Integrated Microbiome and Metabolome Analysis Reveals Hypothalamic-Comorbidities Related Signatures in Craniopharyngioma.

Craniopharyngioma (CP) is an intracranial tumor with high mortality and morbidity. Though biologically benign, CP will damage the hypothalamus, inducing comorbidities such as obesity, metabolic syndrome, and cognitive impairments. The roles of gut microbiome and serum metabolome in CP-associated hypothalamic comorbidities are aimed to be explored. Patients with CP are characterized by increased Shannon diversity, Eubacterium, Clostridium, and Roseburia, alongside decreased Alistipes and Bacteroides. CP-enriched taxa are positively correlated with dyslipidemia and cognitive decline, while CP-depleted taxa are negatively associated with fatty liver. Subsequent serum metabolomics identified notably up-regulated purine metabolism, and integrative analysis indicated an association between altered microbiota and elevated hypoxanthine. Phenotypic study and multi-omics analysis in the Rax-CreERT2::BrafV600E/+::PtenFlox/+ mouse model validated potential involvement of increased Clostridium and dysregulated purine metabolism in hypothalamic comorbidities. To further consolidate this, intervention experiments are performed and it is found that hypoxanthine co-variated with the severity of hypothalamic comorbidities and abundance of Clostridium, and induced dysregulated purine metabolism along with redox imbalance in target organs (liver and brain cortex). Overall, the study demonstrated the potential of increased Clostridium and up-regulated purine metabolism as signatures of CP-associated hypothalamic-comorbidities, and unveiled that elevated Clostridium, dysregulated purine metabolism, and redox imbalance may mediate the development and progression of CP-associated hypothalamic-comorbidities.

Treatment Strategies and Long-Term Outcomes in Silent Corticotroph Adenomas: A Single-Center Retrospective Study of 367 Cases.

BACKGROUND AND OBJECTIVES: Silent corticotroph adenoma (SCA) is a high-risk pituitary neuroendocrine tumor (PitNET) which exhibits more aggressive behavior than other nonfunctioning PitNETs. Some SCAs are observed to recur after total resection (TR). We aim to discuss the long-term outcomes after endoscopic endonasal surgery for SCAs and explore optimal treatment after operation. METHODS: Clinical data and intraoperative videos from 367 SCAs who underwent endoscopic endonasal surgery were retrospectively collected. Patients were categorized into TR and subtotal resection (STR) groups according to 3-month postoperative MRIs. Based on close-up intraoperative observation of the relationship between tumor and pituitary gland, diaphragm, and medial wall cavernous sinus, patients in the TR group were further subdivided into gross total resection (GTR) and near total resection (NTR) groups. Patients in the STR group were subdivided as STR followed by observation (STR + ob) and STR followed by adjuvant stereotactic radiosurgery (SRS) (STR + SRS). Kaplan-Meier analysis was used to compare the event-free survival among these subgroups. RESULTS: Headache (27.5%) and vision loss (55.3%) were the most common presenting symptoms. Cavernous sinus (CS) invasion was confirmed intraoperatively in 167 (45.5%) patients. After operation, 175 (47.7%), 83 (22.6%), 32 (8.7%), and 77 (21%) patients were divided into GTR, NTR, STR + ob, and STR + SRS groups, respectively. The mean follow-up time was 40.9 ± 25.8 months. There were 0, 17 (20.5%), 9 (28.1%), and 4 (5.2%) patients noted to have PitNET recurrence or progression in GTR, NTR, STR + ob, and STR + SRS groups, respectively. Event-free survival distribution in the NTR group was similar to that in the STR + ob group (P = .696), which was significantly lower than that in the STR + SRS group (P = .008). Adrenocorticotropic hormone (ACTH)-negative SCAs have lower preoperative ACTH levels and were more likely to invade CS than ACTH-positive SCAs. CONCLUSION: CS invasion was commonly seen in SCAs, often precluding GTR. Radical surgery and close follow-up were proposed. Early postoperative adjuvant SRS for remnant tumor should be considered.

