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Cushing’s disease patients whose pituitary tumors carry a USP8 mutation are more likely to achieve remission after surgery than those without such mutations, a retrospective Italian study found. The study, “Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas,” was published in the journal Endocrine. Cushing’s disease is a condition where a tumor on the pituitary gland produces too much of the adrenocorticotropin hormone (ACTH), which will act on the adrenal gland to make cortisol in excess. While rare, the condition can be life-threatening, as excess cortisol is linked to an increased risk of infections and cardiovascular complications, along with an increased likelihood of obesity and diabetes. The reasons some patients develop these pituitary adenomas are far from understood, but researchers recently found that some of these patients show mutations in the USP8 gene. These appear to increase EGFR signaling which, in turn, has a stimulatory role for the synthesis of ACTH. But more than influencing the development of Cushing’s disease, researchers believe the USP8 mutations may also determine response to treatment. Thus, a team in Italy examined whether patients with USP8 mutations presented different clinical features and responded differently to the standard surgical procedure, called transsphenoidal pituitary surgery. The study included 92 patients with ACTH-secreting pituitary tumors who received surgery at the neurosurgical department of the Istituto Scientifico San Raffaele in Milan between 1996 and 2016. “All surgical procedures were performed by the same experienced neurosurgeon, which is one of the most important factors affecting early and late surgical outcome of pituitary adenomas,” researchers explained. Among study participants, 22 (23.9%) had mutations in the USP8 gene, but these mutations were significantly more common in women than in men — 28.7% vs. 5.3%. Researchers think estrogens — a female sex hormone — may have a role in the development of mutated pituitary tumors. Overall, the two groups had similar tumor size and aggressiveness and similar ACTH and cortisol levels before surgery. But among those with microadenomas — tumors smaller then 10 mm in diameter — USP8-mutated patients had significantly larger tumor diameters. After receiving surgery, 81.5% of patients achieved surgical remission — deemed as low cortisol levels requiring glucocorticoid replacement therapy, normal cortisol levels in urine, and normal response to a dexamethasone-suppression test. But remission rates were significantly higher among those with USP8 mutations — 100% vs. 75.7%. Also, USP8 mutation carriers required steroid replacement therapy for shorter periods, despite ACTH and cortisol levels being similar among the two groups after surgery. Among patients who entered remission, 12 (16%) saw their disease return. While more patients with USP8 mutations experienced a recurrence — 22.7% vs. 13.2% — this difference was not significant. After five years, 73.8% of UPS8-mutated patients remained alive and recurrence-free, which researchers consider comparable to the 88.5% seen in patients without the mutation. Researchers also tested sex, age at surgery, and post-surgical ACTH and cortisol levels as possible predictors of disease recurrence, but none of these factors was associated with this outcome. “ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated on by a single neurosurgeon. Recurrence rates are not related with USP8-variant status,” researchers concluded. From https://cushingsdiseasenews.com/2018/10/23/cushings-disease-patients-usp8-mutations-more-likely-achieve-remission-after-surgery/
MaryO posted a topic in News Items and ResearchMinimally invasive diagnostic methods and transnasal surgery may lead to remission in nearly all children with Cushing’s disease, while avoiding more aggressive approaches such as radiation or removal of the adrenal glands, a study shows. The study, “A personal series of 100 children operated for Cushing’s disease (CD): optimizing minimally invasive diagnosis and transnasal surgery to achieve nearly 100% remission including reoperations,” was published in the Journal of Pediatric Endocrinology and Metabolism. Normally, the pituitary produces adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce cortisol. When a patient has a pituitary tumor, that indirectly leads to high levels of cortisol, leading to development of Cushing’s disease (CD). In transnasal surgery (TNS), a surgeon goes through the nose using an endoscope to remove a pituitary tumor. The approach is the first-choice treatment for children with Cushing’s disease due to ACTH-secreting adenomas — or tumors — in the pituitary gland. Micro-adenomas, defined as less than 4 mm, are more common in children and need surgical expertise for removal. It is necessary to determine the exact location of the tumor before conducting the surgery. Additionally, many