Presurgical Medical Treatment in Prolactinomas: Surgical Implications and Pathological Characteristics From 290 Cases.

OBJECTIVE: To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. METHODS: A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. RESULTS: Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P < .001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P = .047). CONCLUSION: This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging.

Interaction between ferroptosis and TNF-α: Impact in obesity-related osteoporosis.

The relationship of obesity and osteoporosis has been widely studied over the past years. However, the implications of obesity for bone health remain controversial, and the underlying molecular mechanism is not yet fully understood. This study demonstrated that high-fat diet-induced obesity leads to significantly decreased bone volume/tissue volume (BV/TV), trabecular number (Tb.N), and cortical thickness (Ct.Th) of male rat femur after mechanical loading effects of body weight were controlled. HFD-induced obese rats exhibited attenuated expression of ferroptosis inhibitory protein SLC7A11 and GPX4 in bone tissues, which was correlated with elevated serum TNF-α concentration. Ferroptosis inhibitor administration could effectively rescue decreased osteogenesis-associated type H vessels and osteoprogenitors, and downregulate serum levels of TNF-α to ameliorate bone loss in obese rats. Since ferroptosis and TNF-α both affect bone and vessel formation, we further investigated the interaction between ferroptosis and TNF-α, and its impact in osteogenesis and angiogenesis in vitro. In human osteoblast-like MG63 and umbilical vein endothelial cells (HUVEC), TNF-α/TNFR2 signaling promoted cystine uptake and GSH biosynthesis to provide protection against low-dose ferroptosis inducer erastin. While, TNF-α/TNFR1 facilitated ferroptosis in the presence of high-dose erastin through ROS accumulation. Moreover, TNF-α regulated ferroptosis-induced osteogenic and angiogenic dysfunctions based on its ferroptosis regulatory role. Meanwhile, ferroptosis inhibitors could reduce intracellular ROS overproduction and enhance osteogenesis and angiogenesis in TNF-α-treated MG63 and HUVECs. This study revealed the interaction between ferroptosis and TNF-α and its impact in osteogenesis and angiogenesis, which provides new insights into the pathogenesis and regenerative therapy of obesity-related osteoporosis.

Single-cell sequencing identifies differentiation-related markers for molecular classification and recurrence prediction of PitNET.

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors with variable recurrence rate. Currently, the recurrence prediction is unsatisfying and can be improved by understanding the cellular origins and differentiation status. Here, to comprehensively reveal the origin of PitNET, we perform comparative analysis of single-cell RNA sequencing data from 3 anterior pituitary glands and 21 PitNETs. We identify distinct genes representing major subtypes of well and poorly differentiated PitNETs in each lineage. To further verify the predictive value of differentiation biomarkers, we include an independent cohort of 800 patients with an average follow-up of 7.2 years. In both PIT1 and TPIT lineages, poorly differentiated groups show significantly higher recurrence rates while well-differentiated groups show higher recurrence rates in SF1 lineage. Our findings reveal the possible origin and differentiation status of PitNET based on which new differentiation classification is proposed and verified to predict tumor recurrence.

Self-reported symptoms in patients with acromegaly: a 6-month follow-up in a single neurosurgical center.

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.

Integrated proteogenomic characterization across major histological types of pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors. Due to its extensive tumor heterogeneity and the lack of high-quality tissues for biomarker discovery, the causative molecular mechanisms are far from being fully defined. Therefore, more studies are needed to improve the current clinicopathological classification system, and advanced treatment strategies such as targeted therapy and immunotherapy are yet to be explored. Here, we performed the largest integrative genomics, transcriptomics, proteomics, and phosphoproteomics analysis reported to date for a cohort of 200 PitNET patients. Genomics data indicate that GNAS copy number gain can serve as a reliable diagnostic marker for hyperproliferation of the PIT1 lineage. Proteomics-based classification of PitNETs identified 7 clusters, among which, tumors overexpressing epithelial-mesenchymal transition (EMT) markers clustered into a more invasive subgroup. Further analysis identified potential therapeutic targets, including CDK6, TWIST1, EGFR, and VEGFR2, for different clusters. Immune subtyping to explore the potential for application of immunotherapy in PitNET identified an association between alterations in the JAK1-STAT1-PDL1 axis and immune exhaustion, and between changes in the JAK3-STAT6-FOS/JUN axis and immune infiltration. These identified molecular markers and alternations in various clusters/subtypes were further confirmed in an independent cohort of 750 PitNET patients. This proteogenomic analysis across traditional histological boundaries improves our current understanding of PitNET pathophysiology and suggests novel therapeutic targets and strategies.

