Cortisol Levels Predict Remission in Cushing’s Patients Undergoing Transsphenoidal Surgery

In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”

From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/

Adrenal incidentalomas—do they need follow up?

Are adrenal incidentalomas, which are found by chance on imaging, really harmless? In this paper, the authors looked at 32 studies, including 4121 patients with benign non-functioning adrenal tumours (NFATs) or adenomas that cause mild autonomous cortisol excess (MACE).

Only 2.5% of the tumours grew to a clinically significant extent over a mean follow-up period of 50 months, and no one developed adrenal cancer. Of those patients with NFAT or MACE, 99.9% didn’t develop clinically significant hormone (cortisol) excess. This was a group (especially those with MACE) with a high prevalence of hypertension, diabetes, and obesity. This could be because adrenal adenomas promote cardiometabolic problems, or vice versa, or maybe this group with multimorbidities is more likely be investigated.

Adrenal incidentalomas are already found in around 1 in 20 abdominal CT scans, and this rate is likely to increase as imaging improves. So it’s good news that this study supports existing recommendations, which say that follow-up imaging in the 90% of incidentalomas that are smaller than 4 cm diameter is unnecessary.

From https://blogs.bmj.com/bmj/2019/07/03/ann-robinsons-journal-review-3-july-2019/

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

Vision Loss The First Sign Of Adrenal Tumour In 42-Year-Old Patient

A 42-year-old woman who presented to hospital with acute vision loss in her right eye was diagnosed with a benign tumour in her adrenal gland.

Writing in BMJ Case Reports, clinicians described how the patient presented with a visual acuity of 6/36 in her right eye and 6/6 in her left eye.

Investigations revealed an exudative retinal detachment in her right eye as well as a pigment epithelial detachment.

The patient had multifocal central serous retinopathy in both eyes.

The woman, who had hypertension and diabetes, was diagnosed with Cushing syndrome and a right adrenal adenoma was also discovered.

During a treatment period that spanned several years, the patient received an adrenalectomy followed by a maintenance dose of steroids.

The patient subsequently developed central serous retinopathy again which the clinicians believe might be related to steroid use.

The authors advised “careful deliberation” in prescribing a maintenance dose of steroids following removal of the adrenal glands because of the potential link to retinopathy.

From https://www.aop.org.uk/ot/science-and-vision/research/2018/12/17/vision-loss-the-first-sign-of-adrenal-tumour-in-42-year-old-patient

Cushing’s Patient Exhibits Cortisol-Secreting Lesions in Both Adrenal Glands

In rare cases, Cushing’s syndrome may be caused by cortisol-secreting masses in both adrenal glands, a case report shows.

The study with that finding, “ACTH-independent Cushing’s syndrome with bilateral cortisol-secreting adrenal adenomas: a case report and review of literatures” was published in BMC Endocrine Disorders.

Cushing’s syndrome results from the prolonged secretion of excess cortisol. While most cases are caused by tumors in the pituitary gland, up to 20 percent result from tumors in the adrenal glands.

Occasionally, Cushing’s syndrome is caused by masses in both adrenal glands, which may be similar or display different properties. “Determining the nature and function of bilateral adrenal masses is always a challenge in clinical practice,” researchers said.

Now, physicians at Sichuan University in China, reported the case of a 55-year-old woman who complained of difficulty breathing for more than 10 years.

The patient had developed obesity of the trunk and face over the past two years, and had been diagnosed with hypertension 10 years before. She also had high lipid levels for the past five years.

The patient was taking Avapro (irbesartan), Lopressor (metoprolol), Procardia XL (nifedipine), and statins for these disorders. No other health conditions or treatments were reported.

Physical examination showed a moon-shaped face, truncal obesity, and accumulation of fat in the back of the neck and upper back (aka buffalo hump). She also had discoloration of the lower limbs, with slight fluid accumulation and muscle weakness.

Routine blood analysis did not reveal significant changes, but hormone analysis showed high cortisol levels and low adrenocorticotropic hormone (ACTH) was low.

The amount of 24-hour urine-free cortisol was almost five times higher than the upper normal limit. Also, the patients had reduced response to corticosteroids treatment, showing even higher cortisol levels upon treatment with 1 mg dexamethasone. Additional evaluations revealed reduced bone mineral density, indicative of osteoporosis.

Together, the findings led to a diagnosis of ACTH-independent Cushing’s syndrome.

To identify what was causing Cushing’s syndrome, the team looked at the adrenal glands. They detected three lesions, one on the right side measuring 2.5 centimeters, and two on the left side, with 2.3 cm and 0.6 cm respectively. The masses in both sides were actively producing cortisol in similar proportions.

These results confirmed that the patient had Cushing’s syndrome induced by bilateral adrenal excessive cortisol secretion.

Because the patient had poor cardiac function, researchers planned a two-step operation. First, they removed the right adrenal gland laparoscopically, followed by the left adrenal gland two months later. The patient started replacement therapy with hydrocortisone, and her cortisol levels improved significantly, returning to normal levels. She also lost 4 kilograms (8.8 pounds) of body weight in the following year.

“The optimal treatment for patients with bilateral cortisol-secreting adenomas remains uncertain,” the researchers wrote. Although there are no reports of recurrence after surgical treatment, the long-term outcome of these patients remains unclear, and “lifelong follow-up of the patient is required,” they added.

Bilateral cortisol-secreting adrenal adenomas are rare, having been reported in only 15 other studies, the team wrote. Interestingly, some features reported in this study also were identified by other researchers, including the fact that bilateral cortisol-secreting adrenal lesions are more predominantly found in females during adulthood. Also, the size of the lesions commonly range between 1 to 5 centimeters when detected, and appear at approximately the same time in both adrenal glands.

Although there are no treatment guidelines for these cases, surgical removal of the lesions or adrenal glands, plus glucocorticoid replacement therapy, is the mostly used therapeutic approach. Importantly, the researchers noted that patients who underwent partial gland removal were able to withdraw from glucocorticoid replacement therapy during follow-up.

From https://cushingsdiseasenews.com/2018/05/03/cushings-patient-has-cortisol-secreting-lesions-in-both-adrenal-glands/

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