Cushing's disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the ...deubiquitinase gene USP8 occur in 35-62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease.
Acromegaly is characterized by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), accompanied by a compromise in the perception of wellness. The Patient-Assessed ...Acromegaly Symptom Questionnaire (PASQ) is relevant to assessing signs and symptoms but is mainly used to evaluate the efficacy of a pharmacological intervention. To explore the perioperative variation in symptom severity, the divergence between subgroups stratified according to clinical outcomes or treatment modalities, and the interaction between symptom scores and clinical indices, we prospectively recruited 106 patients with acromegaly from 2016 to 2018. Oral glucose tolerance and GH tests were performed, and PASQ was administered before treatment and 6 months postoperatively. Patients were divided into active (n = 49) and remission (n = 57) groups according to postoperative GH and IGF-1 levels. PASQ scores and GH and IGF-1 levels decreased significantly postoperatively in both groups. A significantly higher preoperative headache score and greater extent of decrease in arthralgia were seen in the active and remission groups, respectively. No significant variation in PASQ scores was found between patients receiving surgery alone and those receiving preoperative somatostatin analogs. Preoperative fasting GH (GH0) levels were positively correlated with preoperative excessive perspiration. Further regression analyses validated the variation in GH0 as a noteworthy determinant of the extent of change in soft-tissue swelling, excessive perspiration, fatigue, and total PASQ scores. Patient-reported symptoms were substantially alleviated after surgery, independent of endocrine remission or use of preoperative somatostatin. A GH level decrease was a notable coefficient for PASQ scores.
•MRTA on CE 3D-SPACE images may help assess PMA consistency noninvasively.•Second-order textures performed better than first-order features.•Hard PMAs contained greater inhomogeneous textures than ...soft ones.•More appropriate surgical approaches can be planned preoperatively based on MRTA.
To explore the value of magnetic resonance textural analysis (MRTA) in assessing consistency of pituitary macroadenoma (PMA) based on contrast enhanced (CE) three-dimensional sampling perfection with application-optimized contrasts by using different flip angle evolution (3D-SPACE) images.
Fifty-three patients with PMAs that underwent CE 3D-SPACE scanning by 3.0 T MRI and endoscopic trans-sphenoidal surgery were included in the present study. Consistency levels of PMAs were evaluated intraoperatively by two neurosurgeons. Each resection specimen was stained with H&E and anti-collagen IV. MRTA was conducted and texture features were calculated. An unpaired t-test was used to analyze the differences of texture features between soft and hard PMAs. ROC curves by individual and combined features were used to calculate the diagnostic accuracy of MRTA in predicting PMA consistency.
First-order energy and second-order correlation negatively correlated with hard PMAs, while first-order entropy and second-order variance, sum variance, and sum entropy positively correlated with stiffness. All showed significant differences between soft and hard PMAs (P < 0.05). Diagnostic accuracy of combined negative features could achieve an AUC of 0.819, sensitivity of 88.9%, specificity of 61.5%, PPV of 70.6%, NPV of 84.2% and positive features could achieve an AUC of 0.836, sensitivity of 85.2%, specificity of 69.2%, PPV of 74.2%, NPV of 81.8% (P < 0.001).
MRTA using CE 3D-SPACE images is helpful for assessing PMA consistency preoperatively and noninvasively.
Objective
Gonadal and sexual disturbances are commonly encountered in patients with Cushing’s disease. Nevertheless, the prevalence of hypogonadism in male Cushing’s disease, the risk factors as well ...as the recovery time have been scarcely reported. Therefore, we aimed to explore the prevalence of hypogonadism at baseline and its determinants. In addition, the recovery time of hypogonadism and risk factors for unrecovered gonadal axis in male Cushing’s disease with biochemical remission were investigated.
Methods
We reviewed medical records of males with Cushing’s disease managed between 2010 and 2020. Fifty-two male patients were enrolled according to the criteria. Each case attained biochemical remission after transsphenoidal surgery. Demographic details, clinical features, 24-hour UFC, hormonal profile serum PRL, FSH, LH, TT, ACTH, cortisol, TT4/FT4, TT3/ FT3, TSH and IGF-1 were measured at baseline and during follow-up. The maximal tumor diameter on MRI was recorded at diagnosis.
