Why It’s Safer Than Ever To Remove Pituitary Tumors

Removing a pituitary tumor by surgery can be tricky. The gland is surrounded by carotid arteries, optic nerves, and lots of important brain matter. Nor is it easy to access or visualize. But with the help of revolutionary technology and modern expertise, surgeons are now able to remove pituitary tumors in a safe and minimally invasive way. / Image courtesy of Mayfield Brain & Spine

There are three basic things you should know about your pituitary gland: it’s buried away at the base of your brain; it’s very important; and, alas, it has a habit of growing tumors.

Did your pulse quicken a tiny bit at mention of “tumors?” If so, it’s because your thyroid told it to, on instructions from your pituitary gland. But now it’s normal again, right? For that you can thank cortisol, which your pituitary gland told your adrenal glands to make in response to stress.

That’s just the tip of the iceberg, according to Yair Gozal, MD, neurosurgeon at Mayfield Brain & Spine.

“The pituitary gland is also known as the master gland,” he explains. “It regulates the release of hormones from other glands, controlling blood pressure, urine output, body temperature, growth, metabolism, lactation, ovulation, testosterone, stress response, and more.”

That of course means when something is wrong with your pituitary gland—say, a tumor—the symptoms can vary. Perhaps the tumor grows from the part of the pituitary gland that produces prolactin, which regulates sexual function. In that case, a prolactinoma will result in halted menstruation or erectile disfunction (among other things.) Alternatively, suppose the tumor grows from the part of the pituitary gland that produces growth hormone. These tumors cause gigantism in children and acromegaly in adults (again, among other things.)

So it follows, the part of the pituitary gland where the tumor grows will determine its symptoms. But these only account for “functioning” tumors—that is, tumors that secrete too much or too little of a particular hormone. Other tumors, termed “non-functioning,” do not secrete hormones at all. These buggers just take up space until they begin pressing on adjacent parts of the brain that would rather not be pressed on. Symptoms include headache, vision loss, nausea, vomiting, or fatigue. Non-functioning tumors can also pinch the pituitary gland itself, resulting in a broad-based loss of pituitary function.

Pituitary tumors are unusually common. Fifteen percent of adults have one. Most do not cause symptoms or require treatment. If you have one that does, your treatment may involve medication, radiation, and surgery.

Removing a pituitary tumor by surgery can be tricky. The gland is surrounded by carotid arteries, optic nerves, and lots of important brain matter. Nor is it easy to access or visualize. But with the help of revolutionary technology and modern expertise, surgeons are now able to remove pituitary tumors in a safe and minimally invasive way.

For the vast majority of cases, surgeons opt for a transsphenoidal approach. Here, the surgeon inserts an endoscope through the nostril to reach the pituitary gland. The endoscope’s camera relays video to a monitor, which allows the surgeon to visualize the tumor and be precise while removing it. Nowadays the surgeon is further aided by computer image guidance. The computer system gives the surgeon a real-time, three-dimensional model of his or her instruments in the operating space, adding extra degrees of precision—and safety—to the procedure.

“Technology has really moved ahead in this field,” says Gozal. “You get such good visualization. It’s made the operation relatively straightforward.”

Straightforward, that is, for a multidisciplinary team of neurosurgeons, ENT surgeons, and endocrinologists equipped with all that technology and all their training.

“I wouldn’t go anywhere that didn’t have a team for this,” says Gozal. “It’s all about developing expertise. That’s the key. It’s the expertise that has made this safer to do.”

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Internationally recognized as a leader in neurological surgery, Mayfield has forged a rich and lasting heritage through technical innovation, research, and a commitment to patient care. Mayfield physicians are continuously recognized among the Best Doctors in America and Top Doctors in Greater Cincinnati.

Mayfield Brain & Spine has four convenient locations in Greater Cincinnati: Rookwood Exchange (3825 Edwards Road, Suite 300, Cincinnati, 45209); Green Township (6130 Harrison Ave., 45247); West Chester (9075 Centre Point Drive, 45069); and Northern Kentucky (350 Thomas More Parkway, Suite 160, Crestview Hills, 41017).

 

From https://local12.com/sponsored/why-its-safer-than-ever-to-remove-pituitary-tumors

Surgical Removal of Pituitary Adenomas Through the Nose Remains an Effective Treatment for Pediatric Patients

Removal of pituitary adenomas by inserting surgical instruments through the nose (transsphenoidal resection) remains the best treatment option for pediatric patients, despite its inherent technical difficulties, a new study shows.

The study, “Transsphenoidal surgery for pituitary adenomas in pediatric patients: a multicentric retrospective study,” was published in the journal Child’s Nervous System.

Pituitary adenomas are rare, benign tumors that slowly grow in the pituitary gland. The incidence of such tumors in the pediatric population is reported to be between 1% and 10% of all childhood brain tumors and between 3% and 6% of all surgically treated adenomas.

