FDA Approves High-resolution MRI, Better at Spotting Pituitary Tumors in Cushing’s Patients

The U.S. Food and Drug Administration has approved the clinical use of a magnetic resonance imaging (MRI) scanner — the ultra-high-field 7T Terra MRI — with unprecedented resolution that allows for more reliable images of the brain.

The approach recently allowed the precise localization of a small tumor in the pituitary gland, which standard MRI had failed to spot, in a patient with Cushing’s disease.

So far, only one scanner of this kind exists in the U.S.. It was installed in February 2017 at the Mark and Mary Stevens Neuroimaging and Informatics Institute (INI) of the Keck School of Medicine, University of Southern California (USC).

The new scanner has an increased magnetic field strength of 7 Tesla, which is more than four times that of conventional MRI. This property greatly improves the instrument’s signal-to-noise ratio, dramatically increasing the spatial resolution and contrast of its images so that scientists can visualize the human living brain in high-definition and with unprecedented detail.

The 7T Terra is ideal for high-resolution neuroimaging, exploration of neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and diagnosis and treatment of other brain diseases, a USC news story by Zara Greenbaum states.

Earlier this year, a report described the case of women with Cushing’s disease with a pituitary adenoma (slow-growing, benign tumor in the pituitary gland) that was possible to localize only with the new 7T MRI.

Based on laboratory analysis that revealed high levels of adrenocorticotropic hormone(ACTH) and cortisol, the doctors suspected a pituitary adenoma and recommended the patient for surgery. However, they ignored the precise location of the tumor, which failed to be detected by standard MRI scanners (1T and 3T).

    Two hours before surgery, the woman underwent a 7T MRI scan which finally identified with high precision the location of the adenoma, a very small tumor of 8 mm on the right side of the pituitary gland.

    “The 7T may save patients an invasive procedure. It also makes it easier for neurosurgeons to selectively remove a tumor without damaging surrounding areas,” said Gabriel Zada, MD, associate professor of neurological surgery at the Keck School.

    Since its arrival, the device has supported exploratory research into both healthy and diseased brains.

    Now the scanner’s advanced imaging technology can be used to help with diagnosis, treatment and monitoring of patients with neurological diseases, including Cushing’s disease.

    “This device, which has already made its mark as a powerful tool to advance research in the neurosciences, is now accessible to clinical populations in addition to researchers,” said Arthur W. Toga, PhD, provost professor and chair at the Keck School and director of the USC Stevens INI.

    “Clinicians across the university and beyond can now leverage all the benefits of increased spatial resolution to serve patients in need,” he said.

    Adapted from https://cushingsdiseasenews.com/2018/11/06/fda-oks-high-resolution-mri-better-spotting-pituitary-tumor-cushings/

    Night Cortisol Levels for Diagnosing Cushing’s Syndrome Less Accurate in Clinical Practice

    Salivary cortisol levels can be used to diagnose Cushing’s syndrome with relatively high reliability, but each test center should establish its own measurement limits depending on the exact method used for the test, a study from Turkey shows.

    Researchers, however, caution that late-night salivary cortisol measurements in clinical practice is likely to be less accurate than that seen in controlled studies, and some patients might require additional tests for a correct diagnosis.

    The study, “Diagnostic value of the late-night salivary cortisol in the diagnosis of clinical and subclinical Cushing’s syndrome: results of a single-center 7-year experience,” was published in the Journal of Investigative Medicine

    In healthy individuals, the levels of cortisol — a steroid hormone secreted by the adrenal glands — go through changes over a 24-hour period, with the lowest levels normally detected at night.

    But this circadian rhythm is disrupted in certain diseases such as Cushing’s syndrome, where night cortisol levels can be used as a diagnostic tool.

    Among the tests that can be used to detect these levels are late-night serum cortisol (LNSeC) and late-night salivary cortisol (LNSaC) tests. Since it uses saliva samples, LNSaC is more practical and does not require hospitalization, so it is often recommended for the diagnosis of Cushing’s syndrome.