Combined simultaneous transsphenoidal and transcranial regimen improves surgical outcomes in complex giant pituitary adenomas: a longitudinal retrospective cohort study.

BACKGROUND: Surgical treatment of complex giant pituitary adenomas (GPAs) presents significant challenges. The efficacy and safety of combining transsphenoidal and transcranial approaches for these tumors remain controversial. In this largest cohort of patients with complex GPAs, we compared the surgical outcomes between those undergoing a combined regimen and a non-combined regimen. We also examined the differences in risks of complications, costs, and logistics between the two groups, which might offer valuable information for the appropriate management of these patients. PATIENTS AND METHODS: This was a multicenter retrospective cohort study conducted at 13 neurosurgical centers. Consecutive patients who received a combined or non-combined regimen for complex GPAs were enrolled. The primary outcome was gross total resection, while secondary outcomes included complications, surgical duration, and relapse. A propensity score-based weighting method was used to account for differences between the groups. RESULTS: Out of 647 patients [298 (46.1%) women, mean age: 48.5 ± 14.0 years] with complex GPAs, 91 were in the combined group and 556 were in the noncombined group. Compared with the noncombined regimen, the combined regimen was associated with a higher probability of gross total resection [50.5% vs. 40.6%, odds ratio (OR): 2.18, 95% confidence interval (CI): 1.30-3.63, P = 0.003]. The proportion of patients with life-threatening complications was lower in the combined group than in the non-combined group (4.4% vs. 11.2%, OR: 0.25, 95% CI: 0.08-0.78, P = 0.017). No marked differences were found between the groups in terms of other surgical or endocrine-related complications. However, the combined regimen exhibited a longer average surgery duration of 1.3 h ( P < 0.001) and higher surgical costs of 22,000 CNY (~ 3,000 USD, P = 0.022) compared with the noncombined approach. CONCLUSIONS: The combined regimen offered increased rates of total resection and decreased incidence of life-threatening complications, which might be recommended as the first-line choice for these patients.

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.

Assessment of quality of life in patients with craniopharyngioma and identification of risk factors for compromised overall wellness

ABSTRACT Objective: Quality of Life (QoL) has been a multifactorial concerning issue in oncology. We aimed to inspect the pre-operative QoL among patients with craniopharyngioma and to explore the potential correlations between parameters of QoL and clinical indices. Subjects and methods: We enrolled a total of 109 patients with craniopharyngioma. We utilized Short Form 36 (SF-36), Symptom Check List-90, Generalized Anxiety Disorder Questionnaire scale (GAD7), Patient Health Questionnaire Depression (PHQ9) and Pittsburgh Sleep Quality Index to prospectively evaluated their QoL. Parameters of QoL along with clinical indices were compared among sub-groups divided according to Puget classification. Correlation analyses and regression analyses were performed to detect influential determinants to self-reported wellness. Results: Patients presented impaired QoL compared with general population ( p < 0.001), as assessed by SF-36. Correlation analyses indicated the detrimental influence resulting from central diabetes insipidus (CDI). Multivariate linear regression unveiled the adverse effect of CDI on Mental Component Summary (coefficient = −13.869, p = 0.007), GAD7 total score (coefficient = 2.072, p = 0.049) as well as PHQ9 total score (coefficient = 3.721, p = 0.001). Multivariate logistic regression verified CDI as a risk factor of developing depressive symptoms (OR = 6.160, p = 0.001). Conclusion: QoL of patients with craniopharyngioma was remarkably compromised before operation. CDI exerted detrimental influences on patients' QoL and it might serve as a marker for early identification of patients at risk of depression.

Assessment of quality of life in patients with craniopharyngioma and identification of risk factors for compromised overall wellness.

