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MaryO

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  1. Eleni Papakokkinou, Marta Piasecka, Hanne Krage Carlsen, Dimitrios Chantzichristos, Daniel S. Olsson, Per Dahlqvist, Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye, Britt Edén Engström, Pia Burman, Cecilia Follin, David Petranek, Eva Marie Erfurth, Jeanette Wahlberg, Bertil Ekman, Anna-Karin Åkerman, Erik Schwarcz, Gudmundur Johannsson, Henrik Falhammar & Oskar Ragnarsson Abstract Purpose Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources Systematic literature search in four databases. Study Selection Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)]. Conclusions Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS. Introduction Cushing´s disease (CD) is a rare disorder associated with excess morbidity and increased mortality [1, 2]. Previously, bilateral adrenalectomy (BA) was the mainstay treatment for CD. During the last decades, however, other treatment modalities have emerged, including pituitary surgery, radiotherapy and medical treatments. Despite this, BA is still considered when other treatment options have failed to achieve remission, or when a rapid relief of hypercortisolism is necessary [3]. BA is considered to be a safe and effective treatment for CD [4], especially after the laparoscopic approach was introduced during the 1990s [5]. There are, however, significant drawbacks with BA, mainly the unavoidable chronic adrenal insufficiency, as well as the risk for Nelson’s syndrome (NS), i.e., growth of the remaining pituitary tumor and excessive production of ACTH, that may cause optic nerve or chiasmal compression and mucocutaneous hyperpigmentation [6]. The prevalence of NS varies between studies, mainly due to a lack of consensus on the definition and diagnostic criteria for the syndrome [7, 8]. Previously published studies are also inconsistent as to whether factors such as previous radiotherapy, age at BA, gender and duration of CD, may affect the risk of developing NS. Furthermore, high ACTH concentrations after BA have been suggested as a risk factor for developing NS [9,10,11,12]. Thus, the primary aim of this systematic review and meta-analysis was to estimate the prevalence of NS after BA for CD, both the total prevalence of NS as well the prevalence of NS requiring treatment with pituitary surgery and/or radiotherapy. The secondary aim was to investigate risk factors associated with development of NS. Methods A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13]. The PICO process was applied for the definition of the research question and eligibility criteria for the literature search. The protocol of this review was registered in the PROSPERO database (CRD42020163918). Search strategy We searched PubMed, Embase, Cochrane Library and Web of Science on February 25th 2020, with no start date restriction, for relevant articles by using the following terms: “Cushing´s syndrome” or “Cushing´s disease” or “Hypercortisolism” or “Pituitary ACTH hypersecretion” or “corticotroph tumor” or “corticotroph tumors” or “corticotroph adenoma” or “corticotroph adenomas” or “corticotropinoma” or “corticotropinomas” or “corticotrophinoma” or “corticotrophinomas” or “ACTH pituitary adenoma” or “ACTH pituitary adenomas” or “adrenocorticotropin pituitary adenoma” or “adrenocorticotropin pituitary adenomas” AND “bilateral adrenalectomy” or “bilateral adrenalectomies” or “total adrenalectomy” or “total adrenalectomies”. A detailed description of the search strategy is given in the Supplementary. Also, references of the included studies and relevant review articles were checked manually for additional articles. A new search was performed on January 12th 2021, prior submission, to identify any new publications. Study selection and eligibility criteria Eligible studies were observational studies (cohort or cross-sectional studies) reporting the prevalence of NS in adult patients with CD treated with BA. Studies including only children (age < 18 years), review articles, letters, commentaries and meeting abstracts were excluded. Moreover, case reports, case-series and studies with a population of fewer than 10 cases were excluded. Also, studies written in languages other than English were not considered for inclusion. Data collection process and data extraction Titles and abstracts from all identified articles were screened for eligibility and further full-text assessment by three independent investigators (EP, MP, OR). Discrepancies were resolved through discussion and consensus. Duplicate articles and studies with overlapping populations were excluded. In the latter case, the publication with the largest population, more comprehensive information on relevant clinical variables and/or lowest risk of bias was included. Full-text assessment and data extraction were conducted independently by the same investigators as above. Data on the following predefined variables were extracted: first author, year of publication, region/hospital, study period, characteristics of the study population (number of patients, gender, follow-up, age at CD, age at BA, previous treatment with radiotherapy and/or pituitary surgery, ACTH concentrations at BA, MRI findings at CD and at BA), intervention (BA as primary or secondary treatment, remission status) and outcome (criteria for NS, number of patients with NS, age at NS, time from BA to NS, ACTH concentrations one year after BA, number of patients treated for NS, type of treatment; pituitary radiotherapy and/or pituitary surgery). One of the studies included in the meta-analysis is our nationwide Swedish study on CD [2]. Additional clinical data, not provided in the original publication, was retrieved and used in the current analysis (Table 1). Table 1 Characteristics of the included studies Full size table Risk of bias assessment The Newcastle–Ottawa Scale [14], modified to suit the current study, was used for assessment of risk of bias of all included studies. Three investigators (EP, MP, OR) assessed the studies independently, and any disagreements were resolved by discussion. Selection, comparability and outcome were assessed through predefined criteria. All studies that provided information on NS as outcome, and/or corticotroph tumor progression, were included, and the definition as well as the treatment of NS were recorded (Table 1 and Table S1). A clear definition of NS and information on treatment were considered to be two of the most important components of the quality assessment. We considered the definition of NS to be clear when it included either a new visible pituitary tumor or progression of a pituitary tumor remnant following BA, alone, or in combination with high ACTH concentrations and/or hyperpigmentation. Detailed description of the criteria for the risk of bias assessment is provided in the Supplementary file. Studies with an overall score ≥ 5 (max overall grade 😎 and a clear definition of NS, were considered to have a low risk of bias. Data synthesis and statistical analysis Primary endpoints were the prevalence of NS, as well as the prevalence of pituitary-specific treatment for NS. Descriptive data are presented as median (range or interquartile range; IQR). Meta-analysis was performed by using the meta package in R (version 4.0.3) [15]. Statistical pooling was performed according to random-effects model due to the clinical heterogeneity among the included studies [16]. For all analyses, indices of heterogeneity, I2 statistics and Cochrane’s Q test, are reported. For the primary outcomes we estimated pooled prevalence with 95% confidence intervals (95% CI). Statistical significance was defined as P < 0.05. The possibility of publication bias was assessed by visual inspection of funnel plots as well as with the Egger’s test [17]. Sensitivity analyses were performed by excluding studies with an overall risk of bias < 5, and studies where information on diagnostic criteria for NS was lacking. By choosing the overall risk of bias < 5, all studies without adequate follow-up were also excluded (Table S2). Also, another sensitivity analysis was performed by including all studies reporting the number of patients with NS who received treatment for NS (Table 1). Subgroup analyses were performed to investigate factors that may affect the prevalence of NS, namely pituitary radiotherapy prior to BA, prophylactic pituitary radiotherapy, overall radiotherapy (prior to BA or prophylactic), pituitary surgery (transcranial or transsphenoidal surgery) prior to BA, and BA as primary or secondary treatment. For these outcomes, we estimated relative risks (RRs), or pooled prevalence, with 95% CIs. Also, in a subgroup analysis, the prevalence (with 95% CI) of NS and treatment for NS were estimated in studies where MRI was used at diagnosis and during follow-up. Uni- and bivariate meta-regression was used to investigate whether the prevalence of NS was influenced by median follow-up time or age at BA. The meta-analysis was performed by using the Metareg command in R. The estimated association is reported as β coefficient. Role of funding source The funding source had no role in the design and conduction of the study; i.e., collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Results Identification and description of included studies After removal of duplicates, 1702 articles were identified (Fig. 1). Three additional articles were found after checking the reference lists of identified articles and review papers. After reviewing titles, abstracts and full-text articles, 48 articles were considered eligible for further analysis. Of these, however, 11 articles were excluded due to overlapping or identical patient cohorts. Thus, 37 studies published between 1976 and 2020, were included in the current meta-analysis (Fig. 1). All studies had a retrospective observational design. Characteristics of the included studies are presented in Table 1. Two of the included studies had an overlapping cohort where one was used for the main outcome [18] and one [19] for the subgroup analyses on the influence of radiotherapy on the development of NS. An overview of risk of bias assessment of the eligible studies is provided in Table S2. Fig. 1 Flowchart of study selection Full size image In total, 1316 patients with CD treated with BA were included. The median follow-up after BA was 7 years (23 studies, range 3.3–22). Median age at BA in patients with NS was 31 years (13 studies, IQR 26–34). Median time from BA to the diagnosis of NS was 4 years (19 studies) with the shortest reported time being 2 months [20] and the longest 39 years [2]. At diagnosis of NS, hyperpigmentation was reported in 155 of 188 (82%) patients (19 studies) and chiasmal compression in 24 of 129 (19%) patients [11 studies]. Prevalence of NS Thirty-six of 37 studies, with total 1316 patients with CD treated with BA, were included [2, 18, 20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Reported prevalence of NS ranged from 4 to 60%. The mean pooled prevalence was 26% (95% CI 22–31%) with a moderate to high