    So far, though, there has been no consensus regarding cutoff values and the sensitivity of the test.

    Mustafa Kemal Balci, MD, and his team at the Akdeniz University in Turkey aimed to evaluate the diagnostic use of LNSaC in patients with clinical Cushing’s syndrome and in those with subclinical Cushing’s syndrome — people with excess cortisol but without signs of the disease.

    The study involved 58 patients with clinical Cushing’s syndrome (CCS), 53 with subclinical Cushing’s syndrome (SCS), and 213 patients without Cushing’s syndrome who were used as controls.

    Saliva and serum cortisol levels were measured in all patients, and statistical tests were used to study differences in these levels among the three groups of patients.

    In CSC patients, the median cortisol levels were 0.724 micrograms per deciliter of blood (µg/dL), which dropped to 0.398 and 0.18 in patients with subclinical disease and controls.

    The optimal cutoff point to distinguish patients with clinical Cushing’s was set at 0.288 µg/dL, where 89.6% of patients identified as positive actually have the disease (sensitivity), and 81.6% of patients deemed as negative were without the disease (specificity).

    With a lower cutoff point — 0.273 µg/dL — researchers were also able to identify patients with subclinical disease with high sensitivity and specificity.

    While the test showed high sensitivity and specificity values for clinical Cushing’s syndrome, its diagnostic performance was lower than expected in daily clinical practice, researchers said.

    “The diagnostic performance of late-night salivary cortisol in patients with subclinical Cushing’s syndrome was close to its diagnostic performance in patients with clinical Cushing’s syndrome,” researchers wrote.

    However, regarding the application of this test in other centers, they emphasize that “each center should determine its own cut-off value based on the method adopted for late-night salivary cortisol measurement, and apply that cut-off value in the diagnosis of Cushing’s syndrome.”

    From https://cushingsdiseasenews.com/2018/07/31/late-night-salivary-cortisol-levels-questioned-diagnosis-cushings-syndrome/

    Measuring TSH Levels Could Improve Diagnosis for Cushing’s Syndrome

    Measuring the variation in thyroid stimulating hormone blood levels between midnight and morning may be better for diagnosing Cushing’s syndrome than current approaches, a study suggests. 

    The study, “TSH ratio as a novel diagnostic method for Cushing’s syndrome,” was published in the Endocrine Journal

    Cushing’s syndrome (CS) is a condition characterized by excess cortisol in the blood, which can lead to a variety of issues, including obesity, high blood pressure, abnormal lipid levels, osteoporosis, depression, and cognitive impairments.

    In some cases, patients have high cortisol levels, but lack the typical physical features of Cushing’s syndrome. These patients are considered to have subclinical Cushing’s syndrome (SCS), and are at higher risk for cardiovascular disease.

    Being able to properly diagnose CS and SCS is of utmost importance for proper intervention and treatment of these patients.

    Current methods of diagnosis rely on dexamethasone suppressing tests or late-night salivary and blood cortisol tests, as well as measurements of cortisol in urine. However, because cortisol is a stress-hormone, it can be elevated in cases of mental or physical stress, leading to false positive results on these tests. 

    Researchers in this study examined if another hormone, called the thyroid stimulating hormone (TSH), could be used to diagnose Cushing’s syndrome with better accuracy.

    TSH is a hormone that stimulates the thyroid gland and whose secretion is affected by the body’s circadian rhythm. Its highest levels in the blood are usually seen in the late evening or early morning. However, patients with CS or SCS lack this nocturnal increase in TSH levels, which could be useful as a new diagnostic approach.

    The study recruited 142 patients with suspected CS and SCS, and 21 patients with depression, being treated at the Osaka University Hospital in Japan.

    Patients received the ordinal screening tests for Cushing’s syndrome, along with measurements of their midnight-to-morning TSH levels.

    After taking the tests, only 20 patients were diagnosed as having Cushing’s, including 12 with over (normal) Cushing’s syndrome and 10 with subclinical Cushing’s syndrome.

