New ACTH Detection Method Improves Cure Rates in Cushing’s Disease Patients

Posted on October 20, 2017 by MaryO

Researchers have identified a new, quick method for detecting ACTH-producing tumors – called Elecsys – that can improve the cure rates of Cushing’s disease patients undergoing surgery.

The study, “Long-term outcomes of tissue-based ACTH-antibody assay–guided transsphenoidal resection of pituitary adenomas in Cushing disease,” was published in the Journal of Neurosurgery.

Transsphenoidal resection (TSR) – a surgical procedure performed through the nose and sphenoid sinus to remove a pituitary tumor – has been the method of choice for treatment for Cushing’s disease.

However, it often fails to localize the tumor with precision, leading to an incomplete resection (removal). This is likely a result of the preoperative methods used to guide surgeons before surgery, which include both magnetic resonance imaging (MRI) and a minimally invasive procedure called bilateral inferior petrosal sinus sampling (BIPSS) that measures ACTH in the veins that drain the pituitary gland.

However, both “suffer from suboptimal sensitivity and thus allow for incomplete resections, specially if pathological frozen sections fail to identify tumor,” researchers wrote.

MRI, for example, detects only 50 percent of Cushing’s adenomas, limiting surgeons’ ability to conduct curative TSR surgeries. Therefore, better diagnostic and tumor localization techniques are needed to increase the likelihood that initial surgeries can remove the entire tumor and cure patients.

A team of researchers at Yale School of Medicine evaluated a new method for guiding tumor localization during TSR. The method – a double-antibody sandwich assay for ACTH – is performed in the operating room in resected pituitary samples from patients. ACTH (adrenocorticotropic hormone) is a hormone produced in the pituitary gland in the brain, that simulated cortisol production in the adrenal glands. In patients with Cushing disease the pituitary gland releases too much ACTH.

In the new method – called Elecsys – samples are squeezed between sandwich-like system composed of two antibodies that recognize two sections of the ACTH protein. The three-step procedure is quick, allowing doctors to analyze samples in the operating room and determine if they have removed the entire tumors.

The performance and outcomes associated with the Elecsys were assessed by reviewing data of tissue samples from 14 patients with ACTH-secreting adenomas, who underwent TSR surgeries between 2009 and 2014.

“The intraoperative TSR protocol was modified with the introduction of the ACTH assay such that if either the assay or the frozen-section pathology returned results positive for tumor, that area of the gland was resected,” the researchers explained.

The new ACTH method detected tumor tissue and was capable of distinguishing it from normal tissue with a 95% sensitivity and 71.3% specificity. These values are comparable to those using the standard method for tumor localization, which requires frozen sections of the tumor. This suggests that the test can be used either in conjunction with or in place of frozen sections.

Also, 85.7% of the patients achieved long-term disease remission, with the remission rate exceeding the rate with previous methods (71.9%).

Overall, “these preliminary findings reflect the promising potential of tissue-based ACTH-antibody-guided assay for improving the cure rates of Cushing’s disease patients undergoing TSR. Further studies with larger sample sizes, further refinements of assay interpretation, and longer-term follow-ups are needed,” the study concluded.

From https://cushingsdiseasenews.com/2017/10/19/acth-detection-method-improved-cure-rates-cushings-disease-study-shows/

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Intraoperative MRI improves complete resection of pituitary macroadenoma

Posted on October 18, 2017 by MaryO
Endocrine Today, October 2017
Brooke Swearingen, MD; Stephanie L. Lee, MD, PhD, ECNU

A 63-year-old man was referred to the Massachusetts General Hospital Neuroendocrine & Pituitary Tumor Clinical Center for management of a pituitary macroadenoma. He experienced increasingly severe retro-orbital headaches in the past year. He reported no double vision, fatigue, orthostatic dizziness, change in beard growth or reduction in libido. An outside head CT scan showed an enlarged pituitary gland.