Increased Risk of Ocular Hypertension in Patients With Cushing's Disease.

PRCIS: An increased risk of ocular hypertension was seen in Cushing's disease. INTRODUCTION: Systemic steroid use is a significant risk factor for increased intraocular pressure (IOP). The incidence of ocular hypertension may rise to 30%-40% of the general population due to topical or systemic glucocorticoid usage. However, the incidence of ocular hypertension in endogenous hypercortisolemia, as well as the ophthalmological outcomes after endocrine remission due to surgical resection, remain unknown. MATERIALS AND METHODS: The IOP, visual field, and peripapillary retinal nerve fiber layer thickness were documented in all patients with Cushing's disease (CD) admitted to a tertiary pituitary center for surgery from January to July 2019. Patients with acromegaly and patients with nonfunctioning pituitary adenoma (NFPA) during the same study period served as controls. We calculated the odds ratio (OR), identified the risk factors of developing ocular hypertension, and presented postoperative trends of the IOP. RESULTS: A total of 52 patients (38.4±12.4 y old) with CD were included. The IOP was higher in patients with CD (left 19.4±5.4 mm Hg and right 20.0±7.1 mm Hg) than in patients with acromegaly (left 17.5±2.3 mm Hg and right 18.6±7.0 mm Hg, P =0.033) and patients with NFPA (left 17.8±2.6 mm Hg and right 17.4±2.4 mm Hg, P =0.005). A total of 21 eyes (20.2%) in patients with CD were diagnosed with ocular hypertension compared with 4 eyes (4.7%) in the acromegaly group and 4 eyes (4.5%) in the NFPA group. The OR of developing ocular hypertension in patients with CD was 5.1 [95% confidence interval (CI), 1.3-25.1, P =0.029] and 6.6 (95% CI, 1.8-30.3, P =0.007) when compared with the 2 control groups. Among patients with CD, those with a higher urine-free cortisol were more likely to develop ocular hypertension (OR=19.4, 95% CI, 1.7-72.6). The IOP decreased at 1 month after surgery in patients with CD, and the change was sustained for 3 months after surgery. CONCLUSIONS: An increased risk of ocular hypertension was seen in CD and suggests that endogenous hypercortisolemia should be considered as part of the glaucoma assessment. This result warrants the discretion of both ophthalmologists and neuroendocrinologists.

Transcription Factor ASCL1 Acts as a Novel Potential Therapeutic Target for the Treatment of the Cushing's Disease.

BACKGROUND: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway. METHODS: RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation, and apoptosis were studied in vitro. The effectiveness of an ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells on Ascl1 knockdown combined with published chromatin immunoprecipitation sequencing data and dual luciferase assays were used to explore downstream pathways. RESULTS: ASCL1 was exclusively overexpressed in USP8-mutant and wild-type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. An ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. CONCLUSION: Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target the treatment of CD. SUMMARY: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF, and USP48. Moreover, few effective medical therapies are currently available for the treatment of CD. Here, using a multiomics approach, we first report the aberrant overexpression of the transcription factor gene ASCL1 in USP8-mutant and wild-type tumors of CD. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in mouse AtT-20 cells. Notably, an ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. Importantly, ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. Thus, our findings improve understanding of CD pathogenesis and suggest that ASCL1 is a potential therapeutic target the treatment of CD.

Risk factors of epistaxis after endoscopic endonasal skull base surgeries.