Objective: Quality of Life (QoL) has been a multifactorial concerning issue in oncology. We aimed to inspect the pre-operative QoL among patients with craniopharyngioma and to explore the potential correlations between parameters of QoL and clinical indices. Subjects and methods: We enrolled a total of 109 patients with craniopharyngioma. We utilized Short Form 36 (SF-36), Symptom Check List-90, Generalized Anxiety Disorder Questionnaire scale (GAD7), Patient Health Questionnaire Depression (PHQ9) and Pittsburgh Sleep Quality Index to prospectively evaluated their QoL. Parameters of QoL along with clinical indices were compared among sub-groups divided according to Puget classification. Correlation analyses and regression analyses were performed to detect influential determinants to self-reported wellness. Results: Patients presented impaired QoL compared with general population (p < 0.001), as assessed by SF-36. Correlation analyses indicated the detrimental influence resulting from central diabetes insipidus (CDI). Multivariate linear regression unveiled the adverse effect of CDI on Mental Component Summary (coefficient = -13.869, p= 0.007), GAD7 total score (coefficient = 2.072, p = 0.049) as well as PHQ9 total score (coefficient = 3.721, p = 0.001). Multivariate logistic regression verified CDI as a risk factor of developing depressive symptoms (OR = 6.160, p = 0.001). Conclusion: QoL of patients with craniopharyngioma was remarkably compromised before operation. CDI exerted detrimental influences on patients' QoL and it might serve as a marker for early identification of patients at risk of depression.

Development and Validation of a Clinical Prediction Model for Venous Thromboembolism Following Neurosurgery: A 6-Year, Multicenter, Retrospective and Prospective Diagnostic Cohort Study.

BACKGROUND: Based on the literature and data on its clinical trials, the incidence of venous thromboembolism (VTE) in patients undergoing neurosurgery has been 3.0%~26%. We used advanced machine learning techniques and statistical methods to provide a clinical prediction model for VTE after neurosurgery. METHODS: All patients (n = 5867) who underwent neurosurgery from the development and retrospective internal validation cohorts were obtained from May 2017 to April 2022 at the Department of Neurosurgery at the Sanbo Brain Hospital. The clinical and biomarker variables were divided into pre-, intra-, and postoperative. A univariate logistic regression (LR) was applied to explore the 67 candidate predictors with VTE. We used a multivariable logistic regression (MLR) to select all significant MLR variables of MLR to build the clinical risk prediction model. We used a random forest to calculate the importance of significant variables of MLR. In addition, we conducted prospective internal (n = 490) and external validation (n = 2301) for the model. RESULTS: Eight variables were selected for inclusion in the final clinical prediction model: D-dimer before surgery, activated partial thromboplastin time before neurosurgery, age, craniopharyngioma, duration of operation, disturbance of consciousness on the second day after surgery and high dose of mannitol, and highest D-dimer within 72 h after surgery. The area under the curve (AUC) values for the development, retrospective internal validation, and prospective internal validation cohorts were 0.78, 0.77, and 0.79, respectively. The external validation set had the highest AUC value of 0.85. CONCLUSIONS: This validated clinical prediction model, including eight clinical factors and biomarkers, predicted the risk of VTE following neurosurgery. Looking forward to further research exploring the standardization of clinical decision-making for primary VTE prevention based on this model.

Severe hypernatremia during postoperative care in patients with craniopharyngioma.

Purpose: We aimed to describe and predict the risk of severe hypernatremia after surgical resection of craniopharyngioma and to identify the association of water intake, urine output, and sodium level change in the patients. Method: The outcome was postoperative severe hypernatremia. We identified risk factors associated with hypernatremia using multivariable regression. We trained machine learning models to predict the outcome. We compared serum sodium change, intravenous input, oral input, total input, urine output, and net fluid balance according to different nurse shifts. Results: Among 234 included patients, 125 developed severe hypernatremia after surgery. The peak incidence occurred during day 0 and day 6 after surgery. The risk was increased in patients with gross total resection (odds ratio (OR) 2.41, P < 0.001), high Puget classification (OR 4.44, P = 0.026), preoperative adrenal insufficiency (OR 2.01, P = 0.040), and preoperative hypernatremia (OR 5.55, P < 0.001). The random forest algorithm had the highest area under the receiver operating characteristic curve (0.770, 95% CI, 0.727-0.813) in predicting the outcome and was validated in the prospective validation cohort. Overnight shifts were associated with the highest serum sodium increase (P = 0.010), less intravenous input (P < 0.001), and less desmopressin use (P < 0.001). Conclusion: The overall incidence of severe hypernatremia after surgical resection of craniopharyngioma was significant, especially in patients with gross total resection, hypothalamus distortion, preoperative adrenal insufficiency, and preoperative severe hypernatremia. Less intravenous input and less desmopressin use were associated with serum sodium increases, especially during overnight shifts.