heterogeneity (I2 67%, P < 0.01) (Fig. 2). The Egger’s test was statistically significant (P = 0.01), but visual inspection showed no obvious asymmetry. The significant Egger’s test indicates publication bias, probably explained by the fact that case reports and cohorts with fewer than 10 participants were excluded (Fig. S1). Fig. 2 Forest plot showing individual studies and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease. *Additional data Full size image In a sensitivity analysis, excluding all studies with high risk of bias (overall score < 5) and no clear definition of NS, the pooled prevalence was 31% (95% CI 24–38%; I2 76%, 17 studies, 822 patients; P < 0.01) (Fig. S2). In a subgroup analysis, the prevalence of NS in studies where MRI was used at diagnosis and during follow-up was 38% (Fig. 3; 95% CI 27–50%; I2 71%, 7 studies, 280 patients; P < 0.01). Fig. 3 Forest plot showing individual studies using magnetic resonance imaging and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease Full size image Prevalence of treated NS The pooled prevalence of treatment for NS was 21% (95% CI 18–26%; I2 52%, P < 0.01) (Table 1; 29 studies with 1074 patients). Thus, the pooled prevalence was slightly lower, compared to the pooled prevalence of NS in total, as well as the heterogeneity (Fig. S3). The funnel plot showed no asymmetry and Egger’s test was not statistically significant, indicating low possibility of publication bias (Fig. S4). In a subgroup analysis, the prevalence of treated NS in studies where MRI was used at diagnosis and during follow-up was 25% (95% CI 17–35%; I2 61%, 7 studies; P = 0.02). The indication for treatment was progression of the pituitary tumor in 23 out of 28 patients (82%, five studies), optic chiasmal compression in 11 out of 91 patients (12%, 11 studies), while four patients out of 14 (one study) had both these indications for treatment. Twenty-six studies provided information on treatment modalities (pituitary surgery and/or radiotherapy). Seventy-three out of 201 patients with NS (36%) were treated with pituitary surgery, 86 (43%) with radiotherapy and 41 (20%) received both treatments. Radiotherapy Nineteen studies provided information on radiotherapy prior to BA. However, nine studies had no events and no patients in one of the arms (radiotherapy or no radiotherapy) (Table S3). Thus, ten studies were eligible for further estimation, showing that the risk for NS in patients treated with radiotherapy prior to BA was comparable to the risk in patients not treated with radiotherapy (RR 0.9, 95% CI 0.5–1.6; 10 studies with 564 patients) (Fig. 4). Fig. 4 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with radiotherapy prior to bilateral adrenalectomy versus no radiotherapy. RR could not be calculated when there were no cases in the RTX or no RTX arms, and when no events in either arm. *Additional data. RTX, radiotherapy prior to bilateral adrenalectomy or prophylactic radiotherapy Full size image Thirteen studies provided information on prophylactic radiotherapy. However, only one study provided applicable data for calculating RR, thus subgroup analysis was not performed (Table S4). In that study [20], none of the seventeen patients who received prophylactic radiotherapy developed NS, while 11 of 22 patients without radiotherapy developed NS after a mean follow-up of 4.4 years (range 10–16 years). By using studies with information on either previous or prophylactic radiotherapy (11 studies with 603 patients; Table S5), the pooled RR was 0.8 (95% CI 0.5–1.5). Pituitary surgery prior to BA Of 21 studies with information on pituitary surgery prior to BA (Table S6), only ten provided information for estimation of RR. A pooled RR of 0.6 (10 studies with 430 patients; 95% CI 0.4–1.0) was found (Fig. 5), indicating that the risk for developing NS was not influenced by previous pituitary surgery. Fig. 5 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with pituitary surgery prior to bilateral adrenalectomy versus no pituitary surgery. RR could not be calculated when there were no cases in the surgery or no surgery arms, and when no events in either arm. *additional data. Abbreviations: Surgery, pituitary surgery prior to bilateral adrenalectomy Full size image BA as primary or secondary treatment for CD Information on whether patients with NS were treated primarily with BA or not, was provided in ten and nine studies, respectively (Fig. S5 and S6). The pooled prevalence of NS was 26% (95% CI 20–33%) for patients treated primarily with BA and 22% (95% CI 15–31%) for patients who had been treated with pituitary surgery and/or radiotherapy prior to BA. ACTH concentrations one year after BA Four studies provided information on ACTH concentrations during the first year after BA [45, 49, 52, 53]. In a study by Assié et al. the median ACTH concentration in patients who developed NS was 301 pmol/L, compared to 79 pmol/L in patients without NS (upper range of limit; URL 13 pmol/L) [52]. The median ACTH concentration in a study by Cohen et al. was 105 pmol/L in the NS group compared to 18 pmol/L in patients without NS (P = 0.007) (URL 10 pmol/L) [49]. Also, in a study by Das et al., there was a statistically significant difference in ACTH concentrations one year after BA between patients with and without NS (110 vs 21 pmol/L respectively; P = 0.002) [53]. On the contrary, Espinosa-de-Los-Monteros et al.found no difference in ACTH concentrations between the patients with NS and those without NS [45]. Thus, three of four studies found that high ACTH concentrations one year after BA were associated with the development of NS. However, since the ACTH assays and the conditions when ACTH was collected were different in these studies (Table S7), further comparison or a meta-analysis on ACTH levels after BA was not considered feasible. Influence of age at BA and duration of follow-up on prevalence of NS In a meta-regression analysis, age at BA (β-coefficient = – 0.03, P = 0.4; Fig. 6) and median duration of follow-up (β-coefficient = 0.01, P = 0.7; Fig. S7) were not associated with prevalence of NS. After adjustment for follow-up, age at BA was still not associated with prevalence of NS (β-coefficient = -0.03, P = 0.4). Fig. 6 Bubble plot showing the influence of age at BA on the prevalence of Nelson’s syndrome. The bubble sizes are proportional to the weight of the studies in the meta-analysis. Coefficient estimate (β) and p value for the effect of age at BA are indicated by the regression line Full size image Discussion In this study we have for the first time evaluated the pooled prevalence of NS by using a meta-analysis on data from 36 studies, including more than 1300 patients with CD treated with BA. The overall prevalence of NS was 26% and the median time from BA to diagnosis of NS was 4 years, ranging from 0.2 to 39 years. The prevalence of patients requiring pituitary-specific treatment for NS was 21%. Furthermore, radiotherapy and pituitary surgery prior to BA, as well as age at BA, did not seem to affect the risk of developing NS. Various definitions have been used for NS over the past decades [12]. Historically, the diagnosis was based on clinical findings related to mucocutaneous hyperpigmentation and chiasmal compression, together with signs of an enlarged sella turcica on skull radiography [6]. Since then, the diagnosis of NS in most studies has been based on (i) radiological evidence of a pituitary tumor that becomes visible, or a progression of a preexisting tumor, (ii) “high” ACTH concentrations, and (iii) hyperpigmentation [54]. In the studies with the highest prevalence of NS [45, 46], the diagnosis was based on rising ACTH concentrations and an expanding pituitary mass, where 2 mm increment in tumor size on MRI was considered to be a significant growth. On the contrary, the criteria for NS in studies with the lowest prevalence were based on hyperpigmentation, often but not always combined with a pituitary tumor responding to radiotherapy and/or a radiographic evidence of pituitary tumor on skull radiography [21, 23]. Thus, the great variance in the prevalence of NS between studies can, at least partly, be explained by the different definitions of NS. Consequently, in an expert opinion published in 2010, it was suggested that the diagnosis of NS should be based on an elevated level of ACTH >500 ng/L (110 pmol/L) in addition to rising levels of ACTH on at least three consecutive occasions and/or an expanding pituitary mass on MRI or CT following BA [54]. Similarly, in a recently published expert consensus recommendation, based on a systematic review, it was suggested that NS should be defined as radiological progression or new detection of a pituitary tumor on a thin-section MRI [55]. Furthermore, the authors recommend active surveillance with MRI three months after BA, and every 12 months for the first 3 years, and every 2–4 years thereafter, based on clinical findings. The meta-regression of the current analysis did not show an association between median follow-up time and prevalence of NS. Nevertheless, NS occurred as early as 2 months [20], and up to 39 years after BA [2], supporting that life-long surveillance after BA is necessary for patients with CD. Active surveillance with MRI was more common in studies published during the last two decades. In fact, the use of MRI in recent studies resulted in earlier detection of a growing pituitary adenoma and, subsequently, contributed to a higher prevalence of NS. Namely, the seven studies including patients treated with BA after 1990 and using MRI reported higher prevalence of NS, both overall NS and treated NS. Whether factors such as pituitary radiotherapy affects the risk for development of NS has been evaluated in several studies. Some studies have shown that radiotherapy prior to BA, or administrated prophylactically, can prevent or delay the development of NS [20, 39]. On the contrary, other studies have not demonstrated a protective effect of radiotherapy prior to BA [18, 37] and, moreover, one study found an association with tumor progression [46]. Nevertheless, the current meta-analysis indicates that radiotherapy prior to BA does not decrease the risk of developing NS. Neither did previous pituitary surgery affect the risk for NS. Elevated ACTH concentrations during the first year after BA have been considered to be a strong predictor of NS [49, 52]. In fact, seven studies in the current analysis included cut-off levels for ACTH concentration, arbitrarily defined, for the diagnosis of NS [18, 25, 34, 36, 41, 45, 49]. Due to the different ACTH assays, and different conditions when ACTH was collected, no further analysis on ACTH levels was performed. Nevertheless, four studies [45, 49, 52, 53] reported ACTH concentrations one year after BA in both patients with and without NS. Three of these studies found that high ACTH concentrations one year after BA [49, 52, 53] were associated with pituitary tumor progression. Thus, these findings support the suggestion that ACTH should be monitored following BA in patients with CD [54, 55]. The