surgeons perform radiotherapy or bilateral adrenalectomy (removal of both adrenal glands) after the surgery. However, these options are not ideal as they can be detrimental to children who need to re-establish normal growth and development patterns. Dieter K. Lüdecke, a surgeon from Germany’s University of Hamburg, has been able to achieve nearly 100% remission while minimizing the need for pituitary radiation or bilateral adrenalectomy. In this study, researchers looked at how these high remission rates can be achieved while minimizing radiotherapy or bilateral adrenalectomy. Researchers analyzed 100 patients with pediatric CD who had been referred to Lüdecke for surgery from 1980-2009. Data was published in two separate series — series 1, which covers patients from 1980-1995, and series 2, which covers 1996-2009. All the surgeries employed direct TNS. Diagnostic methods for CD have improved significantly over the past 30 years. Advanced endocrine diagnostic investigations, such as testing for levels of salivary cortisol in the late evening and cortisol-releasing hormone tests, have made a diagnosis of CD less invasive. This is particularly important for excluding children with obesity alone from children with obesity and CD. Methods to determine the precise location of micro-adenomas have also improved. The initial methodology to localize tumors was known as inferior petrosal sinus sampling (IPSS), an invasive procedure in which ACTH levels are sampled from the veins that drain the pituitary gland. In series 1, IPSS was performed in 24% of patients, among which 46% were found to have the wrong tumor location. Therefore, IPSS was deemed invasive, risky, and unreliable for this purpose. All adenomas were removed with extensive pituitary exploration. Two patients in series 1 underwent early repeat surgery; all were successful. Lüdecke introduced intraoperative cavernous sinus sampling (CSS), an improved way to predict location of adenomas. This was found to be very helpful in highly select cases and could also be done preoperatively for very small adenomas. In series 2, CSS was used in only 15% of patients thanks to improved MRI and endocrinology tests. All patients who underwent CSS had correct localization of their tumors, indicating its superiority over IPSS. In series 2, three patients underwent repeat TNS, which was successful. In these recurrences, TNS minimized the need for irradiation. The side effects of TNS were minimal. Recurrence rate in series 1 was 16% and 11% in series 2. While Lüdecke’s patients achieved a remission rate of 98%, other studies show cure rates of 45-69%. Only 4% of patients in these two series received radiation therapy. “Minimally invasive unilateral, microsurgical TNS is important functionally for both the nose and pituitary,” the researchers concluded. “Including early re-operations, a 98% remission rate could be achieved and the high risk of pituitary function loss with radiotherapy could be avoided.” From https://cushingsdiseasenews.com/2018/09/04/minimally-invasive-methods-yield-high-remission-in-cushings-disease-children/
A plasma adrenocorticotropic hormone suppression test performed shortly after surgical adenomectomy may accurately predict both short- and long-term remission of Cushing’s disease, according to research published in Pituitary. “Cushing’s disease is caused by hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, resulting in hypercortisolism,” Erik Uvelius, MD, of the department of clinical sciences, Skåne University Hospital, Lund University, Sweden, and colleagues wrote in the study background. “Surgical adenomectomy is the first line of treatment. Postoperative remission is reported in 43% to 95% of cases depending on factors such as adenoma size, finding of pituitary adenoma on preoperative MRI and surgeons’ experience. However, there is no consensus on what laboratory assays and biochemical thresholds should be used in determining or predicting remission over time.” In the study, the researchers retrospectively gathered data from medical records of 28 patients who presented with Cushing’s disease to Skåne University Hospital between November 1998 and December 2011, undergoing 45 transsphenoidal adenomectomies. On postoperative days 2 and 3, oral betamethasone was administered (1 mg at 8 a.m., 0.5 mg at 2 p.m., and 0.5 mg at 8 p.m.). Researchers assessed plasma cortisol and plasma ACTH before betamethasone administration and again at 24 and 48 hours, and measured 24-urinary free cortisol on postoperative day 3. At 3 months postoperatively and then annually, plasma concentrations of morning cortisol and ACTH along with urinary-free cortisol and/or a low-dose dexamethasone suppression test were evaluated at the endocrinologists’ discretion. The researchers defined remission as lessening of clinical signs and symptoms of hypercortisolism, as well as laboratory confirmation through the various tests. The researchers used Youden’s