Results
Hypogonadotropic hypogonadism was observed in thirty-nine patients (75%) at diagnosis. Total testosterone was negatively correlated with ACTH and 24-hour UFC. Midnight serum ACTH level at diagnosis was significantly associated with hypogonadism after adjusting for confounding factors. Thirty-two (80%) patients achieved eugonadism within 12 months after the surgery, of which twenty-eight (87.5%) achieved eugonadism within 3 months. Seven patients were persistently hypogonadal during the follow-up (≥1 year), mainly due to the hypopituitarism as a complication of the therapies such as surgery.
Conclusion
Hypogonadotropic hypogonadism is frequent in male Cushing’s disease, but it is reversible in most cases within one-year follow-up after remission.
Purpose
Patients with Cushing’s disease (CD) experienced transient central adrenal insufficiency (CAI) after successful surgery. However, the reported recovery time of hypothalamic-pituitary-adrenal ...(HPA) axis varied and the related factors which could affect recovery time of HPA axis had not been extensively studied. This study aimed to analyze the duration of CAI and explore the factors affecting HPA axis recovery in post-operative CD patients with biochemical remission.
Methods
Medical records of diagnosis with CD in Huashan Hospital were reviewed between 2014 and 2020. 140 patients with biochemical remission and regular follow-up after surgery were enrolled in this retrospective cohort study according to the criteria. Demographic details, clinical and biochemical information at baseline and each follow-up (within 2 years) were collected and analyzed.
Results
Overall, 103 patients (73.6%) recovered from transient CAI within 2 years follow-up and the median recovery time was 12 months 95% confidence intervals (CI): 10–14. The age was younger and midnight ACTH at baseline was significantly lower, while the TT3 and FT3 levels were significantly higher in patients with recovered HPA compared to patients with persistent CAI at 2-year follow-up (
p
< 0.05). In persistent CAI group, more patients underwent partial hypophysectomy. TT3 at diagnosis was an independent related factor of the recovery of HPA axis, even after adjusting for gender, age, duration, surgical history, maximum tumor diameter, surgical strategy, and postoperative nadir serum cortisol level (
p
= 0.04, OR: 6.03, 95% CI: 1.085, 22.508). Among patients with unrecovered HPA axis at 2-year follow-up, 23 CAI patients (62%) were accompanied by multiple pituitary axis dysfunction besides HPA axis, including hypothyroidism, hypogonadism, or central diabetes insipidus.
Conclusion
HPA axis recovered in 73.6% of CD patients within 2 years after successful surgery, and the median recovery time was 12 months. TT3 level at diagnosis was an independent related factor of postoperative recovery of HPA axis in CD patients. Moreover, patients coexisted with other hypopituitarism at 2-year follow-up had a high probability of unrecovered HPA axis.
Coal water slurry (CWS) was prepared from lignite washery tailings. Its moisture content can be subdivided into two forms: free water (surface adsorption water) and bound water, i.e., interparticle, ...capillary, adhesion and internal adsorption water. The effect on moisture distribution of three distinct dispersants was studied through thermal drying and TG–DSC analysis. A new test method combining thermal drying and bond strength analysis was put forward for a thorough moisture distribution. The new method showed reasonable results and arrives at the same conclusion as the TG–DSC method. The addition of dispersants increased the free water content and decreased the bound water content, in particular those of interparticle and capillary water. Also there was a slight decrease in total moisture, compared to CWS prepared without dispersant. The moisture distribution showed its biggest change with dispersant CLS (calcium lignosulfonate), followed by dispersant NDF (a co-polymer of methylene naphthalene sulfonate, styrene sulfonate and maleate), and ended up with NNO (sodium methylene bis-naphthalene sulfonate).
Display omitted
•The effect of three anionic dispersants on moisture distribution of CWS was studied.•The study is conducted by means of thermal drying and TG–DSC analysis.•A new method for moisture distribution was proposed and proved to be reasonable.•Dispersants affect the moisture distribution of CWS in this order: CLS>NDF>NNO.•The effect of dispersants on water in CWS with physical adsorption is much greater.
Introduction
It is a common view that consistency and blood supply of pituitary adenoma (PA) can influence the surgical effect. The aim of this study was to determine whether MRI signal intensity ...(SI) was correlated to the consistency or blood supply of pituitary macroadenoma.
Methods
Forty eight pituitary macroadenoma patients were underwent preoperative MRI, including precontrast and contrast-enhanced (CE) T1-spin echo (T1-SE) imaging, CE-sampling perfection with application-optimized contrasts by using different flip angle evolutions (SPACE) imaging, and perfusion-weighted imaging (PWI). The tumor consistency and blood supply were determined by neurosurgeons. The expression of collagen IV and MIB-1 was detected with immunohistology. The correlation of the relative SI (rSI) values (tumor to normal frontal white matter SI) and PWI data to the tumor consistency, blood supply, and the expression level of collagen IV and MIB-1 was statistically studied by Kruskal–Wallis rank test (K–W test).
