Pituitary Gland Resection May Help Manage Presumed Cushing’s Patients

 

The surgical removal of two-thirds of the pituitary gland is associated with high initial remission rates and low operative morbidity in patients with suspected Cushing’s disease, when no tumor is found on the gland during surgical exploration.

Cushing’s disease (CD) is caused by increased levels of glucocoticosteroids, such as adrenocorticotropic hormone (ACTH), circulating in the blood.

In nearly 70 percent of cases this happens as a result of benign tumors on the pituitary gland, which produce excess ACTH. In these patients, the most effective and first-line treatment is surgical removal of the pituitary gland tumor.

During the diagnostic stage, clinicians use several methods to identify and localize the source of excessive ACTH. But these methods can fail, and the presence of a tumor in the pituitary is not always confirmed. If the tumor remains unidentified during surgical exploration, it falls to the surgeon’s discretion about how to manage their patients.

Researchers at the University of Colorado Denver School of Medicine provided an overview of their experience on the management of patients with presumed Cushing’s disease who underwent surgical treatment.

The study, “Negative surgical exploration in patients with Cushing’s disease: benefit of two-thirds gland resection on remission rate and a review of the literature,” was published in the Journal of Neurosurgery.

“The diagnosis and treatment of CD is one of the most challenging entities that pituitary neurosurgeons, endocrinologists, and pathologists face,” the researchers wrote. “The ability to make a correct diagnosis and deliver a high likelihood of remission after surgery relies heavily on the performance of a meticulous workup and rational surgical strategy.”

The team retrospectively analyzed all cases that had been referred to the Department of Neurosurgery of CU School of Medicine between 1989 and 2011 for a potential ACTH-secreting pituitary tumor.

During this period, 161 cases of Cushing’s patients who underwent surgical tumor resection were reported. In 22 patients, the surgeon was unable to detect a tumor.

In these cases the surgical team decided to remove two-thirds of the gland, with resection of the lateral and inferior portions of the pituitary. All 22 patients were treated using a consistent technique performed by a single surgeon.

Posterior tissue analysis confirmed that six of these patients had pituitary ACTH-secreting tumors. In the remaining 16 patients, no tumor was identified. In three patients the team believed that overproduction of ACTH could be due to an overgrowth of ACTH-secreting cells rather than expansion.

The team believes that these findings underscore the difficulty of accurately diagnosing very small pituitary tumors pre- and post-operatively.

The 22 patients were followed for a mean time of 98.9 months, or 8.2 years. No remissions were observed in the six patients who had ACTH-secreting tumors or in 12 of the remaining patients. Blood analysis in follow-up exams confirmed these patients had normal levels of glucocoticosteroids.

Four patients continued to show persistent elevated amounts of ACTH. Additional clinical evaluations revealed that two patients had ACTH-secreting lung tumors, and one patient was suspected of having an ACTH-secreting tumor on a brain region close to the pituitary. There was one case where the clinical team was unable to identify the origin of elevated ACTH.

Only three patients required hormone replacement after the two-thirds gland removal to overcome a newly detected hormone deficit. The approach used by the surgical team was, overall, found to be safe with no severe side effects reported.

“Currently, when the neurosurgeon is faced with the inability to identify a discrete adenoma intraoperatively, there is little uniformity in the literature as to how to proceed,” the team wrote. “We believe this [pituitary resection] approach will be useful to help guide surgeons in the operative treatment of this particularly difficult group of patients.”

From https://cushingsdiseasenews.com/2017/12/14/pituitary-gland-resection-may-help-presumed-cushings-disease-patients/

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/

Long-acting Signifor Has Similar Safety Profiles as Twice-daily Treatment in Cushing’s Patients, Trial Showed

A long-acting, once-a-month treatment of Signifor (pasireotide) normalized cortisol levels in 40% of patients with Cushing’s disease whose disease had recurred after surgery, or who were not candidates for surgery, according to new data from a Phase 3 trial.

The safety profiles of the once-monthly regimen proved to be similar to standard twice-daily Signifor treatments, researchers found.

The study, “Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial,” was published in the journal The Lancet Diabetes & Endocrinology.

Novartis‘ Signifor in its twice-daily injection formulation has already been approved for treating Cushing’s in the U.S. and elsewhere.

The 12-month, Phase 3 trial (NCT01374906) was conducted at 57 sites in 19 countries. The study included 150 patients with Cushing’s whose cortisol levels had risen or not dropped at all after surgery, or who were unable to undergo surgery.