prevalence of treatment for NS (21%), and the heterogeneity index (52%), were slightly lower than in the analysis of total prevalence of NS (26%, I2 67%). The majority of the patients was treated with radiotherapy, followed by pituitary surgery and combination of pituitary surgery and radiotherapy. Today, surgical removal of the pituitary tumor is considered to be the first-line therapy of NS whereas radiotherapy is considered if surgery has failed or is not possible [12, 54, 56]. In a large multi-center study by Fountas et al., the 10-year progression-free survival rates after surgery alone, or with radiotherapy, for patients with NS was 80% and 81%, respectively [57]. In comparison, progression-free survival rate in patients who did not receive treatment was 51%. Reports on the efficacy of medical therapy for NS have shown inconsistent results [56]. Strengths and limitations This is the largest systematic review, and the first meta-analysis, on NS published to date. However, some limitations have to be acknowledged. Most important are the different diagnostic methods used to detect NS, and the different definitions of the syndrome between the studies. The majority of the studies have used the combination of hyperpigmentation, high ACTH concentrations and radiological findings for the diagnosis of NS. Notwithstanding these common criteria, there were still differences in the cut-offs of ACTH levels, the use of different radiological modalities over time as well as the radiological definition of progress of pituitary tumors. Moreover, in some studies radiological findings were used solely or in combination with either hyperpigmentation and/or bitemporal hemianopsia, ACTH concentrations or response to treatment of NS. Furthermore, in several studies a clear definition of NS was not provided. Nevertheless, we consider our attempt to address the heterogeneity of the included studies, through systematic review, quality assessment, and sensitivity and subgroup analyses to be a strength. Conclusions The risk of NS after BA in patients with CD is considerable and may first become clinically evident many decades later. Thus, life-long close follow-up is necessary for an early detection of a growing pituitary tumor, and adequate treatment when needed. Although this meta-analysis did not find prior surgery or radiotherapy to be associated with risk of NS, the findings are based on a limited number of studies. Thus, in order to individualize the treatment for patients with CD, further studies are needed where these and other factors possibly associated with risk of NS are evaluated. Data availability The data generated or analyzed during this study are included in this published article or in the Supplementary file. Abbreviations CD: Cushing's disease BA: Bilateral adrenalectomy NS: Nelson’s syndrome ACTH: Adrenocorticotropic hormone RR: Relative risk MRI: Magnet resonance imaging CT: Computer tomography References 1. Papakokkinou E, Olsson DS, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K, Bensing S, Hoybye C, Eden-Engstrom B, Burman P, Bonelli L, Follin C, Petranek D, Erfurth EM, Wahlberg J, Ekman B, Akerman AK, Schwarcz E, Bryngelsson IL, Johannsson G, Ragnarsson O (2020) Excess morbidity persists in patients with cushing's disease during long-term remission: a swedish nationwide study. J Clin Endocrinol Metab 105(8):2616–2624 2. Ragnarsson O, Olsson DS, Papakokkinou E, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K, Bensing S, Hoybye C, Eden-Engstrom B, Burman P, Bonelli L, Follin C, Petranek D, Erfurth EM, Wahlberg J, Ekman B, Akerman AK, Schwarcz E, Bryngelsson IL, Johannsson G (2019) Overall and disease-specific mortality in patients with cushing disease: a swedish nationwide study. J Clin Endocrinol Metab 104(6):2375–2384 PubMed Article Google Scholar 3. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A, Endocrine S (2015) Treatment of cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100(8):2807–2831 CAS PubMed PubMed Central Article Google Scholar 4. Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J, Reincke M (2013) Clinical review: outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 98(10):3939–3948 CAS PubMed Article Google Scholar 5. Reincke M, Ritzel K, Osswald A, Berr C, Stalla G, Hallfeldt K, Reisch N, Schopohl J, Beuschlein F (2015) A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur J Endocrinol 173(4):M23-32 CAS PubMed Article Google Scholar 6. Nelson DH, Meakin JW, Dealy JB Jr, Matson DD, Emerson K Jr, Thorn GW (1958) ACTH-producing tumor of the pituitary gland. N Engl J Med 259(4):161–164 CAS PubMed Article Google Scholar 7. Guerin C, Taieb D, Treglia G, Brue T, Lacroix A, Sebag F, Castinetti F (2016) Bilateral adrenalectomy in the 21st century: when to use it for hypercortisolism? Endocr Relat Cancer 23(2):R131-142 CAS PubMed Article Google Scholar 8. Katznelson L (2015) Bilateral adrenalectomy for Cushing’s disease. Pituitary 18(2):269–273 CAS PubMed Article Google Scholar 9. Banasiak MJ, Malek AR (2007) Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management. Neurosurg Focus 23(3):E13 PubMed Article Google Scholar 10. Assie G, Bahurel H, Bertherat J, Kujas M, Legmann P, Bertagna X (2004) The Nelson’s syndrome revisited. Pituitary. 7(4):209–215 PubMed Article Google Scholar 11. Ragnarsson O (2020) Cushing’s syndrome disease monitoring: recurrence, surveillance with biomarkers or imaging studies. Best Pract Res Clin Endocrinol Metab. 34(2):101382 PubMed Article Google Scholar 12. Fountas A, Karavitaki N (2020) Nelson’s syndrome: an update. Endocrinol Metab Clin North Am 49(3):413–432 PubMed Article Google Scholar 13. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097 PubMed PubMed Central Article Google Scholar 14. Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp 15. Balduzzi S, Rucker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 22(4):153–160 PubMed Article Google Scholar 16. Lau J, Ioannidis JP, Schmid CH (1998) Summing up evidence: one answer is not always enough. Lancet 351(9096):123–127 CAS PubMed Article Google Scholar 17. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634 CAS PubMed PubMed Central Article Google Scholar 18. Smith PW, Turza KC, Carter CO, Vance ML, Laws ER, Hanks JB (2009) Bilateral adrenalectomy for refractory Cushing disease: a safe and definitive therapy. J Am Coll Surg 208(6):1059–1064 PubMed Article Google Scholar 19. Mehta GU, Sheehan JP, Vance ML (2013) Effect of stereotactic radiosurgery before bilateral adrenalectomy for Cushing’s disease on the incidence of Nelson’s syndrome. J Neurosurg 119(6):1493–1497 PubMed Article Google Scholar 20. Gil-Cardenas A, Herrera MF, Diaz-Polanco A, Rios JM, Pantoja JP (2007) Nelson's syndrome after bilateral adrenalectomy for Cushing's disease. Surgery. 141(2):147–151 21. Moore TJ, Dluhy RG, Williams GH, Cain JP (1976) Nelson’s syndrome: frequency, prognosis, and effect of prior pituitary irradiation. Ann Intern Med 85(6):731–734 CAS PubMed Article Google Scholar 22. Nabarro JDN (1977) ACTH secreting pituitary tumours. J R Coll Physicians Lond 11(4):363–375 CAS PubMed PubMed Central Google Scholar 23. Scott HW Jr, Liddle GW, Mulherin JL Jr, McKenna TJ, Stroup SL, Rhamy RK (1977) Surgical experience with Cushing’s disease. Ann Surg 185(5):524–534 PubMed PubMed Central Article Google Scholar 24. Cohen KL, Noth RH, Pechinski T (1978) Incidence of pituitary tumors following adrenalectomy. A long-term follow-up study of patients treated for Cushing’s disease. Arch Internal Med 138(4):575–579 CAS Article Google Scholar 25. Jordan RM, Cook DM, Kendall JW, Kerber CW (1979) Nelson’s syndrome and spontaneous pituitary tumor infarction. Arch Intern Med 139(3):340–342 CAS PubMed Article Google Scholar 26. Barnett AH, Livesey JH, Friday K, Donald RA, Espiner EA (1983) Comparison of preoperative and postoperative ACTH concentrations after bilateral adrenalectomy in Cushing’s disease. Clin Endocrinol (Oxf) 18(3):301–305 CAS Article Google Scholar 27. Kasperlik-Zaluska AA, Nielubowicz J, Wislawski J, Hartwig W, Zaluska J, Jeske W, Migdalska B (1983) Nelson’s syndrome: incidence and prognosis. Clin Endocrinol (Oxf) 19(6):693–698 CAS Article Google Scholar 28. Kelly WF, MacFarlane IA, Longson D, Davies D, Sutcliffe H (1983) Cushing’s disease treated by total adrenalectomy: long-term observations of 43 patients. Q J Med 52(206):224–231 CAS PubMed Google Scholar 29. Kuhn JM, Proeschel MF, Seurin DJ, Bertagna XY, Luton JP, Girard FL (1989) Comparative assessment of ACTH and lipotropin plasma levels in the diagnosis and follow-up of patients with Cushing’s syndrome: a study of 210 cases. Am J Med 86(6 Pt 1):678–684 CAS PubMed Article Google Scholar 30. Grabner P, Hauerjensen M, Jervell J, Flatmark A (1991) Long-term results of treatment of cushings-disease by adrenalectomy. Acta Chirurgica- Eur J Surgery 157(8):461–464 CAS Google Scholar 31. McCance DR, Russell CF, Kennedy TL, Hadden DR, Kennedy L, Atkinson AB (1993) Bilateral adrenalectomy: low mortality and morbidity in Cushing’s disease. Clin Endocrinol 39(3):315–321 CAS Article Google Scholar 32. Zeiger MA, Fraker DL, Pass HI, Nieman LK, Cutler GB Jr, Chrousos GP, Norton JA (1993) Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalectomy. Surgery 114(6):1138–1143 CAS PubMed Google Scholar 33. Favia G, Boscaro M, Lumachi F, D’Amico DF (1994) Role of bilateral adrenalectomy in Cushing’s disease. World J Surg 18(4):462–466 CAS PubMed Article Google Scholar 34. Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg P (1994) Patient’s age is a simple predictive factor for the development of Nelson’s syndrome after total adrenalectomy for Cushing’s disease. J Clin Endocrinol Metab 79(3):887–889 CAS PubMed Google Scholar 35. Misra D, Kapur MM, Gupta DK (1994) Incidence of Nelson’s syndrome and residual adrenocortical function in patients of Cushing’s disease after bilateral adrenalectomy. J Assoc Physicians India 42(4):304–305 CAS PubMed Google Scholar 36. Jenkins PJ, Trainer PJ, Plowman PN, Shand WS, Grossman AB, Wass JA, Besser GM (1995) The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab 80(1):165–171 CAS PubMed Google Scholar 37. Pereira MA, Halpern A, Salgado LR, Mendonca BB, Nery M, Liberman B, Streeten DH, Wajchenberg BL (1998) A study of patients with Nelson’s syndrome. Clin Endocrinol (Oxf) 49(4):533–539 CAS Article Google Scholar 38. Imai T, Kikumori T, Funahashi H, Nakao A (2000) Surgical management of Cushing’s syndrome. Biomed Pharmacother 54(1):140–145 Article Google Scholar 39. Nagesser SK, van Seters AP, Kievit J, Hermans J, Krans HM, van de Velde CJ (2000) Long-term results of total adrenalectomy for Cushing’s disease. World J Surg 24(1):108–113 CAS PubMed Article Google Scholar 40. Hofmann BM, Fahlbusch R (2006) Treatment of Cushing’s disease: A retrospective clinical study of the latest 100 cases. Pituitary Surgery - A Modern Approach 34:158–184 Article Google Scholar 41. Thompson SK, Hayman AV, Ludlam WH, Deveney CW, Loriaux DL, Sheppard BC (2007) Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing’s disease: a 10-year experience. Ann Surg 245(5):790–794 PubMed PubMed Central Article Google Scholar 42. Ding XF, Li HZ, Yan WG, Gao Y, Li XQ (2010) Role of adrenalectomy in recurrent Cushing’s disease. Chin Med J 123(13):1658–1662 PubMed Google Scholar 43. Osswald A, Plomer E, Dimopoulou C, Milian M, Blaser R, Ritzel K, Mickisch A, Knerr F, Stanojevic M, Hallfeldt K, Schopohl J, Kuhn KA, Stalla G, Beuschlein F, Reincke M (2014) Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. Eur J Endocrinol 171(2):209–215 CAS PubMed Article Google Scholar 44. Prajapati OP, Verma AK, Mishra A, Agarwal G, Agarwal A, Mishra SK (2015) Bilateral adrenalectomy for Cushing’s syndrome: pros and cons. Indian J Endocrinol Metabol 19(6):834–840 CAS Article Google Scholar 45. Espinosa-de-Los-Monteros AL, Sosa-Eroza E, Espinosa E, Mendoza V, Arreola R, Mercado M (2017) Long-term outcome of the different treatment alternatives for recurrent and persistent cushing disease. Endocrine Pract: Off J Am College Endocrinol Am Assoc Clin Endocrinol 23(7):759–767 Article Google Scholar 46. Graffeo CS, Perry A, Carlstrom LP, Meyer FB, Atkinson JLD, Erickson D, Nippoldt TB, Young WF, Pollock BE, Van Gompel JJ (2017) Characterizing and predicting the Nelson-Salassa syndrome. J Neurosurg 127(6):1277–1287 CAS PubMed Article Google Scholar 47. Nankova A, Yaneva M, Elenkova A, Tcharaktchiev D, Marinov M, Hadzhiyanev A, Sechanov T, Gantchev G, Todorov G, Kirilov G, Kalinov K, Andreeva M, Zacharieva S (2018) Cushing’s syndrome: a historic review of the treatment strategies and corresponding outcomes in a single tertiary center over the past half-century. Hormone Metab Res 50(4):280–289 CAS Article Google Scholar 48. Chiloiro S, Giampietro A, Raffaelli M, D’Amato G, Bima C, Lauretti L, Anile C, Lombardi CP, Rindi G, Bellantone R, De Marinis L, Pontecorvi A, Bianchi A (2019) Synchronous bilateral adrenalectomy in ACTH-dependent hypercortisolism: predictors, biomarkers and outcomes. Endocrine 66(3):642–649 CAS PubMed Article Google Scholar 49. Cohen AC, Goldney DC, Danilowicz K, Manavela M, Rossi MA, Gomez RM, Cross GE, Bruno OD (2019) Long-term outcome after bilateral adrenalectomy in Cushing’s disease with focus on Nelson’s syndrome. Arch Endocrinol Metab 63(5):470–477 50. Nagendra L, Bhavani N, Pavithran PV, Kumar GP, Menon UV, Menon AS, Kumar L, Kumar H, Nair V, Abraham N, Narayanan P (2019) Outcomes of bilateral adrenalectomy in Cushing’s syndrome. Indian J Endocrinol Metab 23(2):193–197 PubMed PubMed Central Article Google Scholar 51. Sarkis P, Rabilloud M, Lifante JC, Siamand A, Jouanneau E, Gay E, Chaffanjon P, Chabre O, Raverot G (2019) Bilateral adrenalectomy in Cushing’s disease: altered long-term quality of life compared to other treatment options. Ann Endocrinol 80(1):32–37 Article Google Scholar 52. Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X (2007) Corticotroph tumor progression after adrenalectomy in Cushing’s disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 92(1):172–179 CAS PubMed Article Google Scholar 53. Das L, Bhansali A, Pivonello R, Dutta P, Bhadada SK, Ahuja CK, Mavuduru R, Kumar S, Behera A, Saikia UN, Dhandapani S, Walia R (2020) ACTH increment post total bilateral adrenalectomy for Cushing’s disease: a consistent biosignature for predicting Nelson’s syndrome. Pituitary 23(5):488–497 CAS PubMed Article Google Scholar 54. Barber TM, Adams E, Ansorge O, Byrne JV, Karavitaki N, Wass JA (2010) Nelson’s syndrome. Eur J Endocrinol 163(4):495–507 CAS PubMed Article Google Scholar 55. Reincke M, Albani A, Assie G, Bancos I, Brue T, Buchfelder M, Chabre O, Ceccato F, Daniele A, Detomas M, Di Dalmazi G, Elenkova A, Findling J, Grossman AB, Gomez-Sanchez CE, Heaney AP, Honegger J, Karavitaki N, Lacroix A, Laws ER, Losa M, Murakami M, Newell-Price J, Pecori Giraldi F, Perez-Rivas LG, Pivonello R, Rainey WE, Sbiera S, Schopohl J, Stratakis CA, Theodoropoulou M, van Rossum EFC, Valassi E, Zacharieva S, Rubinstein G, Ritzel K (2021) Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome): systematic review and expert consensus recommendations. Eur J Endocrinol. https://doi.org/10.1530/EJE-20-1088 56. Patel J, Eloy JA, Liu JK (2015) Nelson’s syndrome: a review of the clinical manifestations, pathophysiology, and treatment strategies. Neurosurg Focus 38(2):E14 PubMed Article Google Scholar 57. Fountas A, Lim ES, Drake WM, Powlson AS, Gurnell M, Martin NM, Seejore K, Murray RD, MacFarlane J, Ahluwalia R, Swords F, Ashraf M, Pal A, Chong Z, Freel M, Balafshan T, Purewal TS, Speak RG, Newell-Price J, Higham CE, Hussein Z, Baldeweg SE, Dales J, Reddy N, Levy MJ, Karavitaki N (2020) Outcomes of patients with Nelson's syndrome after primary treatment: a multicenter study from 13 UK pituitary centers. J Clin Endocrinol Metab 105(5):1527–1537 Download references Acknowledgements We would like to thank Therese Svanberg, librarian at the Medical Library at Sahlgrenska University Hospital for her expert assistance with the literature search. Funding Open access funding provided by University of Gothenburg. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-593301) and a grant from the Gothenburg Society of Medicine. Author information Affiliations Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson The Department of Endocrinology, Sahlgrenska University Hospital, Blå stråket 5, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson Department of Environmental and Occupational Health School of Public Health and Community Medicine, University of Gothenburg, 4053, Gothenburg, Sweden Hanne Krage Carlsen Department of Public Health and Clinical Medicine, Umeå University, 901 87, Umeå, Sweden Per Dahlqvist Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology, Karolinska University Hospital, 171 76, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology and Diabetes, Uppsala University Hospital, and Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, 751 85, Uppsala, Sweden Britt Edén Engström Department of Endocrinology, Skåne University Hospital, University of Lund, 205 02, Malmö, Sweden Pia Burman Department of Endocrinology, Skåne University Hospital, 222 42, Lund, Sweden Cecilia Follin, David Petranek & Eva Marie Erfurth Department of Endocrinology and Department of Medical and Health Sciences, Linköping University, 581 83, Linköping, Sweden Jeanette Wahlberg & Bertil Ekman Department of Internal Medicine, School of Health and Medical Sciences, Örebro University, 702 81, Örebro, SE, Sweden Jeanette Wahlberg, Anna-Karin Åkerman & Erik Schwarcz Corresponding author Correspondence to Oskar Ragnarsson. Ethics declarations Conflict of interest The authors have nothing to disclose. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 1208 kb) Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions About this article Cite this article Papakokkinou, E., Piasecka, M., Carlsen, H.K. et al. Prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with cushing’s disease: a systematic review and meta-analysis. Pituitary (2021). https://doi.org/10.1007/s11102-021-01158-z Download citation Accepted18 May 2021 Published25 May 2021 DOIhttps://doi.org/10.1007/s11102-021-01158-z Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords Bilateral adrenalectomy Cushing’s disease Corticotroph adenoma Nelson’s syndrome From https://link.springer.com/article/10.1007/s11102-021-01158-z
  2. Osilodrostat therapy was found to be effective in improving blood pressure parameters, health-related quality of life, depression, and other signs and symptoms in patients with Cushing disease, regardless of the degree of cortisol control, according to study results presented at the 30th Annual Scientific and Clinical Congress of the American Association of Clinical Endocrinologists (ENVISION 2021). Investigators of the LINC 3 study (ClinicalTrials.gov Identifier: NCT02180217), a phase 3, multicenter study with a double-blind, randomized withdrawal period, sought to assess the effects of twice-daily osilodrostat (2-30 mg) on signs, symptoms, and health-related quality of life in 137 patients with Cushing disease. Study endpoints included change in various parameters from baseline to week 48, including mean urinary free cortisol (mUFC) status, cardiovascular-related measures, physical features, Cushing Quality-of-Life score, and Beck Depression Inventory score. Participants were assessed every 2, 4, or 12 weeks depending on the study period, and eligible participants were randomly assigned 1:1 to withdrawal at week 24. The median age of participants was 40.0 years, and women made up 77.4% of the cohort. Of 137 participants, 132 (96%) achieved controlled mUFC at least once during the core study period. At week 24, patients with controlled or partially controlled mUFC showed improvements in blood pressure that were not seen in patients with uncontrolled mUFC; at week 48, improvement in blood pressure occurred regardless of mUFC status. Cushing Quality-of-Life and Beck Depression Inventory scores, along with other metabolic and cardiovascular risk factors, improved from baseline to week 24 and week 48 regardless of degree of mUFC control. Additionally, most participants reported improvements in physical features of hypercortisolism, including hirsutism, at week 24 and week 48. The researchers indicated that the high response rate with osilodrostat treatment was sustained during the 48 weeks of treatment, with 96% of patients achieving controlled mUFC levels; improvements in clinical signs, physical features, quality of life, and depression were reported even among patients without complete mUFC normalization. Disclosure: This study was sponsored by Novartis Pharma AG; however, as of July 12, 2019, osilodrostat is an asset of Recordati AG. Please see the original reference for a full list of authors’ disclosures. Visit Endocrinology Advisor‘s conference section for complete coverage from the AACE Annual Meeting 2021: ENVISION. Reference Pivonello R, Fleseriu M, Newell-Price J, et al. Effect of osilodrostat on clinical signs, physical features and health-related quality of life (HRQoL) by degree of mUFC control in patients with Cushing’s disease (CD): results from the LINC 3 study. Presented at: 2021 AACE Virtual Annual Meeting, May 26-29, 2021. From https://www.endocrinologyadvisor.com/home/conference-highlights/aace-2021/osilodrostat-improves-blood-pressure-hrqol-and-depression-in-patients-with-cushing-disease/
  3. MaryO

    Advice

    Wow, Letisia - your numbers are very high. I'd definitely ask the endo about your numbers and the possibility of Cushing's. If s/he blows you off please try to find another one. You said you were taking progesterone. That can cause your cortisol numbers to go up but you need to talk to your doctor so s/he is aware of your concerns. What are your symptoms? Your doctor needs to hear about those, too. If you have "before" pictures, those can be really useful, especially if you've gained a lot of weight, gotten a buffalo hump, grown facial hair, etc. Best of luck to you and please keep up posted! If you join these boards, you'll find lots of potentially helpful info already available to you.