BACKGROUND: Epistaxis after endoscopic endonasal skull base surgeries does not typically occur as an accidental circumstance but often results from multiple factors. We aimed to assess the possible risk factors associated with postoperative epistaxis. METHODS: Patients who underwent endoscopic endonasal skull base surgery at Huashan hospital from August 2018 to November 2019 were enrolled in the study. Postoperative epistaxis was defined as severe, persistent, or recurrent arterial nosebleed, which required therapeutic intervention. Patients were divided into the epistaxis and no epistaxis groups. The incidence, clinical characteristics, management, and intraoperative findings were recorded. RESULTS: A total of 762 patients were included in the study. 20 (2.6%) patients experienced postoperative epistaxis, which happened in a delayed fashion between 6 and 30 postoperative days. Multivariate logistic regression analysis showed that arterial hypertension (OR=3.394, 95%CI: 1.094-10.531, P = 0.034) and preoperative systolic blood pressure (SBP) (OR=1.035, 95%CI: 1.002-1.068) were identified as predictors for postoperative epistaxis. The bleeding sites were identified at the left posterior septal artery (PSA) in 10 (62.5%) cases, the right PSA in 4 (25%) cases, the left palatovaginal artery in 1 (6.25%) case, and the right inferior turbinate branch of the posterior lateral nasal artery in 1 (6.25%) case, respectively. Direct bipolar cauterization was used to stop the bleeding. After definitive treatment, no patients had recurrent epistaxis. CONCLUSIONS: Arterial hypertension and preoperative SBP were associated with postoperative epistaxis after endoscopic endonasal skull base surgery, and the left PSA contributed to the dominant site of bleeding during surgical re-exploration.

The p300 Inhibitor A-485 Exerts Antitumor Activity in Growth Hormone Pituitary Adenoma.

CONTEXT: Growth hormone pituitary adenoma (GHPA), a major subtype of pituitary adenoma (PA), can lead to progressive somatic disfigurement, multiple complications, and even increased mortality. The efficacy of current treatments is limited; thus, a novel pharmacological treatment is urgently needed. As a histone acetyltransferase (HAT) coactivator, p300 can regulate the transcription of several genes that are crucial for PA tumorigenesis and progression. However, the role of p300 and its catalytic inhibitor in GHPA is still unclear. OBJECTIVE: We aimed to identify the expression of p300 in GHPA and in normal pituitary glands. METHODS: The expression of p300 was detected in GHPA and normal pituitary tissues. Genetic knockdown was performed by siRNA. The efficacy of the p300 inhibitor A-485 in the cell cycle, proliferation, apoptosis, and hormone secretion was investigated by flow cytometry, ELISAs, Western blotting, and qRT-PCR. RNA sequencing, bioinformatic analysis, and subsequent validation experiments were performed to reveal the potential biological mechanism of A-485. RESULTS: High expression of p300 was found in GHPA tissues compared with normal pituitary tissues. Knockdown of p300 inhibited cell proliferation and clone formation. Treatment with A-485 suppressed cell growth and inhibited the secretion of GH in vitro and in vivo. Further mechanistic studies showed that A-485 could downregulate the expression or activity of several oncogenes, such as genes in the Pttg1, c-Myc, cAMP and PI3K/AKT/mTOR signaling pathways, which are crucial for PA tumorigenesis and progression. CONCLUSION: Our findings demonstrate that inhibition of HAT p300 by its selective inhibitor A-485 is a promising therapy for GHPA.

Collagen sponge is as effective as autologous fat for grade 1 intraoperative cerebral spinal fluid leakage repair during transsphenoidal surgery.

OBJECTIVE: To compare the efficacy of collagen sponge graft versus autologous fat graft in repairing grade 1 intraoperative CSF leakage and identify potential risk factors for failure repairing. METHODS: We retrospectively recruited patients with grade 1 intraoperative CSF leakage repaired either with a collagen sponge (Group A), with autologous fat graft (Group B), or with only bipolar coagulation and gel foam packing (Group C). Patients with previous radiotherapy, repaired with additional materials, received postoperative lumbar drainage or without sufficient follow-up data were excluded. The primary outcome was the incidence of postoperative CSF leakage. We used propensity score matching to adjust for confounding when comparing Group A and Group B. RESULTS: 459 patients (277 female and 182 male) were recruited. Among them, 296 patients were in Group A, 146 patients were in Group B, and the other 17 patients were in Group C. After propensity score matching, 146 and 146 patients were included in group A and group B, respectively. No difference was observed for the primary outcome in the matched cohort (p = 0.654) with three patients in Group A (1.0% and 2.1% before and after matching, respectively) and two patients in Group B (1.4% and 1.4% before and after matching, respectively) developed postoperative CSF leakage, respectively. Patients repaired only with gel foam and/or bipolar coagulation (OR 770.5, p < 0.001) and older age (OR 1.16, p < 0.001) were associated with a higher likelihood of postoperative CSF leakage. CONCLUSIONS: Collagen sponge is as effective as an autologous fat graft for grade 1 intraoperative CSF leakage repair during transsphenoidal surgery. Repair with gel foam and/or bipolar coagulation and older age are associated with a higher likelihood of postoperative CSF leakage.

Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases.

The short-term effects of long-acting somatostatin analogues (SSAs) on lipid profiles in patients with acromegaly are not well studied. We retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After SSAs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=-0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, our current study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly.

Impact of Pituitary Stalk Preservation on Tumor Recurrence/Progression and Surgically Induced Endocrinopathy After Endoscopic Endonasal Resection of Suprasellar Craniopharyngiomas.

Objective: To investigate the factors associated with recurrence/progression after endoscopic endonasal resection of suprasellar craniopharyngiomas. Special attention was paid to assess the impact of pituitary stalk preservation on tumor recurrence/progression and endocrinological outcomes. Methods: We retrospectively recruited 73 patients with suprasellar craniopharyngiomas undergone endoscopic endonasal approach (EEA) surgery from September 2014 to May 2019 and assessed their clinical characteristics, surgical outcomes, and recurrence/progression. Stalk preservation or sacrifice was determined by reviewing operative records, videos, and post-operative magnetic resonance imaging. Results: Gross total resection (GTR) was achieved in 51 cases (69.9%). Tumor recurrence was seen in 5 cases (9.8%) and progression was seen in 8 cases (36.4%), respectively. GTR (OR = 0.248 CI 0.081-0.759; p = 0.015) was the only independent factor influencing recurrence/progression. Kaplan-Meier survival analysis showed that the mean recurrence/progression-free survival were 53 (95% CI 48-59) and 39 (95% CI 28-50) months, respectively, in patients with and without GTR (p = 0.011). Pituitary stalk preservation was more common in cases with peripheral type tumors (83% vs. 30%, p < 0.01). Preserving the pituitary stalk does not appear to decrease the percentage of GTR (75.5% vs. 55.0%, p = 0.089), or increase the rate of tumor recurrence (12.5% vs. 0%, p = 0.508) or progression (46.2% vs. 22.2%, p = 0.486). However, surgically induced hypothyroidism (60.5% vs. 100%, p = 0.041) and diabetes insipidus (35.1% vs. 81.8%, p = 0.017) were significantly lower in patients with stalk preservation. For patients who had hypopituitarism before EEA, there was no difference between those with and without stalk preservation regarding post-operative hypopituitarism (p > 0.05). Conclusion: GTR is the only independent predictor of recurrence/progression after EEA surgery for suprasellar craniopharyngiomas. Preserving the pituitary stalk does not appear to increase the risk of non-GTR and tumor recurrence/progression and might help reduce the risk of surgically induced hypothyroidism and diabetes insipidus. We recommend preserving the pituitary stalk in peripheral type suprasellar craniopharyngiomas with normal pituitary function, especially in cases without hypothyroidism or diabetes insipidus. On the other hand, stalk sacrifice could be considered in central type tumors with severe pre-operative endocrinopathy.

Treatment of acromegaly by rosiglitazone via upregulating 15-PGDH in both pituitary adenoma and liver.

Rosiglitazone, a synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligand, has been reported to reduce growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in 10 patients with acromegaly. However, the mechanisms remain unknown. Here, we reveal that PPARγ directly enhances 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression, whose expression is decreased and negatively correlates with tumor size in acromegaly. Rosiglitazone decreases GH production and promotes apoptosis and autophagy in GH3 and primary somatotroph adenoma cells and suppresses hepatic GH receptor (GHR) expression and IGF-1 secretion in HepG2 cells. Activating the PGE2/cAMP/PKA pathway directly increases GHR expression. Rosiglitazone suppresses tumor growth and decreases GH and IGF-1 levels in mice inoculated subcutaneously with GH3 cells. The above effects are all dependent on 15-PGDH expression. Rosiglitazone as monotherapy effectively decreases GH and IGF-1 levels in all nineteen patients with active acromegaly. Evidence suggests that rosiglitazone may be an alternative pharmacological approach for acromegaly by targeting both pituitary adenomas and liver.