    Patients with Cushing’s had significantly lower midnight TSH levels than non-Cushing’s patients. No differences were seen in morning levels between the groups. Of note, TSH ratio was maintained in patients with depression, suggesting TSH levels could be used to diagnose Cushing’s in patients with depression.

    Researchers observed that serum TSH ratio had powerful diagnostic accuracy. Among patients identified as having Cushing’s, 90% actually had the disease. And among patients excluded for Cushing’s, 95% did not have the condition. These sensitivity and specificity rates were better than with current diagnostic approaches.

    However, when considering this test, patients with a severe TSH deficiency must be taken into account.

    Overall, these results suggest that the midnight-to-morning serum TSH ratio is a potential new way to diagnose both CS and SCS with a higher specificity than the current diagnostic methods

    “The strength of our current survey is its prospective design and the evaluation of not only overt CS but also SCS. The limitation is the relatively small number of CS group patients, especially overt CD,” the researchers wrote.

    “New prospective studies will be needed with a larger number of patients in order to further clarify the optimal TSH ratio in the diagnosis of CS,” the study concluded. 

    From https://cushingsdiseasenews.com/2018/06/28/measuring-tsh-levels-may-improve-cushings-syndrome-diagnosis-study/

    Gene test for growth hormone deficiency developed

    A new test developed by University of Manchester and NHS scientists could revolutionise the way children with growth hormone deficiency are diagnosed.

    Children suspected of having GHD – which cause growth to slow down or stop and other serious physical problems—currently require a test involving fasting for up to 12 hours.

    The fasting is followed by an intravenous infusion in hospital and up to 10 blood tests over half a day to measure growth hormone production.

    Because the current test is unreliable, it often has to be done twice before growth hormone injections can be prescribed.

    Now the discovery—which the team think could be available within 2 to 5 years -could reduce the process to a single blood test, freeing up valuable time and space for the NHS.

    Dr. Adam Stevens from The University of Manchester and Dr. Philip Murray from Manchester University NHS Foundation Trust, were part of the team whose results are published in JCI Insight today.

    Dr. Stevens said: “We think this is an important development in the way doctors will be able to diagnose growth hormone deficiency – a condition which causes distress to many thousands of children in the UK

    “This sort of diagnostic would not be available even a few years ago but thanks to the enormous computing power we have, and advances in genetics, it is now possible for this aspect of care to be made so much easier for patients – and the NHS.

    “These volume of data involved is so huge and complicated that traditional data-processing application software is inadequate to deal with it.”

    Comparing data from 72 patients with GHD and 26 healthy children, they used high powered computers to examine 30,000 genes—the full gene expression- of each child.

    A sophisticated mathematical technique called Random Forest Analysis analysed around three million separate data points to compare different gene patterns between the children with and without GHD.

    The research identified 347 genes which when analysed with the computer algorithm can determine whether a child has GHD or not and thus whether they will benefit from treatment.

    Growth hormone deficiency (GHD) occurs when the pituitary gland—which is size of a pea- fails to produce enough growth hormone. It more commonly affects children than adults.

    Many teenagers with GHD have poor bone strength, fatigue and lack stamina as well as depression, lack of concentration, poor memory and anxiety problems.

    GHD occurs in roughly 1 in 5,000 people. Since the mid-1980s, synthetic growth hormones have been successfully used to treat children—and adults—with the deficiency.

    Dr. Murray added: “This study provides strong proof of concept, but before it is in a position to be adopted by the NHS, we must carry out a further validation exercise which will involve comparing our new diagnostic with the existing test.

    “Once we have crossed that hurdle, we hope to be in a position for this to be adopted within 2 to 5 years – and that can’t come soon enough for these children.”

    Child Growth Foundation manager Jenny Child’s daughter has Growth Hormone Deficiency.