Between Dec. 28, 2011, and Dec. 9, 2014, participants were randomized to receive either 10 mg or 30 mg of Signifor every four weeks, via an injection to the muscle. If, after four months of therapy, cortisol urinary levels (mUFC) were 50% greater than the upper normal limit, the dose could be increased from 10 mg to 30 mg, or from 30 mg to 40 mg. It could also be increased after seven, nine, or 12 months if the mUFC concentration was greater than normal.

The goal was to normalize average concentrations of free cortisol in the urine to less than or equal to the upper normal limit at month seven. It was met by 31 of the 74 patients in the 10 mg group (41.9%) and 31 of the 76 patients in the 30 mg group (40.8%).

The most common adverse events were hyperglycemia (high concentration of blood sugar), diarrhea, cholelithiasis (gall stones), diabetes, and nausea.

The researchers consider this treatment to be a good option for patients whose disease has returned after surgery, or who cannot undergo surgery. The long-lasting treatment schedule of one injection per month is more convenient for patients than the twice-daily subcutaneous injection, making it more likely that they would not discontinue treatment.

“Surgical resection of the causative pituitary adenoma is the first-line treatment of choice for most patients with Cushing’s disease, which leads to remission in greater than 75% of patients if done by an expert pituitary surgeon,” wrote Dr. Andre Lacroix, MD, a professor in the Department of Medicine at the University of Montreal teaching hospital, and colleagues.

“However, surgery is not always successful, and disease recurrence can occur several years after initial remission, while some patients refuse or are not candidates for surgery. As a result, many patients require additional treatment options.”

“Long-acting pasireotide normalized mUFC concentration in about 40% of patients with Cushing’s disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide,” the team wrote in the study.

“Long-acting pasireotide is an efficacious treatment option for some patients with Cushing’s disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule,” researchers concluded.

From https://cushingsdiseasenews.com/2017/10/31/long-acting-signifor-for-cushings-disease-has-similar-efficacy-and-safety-as-twice-daily-treatment/

Study Highlights Importance of Clinical Follow-Up in Cushing’s Patients After Adenoma Removal

A rare case of Cushing’s syndrome (CS) in a 17-year-old patient with multiple pituitary adenomas highlights the importance of clinical follow-up in order to determine the best treatment options for patients.

The study, “A rare case of multiple pituitary adenomas in an adolescent Cushing disease presenting as a vertebral compression fracture,” was published in the journal Annals of Pediatric Endocrinology and Metabolism

CS is a very rare disease with an incidence of 0.7-2.4 cases per million, per year. It is caused by exposure to very high levels of the hormone cortisol. In children, the most common symptom is weight gain without height gain. In some rare cases, tumors known as multiple pituitary adenomas (MPAs) appear, and patients have elevated levels of adrenocorticotropic hormone (ACTH). Surgical removal through transsphenoidal surgery (TSS) is considered the best treatment, and the first TSS has a success rate of more than 90%.

However, since 15% of patients have a recurrence, ongoing monitoring and follow-up after TSS are important. The importance of this follow-up care is highlighted in a recent case report.

The study described the case of a 17-year-old male adolescent who was 149.5 cm tall (4’9″) and weighed 63.6 kg (140 lbs). The patient was referred to a hospital for the evaluation of a vertebral compression fracture and obesity. Over four years, the patient gained 23 kg (51 lbs) without an increase in height. Despite showing many of the features of CS, this patient had not been previously diagnosed with CS.

He had high levels of ACTH and cortisol, and an MRI suggested the presence of an 8-mm (0.8 cm) micro-adenoma. After TSS, the patient’s morning ACTH and cortisol levels were reduced, and a persistent headache had improved. But there was no reduction in weight.

Three months after the TSS, the patient’s body mass index did not show improvement, and both cortisol and ACTH levels were elevated again. MRI revealed a new 9 mm (0.9 cm) micro-adenoma, which was removed with a second TSS. However, cortisol and ACHT remained elevated after the second surgery, with no evidence of a pituitary tumor in MRI scans.

Researchers recommended additional options, such as total removal of the pituitary gland, radiotherapy, or removal of both adrenal glands, options that the patient and his family declined. He continued to receive treatment for osteoporosis, hypertension, and increased lipid levels.