  4. Data from LINC3 and LINC4 provide insight into the impact of dosing titration schedules on risk of hypocortisolism-related adverse events associated with osilodrostat use in patients with Cushing's disease. Data from a pair of phase 3 studies presented at the American Academy of Clinical Endocrinology’s 30th Annual Meeting (AACE 2021) is providing insight into the effect of dose titration schedules with use of osilodrostat (Isturisa) in patients with Cushing’s disease. Presented by Maria Fleseriu, MD, of Oregon Health and Science University, the analysis of the LINC3 and LINC4 demonstrated the more gradual titration occurring in LINC4 resulted in a lower proportion of hypocortisolism-related adverse events, suggesting up-titration every 3 weeks rather than every 2 weeks could help lower event risk without compromising mean urinary free cortisol (mUFC) control. “For patients with Cushing’s disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response/tolerability aimed at normalizing cortisol levels,” concluded investigators. With approval from the US Food and Drug Administration in March 2020 for patients not eligible for pituitary surgery or have undergone the surgery but still have the disease, osilodrostat became the first FDA-approved therapy address cortisol overproduction by blocking 11β-hydroxylase. Based on results of LINC3, data from the trial, and the subsequent LINC4 trial, provide the greatest available insight into use of the agent in this patient population. The study presented at AACE 2021 sought to assess whether slow dose up titration might affect rates of hypocortisolism-related adverse events by comparing titration schedules from both phase 3 trials. Median osilodrostat exposure was 75 (IQR, 48-117) weeks and 70 (IQR, 49-87) weeks in LINC3 and LINC4, respectively. The median time to first mUFC equal to or less than ULN was 41 (IQR, 30-42) days in LINC3 and 35 (IQR, 34-52) days in LINC4. Adverse events potentially related to hypocortisolism were more common among patients in LINC3 (51%, n=70) than LINC4 (27%, n=20). Upon analysis of adverse events, investigators found the most commonly reported type of adverse event was adrenal insufficiency, which included events of glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased urinary free cortisol. Results incited the majority of hypocortisolism-related adverse events occurred during the dos titration periods of each trial. In LINC3, 54 of the 70 (77%) hypocortisolism-related adverse events occurred by week 26. In comparison, 58% of hypocortisolism-related adverse events occurring in LINC4 occurred prior to week 12. Investigators noted most of events that occurred were mild or moderate and managed with dose interruption or reduction of osilodrostat or concomitant medications. This study, “Effect of Dosing and Titration of Osilodrostat on Efficacy and Safety in Patients with Cushing's Disease (CD): Results from Two Phase III Trials (LINC3 and LINC4),” was presented at AACE 2021. From https://www.endocrinologynetwork.com/view/fda-panels-votes-to-support-teplizumab-potential-for-delaying-type-1-diabetes
  5. Dr. Irmanie Hemphill, who first thought her weight gain was due to having a baby. Doctors at Cleveland Clinic Florida in Weston diagnosed her with a tumor in the pituitary gland in her brain. In the summer of 2019, Irmanie Hemphill gained a lot of weight, developed acne and had high blood pressure. She attributed it to her body adjusting from giving birth just six weeks prior. “I was thinking maybe it was just hormonal changes from having a baby,” said Hemphill, 38, of Pembroke Pines. But when Hemphill, a family medicine physician, saw that her nails were turning dark and she gained five pounds within a week, she knew it was something more serious. Blood tests ordered by her physician came back normal, with the exception of high levels of cortisol detected via a urine cortisol test, which she requested after researching her symptoms online. The next step was to find out where the excess cortisol was coming from: either her kidneys or her adrenal glands, which produce hormones in response to signals from the pituitary gland in the brain. The first MRI of her brain did not detect anything abnormal, so her endocrinologist attributed her symptoms to her body adjusting post-pregnancy. Hemphill sought a second opinion at Cleveland Clinic Weston, where more MRIs of her brain, combined with an Inferior Petrosal Sinus Sampling (IPSS) procedure, detected she had a tumor on her pituitary gland. That led her to be diagnosed with Cushing’s Disease — caused by excess cortisol. TWO TYPES OF PITUITARY TUMORS There are two types of pituitary tumors: those that produce active hormones, like the one Hemphill had, and those that do not, which grow in size over time and do not manifest symptoms right away. Hemphill’s tumor was producing adrenocorticotropic hormone (ACTH), which causes the adrenal gland to produce more cortisol. Many people with Cushing’s Disease experience high blood pressure and high blood sugar, muscle fatigue, easy bruising and brain fog. If left untreated, the condition can lead to pulmonary embolisms, diabetes, osteoporosis, strokes and heart attacks. “It was a little bit of relief but also sadness,” said Hemphill, of finding out her diagnosis. “I was very happy that I got a diagnosis but now it’s like, what’s the next step?” LESS INVASIVE WAY TO REMOVE A PITUITARY TUMOR Hospitals in South Florida are at the forefront in developing new research, techniques and technologies for pituitary tumors. The tiny bean-shaped pituitary gland is located at the base of the brain and controls many of the body’s hormonal and metabolic functions. Last June, neurosurgeon Dr. Hamid Borghei-Razavi of Cleveland Clinic Weston removed Hemphill’s pituitary tumor through her nose. This type of procedure allows surgeons to remove the tumor without damaging the brain. “It’s a less-invasive approach compared to 20 years ago, when pituitary tumors were removed through the cranium,” he said. “Now, with new technologies, more than 95% of pituitary tumors can be removed through the nose.” The procedure takes just a few hours to complete, based on the size and location of the tumor. Patients usually stay at the hospital for one to two days afterward for observation. The removal of Hemphill’s tumor, which was three to four millimeters in size, put an end to her Cushing’s Disease and her symptoms, though it took six months to a year for Hemphill to feel normal. (She was prescribed cortisol for six months until her adrenal glands could restart producing cortisol on their own.) “Sometimes it’s very hard to make a diagnosis for pituitary tumors because we don’t see them in the MRIs,” said Borghei-Razavi. “We call it MRI Negative Cushing’s Syndrome. It means we don’t see it in the MRI, but the cells are there,” he said. Borghei-Razavi and Hemphill credit the Inferior Petrosal Sinus Sampling (IPSS) test as pinpointing her tumor. Cleveland Clinic Weston is among only a handful of medical practices in South Florida that use this technique. Three Ways to Remove the Tumor Most pituitary tumors are benign. The challenge is when it comes to removing the tumor. “Pituitary tumors come in all shapes and sizes,” says Dr. Zoukaa Sargi, a head and neck surgeon at Sylvester Comprehensive Cancer Center at the University of Miami. “There are non-functional tumors that do not secrete hormones that can reach extreme sizes of up to 10 centimeters before coming to medical attention. This is the equivalent of the size of a grapefruit,” he says. “Then there are functional tumors that produce hormones that are typically discovered much sooner and can be only a few millimeters in size before coming to medical attention. A small proportion, less than 1%, are malignant,” he adds. There are three treatment options for pituitary tumors: surgical removal, medical therapy and radiation. “Medical therapy is only applicable in certain functional tumors that produce hormones,” says Dr. Ricardo Komotar, a neurosurgeon who is director of the Sylvester Comprehensive Cancer Center Brain Tumor Initiative. “Radiation is an option primarily for inoperable tumors with high surgical risk. Surgical removal is the optimal treatment in the vast majority of pituitary cases, conferring the greatest benefit with the lowest morbidity,” he says. Dr. Rupesh Kotecha, chief of radiosurgery at Miami Cancer Institute (MCI), part of Baptist Health South Florida, says there are a number of different hormones that the pituitary gland can secrete. “Prolactin is the most common form of pituitary adenoma that’s functioning and accounts for 30% to 50%,” he said. Excess prolactin can cause the production of breast milk in men and in women who are not pregnant or breastfeeding. Kotecha said the next most common are growth-hormone secreting tumors, which occur in 10% of patients. ACTH-secreting adenomas — the kind that Hemphill had — account for 5% of patients, while 1% secrete TSH, which causes the thyroid gland to be overactive. MCI’s Proton Therapy delivers high-dose radiation that treats the tumor’s area, allowing for surrounding tissues and organs to be spared from the effects of radiation. “The pituitary gland essentially sits in the middle of the brain,” says Kotecha. “It’s sitting in the middle of all of these critical structures.” From https://www.miamiherald.com/living/health-fitness/article251653033.html
  6. — Gradual dose escalation had fewer adverse events, same therapeutic benefit, as quicker increases by Kristen Monaco, Staff Writer, MedPage Today May 27, 2021 A more gradual increase in oral osilodrostat (Isturisa) dosing was better tolerated among patients with Cushing's disease, compared with those who had more accelerated increases, a researcher reported. Looking at outcomes from two phase III trials assessing osilodrostat, only 27% of patients had hypocortisolism-related adverse events if dosing was gradually increased every 3 weeks, said Maria Fleseriu, MD, of Oregon Health & Science University in Portland, in a presentation at the virtual meeting of the American Association of Clinical Endocrinology (AACE). On the other hand, 51% of patients experienced a hypocortisolism-related adverse event if osilodrostat dose was increased to once every 2 weeks. Acting as a potent oral 11-beta-hydroxylase inhibitor, osilodrostat was first approved by the FDA in March 2020 for adults with Cushing's disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. The drug is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets. The approval came based off of the positive findings from the complementary LINC3 and LINC4 trials. The LINC3 trial included 137 adults with Cushing's disease with a mean 24-hour urinary free cortisol concentration (mUFC) over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL). During the open-label, dose-escalation period, all the participants were given 2 mg of osilodrostat twice per day, 12 hours apart. Over this 12-week titration phase, dose escalations were allowed once every 2 weeks if there were no tolerability issues to achieve a maximum dose of 30 mg twice a day. After this 12-week dose-escalation schedule, additional bumps up in dose were permitted every 4 weeks. The median daily osilodrostat dose was 7.1 mg. The LINC4 trial included 73 patients with Cushing's disease with an mUFC over 1.3 times the upper limit of normal. The 48 patients randomized to receive treatment were likewise started on 2 mg bid of osilodrostat. However, this trial had a more gradual dose-escalation schedule, as doses were increased only every 3 weeks to achieve a 20 mg bid dose. After the 12-week dose-escalation phase, patients on a dose over 2 mg bid were restarted on 2 mg bid at week 12, where dose escalations were permitted once every 3 weeks thereafter to achieve a maximum 30 mg bid dose during this additional 36-week extension phase. Patients in this trial achieved a median daily osilodrostat dose of 5.0 mg. In both studies, patients' median age was about 40 years, the majority of patients were female, and about 88% had undergone a previous pituitary surgery. When comparing the adverse event profiles of both trials, Fleseriu and colleagues found that more than half of patients on the 2-week dose-escalation schedule experienced any grade of hypercortisolism-related adverse events. About 10.2% of these events were considered grade 3. About 28% of these patients had adrenal insufficiency -- the most common hypercortisolism-related adverse event reported. This was a catch-all term that include events like glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased cortisol, Fleseriu explained. Conversely, only 27.4% of patients on a 3-week dose escalation schedule experienced a hypercortisolism-related adverse event, and only 2.7% of these were grade 3. No grade 4 events occurred in either trial, and most events were considered mild or moderate in severity. "These adverse events were not associated with any specific osilodrostat dose of mean UFC level," Fleseriu said, adding that most of these events occurred during the initial dose-escalation periods. About 60% and 58% of all hypocortisolism-related adverse events occurred during the dose titration period in the 2-week and 3-week dose-escalation schedules, respectively. These events were managed via dose reduction, a temporary interruption in medication, and/or a concomitant medication. Very few patients in either trial permanently discontinued treatment due to these adverse events, Fleseriu noted. "Despite differences in the frequency of dose escalation, the time to first mUFC normalization was similar in the LINC3 and LINC4 studies," she said, adding that "gradual increases in osilodrostat dose from a starting dose of 2 mg bid can mitigate hypocortisolism-related adverse events without affecting mUFC control." "For patients with Cushing's disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response and tolerability aimed at normalizing cortisol levels," Fleseriu concluded. Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and dermatology news. Based out of the New York City office, she’s worked at the company for nearly five years. Disclosures The LINC3 and LINC4 trials were funded by Novartis. Fleseriu reported relationships with Novartis, Recordati, and Strongbridge Biopharma. Primary Source American Association of Clinical Endocrinology Source Reference: Fleseriu M, et al "Effect of dosing and titration of osilodrostat on efficacy and safety in patients with Cushing's disease (CD): Results from two phase III trials (LINC3 and LINC4)" AACE 2021. From https://www.medpagetoday.com/meetingcoverage/aace/92824?xid=nl_mpt_DHE_2021-05-28&eun=g1406328d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily Headlines Top Cat HeC 2021-05-28&utm_term=NL_Daily_DHE_dual-gmail-definition
  7. HRA Pharma Rare Diseases, an affiliate of privately-held French healthcare company HRA Pharma, has revealed data from the six-month extension of PROMPT, the first ever prospective study designed to evaluate metyrapone long-term efficacy and tolerability in endogenous Cushing’s syndrome. After confirming good efficacy and safety of metyrapone in the first phase of the study that ran for 12 weeks, the results of the six-month extension showed that metyrapone successfully maintains low urinary free cortisol (UFC) levels with good tolerability. The data will be presented at the European Congress of Endocrinology 2021 next week. Metyrapone is approved in Europe for the treatment of endogenous Cushing’s syndrome. It works by inhibiting the 11-beta-hydroxylase enzyme, the final step in cortisol synthesis. From https://www.thepharmaletter.com/in-brief/brief-metyrapone-effective-and-safe-in-endogenous-cushing-s-syndrome-in-long-term-says-hra-pharma-rare-diseases
  8. This article was originally published here Endocrinol Diabetes Metab Case Rep. 2021 May 1;2021:EDM210038. doi: 10.1530/EDM-21-0038. Online ahead of print. ABSTRACT SUMMARY: In this case report, we describe the management of a patient who was admitted with an ectopic ACTH syndrome during the COVID pandemic with new-onset type 2 diabetes, neutrophilia and unexplained hypokalaemia. These three findings when combined should alert physicians to the potential presence of Cushing’s syndrome (CS). On admission, a quick diagnosis of CS was made based on clinical and biochemical features and the patient was treated urgently using high dose oral metyrapone thus allowing delays in surgery and rapidly improving the patient’s clinical condition. This resulted in the treatment of hyperglycaemia, hypokalaemia and hypertension reducing cardiovascular risk and likely risk for infection. Observing COVID-19 pandemic international guidelines to treat patients with CS has shown to be effective and offers endocrinologists an option to manage these patients adequately in difficult times. LEARNING POINTS: This case report highlights the importance of having a low threshold for suspicion and investigation for Cushing’s syndrome in a patient with neutrophilia and hypokalaemia, recently diagnosed with type 2 diabetes especially in someone with catabolic features of the disease irrespective of losing weight. It also supports the use of alternative methods of approaching the diagnosis and treatment of Cushing’s syndrome during a pandemic as indicated by international protocols designed specifically for managing this condition during Covid-19. PMID:34013889 | DOI:10.1530/EDM-21-0038 From https://www.docwirenews.com/abstracts/rapid-control-of-ectopic-cushings-syndrome-during-the-covid-19-pandemic-in-a-patient-with-chronic-hypokalaemia/
  9. High blood sugar or glucose, also called hyperglycemia, occurs when there is too much sugar in the blood. High blood sugar is the primary symptom that underlies diabetes, but it can also occur in people who don’t have type 1 or type 2 diabetes, either because of stress or trauma, or gradually as a result of certain chronic conditions. It is important to manage high blood sugar, even if you don’t have diabetes, because elevated blood glucose can delay your ability to heal, increase your risk of infections, and cause irreversible damage to your nerves, blood vessels, and organs, such as your eyes and kidneys. Blood vessel damage from high blood sugar also increases your risk of heart attack and stroke. Non-Diabetic Hyperglycemia and Prediabetes You are considered to have impaired glucose tolerance or prediabetes if you have a fasting glucose level between 100–125 mg/dL, and hyperglycemia if your fasting blood glucose level is greater than 125 mg/dL, or greater than 180 mg/dL one to two hours after eating. The body obtains glucose mainly through carbohydrate consumption, but also through the breakdown of glycogen to glucose—a process called glycogenolysis—or conversion of non-carbohydrate sources to glucose—called gluconeogenesis—that primarily occurs in the liver. While 50% to 80% of glucose is used by the brain, kidneys, and red blood cells for energy, the remaining supply of glucose is used to produce energy. It is stored as glycogen in the liver and muscles, and can be tapped into at a later time for energy or converted into fat tissue. In healthy people, blood glucose levels are regulated by the hormone insulin to stay at a steady level of 80–100 mg/dL. Insulin maintains steady blood sugar by increasing the uptake and storage of glucose and decreasing inflammatory proteins that raise blood sugar when there is an excess of glucose in the blood. Certain conditions can increase your blood glucose levels by impairing the ability of insulin to transport glucose out of the bloodstream. When this occurs, you develop hyperglycemia, which puts you at an increased risk of prediabetes, diabetes, and related complications. Common Causes Cushing’s Syndrome Cushing’s syndrome results from excess secretion of the adrenocorticotropic hormone, a hormone produced in the anterior portion of the pituitary gland that causes excess cortisol to be produced and released from the adrenal glands. Pituitary adenomas, or tumors of the pituitary gland, are the cause of Cushing’s syndrome in more than 70% of cases, while prolonged use of corticosteroid medication can also significantly increase the risk. People with Cushing’s syndrome are at an increased risk of developing impaired glucose tolerance and hyperglycemia as a result of increased levels of cortisol throughout the body. Cortisol is a hormone that counteracts the effects of insulin by blocking the uptake of glucose from the bloodstream, thereby increasing insulin resistance and maintaining high blood sugar levels. Elevated cortisol levels also partially decrease the release of insulin from where it is produced in the pancreas. Approximately 10% to 30% of people with Cushing’s syndrome will develop impaired glucose tolerance, while 40% to 45% will develop diabetes. Corticosteroid medication is often prescribed to decrease inflammation throughout the body, but can lead to the development of Cushing’s syndrome and hyperglycemia because it activates specific enzymes that increase the conversion of non-carbohydrate molecules into glucose (gluconeogenesis). Corticosteroids also disrupt pancreatic cell function by inhibiting cell signaling pathways involved in the release of insulin from the pancreas. Read other causes at https://www.verywellhealth.com/causes-blood-sugar-rise-in-non-diabetics-5120349
  10. Abstract Background Subclinical Cushing’s disease (SCD) is defined by corticotroph adenoma-induced mild hypercortisolism without typical physical features of Cushing’s disease. Infection is an important complication associated with mortality in Cushing’s disease, while no reports on infection in SCD are available. To make clinicians aware of the risk of infection in SCD, we report a case of SCD with disseminated herpes zoster (DHZ) with the mortal outcome. Case presentation An 83-year-old Japanese woman was diagnosed with SCD, treated with cabergoline in the outpatient. She was hospitalized for acute pyelonephritis, and her fever gradually resolved with antibiotics. However, herpes zoster appeared on her chest, and the eruptions rapidly spread over the body. She suddenly went into cardiopulmonary arrest and died. Autopsy demonstrated adrenocorticotropic hormone-positive pituitary adenoma, renal abscess, and DHZ. Conclusions As immunosuppression caused by SCD may be one of the triggers of severe infection, the patients with SCD should be assessed not only for the metabolic but also for the immunodeficient status. Read the rest of the article at https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-021-00757-y
  11. The FDA accepted for review a new drug application for the steroidogenesis inhibitor levoketoconazole for the treatment of endogenous Cushing’s syndrome, according to an industry press release. “We are pleased with the FDA’s acceptance for filing of the Recorlev new drug application,” John H. Johnson, CEO of Strongbridge Biopharma, said in the release. “We believe this decision reflects the comprehensive clinical evidence that went into the NDA submission, including the positive and statistically significant efficacy and safety results from the multinational phase 3 SONICS and LOGICS studies evaluating Recorlev as a potential treatment option for adults with endogenous Cushing’s syndrome. We are advancing our commercial readiness plans and look forward to potentially bringing a new therapeutic option to the Cushing’s syndrome community in the first quarter of 2022.” As Healio previously reported, top-line findings from the LOGICS study demonstrated that levoketoconazole (Recorlev, Strongbridge Biopharma) improved and normalized morning urinary free cortisol concentrations for adults with endogenous Cushing’s disease compared with placebo. The drug was generally well tolerated, with safety data mirroring those from the earlier phase 3 SONICS trial. Endogenous Cushing’s syndrome — caused by chronic hypercortisolism — is rare, with estimates ranging from 40 to 70 people per million affected worldwide, according to the National Institute of Diabetes and Digestive and Kidney Diseases. The FDA set a Prescription Drug User Fee Act target action date of Jan. 1, 2022, for levoketoconazole, according to the company. The FDA letter made no mention of a plan to hold an advisory committee meeting. From https://www.healio.com/news/endocrinology/20210513/fda-accepts-nda-for-novel-cushings-syndrome-treatment
  12. This is a 30 min Online Survey and Compensation is $50.00 Sign up at the link below to receive an email invite to the study and see if you qualify https://rarepatientvoice.com/CushingsHelp/
  13. Prayers and much love to Cushies who have lost their mothers, to friends who have lost their child, to friends who gave their child the amazing gift of adoption and can not celebrate today with their babies, and to our precious friends who have not been able to have a child yet, you are all precious in God’s eyes. May each of you feel His peace this weekend.