Digital image analysis allows objective stratification of patients with silent PIT1-lineage pituitary neuroendocrine tumors.

Studies describing the clinical presentation and prognosis of patients with silent PIT1 (pituitary specific transcription factor)-lineage pituitary neuroendocrine tumors (PitNETs) are rare. We identified patients with positive PIT1 tumor staining but without evidence of hormone hypersecretion at a tertiary center. Clusters were obtained according to cell morphology and immunostaining from each patient's digitally segmented whole slide image. We compared the clinical presentations, radiological features, and prognoses of the different clusters. We identified 146 patients (68 male, 42.9 ± 14.1 years old) with silent PIT1-lineage PitNETs. Morphology clustering suggested that tumors with large nuclei and apparent eccentricity were associated with a higher proportion of aggressiveness and a higher hazard of recurrence [hazard ratio (HR): 2.64, (95% CI, 1.06-6.55), p = 0.037]. Immunohistochemical clustering suggested that tumors with thyroid stimulating hormone (TSH) staining or all negative PIT1-lineage hormones were associated with a higher proportion of aggressiveness and a higher risk of recurrence [HR: 12.4, (95% CI, 1.60-93.5), p = 0.015]. We obtained three-tier risk profiles by combining morphological and immunohistochemical clustering. Patients with the high-risk profile presented the highest recurrence rate compared with those in the medium-risk and low-risk profiles [HR: 3.54, (95% CI, 1.40-8.93), p = 0.002]. In conclusion, digital image analysis based on cell morphology and immunohistochemical staining allows objective stratification of patients with silent PIT1-lineage tumors. Typical morphological characteristics of high-risk tumors are large tumor nuclei and high eccentricity, and typical immunostaining characteristics are TSH staining or negative staining for all PIT1-lineage hormones.

Ectopic recurrence craniopharyngioma: series report and literature review.

BACKGROUND: Craniopharyngioma is a common intracranial tumor located in the sellar-suprasellar region. Due to the involvement of adjacent structures, it can lead to increased intracranial pressure, visual impairment, and endocrine deficiencies. Surgical resection is the primary treatment, but it is a tough challenge to achieve total resection, which will led to the frequency of recurrences and progressions. Among them, distant spread is extremely rare, but important complication, identifying and providing proper therapy, is crucial. METHODS: We report two cases of ectopic recurrence craniopharyngioma and make a literature review for the published similar case reports. RESULTS: Our literature review revealed 63 cases (including our patient). The onset age in children group and adult group ranges from 2-14 years old (6.70 ± 3.33) to 17-73 years old (40.63 ± 15.58), while the interval year between tumor initiation and ectopic recurrence ranges from 0.17-20 (7.28 ± 6.76) years to 0.3-34 (6.85 ± 7.29). Achieving gross total resection seems not to prevent the ectopic recurrence. The major pathology of ectopic recurrence craniopharyngioma is adamantinomatous type. The most common site of ectopic recurrence is frontal lobe. According to the pathogenesis, 35 cases were seeding along the surgical approach, and 28 cases were seeding via the CSF pathway. CONCLUSION: Ectopic recurrence craniopharyngioma is rare, but it can lead to serious symptoms. Delicate surgical procedure can help to reduce the risk of ectopic recurrence, and standardized follow-up can provide valuable information for treatment.