“In conclusion, we reported the clinical course of Cushing disease with 2 distinct pituitary adenomas. Since there is no consensus as to the best treatment for relapsing or persistent Cushing disease and since only a few cases of MPA among pediatric Cushing disease have been reported, a close followup of tumor status, severity of hypercortisolism, and patients’ perspectives are the major parameters used to determine the best treatment option for each patient. In addition, early recognition and diagnosis of pediatric Cushing disease would lead to earlier recovery, improved growth, and better quality of life,” the researchers wrote.

From https://cushingsdiseasenews.com/2017/10/27/cushings-disease-rare-case-report-highlights-importance-early-diagnosis-follow-up-care/

Long-acting pasireotide safe, effective for recurrent Cushing’s disease

October 20, 2017

In patients with persistent or recurring Cushing’s disease after surgery, monthly pasireotide was safe and effective, leading to normal urinary free cortisol levels in about 40% of patients after 12 months, according to findings from a phase 3 clinical trial.

“Surgical resection of the causative pituitary adenoma is the first-line treatment of choice for most patients with Cushing’s disease, which leads to remission in greater than 75% of patients if done by an expert pituitary surgeon,” Andre Lacroix, MD, professor in the department of medicine at University of Montreal teaching hospital, and colleagues wrote in the study background. “However, surgery is not always successful, and disease recurrence can occur several years after initial remission, while some patients refuse or are not candidates for surgery. As a result, many patients require additional treatment options.”

Lacroix and colleagues analyzed data from 150 patients with a confirmed diagnosis of persistent, recurrent or new Cushing’s disease with mean urinary free cortisol level concentration 1.5 to five times the upper limit of normal, normal or greater than normal plasma and confirmed pituitary source of Cushing’s disease. Patients were recruited between December 2011 and December 2014; those who received mitotane therapy within 6 months, pituitary irradiation within 10 years or previous pasireotide treatment were excluded. Researchers randomly assigned patients to 10 mg (n = 74) or 30 mg (n = 76) monthly intramuscular pasireotide (Signifor LAR, Novartis) for 12 months, with investigators and patients masked to the group allocation and dose. Pasireotide was up-titrated from 10 mg to 30 mg or from 30 mg to 40 mg at month 4, or at month 7, 9 or 12 if urinary free cortisol concentrations remained greater than 1.5 times the upper limit of normal. At month 12, patients considered to be receiving clinical benefit from the therapy (mean urinary free cortisol concentration at or less than the upper limit of normal) could continue to receive it during an open-ended extension phase. The primary outcome was to assess the proportion of patients achieving mean urinary free cortisol concentration less than or equal to the upper limit of normal by month 7, regardless of dose.

Within the cohort, 41.9% of patients in the 10-mg group and 40.8% of patients in the 40-mg group met the primary endpoint at month 7, whereas 5% of patients in the 10-mg group and 13% of patients in the 40-mg group achieved partial control. Researchers did not observe between-sex differences or differences in response among those who did or did not undergo previous surgery.

The number of patients who achieved the primary endpoint at month 7 without an up-titration in dose was smaller, but not significantly different between the 10-mg and 40-mg dose groups (28.4% and 31.6%, respectively), according to researchers. Among those who received an up-titration in dose in the 10-mg and 40-mg groups (42% and 37%, respectively), 32% and 25%, respectively, were considered responders at month 7.

Researchers also observed improvements in several metabolic parameters during the 12-month course of treatment with both doses, including improvements in systolic and diastolic blood pressure; reductions in waist circumference, BMI and body weight; and improvement in scores for the Cushing’s Quality of Life questionnaire. The most common adverse events were hyperglycemia, diarrhea, cholelithiasis, diabetes and nausea.

The researchers noted that, in both dose groups, the reductions in mean urinary free cortisol concentration were observed within 1 month, with concentrations remaining below baseline levels for the 12-month study period.

“This large phase 3 trial showed that long-acting pasireotide administered for 12 months can reduce [median urinary free cortisol] concentrations, is associated with improvements in clinical signs and [health-related quality of life] and has a similar safety profile to that of twice-daily pasireotide,” the researchers wrote, adding that the long-acting formulation provides a convenient monthly administration schedule. – by Regina Schaffer

Disclosures: Novartis funded this study. Lacroix reports he has received grants and personal fees as a clinical investigator, study steering committee member and advisory board member for Novartis, Stonebridge and UpToDate. Please see the study for all other authors’ relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B55988079-312b-478d-8788-036a465b1881%7D/long-acting-pasireotide-safe-effective-for-recurrent-cushings-disease

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