anticipating and recognizing these common failures may help to improve the effectiveness of surgery, symptom management, and overall treatment outcomes.

“The success of surgical intervention can be enhanced greatly by improving patient selection and surgical management by anticipating and subsequently deterring the six common failures described above,” the team concluded. They added that better imaging methods also might improve outcomes for Cushing’s disease patients.

From https://cushingsdiseasenews.com/2018/05/15/cushings-disease-surgery-6-common-failures-found-retrospective-study/

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