scholarly journals The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1761 ◽  
Author(s):  
Silviu Sbiera ◽  
Meik Kunz ◽  
Isabel Weigand ◽  
Timo Deutschbein ◽  
Thomas Dandekar ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Somatic Mutations ◽  
Therapeutic Potential ◽  
Meta Analysis ◽  
Treatment Options ◽  
Rare Condition ◽  
Cushing's Disease ◽  
High Morbidity ◽  
Sequencing Data ◽  
Pathogenic Variants

Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.

scholarly journals P34 Characteristics, diagnosis and management of Cushing’s disease - A systematic review and meta-analysis

BJS Open ◽  
2021 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
Chan Hee Koh ◽  
Danyal Z Khan ◽  
Ronneil Digpal ◽  
Hugo Layard Horsfall ◽  
Hani J Marcus ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Cushing’S Disease ◽  
Meta Analysis ◽  
A Priori ◽  
Pituitary Surgery ◽  
Serum Cortisol ◽  
Cushing's Disease ◽  
Diagnosis And Management ◽  
Over Time

Abstract Introduction The clinical practice and research in the diagnosis and management of Cushing’s disease remains heterogeneous and challenging to this day. We sought to establish the characteristics of Cushing’s disease, and the trends in diagnosis, management and reporting in this field. Methods Searches of PubMed and Embase were conducted. Study protocol was registered a-priori. Random-effects analyses were conducted to establish numerical estimates. Results Our screening returned 159 papers. The average age of adult patients with Cushing’s disease was 39.3, and 13.6 for children. The male:female ratio was 1:3. 8% of patients had undergone previous transsphenoidal resection. The ratio of macroadenomas: microadenomas:imaging-undetectable adenomas was 18:53:29. The most commonly reported preoperative biochemical investigations were serum cortisol (average 26.4µg/dL) and ACTH (77.5pg/dL). Postoperative cortisol was most frequently used to define remission (74.8%), most commonly with threshold of 5µg/dL (44.8%). Average remission rates were 77.8% with recurrence rate of 13.9%. Median follow-up was 38 months. Majority of papers reported age (81.9%) and sex (79.4%). Only 56.6% reported whether their patients had previous pituitary surgery. 45.3% reported whether their adenomas were macroadenoma, microadenoma or undetectable. Only 24.1% reported preoperative cortisol, and this did not improve over time. 60.4% reported numerical thresholds for cortisol in defining remission, and this improved significantly over time (p = 0.004). Visual inspection of bubbleplots showed increasing preference for threshold of 5µg/dL. 70.4% reported the length of follow up. Conclusion We quantified the characteristics of Cushing’s disease, and analysed the trends in investigation and reporting. This review may help to inform future efforts in forming guidelines for research and clinical practice.

scholarly journals Outcome of endoscopic vs microsurgical transsphenoidal resection for Cushing’s disease

2018 ◽  
Vol 7 (1) ◽  
pp. R26-R37 ◽  
Author(s):  
Nidan Qiao
Keyword(s):  
Recurrence Rate ◽  
Cushing’S Disease ◽  
Meta Analysis ◽  
Cushing's Disease ◽  
Recurrence Rates ◽  
Microscopic Surgery ◽  
Significant Difference ◽  
Comprehensive Search ◽  
Definition Of

Introduction It is unclear whether the proportions of remission and the recurrence rates differ between endoscopic transsphenoidal surgery (TS) and microscopic TS in Cushing’s disease (CD); thus, we conducted a systematic review and meta-analysis to evaluate studies of endoscopic TS and microscopic TS. Methods We conducted a comprehensive search of PubMed to identify relevant studies. Remission and recurrence were used as outcome measures following surgical treatment of CD. Results A total of 24 cohort studies involving 1670 adult patients were included in the comparison. Among these studies, 702 patients across 9 studies underwent endoscopic TS, and 968 patients across 15 studies underwent microscopic TS. Similar baseline characteristics were observed in both groups. There was no significant difference in remission between the two groups: 79.7% (95% CI: 73.1–85.0%) in the endoscopic group and 76.9% (95% CI: 71.3–81.6%) in the microscopic group (P = 0.485). It appears that patients who underwent endoscopic surgery experience recurrence less often than patients who underwent microscopic surgery, with recurrence proportions of 11.0% and 15.9%, respectively (P = 0.134). However, if follow-up time is taken into account, both groups had a recurrence rate of approximately 4% per person per year (95% CI: 3.1–5.4% and 3.6–5.1%, P = 0.651). Conclusions We found that remission proportion and recurrence rate were the same in patients who underwent endoscopic TS as in patients who underwent microscopic TS. The definition of diagnosis, remission and recurrence should always be considered in the studies assessing therapeutic efficacy in CD.

scholarly journals Bilateral adrenalectomy in Cushing's disease: Altered long-term quality of life compared to other treatment options