  14. Decreased visual functions and severe headache may be signs of a brain tumor. The pituitary gland is a pea-sized gland located in the bone structure at the base of the brain called Sella Turcica. The pituitary gland, which has a great effect on our body, is a vital organ that regulates the secretion of many hormones such as growth hormone, prolactin hormone, and thyrotropin. Head of Department of Brain and Nerve Surgery, Yeni Yüzyıl University Gaziosmanpaşa Hospital, Assoc. Dr. Mete Karatay said, 'Tumors in the pituitary gland cause many disorders. Therefore, the symptoms should be taken into account and the tumor should be intervened before it grows. ' He gave information about the subject. Pituitary adenomas take the 3rd place after all tumors located in the head, after those originating from the brain itself and its membrane. So it is a relatively common tumor. The reasons for its occurrence are not fully understood. Rarely, they are seen together with inherited diseases. Tumors arising in the pituitary gland show symptoms either due to excessive hormone secretion or due to excessive growth and compression and spread to the surrounding tissues. Adenomas that do not secrete hormones usually grow slowly and can remain asymptomatic for years. Those who secrete hormones show early symptoms due to the effects of hormones in the body. In pituitary adenomas, headache, weakness, decreased visual clarity, vision loss, limitation of eyeball movements, double vision, drooping of the eyelid or visual field (especially loss of the outer quadrants of the eye) can be seen, and brain tumors such as pituitary adenoma should come to mind in these cases. . Other common complaints are the following complaints that develop due to the hormone secretion of the pituitary gland. In excess of prolactin; menstrual irregularities, milk secretion from breast tissue, development in breast tissue, sexual dysfunction in men, decrease in sperm quantity In excess of growth hormone; excessive elongation in adolescence; In adulthood, it causes elongation of the extremities of the body parts such as the chin, tip of the nose, hands and feet, heart problems, sweating, high blood sugar and joint problems. Cushing's - In ACTH excess; fat in abnormal areas of the body, muscle weakness, high blood pressure and blood sugar, skin oily and acne development, stretch marks, psychological problems In excess of TSH; weight loss, palpitations, bowel problems, sweating, restlessness, and irritability In the excess of FSH - LH; menstrual irregularities, sexual function problems, infertility The treatment of pituitary adenomas is done by the endocrinology and neurosurgery units. From an endocrinological standpoint, it is important to restore the body's hormonal balance. Neurosurgeons focus on relieving the pressure on nerve structures. Therefore, these patients are usually treated with a team of endocrinologists and neurosurgeons. Surgery is usually performed in the nasal cavity and is considered one of the difficult neurosurgical operations. The surgeon uses what we call a microscope and endoscope to reach and remove the tumor. Today, the method we call endoscopic surgery is used more frequently. With this method, there is no external scar and shortens the length of stay in the hospital. From https://www.raillynews.com/2021/05/gorme-kaybi-beyin-tumorunun-habercisi-olabilir/
  15. Abstract Background: Cushing’s syndrome is a condition caused by excessive glucocorticoid with insomnia as one of its neuropsychiatric manifestation. Cushing’s syndrome may be caused by excessive adrenocorticotropin hormone (ACTH-dependent), for example from ACTH producing pituitary tumors, or by overproduction of cortisol by adrenocortical tumors. In this report, we presented a case with Cushing’s syndrome manifesting as chronic insomnia with adrenal cortical adenoma and pituitary microadenoma. Case presentation: A 30-year-old woman was consulted from the Neurologic Department to the Internal Medicine Department with the chief complaint of insomnia and worsening headache for 6 months prior to the admission. She had undergone head MRI and abdominal CT scan previously and was found to have both pituitary microadenoma and left adrenal mass. From the physical examination she had clinical signs of Cushing’s syndrome like Cushingoid face and purplish striae on her stomach. Midnight cortisol serum examination was done initially and showed high level of cortisol. High dose dexamethasone suppression test or DST (8 mg overnight) was later performed to help determine the main cause of Cushing’s syndrome. The result failed to reach 50% suppression of cortisol serum, suggestive that the Cushing’s syndrome was not ACTH-dependent from the pituitary but potentially from overproduction of cortisol by the left adrenal mass. Therefore, left adrenalectomy was performed and the histopathological study supported the diagnosis of adrenal cortical adenoma. Conclusion: Chronic insomnia is a very important symptoms of Cushing’s syndrome that should not be neglected. The patient had both microadenoma pituitary and left adrenal mass thus high dose DST test (8 mg overnight) needed to be performed to differentiate the source of Cushing’s syndrome. The result showed only little suppression therefore the pituitary microadenoma was not the source of Cushing’s syndrome and more suggestive from the adrenal etiology. Keywords: Cushing’s syndrome; insomnia; adrenal cortical adenoma; pituitary microadenoma; dexamethasone suppression test Permalink/DOI: https://doi.org/10.14710/jbtr.v7i1.9247I Read the entire article here: https://ejournal2.undip.ac.id/index.php/jbtr/article/view/9247/5440
  16. Please note that if you buy through links in this article, Medical News Today may earn a small commission. Here’s their process. Cortisol is a hormone with various functions throughout the body. However, if a person’s body cannot regulate their cortisol levels, it could lead to a serious health condition. In these cases, home cortisol tests may be useful to indicate when someone might need medical attention. This article discusses: what cortisol is what a home cortisol test is why a person might buy a home cortisol test some home cortisol tests to purchase online when to see a doctor What is cortisol? Cortisol is the stress hormone that affects several systems in the body, including the: nervous system immune system cardiovascular system respiratory system reproductive system musculoskeletal system integumentary system The adrenal glands produce cortisol. Most human body cells have cortisol receptors, and the hormone can help in several ways, including: reducing inflammation regulating metabolism assisting with memory formation controlling blood pressure developing the fetus during pregnancy maintaining salt and water balance in the body controlling blood sugar levels All these functions make cortisol a vital part of maintaining overall health. If the body can no longer regulate cortisol levels, it can lead to several health disorders, such as Cushing’s syndrome and Addison’s disease. Without treatment, these conditions could cause life threatening complications. The body requires certain cortisol levels during times of stress, such as: in the event of an injury during illness during a surgical procedure What are home cortisol tests? A cortisol test usually involves a blood test. However, some may require saliva and urine samples instead. There are several home cortisol tests available to purchase over the counter or online. These allow a person to take a sample of blood, urine, or saliva before sending it off for analysis. After taking a home cortisol test, people can usually receive their results within 2–5 days online or via a telephone call with a healthcare professional. However, there are currently no studies investigating the reliability of these home cortisol tests. Therefore, people should follow up on their test results with a healthcare professional. Why and when do people need them? A person should take a home cortisol test if they feel they may have a cortisol imbalance. If cortisol levels are too high, a person may notice the following: rapid weight gain in the face, chest, and abdomen high blood pressure osteoporosis bruises and purple stretch marks mood swings muscle weakness an increase in thirst and need to urinate If cortisol levels are too low, a person may experience the following symptoms: fatigue loss of appetite unintentional weight loss muscle weakness abdominal pain Additionally, low cortisol levels may lead to: low blood pressure low blood sugar low blood sodium high blood potassium A test can help individuals check their cortisol levels. If the test results show these levels are too high or too low, people should seek medical advice. A cortisol imbalance may be a sign of an underlying condition, which can lead to serious complications without treatment. If a person cannot carry out a home cortisol test, they should speak to a medical professional who can arrange a cortisol test at a healthcare facility. What to look for in a home cortisol test At a clinic or hospital setting, a medical professional will usually take a blood sample and analyze it for an individual’s cortisol levels. Home cortisol tests involve a person taking a sample of blood, urine, or saliva. There are currently no studies investigating the accuracy of these results. However, home cortisol tests may be faster and more convenient than making an appointment with a doctor to take a sample. People may consider several factors when deciding to purchase a home cortisol test, including: Sample type: Some tests require a blood sample, while others need a sample of urine or saliva. With this in mind, a person may wish to buy a product that uses a testing method they are comfortable providing. Test analysis: A person may wish to purchase a product from a company that sends tests to Clinical Laboratory Improvement Amendments (CLIA)-certified labs for analysis. The Food and Drug Administration (FDA), Center for Medicaid Services, and the Centers for Disease Control and Prevention (CDC) regulate these labs to help ensure safety and accuracy. Accuracy: Individuals may wish to speak to a pharmacist or other healthcare professional before purchasing to ensure the test is reliable and accurate. Products Several online retailers offer home cortisol tests. It is important to follow all test instructions to ensure a valid result. Please note, the writer has not tested these products. All information is research-based. LetsGetChecked – Cortisol Test This cortisol test uses the finger prick method to draw blood for the sample. Here are the steps to take and send off a blood sample: Individuals fill in their details on the collection box and activate their testing kit online at the LetsGetChecked website. People need to wash their hands with warm soapy water before using an alcohol swab to clean the finger that they will prick. Once the finger is completely dry, individuals pierce the skin using the lancet in the test kit. A person must wipe away the first drop of blood before squeezing some into the blood collection tube. After closing the tube, individuals must invert it 5–10 times before placing it in the included biohazard bag, which they then place in the box. After following these steps, people can send the sample back to LetsGetChecked using the kit’s prepaid envelope. Test results usually come back within 2–5 days. LetsGetChecked tests samples in the same labs that primary care providers, hospitals, and government schemes use. These labs are CLIA-certified and CAP-accredited. The company also has a team of nurses and doctors available 24 hours a day, 7 days a week, to offer ongoing support. These healthcare professionals are on hand to discuss a person’s results with them over the phone. Everlywell At-Home Cortisol Levels Test Kit – Sleep & Stress Test This Everlywell product uses a urine sample to test a person’s cortisol levels. The test measures the levels of three hormones in a person’s body: cortisol, cortisone, and melatonin. It also measures a person’s creatinine levels. There are three steps with this test: Individuals register their testing kit on Everlywell’s website. A person follows the instructions carefully to take their urine sample. Once they have their urine sample, they place it in the prepaid package and send it off to Everlywell’s labs. Within a few days, individuals will receive their results digitally via the Everlywell website. Medical professionals can also offer helpful insights via their secure platform. As well as sending a personalized report of each marker, Everlywell also sends detailed information about what the results mean. The labs where Everlywell tests samples all carry certification with CLIA. The company also ensures that all results are reviewed and certified by independent board-certified physicians within the person’s specific state.SHOP NOW Healthlabs Cortisol, AM & PM Test Healthlabs offers a cortisol test that tests a person’s cortisol levels twice — once in the morning and once in the evening. The company says they do this because a person’s cortisol levels fluctuate throughout the day. Therefore, by testing twice, they can gather information on this fluctuation. This test uses a blood sample, which a person takes once in the morning and once in the afternoon. They must follow the instructions clearly to ensure they take suitable samples. The manufacturer says that people should collect a morning sample between 7–9 a.m. and an evening sample between 3–5 p.m. They then need to send off their sample for analysis. After testing is complete at a CLIA-certified lab, a person will receive their results, which usually takes between 1–2 days. SHOP NOW When to speak with a doctor A person should undergo a cortisol test if they believe they may have high or low cortisol levels. They can do this at home or speak with a medical professional who can carry out the test for them. People may also wish to seek medical help if they show signs of too much or too little cortisol. This could indicate a potentially serious underlying health issue. Summary Cortisol is an important hormone that affects almost all parts of the body. It has many functions, including reducing inflammation, regulating metabolism, and controlling blood pressure. If a person believes they have high or low cortisol levels, they may wish to take a cortisol test. Usually, these tests take place at a medical practice. However, several home cortisol tests are available to purchase. A person can take these tests at home by providing a urine, blood, or saliva sample. Once a lab analyzes the test, people usually receive their results within a few days. Individuals should follow up any test results with a healthcare professional. No clinics, no stress. Test your cortisol levels from home Test your cortisol level from home with LetsGetChecked. Get free shipping, medical support, and results from accredited labs within 2–5 days. Order today for 30% off. LEARN MORE Last medically reviewed on April 29, 2021 at https://www.medicalnewstoday.com/articles/3-of-the-best-home-cortisol-tests
  17. Highlights • There is a highs suspicion of acute pancreatitis complications for patients with Cushing syndrome. • Corticosteroids are a common cause for both Cushing syndrome and acute pancreatitis. • There are many common etiologies between Cushing syndrome and acute pancreatitis. • Cushing syndrome is a risk factor of acute pancreatitis, need further detailed studies. Abstract Introduction Cushing's syndrome (CS) is a rare and severe disease. Acute pancreatitis is the leading cause of hospitalization. The association of the two disease is rare and uncommon. We report the case of a 37-year-old woman admitted in our service for acute pancreatitis and whose Cushing syndrome was diagnosed during hospitalisation. The aim of this work is to try to understand the influence of de Cushing in acute pancreatitis and to establish a causative relationship between the two diseases. Observation It is a 37-year-old woman with a history of corticosteroid intake for six months, stopped three months ago who consulted for epigastralgia and vomiting. The physical exam found epigastric sensitivity with Cushing syndrome symptoms. A CT scan revealed acute edematous-interstitial pancreatitis stage E of Balthazar classification. 24 h free cortisol of 95 μg/24 h and cortisolemia of 3.4 μg/dl. The patient was treated symptomatically and referred after to endocrinology service for further treatment. Conclusion The association with acute pancreatitis and CS is rare and uncommon. Although detailed studies and evidence are lacking, it can therefore be inferred that CS is one of the risk factors for the onset of acute pancreatitis. The medical treatment and management of acute pancreatitis in those patients do not differ from other pancreatitis of any etiologies. Read the article here.