    She said: Growth Hormone Deficiency isn’t just about growth, as lack of growth hormone impacts the child in many ways, such as lack of strength and they can find it difficult to keep up physically with their peers. It impacts the child’s self-esteem as they are often treated as being much younger, because of their size. Growth hormone treatment allows the child to grow to their genetic potential.

    “A growth hormone stimulation test can be very daunting for both child and parents. The test can make the child feel quite unwell and they can experience headaches, nausea and unconsciousness through hypoglycaemia.”

     Explore further: Northern climes make a difference with growth hormone treatment

    More information: Philip G. Murray et al. Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency, JCI Insight (2018). DOI: 10.1172/jci.insight.93247

    Detailed MRI Analysis Provides Correlations with Clinical Features and Response to Treatment in Cushing’s Disease

    Detailed imaging analysis of patients with Cushing’s disease (CD) and other disorders caused by pituitary adenomas (tumors that arise from the pituitary, a small gland in the brain) provides correlation with clinical characteristics and treatment response, a new Turkish study reports.

    The research, “Clinicopathological significance of baseline T2-weighted signal intensity in functional pituitary adenomas,” appeared in the journal Pituitary.

    Diagnosis of pituitary adenomas is often done with magnetic resonance imaging (MRI), which provides data on the tumor’s localization, its invasiveness, as well as cell death and other changes. However, MRI does not enable precise evaluation of the tumor’s hormone production and behavior.

    Studies on T2-weighted signal intensity (T2-WSI) — one of the basic parameters in MRI scans that highlights fat and water in the body — shows that it correlates with collagen content, degree of fibrosis (scarring), amyloid protein accumulation, and granulation pattern of somatotroph adenomas, which produce excessive levels of growth hormone, causing acromegaly (a hormonal disorder that results from too much growth hormone in the body).

    Evaluation of granulation patterns is key in predicting response to somatostatin analogues (SSAs) treatment, the researchers observed. SSAs are intended to stop excess hormone production.

    In contrast, analysis of T2-WSI in corticotroph adenomas — benign tumors typical in Cushing’s disease patients that release elevated levels of adrenocorticotropin (ACTH) – is still lacking.

    The research team assessed the correlation of T2-WSI with clinical features, granulation patterns, and response to treatment in patients with functional pituitary adenomas (FPAs), which are collectively characterized by excessive production of one or more hormones.

    Specifically, scientists focused on 29 patients with Cushing’s disease, 87 with acromegaly, and 78 with prolactinoma, a type of benign pituitary tumor that produces elevated amounts of prolactin.

    Results showed that while most somatotroph adenomas (53%) were hypointense, which means a darker image on MRI, the majority of prolactinomas (55%) and corticotroph adenomas (45%) were at least generally hyperintense, meaning lighter on image.

    Data also revealed that hyperintense somatotroph adenomas were larger, sparsely granulated, and exhibited reduced shrinkage after treatment with SSAs.

    In contrast, hypointense tumors were associated with higher levels of baseline insulin-like growth factor (IGF)-1% ULN, a predictor of insulin sensitivity, and a better response to SSAs.

    In women with prolactinomas, hyperintensity correlated with smaller tumor diameter. In turn, hypointense prolactinomas were linked with younger age at diagnosis, higher baseline prolactin levels, and resistance to treatment with a dopamine agonist.

    Scientists also found that hyperintense corticotroph adenomas correlated with larger tumor size and a sparsely granulated pattern. No difference was found between hyper and hypointense adenomas on cortisol and ACTH levels.

    Investigators also reported that T2-WSI was not correlated with better surgical outcomes or with recurrent Cushing’s disease. Analysis of tumor shrinkage in these patients was not possible, the researchers noted.

    “Although in present there is no immediate clinical application, we believe that if medical shrinkage of corticotrophs ever became a part of clinical practice, similar analyses could be performed in the future,” the researchers wrote.

    “Further studies with larger series are required in order to make stronger suggestions,” they added.

    From https://cushingsdiseasenews.com/2018/03/23/detailed-mri-analysis-correlates-with-cushings-disease-clinical-features/

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