Erectile Dysfunction Is Associated With Excessive Growth Hormone Levels in Male Patients With Acromegaly.

Objective: To determine the risk factors for erectile dysfunction (ED) in male patients with acromegaly and to prospectively investigate the short-term changes of erectile function after surgery or medical treatment. Methods: Sixty-three male patients were subjected to nocturnal penile tumescence and rigidity (NPTR) test for the evaluation of erectile function. The measurement of serum nitric oxide (NO) was also performed. Twenty-seven patients were re-evaluated by NPTR after surgery or long-term somatostatin analogues (SSA) treatment. Results: Twenty-two patients (34.9%) had ED. Patients with ED showed higher random GH (17.89 [10.97-44.19] µg/L vs 11.63 [4.31-28.80] µg/L, p = 0.020) and GH nadir (GHn) (10.80 [6.69-38.30] µg/L vs 8.76 [3.62-18.19] µg/L, p = 0.044) during oral glucose tolerance test (OGTT). The NO levels of ED patients were lower than non-ED patients (9.15 [5.58-22.48] µmol/L vs 16.50 [12.33-31.78] µmol/L, p = 0.012). After treatment, patients who present improvement in erectile function showed lower post-GHn (0.07 [0.03-0.12] ng/ml vs 1.32 [0.09-3.60] ng/ml, p = 0.048) and post-IGF-1 index (1.03 ± 0.38 vs 1.66 ± 0.95, p = 0.049). The multivariate analysis indicated post-GHn was still associated with the improvement of erectile function after correction of other covariates (OR: 0.059, 95% CI: 0.003-1.043, p = 0.053). Conclusions: Excessive GH is related to ED in male patients with acromegaly. GH normalization after treatment is beneficial for short-term erectile function recovery.

2010 versus the 2000 consensus criteria in patients with normalised insulin-like growth factor 1 after transsphenoidal surgery has high predictive values for long-term recurrence-free survival in acromegaly.

The present study investigated the factors associated with recurrence during long-term follow-up in acromegaly and compared the recurrence rate between patients in remission with 2010 vs 2000 consensus criteria. We retrospectively recruited 133 adult acromegalic patients who had undergone transsphenoidal surgery (TSS) from January 2013 to December 2014 and assessed their clinical characteristics, surgical outcomes and recurrence. Surgical remission was defined as normalised insulin-like growth factor 1 (IGF-1) with nadir growth hormone (GH) during an oral glucose tolerance test (OGTT) < 1 µg/ L no less than 3 months after TSS without adjuvant therapy. Recurrence was defined as persistently reelevated IGF-1 after surgical remission. Cox regression analysis and Kaplan-Meier survival analysis were performed to evaluate the factors associated with recurrence. Remission was achieved in 77 cases (57.9%) after TSS alone. Recurrence was seen in five cases (6.5%) at 12, 12, 12, 36 and 54 months, respectively, after surgery. Cox regression analysis showed that a nadir GH < 0.4 µg /L (vs 0.4-1.0 µg /L) at surgical remission (odds ratio [OR] = 0.106; 95% confidence interval [CI] = 0.017-0.645; P = 0.015) and Ki-67 index (OR = 2.636; 95% CI = 1.023-6.791; P = 0.045) were independent factors influencing recurrence. Kaplan-Meier survival analysis showed that the median recurrence-free survival was 36 months (95% CI = 20-52) for patients with nadir GH 0.4-1.0 µg /L at surgical remission. The median recurrence-free survival for patients with nadir GH < 0.4 µg /L at surgical remission was much longer (ie, required further follow-up to estimate). A failure of GH suppression under 0.4 µg /L during an OGTT in patients with normalised IGF-1 and a higher Ki-67 index are independent predictors of recurrence after surgical remission in GH-secreting pituitary adenomas. Compared to patients with nadir GH < 0.4 µg /L, those with nadir GH 0.4-1.0 µg /L appear to have a significantly higher risk of recurrence.