index to establish the cutoff with the highest sensitivity and specificity in predicting remission over the short term (3 months) and long term (5 years or more). Clinical accuracy of the different tests was illustrated through the area under curve. The study population consisted of mainly women (71%), with a median age of 49.5 years. No significant disparities were seen in age, sex or surgical technique between patients who underwent a primary procedure and those who underwent reoperation. Two of the patients were diagnosed with pituitary carcinoma and 11 had a macroadenoma. ACTH positivity was identified in all adenomas and pathologists confirmed two cases of ACTH-producing carcinomas. Of the 28 patients, 12 (43%) demonstrated long-term remission at last follow-up. Three patients were not deemed in remission after primary surgery but were not considered eligible for additional surgical intervention, whereas 13 patients underwent 17 reoperations to address remaining disease or recurrence. Four patients demonstrated long-term remission after a second or third procedure, equaling 16 patients (57%) achieving long-term remission, according to the researchers. The researchers found that both short- and long-term remission were most effectively predicted through plasma cortisol after 24 and 48 hours with betamethasone. A short-term remission cutoff of 107 nmol/L was predicted with a sensitivity of 0.85, specificity of 0.94 and a positive predictive value of 0.96 and AUC of 0.92 (95% CI, 0.85-1). A long-term remission cutoff of 49 nmol/L was predicted with a sensitivity of 0.94, specificity of 0.93, positive predictive value of 0.88 and AUC of 0.98 (95% CI, 0.95-1). This cutoff was close to the suppression cutoff for the diagnosis of Cushing’s disease, 50 nmol/L. The cutoff of 25 nmol/L showed that the use of such a strict suppression cutoff would cause a low level of true positives and a higher occurrence of false negatives, according to the researchers. “A 48 h 2 mg/day betamethasone suppression test day 2 and 3 after transsphenoidal surgery of Cushing’s disease could safely predict short- and long-term remission with high accuracy,” the researchers wrote. “Plasma cortisol after 24 hours of suppression showed the best accuracy in predicting 5 years’ remission. Until consensus on remission criteria, it is still the endocrinologists’ combined assessment that defines remission.” – by Jennifer Byrne Disclosures: The authors report no relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0fdfb7b0-e418-4b53-b59d-1ffa3f7b8cd3%7D/acth-test-after-adenomectomy-may-accurately-predict-cushings-disease-remission
MaryO posted a topic in News Items and ResearchI think I knew this already but it's still hard to read in print Functional remission did not occur in most patients with Cushing syndrome who were considered to be in biochemical and clinical remission, according to a study published in Endocrine. This was evidenced by their quality of life, which remained impaired in all domains. The term “functional remission” is a psychiatric concept that is deﬁned as an “association of clinical remission and a recovery of social, professional, and personal levels of functioning.” In this observational study, investigators sought to determine the speciﬁc weight of psychological (anxiety and mood, coping, self-esteem) determinants of quality of life in patients with Cushing syndrome who were considered to be in clinical remission. The cohort included 63 patients with hypercortisolism currently in remission who completed self-administered questionnaires that included quality of life (WHOQoL-BREF and Cushing QoL), depression, anxiety, self-esteem, body image, and coping scales. At a median of 3 years since remission, participants had a signiﬁcantly lower quality of life and body satisfaction score compared with the general population and patients with chronic diseases. Of the cohort, 39 patients (61.9%) reported having low or very low self-esteem, while 16 (25.4%) had high or very high self-esteem. Depression and anxiety were seen in nearly half of the patients and they were more depressed than the general population. In addition, 42.9% of patients still needed working arrangements, while 19% had a disability or cessation of work. Investigators wrote, “This impaired quality of life is strongly correlated to neurocognitive damage, and especially depression, a condition that is frequently confounded with the poor general condition owing to the decreased levels of cortisol. A psychiatric consultation should thus be systematically advised, and [selective serotonin reuptake inhibitor] therapy should be discussed.” Reference Vermalle M, Alessandrini M, Graillon T, et al. Lack of functional remission in Cushing's Syndrome [published online July 17, 2018]. Endocrine. doi:10.1007/s12020-018-1664-7 From https://www.endocrinologyadvisor.com/general-endocrinology/functional-remission-quality-of-life-cushings-syndrome/article/788501/