2019 ◽  
Vol 80 (1) ◽  
pp. 32-37 ◽  
Author(s):  
Pauline Sarkis ◽  
Muriel Rabilloud ◽  
Jean-Christophe Lifante ◽  
Anna Siamand ◽  
Emmanuel Jouanneau ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Cushing’S Disease ◽  
Treatment Options ◽  
Bilateral Adrenalectomy ◽  
Cushing's Disease

Outcomes of pituitary surgery for Cushing’s disease: a systematic review and meta-analysis

Pituitary ◽  
2020 ◽  
Vol 23 (5) ◽  
pp. 595-609
Author(s):  
Anna Stroud ◽  
Pearl Dhaliwal ◽  
Raquel Alvarado ◽  
Mark J. Winder ◽  
Benjamin P. Jonker ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cushing’S Disease ◽  
Meta Analysis ◽  
Pituitary Surgery ◽  
Cushing's Disease

scholarly journals Etomidate in the management of severe Cushing’s disease and MRSA bacteraemia in a district general hospital in the United Kingdom

2019 ◽  
Vol 2019 ◽  
Author(s):  
Stephanie Wei Ping Wong ◽  
Yew Wen Yap ◽  
Ram Prakash Narayanan ◽  
Mohammad Al-Jubouri ◽  
Ashley Grossman ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
General Hospital ◽  
Cushing’S Disease ◽  
District General Hospital ◽  
Serum Cortisol ◽  
Cushing's Disease ◽  
High Morbidity ◽  
List Type ◽  
Cortisol Levels

Summary We report our experience on managing a case of florid Cushing’s disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital. Learning points: Severe Cushing’s syndrome is associated with high morbidity and mortality. Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression. Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital. During treatment with etomidate, accumulation of serum 11β-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.

scholarly journals Distinct Late-Night Salivary Cortisol Cut-Off Values for the Diagnosis of Hypercortisolism

2021 ◽  
Vol 53 (10) ◽  
pp. 662-671
Author(s):  
Lukas van Baal ◽  
Marc Wichert ◽  
Denise Zwanziger ◽  
Henning Dralle ◽  
Frank Weber ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Salivary Cortisol ◽  
Cushing's Disease ◽  
Control Group ◽  
High Morbidity ◽  
Reference Ranges ◽  
Ectopic Acth ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Ectopic Acth Production

AbstractDue to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing’s disease and Cushing’s disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.

scholarly journals Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment

Endocrine ◽  
2020 ◽  
Vol 70 (2) ◽  
pp. 218-231
Author(s):  
Leah T. Braun ◽  
German Rubinstein ◽  
Stephanie Zopp ◽  
Frederick Vogel ◽  
Christine Schmid-Tannwald ◽  
...  
Keyword(s):  
Medical Therapy ◽  
Cushing’S Disease ◽  
Small Sample Size ◽  
Case Reports ◽  
Treatment Options ◽  
Pituitary Surgery ◽  
Small Sample ◽  
Bilateral Adrenalectomy ◽  
Cushing's Disease ◽  
Success Rates

Abstract Purpose Recurrence after pituitary surgery in Cushing’s disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD. Methods We systematically screened the literature regarding recurrent and persistent Cushing’s disease using the MESH term Cushing’s disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number < 10) were excluded. Also, papers on CD in pregnancy were not included in this review. Results and conclusions Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: The burden of Cushing's disease: clinical and health-related quality of life aspects

2012 ◽  
Vol 167 (3) ◽  
pp. 311-326 ◽  
Author(s):  
R A Feelders ◽  
S J Pulgar ◽  
A Kempel ◽  
A M Pereira
Keyword(s):  
Quality Of Life ◽  
Cushing’S Disease ◽  
Treatment Options ◽  
Current Treatment ◽  
Cushing's Disease ◽  
Health Related Quality ◽  
Time To Diagnosis ◽  
Related Quality ◽  
Health Related

ObjectiveCushing's disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD.DesignStudies published in English were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, health-related quality of life (HRQoL), treatment outcomes, mortality, prevalence of comorbidities at diagnosis, and reversibility of comorbidities following the treatment.MethodsA two-stage literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD: i) articles published from 2000 to 2012 were identified and ii) an additional hand search (all years) was conducted on the basis of bibliography of identified articles.ResultsAt the time of diagnosis, 58–85% of patients have hypertension, 32–41% are obese, 20–47% have diabetes mellitus, 50–81% have major depression, 31–50% have osteoporosis, and 38–71% have dyslipidemia. Remission rates following transsphenoidal surgery (TSS) are high when performed by expert pituitary surgeons (rates of 65–90%), but the potential for relapse remains (rates of 5–36%). Although some complications can be partially reversed, time to reversal can take years. The HRQoL of patients with CD also remains severely compromised after remission.ConclusionsThese findings highlight the significant burden associated with CD. As current treatment options may not fully reverse the burden of chronic hypercortisolism, there is a need for both improved diagnostic tools to reduce the time to diagnosis and effective therapy, particularly a targeted medical therapy.

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