Machine learning prediction of venous thromboembolism after surgeries of major sellar region tumors.

PURPOSE: To describe and predict the risk of venous thromboembolism (VTE) after surgical resection of major sellar region tumors. METHOD: Patients with sellar region tumors were identified from a database. The outcome was VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) within 60 days after surgery. We trained regression and machine learning models to predict the outcome using baseline characteristics, surgical findings and postoperative laboratory tests. RESULTS: Among 3818 patients included, 124 patients developed VTE after surgery. The total 60-day VTE incidence was 3.2 %, with incidence peak within ten days after the surgery. The risk increased in patients >65 years old (OR 2.96, p < 0.001), in patients with chordoma (OR 3.40, p = 0.006) or craniopharyngioma (OR 1.86, p = 0.036), in patients underwent craniotomy approach (OR 2.78, p = 0.017), in patients with high volume CSF leakage (OR 4.24, p < 0.001), and in patients with longer surgical duration (OR 1.78, p = 0.029). The linear discriminant analysis algorithm had the highest AUC (0.869, 95%CI, 0.840-0.898) in predicting the outcome. The specificity, accuracy, and sensitivity of the best model were 61.8 %, 93.6 %, and 92.8 %, respectively. Risk stratification using our best model suggested that 1.3 % and 24.5 % of the patient developed VTE in the low-risk group and in the high-risk group, respectively. We developed an online decision-support tool available on https://deepvep.shinyapps.io/VTEpred/. CONCLUSION: The overall incidence of VTE after surgical resection of major sellar region tumors was clinically significant, especially in older patients with chordoma or craniopharyngioma.

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.

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.

Single-cell transcriptome reveals cellular hierarchies and guides p-EMT-targeted trial in skull base chordoma.

Skull base chordoma (SBC) is a bone cancer with a high recurrence rate, high radioresistance rate, and poorly understood mechanism. Here, we profiled the transcriptomes of 90,691 single cells, revealed the SBC cellular hierarchies, and explored novel treatment targets. We identified a cluster of stem-like SBC cells that tended to be distributed in the inferior part of the tumor. Combining radiated UM-Chor1 RNA-seq data and in vitro validation, we further found that this stem-like cell cluster is marked by cathepsin L (CTSL), a gene involved in the packaging of telomere ends, and may be responsible for radioresistance. Moreover, signatures related to partial epithelial-mesenchymal transition (p-EMT) were found to be significant in malignant cells and were related to the invasion and poor prognosis of SBC. Furthermore, YL-13027, a p-EMT inhibitor that acts through the TGF-ß signaling pathway, demonstrated remarkable potency in inhibiting the invasiveness of SBC in preclinical models and was subsequently applied in a phase I clinical trial that enrolled three SBC patients. Encouragingly, YL-13027 attenuated the growth of SBC and achieved stable disease with no serious adverse events, underscoring the clinical potential for the precision treatment of SBC with this therapy. In summary, we conducted the first single-cell RNA sequencing of SBC and identified several targets that could be translated to the treatment of SBC.

Global changes in chromatin accessibility and transcription in growth hormone-secreting pituitary adenoma.

PURPOSE: Growth hormone-secreting pituitary adenoma (GHPA) is an insidious disease with persistent hypersecretion of growth hormone and insulin-like growth factor 1, causing increased morbidity and mortality. Previous studies have investigated the transcription of GHPA. However, the gene regulatory landscape has not been fully characterized. The objective of our study was to unravel the changes in chromatin accessibility and transcription in GHPA. METHODS: Six patients diagnosed with GHPA in the Department of Neurosurgery at Huashan Hospital were enrolled in our study. Primary pituitary adenoma tissues and adjacent normal pituitary specimens with no morphologic abnormalities from these six patients were obtained at surgery. RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were applied to investigate the underlying relationship between gene expression and chromatin accessibility changes in GHPA. RESULTS: Totally, 1528 differential expression genes (DEGs) were identified by transcriptomics analyses, including 725 up-regulated and 803 down-regulated. Further, we obtained 64 significantly DEGs including 10 DEGs were elevated and 54 DEGs were negligibly expressed in tumors tissues. The up-regulated DEGs were mainly involved in terms related to synapse formation, nervous system development and secretory pathway. In parallel, 3916 increased and 2895 decreased chromatin-accessible regions were mapped by ATAC-seq. Additionally, the chromatin accessible changes were frequently located adjacent to transcription factor CTCF and Rfx2 binding site. CONCLUSIONS: Our results are the first to demonstrate the landscape of chromatin accessibility in GHPA, which may contribute to illustrate the underlying transcriptional regulation mechanism of this disease.