Imaging and laboratory tests

A pituitary MRI with magnified pituitary slices and gadolinium contrast was ordered. A well-circumscribed “snowman-shaped” sellar mass was identified, measuring 2.6 cm x 2 cm x 1.8 cm (anteroposterior x transverse x craniocaudal) with suprasellar extension (Figure 1). The lesion was heterogeneous on T1-weighted scans after enhancement with IV gadolinium contrast. An area of hypointensity in the superior margin was consistent with a small area of cystic or hemorrhagic degeneration.

Although the mass did not extend laterally into the cavernous sinus, the sellar mass extended upward into the suprasellar cistern through a hole in the dural, the diaphragma sellae, to compress the optic chiasm. The restriction of adenoma growth by the diaphragma sellae results in the snowman shape of the macroadenoma. The optic chiasm and infundibulum (pituitary stalk) could not be identified on coronal or sagittal images (Figure 1). Visual field on confrontation suggested lateral field deficits (bilateral lateral hemianopsia) that were confirmed on formal Goldmann kinetic perimetry visual fields.

Figure 1. Preoperative MRI scan. A large “snowman-shaped” pituitary adenoma (green arrow) has heterogeneous enhancement after gadolinium contrast administration. A small hypodense area in the adenoma likely represented hemorrhage/cystic degeneration (yellow arrow). The tumor does not surround the carotid siphon, an S-shaped portion of the internal carotid artery (red arrows) within the cavernous sinus located laterally from the sella turcica where the pituitary gland resides. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

Source: Stephanie L. Lee, MD, PhD, ECNU. Reprinted with permission.

Initial hormonal evaluation was normal and included morning adrenocorticotropic hormone 18 pg/mL, cortisol 13.64 µg/dL, thyroid-stimulating hormone 2.14 uIU/mL, free thyroxine 1.2 ng/dL and prolactin 12.6 ng/mL. The patient’s morning testosterone level was normal at 324 ng/dL, with follicle-stimulating hormone 2.4 mIU/mL and luteinizing hormone 1.6 mIU/mL. His insulin-like growth factor I level was normal at 124 ng/mL.

Tumor resection

The patient was treated preoperatively with stress-dose hydrocortisone 50 mg. He then underwent transsphenoidal pituitary tumor resection. After the surgeon believed there was an adequate excision of the tumor, the extent of tumor resection was confirmed by an intraoperative MRI (Figure 2 on page 8).

Figure 2. Intraoperative MRI scan. The large macroadenoma is not seen after transsphenoidal surgery. The optic chiasm (yellow arrow) can be seen after removal of the tumor. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

The operation was concluded after the imaging confirmed the complete resection of the pituitary adenoma. The patient’s postoperative course was uneventful. Imaging 4 weeks after the resection confirmed complete resection of the suprasellar mass with residual enhancement of the resection bed and sphenoid sinuses (Figure 3 on page 8). The postoperative MRI revealed a normal optical chiasm and a downward tending of the infundibulum to the residual pituitary gland located inferiorly along the sella turcica (pituitary fossa) of the sphenoid bone. Pathology confirmed a pituitary adenoma. His anterior and posterior pituitary function were normal 6 weeks postoperatively, and his visual field deficit improved.

Intraoperative MRI

Imaging like that used in this case occurs in a specially designed operating room that allows MRI scans during surgery without moving the patient from the surgical table. The MRI is kept in a shielded enclosure during the procedure and then moved along a track into the operating room for imaging. Clinical indications for the use of intraoperative MRI in neurosurgery include resection of pituitary macroadenomas. In the past, these tumors underwent transsphenoidal resection, and the postoperative MRI was performed after 1 or more days after the procedure to check for complete removal. If residual tumor was found, the patients underwent watchful waiting, external radiation or repeat surgery.

The strategic advantage of an intraoperative MRI is that the imaging is performed during the operative procedure, and if there is any residual tumor, surgery can be resumed after the MRI is moved back into the shielded enclosure.