Efficacy and predictors of short-term first-generation somatostatin analog presurgical treatment in acromegaly: A hospital-based study of 237 cases.

OBJECTIVE: 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. DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

Surgical outcomes and multidisciplinary management strategy of Cushing's disease: a single-center experience in China.

OBJECTIVE: The primary aim of this study was to investigate the value of multidisciplinary team (MDT) management in treating patients with Cushing's disease (CD). The secondary aim was to assess the concordance of bilateral inferior petrosal sinus sampling (BIPSS) lateralization with intraoperative observations. METHODS: The authors recruited 124 consecutive patients (128 procedures) who had undergone endoscopic endonasal resection of adrenocorticotropic hormone-secreting pituitary adenomas from May 2014 to April 2018 and assessed their clinical characteristics, surgical outcomes, and adjuvant therapies. The criteria for surgical remission were normalized serum and urinary cortisol levels, which could be suppressed by a low-dose dexamethasone suppression test at 3-months' follow-up without adjuvant treatment. RESULTS: The remission rates of the 113 patients with long-term follow-up (20.3 ± 12.2 months) were 83.2% after surgery alone and 91.2% after adjuvant therapy. The surgical remission rates of macroadenomas, MRI-visible microadenomas, and MRI-negative tumors were 66.7% (12/18), 89.3% (67/75), and 75% (15/20), respectively (p = 0.039). The surgical remission rates had a trend of improvement during the study period (87.5% in 2017-2018 vs 76.5% in 2014, p = 0.517). Multivariate regression analysis showed that a history of previous pituitary surgery (OR 0.300, 95% CI 0.100-0.903; p = 0.032) and MRI-visible microadenoma (OR 3.048, 95% CI 1.030-9.019; p = 0.044) were independent factors influencing surgical remission. The recurrence rate was 3.2% after a mean of 18 months after surgery. The remission rate of postoperative MDT management in patients with persistent disease was higher than non-MDT management (66.7% vs 0%, p = 0.033). In cases with preoperative BIPSS lateralization, 84.6% (44/52) were concordant with intraoperative findings. CONCLUSIONS: MRI-visible microadenoma and primary surgery were independent predictors of surgical remission in CD. The MDT management strategy helps to achieve a better overall outcome. BIPSS may help to lateralize the tumor in MRI-negative/equivocal microadenomas.

Surgical Outcomes and Predictors of Visual Function Alterations After Transcranial Surgery for Large-to-Giant Pituitary Adenomas.

BACKGROUND: Factors associated with visual outcomes after transcranial surgery for large-to-giant pituitary adenomas have not been fully elucidated. METHODS: We recruited 37 patients with large-to-giant pituitary adenomas between January 2014 and December 2016 and assessed their tumor characteristics and surgical outcomes. Visual acuity and visual field were evaluated by visual impairment score before and 3-6 months after transcranial surgery. Multivariable logistic regression analysis was applied to show the factors associated with visual outcomes after surgery. RESULTS: The severity levels of visual impairment before surgery were mild, moderate, severe, and complete in 24.3% (9/37), 24.3% (9/37), 35.1% (13/37), and 16.2% (6/37), respectively. After surgery, the visual function was improved, stabilized, and worsened in 43.2% (16/37), 43.2% (16/37), and 13.5% (5/37) of patients, respectively. Multivariable logistic regression analysis showed that subarachnoid space invasion was the only independent prognostic factor adversely influencing the postoperative visual outcomes. Patients with subarachnoid space invasion had a higher possibility of visual deterioration (36.4% vs. 3.8%; P = 0.021) after transcranial surgery, compared with those without subarachnoid space invasion. CONCLUSIONS: Visual compromise is still an unignorable complication during transcranial surgery for large-to-giant pituitary adenomas. Subarachnoid space invasion indicated by preoperative magnetic resonance imaging was an independent negative predictor for visual outcomes after surgery.

BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.

BACKGROUND: Nonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA. METHODS: The expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes. RESULTS: Immunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis. CONCLUSION: In this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.