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.

Low-rank fusion convolutional neural network for prediction of remission after stereotactic radiosurgery in patients with acromegaly: a proof-of-concept study.

Artificial intelligence approaches to analyze pathological images (pathomic) for outcome prediction have not been sufficiently considered in the field of pituitary research. A total of 5,504 hematoxylin & eosin-stained pathology image tiles from 58 acromegalic patients with a good or poor outcome were integrated with other clinical and genetic information to train a low-rank fusion convolutional neural network (LFCNN). The model was externally validated in 1,536 patches from an external cohort. The primary outcome was the time to the first endocrine remission after stereotactic radiosurgery (SRS). The median time of initial endocrine remission was 43 months (interquartile range [IQR]: 13-60 months) after SRS, and the 24-month initial cumulative remission rate was 57.9% (IQR: 46.4-72.3%). The patient-wise accuracy of the LFCNN model in predicting the primary outcome was 92.9% in the internal test dataset, and the sensitivity and specificity were 87.5 and 100.0%, respectively. The LFCNN model was a strong predictor of initial cumulative remission in the training cohort (hazard ratio [HR] 9.58, 95% confidence interval [CI] 3.89-23.59; p < 0.001) and was higher than that of established prognostic markers. The predictive value of the LFCNN model was further validated in an external cohort (HR 9.06, 95% CI 1.14-72.25; p = 0.012). In this proof-of-concept study, clinically and genetically useful prognostic markers were integrated with digital images to predict endocrine outcomes after SRS in patients with active acromegaly. The model considerably outperformed established prognostic markers and can potentially be used by clinicians to improve decision-making regarding adjuvant treatment choices. © 2022 The Pathological Society of Great Britain and Ireland.

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.

Recommendation to improve the WHO classification of posterior pituitary tumors as a unique entity: evidence from a large case series.

Introduction: Most studies reporting posterior pituitary tumors (PPTs) are small case series or single cases. Methods: Patients with a histological diagnosis of PPT from January 2010 to December 2021 in a tertiary center were identified. We reported clinical symptoms, endocrine assessments, radiological and pathological features, and surgical outcomes of PPTs. Results: A total of 51 patients (23 males, 51.3 ± 10.3 years old) with PPT were included in this study. Major symptoms were visual defects, headache, and hypopituitarism, while diabetes insipidus was uncommon (9.8%). The typical radiological feature was homogeneous enhancement (84.3%) of a regular-shaped mass on T1 contrast imaging without cystic change, calcification, or cavernous sinus invasion. We achieved gross total resection in 38/51 patients (74.5%). Pathologically, all tumors showed thyroid transcription factor 1 immunoreactivity. Among 29 patients with suprasellar PPTs, postoperative hemorrhage due to tumor residue was encountered in 2/15 cases in the transcranial group and 0/14 in the endoscopy group. Patients with spindle cell oncocytoma (SCO) were more likely to be surgically treated (25% vs 0%, P = 0.018), harbor a higher Ki-67 index (16.7% vs 0% > 5% P = 0.050), and present a lower 2-year recurrence-free survival rate (67.5% vs 90.9%) compared with patients with pituicytoma or granular cell tumor. Conclusion: PPTs should be considered in the differential diagnosis of patients with sellar and suprasellar masses with a regular lesion with homogeneous enhancement. SCOs had high proliferation activity and risk of recurrence.

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.