Figure 3. Four-week postoperative MRI scan. The large macroadenoma is not seen after the transsphenoidal survey. The optic chiasm and infundibulum (pituitary stalk) can be seen after resection of the tumor. The pituitary stalk is deviated to the left of the sella where the residual normal thyroid is locate along the sella turcica. The floor of the sella enhances with gadolinium infusion after surgery due to postoperative inflammation. (A) Coronal image. (B) Sagittal image. Abbreviation: SS = spenoid sinus.

It has been reported that the use of intraoperative MRI does not increase complication rates compared with conventional transsphenoidal surgery. Reports on the improvement of gross tumor resection using intraoperative MRI are variable, perhaps due to the expertise of the surgeon. Several reports suggest the use of intraoperative MRI allowed additional resection of noninvasive macroadenomas in 67% to 83% of the patients with a gross tumor resection. These results suggest that a substantial volume reduction and increased gross tumor resection of pituitary macroadenomas occurs with the use of intraoperative MRI compared with standard surgery. One study demonstrated that the gross tumor resection rates of invasive tumors was also improved with the use of intraoperative MRI compared with usual preoperative imaging and surgery (25% vs. 7%).

The use of intraoperative MRI, especially with transsphenoidal reoperations for invasive and noninvasive pituitary macroadenomas, leads to significantly higher “gross tumor resection” rates. This method prevents additional operations or treatment, such as radiation, because it reduces the number of patients with residual adenoma after surgery. This technology is usually found in specialized tertiary care hospitals but should be considered for reoperation for large pituitary macroadenomas or initial operation for large invasive pituitary macroadenomas.

  • References:
  • Boellis A, et al. J Magn Reson Imaging. 2014;doi:10.1002/jmri.24414.
  • Fomekong E, et al. Clin Neurol Neurosurg. 2014;doi:10.1016/j.clineuro.2014.09.001.
  • Tandon V, et al. J Clin Neurosci. 2017;doi:10.1016/j.jocn.2016.10.044.
  • For more information:
  • Stephanie L. Lee, MD, PhD, ECNU, is an Endocrine Today Editorial Board Member. She is associate professor of medicine and director of thyroid health in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center. She can be reached at Boston Medical Center, 88 E. Newton St., Boston, MA 02118; email: stephanie.lee@bmc.org.
  • Brooke Swearingen, MD, is associate professor of surgery (neurosurgery) at Harvard Medical School and co-director of the neurological ICU at Massachusetts General Hospital. He can be reached at bswearingen@partners.org.

Disclosures: Lee and Swearingen report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/print/endocrine-today/%7B23183444-4d29-477b-844f-6eb995ac74f4%7D/intraoperative-mri-improves-complete-resection-of-pituitary-macroadenoma

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Blood Sample from Tributary Adrenal Gland Veins May Help to Diagnose Subclinical Cushing’s Syndrome

Posted on October 18, 2017 by MaryO

Researchers report a new technique for collecting blood samples from tiny veins of the adrenal glands, called super-selective adrenal venous sampling (ssAVS). The technique can be used to help diagnose diseases marked by excessive release of adrenal hormones, such as subclinical Cushing’s syndrome (SCS) or primary aldesteronism (PA).

The study, titled “A Novel Method: Super-selective Adrenal Venous Sampling,” was published in JOVE, the Journal of Visualized Experiments. JOVE has also made a video that demonstrates the procedure.

The adrenal glands are a pair of glands found above the kidneys that produce a variety of hormones, including adrenaline and the steroids aldosterone and cortisol. Excessive production of cortisol in the adrenal glands is the cause SCS, and aldosterone of PA.

These glands have central veins running through them, and three tributary veins (veins that empty into a larger vein). Conventional AVS collects blood from the central veins, but these veins have blood from the adrenal glands as well as blood in wider circulation flowing through them.

ssAVS uses tiny catheters — very long, narrow tubes inserted into blood vessels, called microcatheters — to collect blood from the tributary veins in both adrenal glands. Only blood from the adrenal glands flows through the tributary veins, making analysis of hormone levels easier, and pinpointing the region, or segment, of the gland that is not working properly.