Results
A significant correlation was observed between the tumor consistency and the rSI on precontrast T1-SE imaging (
P
= 0.004) but not on CE T1-SE and CE SPACE imaging. The expression of collagen IV was also significantly associated with rSI on T1-SE imaging (
P
= 0.010). The blood supply was correlated with the relative CBV (rCBV) (
P
= 0.030). In addition, the expression of MIB-1 was correlated with rSI of CE T1-SE imaging (
P
= 0.007).
Conclusion
Our results suggest that T1-SE imaging may be a simple and useful method for predicting consistency of PA. CBV value can provide helpful information for assessing the blood supply of pituitary macroadenoma.
To investigate the role of heat-shock protein Hsp90 in adrenocorticotropic hormone (ACTH)-secreting cells, and to explore the potential clinical application of an inhibitor of Hsp90, ...17-N-allylamino-17-demethoxygeldanamycin(17-AAG) in corticotropinomas also known as "Cushing's disease" (CD).
Culture of mouse pituitary tumor AtT-20/D16v-F2 (ATCC
CRL-1795™) cells and human pituitary ACTH-secreting tumor cells were employed. Hepatocellular carcinoma cell line (HLE) was used to evaluate EGFR inhibition by 17-AAG. Cell viability was evaluated using a commercial kit. The ACTH level was measured by a radioimmunoassay. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to measure expression of proopiomelanocortin (POMC) mRNA. Western blotting was done to measure protein levels.
17-AAG suppressed the viability and proliferation, and promoted the apoptosis, of AtT-20/D16v-F2 cells. 17-AAG suppressed the synthesis and secretion of ACTH in AtT-20/D16v-F2 cells and down-regulated POMC transcription. 17-AAG acted in a similar pattern upon treatment with human pituitary ACTH-secreting tumor cells. Inhibition by 17-AAG was stronger in human pituitary ACTH-secreting tumor cells carrying the ubiquitin-specific protease-8 (
) mutant in comparison with cells carrying wild-type
.
The HSP90 inhibitor 17-AAG reduced the viability and secretory function of human pituitary ACTH-secreting tumor cells, and tumor cells carrying the
mutant were more sensitive to 17-AAG than tumor cells carrying wild-type
. 17-AAG could be a potential treatment option for CD.
To investigate the effectiveness and predictors of short-term somatostatin analog (SSA) presurgical therapy in a large cohort and to assess the correlation between clinical and pathological ...variables.
237 newly diagnosed patients with acromegaly received presurgical SSA treatment for three months were recruited. Clinical characteristics were collected, and response to SSA in hormone and tumor size was evaluated. The correlation between clinical information and pathological variables were analyzed.
After 3 months presurgical SSA therapy, 51 (21.5%) patients were biochemically responsive with ≥50% decrease in IGF-1 while 126 (53.2%) patients showed at least 20% tumor size decrease. Biochemical responders were associated with a smaller maximum tumor diameter (MTD) and an older age (OR, 0.448; P = 0.003; OR, 1.050; P = 0.001). Tumor size responders were associated with a smaller MTD (OR, 0.435; P < 0.001). A combination of MTD < 2 cm and age ≥49 years predicted biochemical responders (PPV, 54.5%; NPV, 86.0%; P < 0.001), while MTD ≤2.2 cm (PPV, 67.1%; NPV, 67.0%; P < 0.001) predicted tumor size responders. Compared to patients with MTD < 2 cm, patients with MTD ≥ 2 cm showed higher percentage of sparsely granulated (SG) adenoma (62.1% vs. 31.3%, P = 0.005). In addition, the percentage of SG adenoma tended to be higher in patients < 49 years than ≥49 years (48.1% and 31.0% P = 0.089).
The baseline MTD and age correlate with granulation patterns and may be used as easily acquired predictors of presurgical SSA treatment in acromegaly. Patients over their 50s with a tumor less than 2 cm in diameter are more likely to have a response to the short-term presurgical SSA therapy.
•The biochemical response rate after short-term SSA presurgical therapy is ~20%.•The tumor size response rate after short-term SSA presurgical therapy is ~50%.•Tumor diameter and age predict the efficacy of short-term SSA presurgical therapy.•Tumor diameter and age correlate with its granulation patterns and Ki-67 index.•Patients over 50s with a tumor < 2 cm are more likely to have a response to SSA.
PDF