Characteristics of patients that develop these pituitary adenomas vary significantly in different studies with regards to their age, gender, size of adenoma, hormonal activity, and recurrence rates.

As the pituitary gland is responsible for hormonal balance, alterations in hormone function due to a pituitary adenoma can significantly affect the quality of life of a child. In most cases, pituitary adenomas can be removed surgically. A common removal method is with a transsphenoidal resection, the goal of which is to completely remove the growing mass and cause the least harm to the surrounding structures.

In this study, the researchers report the surgical treatment of pediatric pituitary adenomas at three institutions. They collected data from 27 children who were operated for pituitary adenoma using one of two types of transsphenoidal surgeries — endoscopic endonasal transsphenoidal surgery (EETS) and transsphenoidal microsurgery (TMS) — at the University Cerrahpasa Medical Faculty in Istanbul, Turkey, at San Matteo Hospital in Pavia, and at the University of Insubria-Varese in Varese, Italy.

The study included 11 males (40.7%) and 16 females (59.3%), with a mean age of 15.3 (ranging between 4 and 18). Medical records indicated that 32 surgical procedures were performed in the 27 patients, as six children required a second operation. Among the patients, 13 had Cushing’s disease, while the rest had growth-hormone-secreting adenomas, prolactinomas, or non-functional adenomas.

The researchers found that most patients underwent remission following their surgery. Among the 27 patients, 22 patients (81.4%) underwent remission while five patients (18.5%) did not. Four patients underwent remission after a second operation.

Based on these findings, the team believes that the transsphenoidal surgical approach adequately removes pituitary tumors and restores normal hormonal balance in the majority of pediatric patients with pituitary adenomas.

“Satisfactory results are reported with both EETS and TMS in the literature,” they wrote. “Despite the technical difficulties in pediatric age, transsphenoidal resection of adenoma is still the mainstay treatment that provides cure in pediatric patients.”

From https://cushingsdiseasenews.com/2019/05/30/transsphenoidal-surgery-effective-remove-pituitaty-adenomas-children-study/

Transsphenoidal Surgery Recommended for Cushing Disease With Inconclusive or Normal MRI

In patients with a diagnosis of Cushing disease in whom magnetic resonance imaging (MRI) shows either no abnormalities or nonspecific abnormalities, surgery is preferable to medical treatment, according to study results published in The Journal of Clinical Endocrinology & Metabolism.

There is a consensus that the first line of treatment for Cushing disease is transsphenoidal surgery to remove the pituitary adenoma causing the disease, with an 80% remission rate following the intervention. However, in the absence of clear evidence of a pituitary adenoma on imaging, there is some controversy regarding the best treatment.

The goal of this retrospective single-center study was to assess the outcomes of surgery in patients with Cushing disease with clear evidence of a pituitary adenoma on MRI compared with outcomes in patients with inconclusive or normal MRI.

The cohort included 195 patients treated with transsphenoidal surgery between 1992 and 2018 (156 women; mean age at surgery, 41 years) classified into 4 MRI groups: 89 patients were found to have microadenoma, 18 had macroadenoma, 44 had nonspecific/inconclusive abnormalities on MRI results, and 44 had normal imaging results.

The researchers reported that MRI performance in their neuroradiology department improved with time; the proportion of inconclusive or normal MRI results decreased from 60% in 1992 to 1996 to 27% in 2012 to 2018 (P =.037).

In analyzing the influence of MRI findings on remission rates, the researchers found no significant difference among the 4 groups: remission rate was 85% for microadenomas, 94% for macroadenomas, 73% for inconclusive MRI, and 75% for negative MRI (P =.11). This finding indicates the overall percentage of patients in remission after transsphenoidal surgery is only slightly lower in those with normal or inconclusive MRI results compared with patients with clear evidence of microadenoma or macroadenoma.

There was no difference in remission rate after a microscopic vs endoscopic surgical approach (P =.16). The researchers found that endoscopic-assisted surgery allowed a higher visualization rate than microscopic-assisted surgery. Although the neurosurgeon had a better visualization rate than MRI (100% vs 72%, respectively), there were some false-positive findings; thus, positive predictive value was similar (84% vs 78%, respectively).

The study had several limitations including the retrospective design. In addition, in light of the long study duration, the researchers noted that changes in MRI technology and surgical procedures occurred over time.

The researchers proposed that after exclusion of nonneoplastic hypercortisolism, patients with Cushing disease, an inconclusive or normal MRI, and a pituitary adrenocorticotropic hormone gradient at bilateral inferior petrosal sampling be directed to an expert neurosurgeon for transsphenoidal surgery rather than treated medically.

 

Reference

Cristante J, Lefournier V, Sturm N, et al. Why we should still treat by neurosurgery patients with Cushing’s disease and a normal or inconclusive pituitary MRI [published online May 14, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2019-00333

From https://www.endocrinologyadvisor.com/home/topics/adrenal/transsphenoidal-surgery-recommended-for-cushing-disease-with-inconclusive-or-normal-mri/

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

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/

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