A medical imaging technique, known as angiography, is used to track the positions of the microcatheters. Angiography is a procedure widely used to visualize the inside of blood vessels and organs, and takes roughly 90 minutes.

The paper reported on the use of ssAVS in three patients with adrenal gland disorders, and one (case #2) was diagnosed with SCS and PA. “Overall, in Cases #1 and #2, the ssAVS method clearly indicated segmental adrenal hormone production, not only for aldosterone, but for cortisol, and enabled these patients to be treated by surgery,”  the researchers reported.

Conventional AVS measures hormone levels in whole glands. It is useful for identifying which of the two glands is diseased, and the type of hormone that is overproduced. But sometimes both glands are affected, and only removal of the diseased parts in both glands is safe and effective.

That’s one of the reasons why ssAVS is so useful. By sampling the smaller, tributary veins in three different regions of each gland, the diseased parts can be identified. The diseased parts can then be removed from both glands, if medically advisable, leaving the healthy parts of the glands intact and functional.

ssAVS is also useful because it collects samples of blood coming directly from the adrenal glands, making analysis of hormone levels more reliable.

Researchers concluded that ssAVS is useful in both the diagnosis of adrenal gland disorders and for research that might lead to new therapies.

“Between October 2014 and September 2015, two angiographers … performed ssAVS on 125 cases … with a 100 % success rate and within a reasonable time (58 – 130 min) without adrenal rupture or thrombosis that required surgery,” they wrote. “The ssAVS method is not difficult for expert angiographers, and, thus, is recommended worldwide to treat PA cases for which cAVS does not represent a viable surgical treatment option.”

From https://cushingsdiseasenews.com/2017/10/17/subclinical-cushings-syndrome-may-be-diagnosed-via-blood-from-tributary-adrenal-gland-veins/

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Increase in Glucose Uptake by Cushing’s Disease-associated Tumors Could Improve Early Detection

Posted on October 13, 2017 by MaryO

An increase in glucose uptake by Cushing’s disease-associated pituitary tumors could improve their detection, new research shows.

The study, “Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1,” appeared in the journal Molecular and Cellular Endocrinology.

The study’s senior author was Dr. Prashant Chittiboina, MD, from the Department of Neurosurgery, Wexner Medical Center, The Ohio State University, in Columbus, Ohio.

Microadenomas – tumors in the pituitary gland measuring less than 10 mm in diameter – that release corticotropin, or corticotropinomas, can lead to Cushing’s disease. The presurgical detection of these microadenomas could improve surgical outcomes in patients with Cushing’s.

But current tumor visualization methodologies – magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) – failed to detect a significant percentage of pituitary microadenomas.

Stimulation with corticotropin-releasing hormone (CRH), which increases glucose uptake, has been suggested as a method of increasing the detection of adenomas with 18F-FDG PET, by augmenting the uptake of 18F-FDG – a glucose analog.

However, previous studies aiming to validate this idea have failed, leading the research team to hypothesize that it may be due to a delayed elevation in glucose uptake in corticotropinomas.

The scientists used clinical data to determine the effectiveness of CRH in improving the detection of corticotropinomas with 18F-FDG PET in Cushing’s disease.

They found that CRH increased glucose uptake in human and mouse tumor cells, but not in healthy mouse or human pituitary cells that produce the adrenocorticotropic hormone (ACTH). Exposure to CRH increased glucose uptake in mouse tumor cells, with a maximal effect at four hours after stimulation.

Similarly, the glucose transporter GLUT1, which is located at the cell membrane, was increased two hours after stimulation, as was GLUT1-mediated glucose transport.

These findings indicate a potential mechanism linking CRH exposure to augmented glucose uptake through GLUT1. Expectedly, the inhibition of glucose transport with fasentin suppressed glucose uptake.