  18. And it is a Squamous Cell Carcinoma :(  Mohs Surgery on Monday.  Drat!  Just Nosing Around

  19. This month marks a little over one year since the first surge of COVID-19 across the United States. April is also Adrenal Insufficiency Awareness month, a good time to review the data on how COVID-19 infection can impact the adrenal glands. The adrenal glands make hormones to help regulate blood pressure and the ability to respond to stress. The hormones include steroids such as glucocorticoid (cortisol), mineralocorticoid (aldosterone), and forms of adrenaline known as catecholamines (norepinephrine, epinephrine, and dopamine). The activity of the adrenal gland is controlled through its relationship with the pituitary gland (the master regulator of hormones in the body). Some common adrenal diseases include the following: Addison’s Disease (where the body attacks the adrenal glands making them dysfunctional) Hyperaldosteronism Cushing’s Syndrome Pheochromocytoma Adrenal Nodules/Masses (termed incidentaloma) Congenital adrenal hyperplasia COVID-19 was found in the adrenal and pituitary glands of some patients who succumbed to the illness, suggesting that these organs might be among the targets for infection. One of the first highly effective therapies for COVID-19 infection was the use of IV steroid (dexamethasone) supplementation in hospitalized patients in patients requiring oxygen. A focused search of COVID-19-related health literature shows 85 peer-reviewed papers that have been published in medical literature specifically on the adrenal gland and COVID-19. This literature focuses on three phases of COVID infection that may impact the adrenal gland: the acute active infection phase, the immediate post-infection phase, and the long-term recovery phase. Medical research has identified that during the acute active infection, the adrenal system is one of the most heavily affected organ systems in the body in patients who have COVID-19 infection requiring hospitalization. In these cases, supplementation with the steroid dexamethasone serves as one of the most powerful lifesaving treatments. Concern has also been raised regarding the period of time just after the acute infection phase – particularly, the development of adrenal insufficiency following cases of COVID-19 hospitalizations. Additionally, some professional societies recommend that for patients who have adrenal insufficiency and are on adrenal replacement therapy, they be monitored closely post-COVID-19 vaccine for the development of stress-induced adrenal insufficiency. In mild-to-moderate COVID-19 cases, there does not seem to be an effect on adrenaline-related hormones (norepinephrine, epinephrine, dopamine). However, in cases of severe COVID-19 infection triggering the development of shock, patients will need supplementation with an infusion of catecholamines and a hormone called vasopressin to maintain their blood pressure. Finally, some studies have addressed the concern of adrenal insufficiency during the long-term recovery phase. Dr Sara Bedrose, adrenal endocrine specialist at Baylor College of Medicine, indicates that studies which included adrenal function in COVID survivors showed a large percentage of patients with suboptimal cortisol secretion during what is called ACTH stimulation testing. Results indicated that most of those cases had central adrenal insufficiency. It was concluded that adrenal insufficiency might be among the long-term consequences of COVID-19 and it seemed to be secondary to pituitary gland inflammation (called hypophysitis) or due to direct hypothalamic damage. Long-term follow-up of COVID 19 survivors will be necessary to exclude a gradual and late-onset adrenal insufficiency. Some patients who have COVID-19 will experience prolonged symptoms. To understand what is happening to them, patients may question whether or not they have a phenomenon called adrenal fatigue. This is a natural question to ask, especially after having such a severe health condition. A tremendous amount of resources are being developed to investigate the source and treatment of the symptoms, and this work has only just begun. However, adrenal fatigue is not a real medical diagnosis. It’s a term to describe a group of signs and symptoms that arise due to underactive adrenal glands. Current scientific data indicate that adrenal fatigue is not in and of itself a medical disease – although a variety of over-the-counter supplements and compounded medications may be advocated for in treatment by alternative medicine/naturopathic practitioners. My takeaway is that we have learned a great deal about the effects COVID-19 infection has on the adrenal glands. Long-term COVID-19 remains an area to be explored – especially in regards to how it may affect the adrenal glands. -By Dr. James Suliburk, associate professor of surgery in the Division of Surgical Oncology and section chief of endocrine surgery for the Thyroid and Parathyroid Center at Baylor College of Medicine From https://blogs.bcm.edu/2021/04/22/how-does-covid-19-impact-the-adrenal-gland/
  20. Biopsy yesterday - they're thinking it's a squamous cell carcinoma.  Drat! 

  21. MaryO

    Advice

    Donkey, I am so sorry to read all that you've been through. Getting a Cushing's diagnosis is the worst, especially when doctors don't believe us. You didn't know what kind of doctor you have that doubts you have Cushing's but it sounds like you need another. Your best choice would be an endocrinologist who has had other Cushing's patients. Even though you aren't obese with striae...not every person has every symptom. The only way to diagnose Cushing's is with testing, not by a list of symptoms. Best of luck to you. I hope you keep us posted on your progress!
  22. Excess mortality among people with endogenous Cushing syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds. Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality ― defined as the ratio of the number of deaths from CS divided by the total number of CS patients ― was 0.05, and the standardized mortality rate was an "unacceptable" three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting. Excess deaths were higher among those with adrenal CS compared to those with Cushing disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, Leeds, United Kingdom. "While mortality has improved since 2000, it is still significantly compromised compared to the background population.... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level," she said. Asked to comment, Maria Fleseriu, MD, told Medscape Medical News that the new data show "we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet.... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery." She noted that although she wasn't surprised by the overall results, "the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing was unexpectedly high despite patients with adrenal cancer being excluded." Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, Oregon, advised, "Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care. "But we should focus more on optimizing more aggressively this care in addition to the specific Cushing treatment," she stressed. In addition, she noted, "Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications.... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS." Largest Study in Scale and Scope of Cushing Syndrome Mortality Endogenous Cushing syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing syndrome). Surgery is the mainstay of initial treatment of Cushing syndrome. If an operation to remove the tumor fails to cause remission, medications are available. Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing disease. "In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing syndrome," Limumpornpetch noted. The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both CS types (n = 1906). Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15 – 7.84). This SMR was higher among patients with adrenal Cushing syndrome (3.3) vs Cushing disease (2.8) (P = .003) and among patients who had active disease (5.7) vs those whose disease was in remission (2.3) (P < .001). The SMR also was worse among patients with Cushing disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004). The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas. Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04). Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%). Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25). Preventing Perioperative Mortality: Consider Thromboprophylaxis Fleseriu told Medscape Medical News that she believes hypercoagulability is "the least recognized complication with a big role in mortality." Because most of the perioperative mortality is due to venous thromboembolism and infections, "thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding." Recently, Fleseriu's group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively. The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population. "Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing syndrome and balanced with individual bleeding risk," Fleseriu advised. A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted. Limumpornpetch commented, "We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population." Limumpornpetch has disclosed no relevant financial relationships. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge. ENDO 2021: The Endocrine Society Annual Meeting: Presented March 20, 2021 Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker. From https://www.medscape.com/viewarticle/949257
  23. Updates on Treating Hypothyroidism Dr. Theodore Friedman will be giving a webinar on Updates on Treating Hypothyroidism. Topics to be discussed include: New articles showing patients prefer desiccated thyroid New thyroid hormone preparations Update on desiccated thyroid recalls New article on why TSH is less important than thyroid hormone measurements What is the difference between desiccated thyroid and synthetic thyroid hormones? Is rT3 important? Sunday • April 25• 6 PM PDT Via Zoom Click here to join the meeting or https://us02web.zoom.us/j/4209687343?pwd=amw4UzJLRDhBRXk1cS9ITU02V1pEQT09 OR +16699006833,,4209687343#,,,,*111116# Slides will be available before the webinar and recording after the meeting at slides Meeting ID: 420 968 7343 Passcode: 111116 Your phone/computer will be muted on entry. There will be plenty of time for questions using the chat button. For more information, email us at mail@goodhormonehealth.com
  24. Updates on Treating Hypothyroidism Dr. Theodore Friedman will be giving a webinar on Updates on Treating Hypothyroidism. Topics to be discussed include: New articles showing patients prefer desiccated thyroid New thyroid hormone preparations Update on desiccated thyroid recalls New article on why TSH is less important than thyroid hormone measurements What is the difference between desiccated thyroid and synthetic thyroid hormones? Is rT3 important? Sunday • April 25• 6 PM PDT Via Zoom Click here to join the meeting or https://us02web.zoom.us/j/4209687343?pwd=amw4UzJLRDhBRXk1cS9ITU02V1pEQT09 OR +16699006833,,4209687343#,,,,*111116# Slides will be available before the webinar and recording after the meeting at slides Meeting ID: 420 968 7343 Passcode: 111116 Your phone/computer will be muted on entry. There will be plenty of time for questions using the chat button. For more information, email us at mail@goodhormonehealth.com
  25. until
    I plan to do the Cushing's Awareness Challenge again. A past year info is here: https://cushieblogger.com/2018/03/11/time-to-sign-up-for-the-cushings-awareness-challenge-2018/ The original page is getting very slow loading, so I've moved my own posts to this newer blog. As always, anyone who wants to join me can share their blog URL with me and I'll add it to the links on the right side, so whenever a new post comes up, it will show up automatically. If the blogs are on WordPress, I try to reblog them all to get even more exposure on the blog, on Twitter and on Facebook at Cushings Help Organization, Inc. If you have photos, and you give me permission, I'll add them to the Pinterest page for Cushing's Help. The Cushing’s Awareness Challenge is almost upon us again! Do you blog? Want to get started? Since April 8 is Cushing’s Awareness Day, several people got their heads together to create the Tenth Annual Cushing’s Awareness Blogging Challenge. All you have to do is blog about something Cushing’s related for the 30 days of April. There will also be a logo for your blog to show you’ve participated. Please let me know the URL to your blog in the comments area of this post, on the Facebook page, in one of the Cushing's Help Facebook Groups, on the message boards or an email and I will list it on CushieBloggers ( http://cushie-blogger.blogspot.com/ ) The more people who participate, the more the word will get out about Cushing’s. Suggested topics – or add your own! In what ways have Cushing’s made you a better person? What have you learned about the medical community since you have become sick? If you had one chance to speak to an endocrinologist association meeting, what would you tell them about Cushing’s patients? What would you tell the friends and family of another Cushing’s patient in order to garner more emotional support for your friend? challenge with Cushing’s? How have you overcome challenges? Stuff like that. I have Cushing’s Disease….(personal synopsis) How I found out I have Cushing’s What is Cushing’s Disease/Syndrome? (Personal variation, i.e. adrenal or pituitary or ectopic, etc.) My challenges with Cushing’s Overcoming challenges with Cushing’s (could include any challenges) If I could speak to an endocrinologist organization, I would tell them…. What would I tell others trying to be diagnosed? What would I tell families of those who are sick with Cushing’s? Treatments I’ve gone through to try to be cured/treatments I may have to go through to be cured. What will happen if I’m not cured? I write about my health because… 10 Things I Couldn’t Live Without. My Dream Day. What I learned the hard way Miracle Cure. (Write a news-style article on a miracle cure. What’s the cure? How do you get the cure? Be sure to include a disclaimer) Give yourself, your condition, or your health focus a mascot. Is it a real person? Fictional? Mythical being? Describe them. Bonus points if you provide a visual! 5 Challenges & 5 Small Victories. The First Time I… Make a word cloud or tree with a list of words that come to mind when you think about your blog, health, or interests. Use a thesaurus to make it branch more. How much money have you spent on Cushing’s, or, How did Cushing’s impact your life financially? Why do you think Cushing’s may not be as rare as doctors believe? What is your theory about what causes Cushing’s? How has Cushing’s altered the trajectory of your life? What would you have done? Who would you have been What three things has Cushing’s stolen from you? What do you miss the most? What can you do in your Cushing’s life to still achieve any of those goals? What new goals did Cushing’s bring to you? How do you cope? What do you do to improve your quality of life as you fight Cushing’s? How Cushing’s affects children and their families Your thoughts…?
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