The researchers consistently observed exaggerated evidence of GLUT1 in human corticotropinomas. In addition, human corticotroph tumor cells showed an increased breakdown of glucose, which indicates that, unlike healthy cells, pituitary adenomas use glucose as their primary source of energy.

Overall, the study shows that corticotropin-releasing hormone (CRH) leads to a specific and delayed increase in glucose uptake in tumor corticotrophs.

“Taken together, these novel findings support the potential use of delayed 18F-FDG PET imaging following CRH stimulation to improve microadenoma detection in [Cushing’s disease],” researchers wrote. The scientists are now conducting a clinical trial to further explore this promising finding.

From https://cushingsdiseasenews.com/2017/10/12/glucose-uptake-in-cushings-disease-could-improve-presurgical-tumor-detection/

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Cortisol Modulator Shows Early Signs of Safety, Efficacy in Healthy Volunteers

Posted on October 11, 2017 by MaryO

The glucocorticoid receptor antagonist CORT125134 is safe and has shown preliminary signs of efficacy in healthy volunteers participating in a Phase 1 trial, say researchers in England.

Their study, “Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study,” appeared in the journal Clinical Pharmacology in Drug Development.”

Cortisol signaling is indirectly controlled by the glucocorticoid receptor (GR). When cortisol binds the GR, the receptor becomes activated and migrates to the nucleus, where it regulates the expression of many genes. This influences a myriad of processes, including inflammation, immune response and brain function.

CORT125134, also known as relacorilant, is being developed by Corcept Therapeutics of Menlo Park, California, for Cushing’s disease patients and others who may benefit from it. The drug is a GR antagonist, blocking the receptor’s activity.

In order to evaluate the safety and tolerability of CORT125134, and learn how it behaves in the body, Corcept researchers conduced a Phase 1 trial in healthy subjects.

The British study, conducted at the Quotient Clinical in Nottingham, included 81 adults who received a single ascending-dose of CORT125134 or placebo, and 48 subjects who received multiple-ascending doses of the drug versus placebo.

Single doses were tested in nine distinct groups. Six tested six different doses of CORT125134, one tested a 150 mg dose in subjects receiving a high-fat meal, and two groups included patients receiving prednisone (a well-known GR activator), prednisone plus Korlym (mifepristone), or prednisone plus CORT125134.

Korlym is a medicine approved for Cushing’s  patients with high blood sugar levels due to high cortisol in circulation. But the drug targets the progesterone receptor and is associated with side effects like pregnancy termination and irregular vaginal bleeding.

Multiple doses, given for up to 14 days, were tested in four additional cohorts. Researchers observed that CORT125134 was rapidly absorbed and eliminated, presenting a suitable profile for once-daily dosing.

Efficacy was determined by CORT125134’s ability to counteract the effects of prednisone. In addition, a single dose of 500 mg or multiple dosing with 250 mg had similar effects as those seen with 600 mg of Korlym — the therapeutic dose used for Cushing’s treatments.

Most common treatment-related adverse events reported in the single-ascending dose part of the study were nausea, vomiting and thirst; most were mild. In those given multiple-ascending doses, adverse events included mild musculoskeletal and connective tissue disorders, as well as gastrointestinal system disorders.

Multiple 500 mg doses exceeded the maximum tolerated dose, as it led to musculoskeletal symptoms that forced researchers to stop treatment.

“This first-in-human study has demonstrated that CORT125134 is well tolerated following single doses up to 500 mg and repeated doses up to 250 mg once daily for 14 days,” researchers wrote. “Pharmacological activity was confirmed following the administration of a single 500-mg dose and daily administration of 250 mg.”

Corcept is now enrolling participants into a Phase 2 open-label trial (NCT02804750) to evaluate CORT125134 in patients with Cushing’s syndrome. This trial is being conducted in the United States and Europe and will include 80 participants. Top-line results are expected in the first quarter of 2018.

From https://cushingsdiseasenews.com/2017/10/10/phase-1-data-demonstrates-efficacy-safety-of-cort125134-in-healthy-volunteers/

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