CD87-targeted BiTE and CAR-T cells potently inhibit invasive nonfunctional pituitary adenomas.

Recently, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor-modified T cells (CAR-Ts) have been shown to have high therapeutic efficacy in hematological tumors. CD87 is highly expressed in solid tumors with an oncogenic function. To assess their cytotoxic effects on invasive nonfunctioning pituitary adenomas (iNFPAs), we first examined CD87 expression and its effects on the metabolism of iNFPA cells. We generated CD87-specific BiTE and CAR/IL-12 T cells, and their cytotoxic effects on iNFPAs cells and in mouse models were determined. CD87 had high expression in iNFPA tissue and cell samples but was undetected in noncancerous brain samples. CD87×CD3 BiTE and CD87 CAR/IL-12 T-cells showed antigenic specificity and exerted satisfactory cytotoxic effects, decreasing tumor cell proliferation in vitro and reducing existing tumors in experimental mice. Overall, the above findings suggest that CD87 is a promising target for the immunotherapeutic management of iNFPAs using anti-CD87 BiTE and CD87-specific CAR/IL-12 T cells.

Unraveling dynamic immunological landscapes in intracerebral hemorrhage: insights from single-cell and spatial transcriptomic profiling.

Intracerebral hemorrhage (ICH) poses a formidable challenge in stroke management, with limited therapeutic options, particularly in the realm of immune-targeted interventions. Clinical trials targeting immune responses post-ICH have encountered setbacks, potentially attributable to the substantial cellular heterogeneity and intricate intercellular networks within the brain. Here, we present a pioneering investigation utilizing single-cell RNA sequencing and spatial transcriptome profiling at hyperacute (1 h), acute (24 h), and subacute (7 days) intervals post-ICH, aimed at unraveling the dynamic immunological landscape and spatial distributions within the cerebral tissue. Our comprehensive analysis revealed distinct cell differentiation patterns among myeloid and lymphocyte populations, along with delineated spatial distributions across various brain regions. Notably, we identified a subset of lymphocytes characterized by the expression of Spp1 and Lyz2, termed macrophage-associated lymphocytes, which exhibited close interactions with myeloid cells. Specifically, we observed prominent interactions between Lgmn+Macro-T cells and microglia through the spp1-cd44 pathway during the acute phase post-ICH in the choroid plexus. These findings represent a significant advancement in our understanding of immune cell dynamics at single-cell resolution across distinct post-ICH time points, thereby laying the groundwork for exploring critical temporal windows and informing the development of targeted therapeutic strategies.

Stereotactically intracerebral transplantation of neural stem cells for ischemic stroke attenuated inflammatory responses and promoted neurogenesis: an experimental study with monkeys.

BACKGROUND: Ischemic stroke is a common neurovascular disorder with high morbidity and mortality. However, the underlying mechanism of stereotactically intracerebral transplantation of human neural stem cell (hNSC) is not well elucidated. MATERIALS AND METHODS: Four days after ischemic stroke induced by Rose Bengal photo-thrombosis, 7 cynomolgus monkeys were transplanted with hNSCs or vehicles stereotactically and followed up for 84 days. Behavioral assessments, magnetic resonance imaging, blood tests, and pathological analysis were performed before and after treatment. The proteome profiles of the left and right precentral gyrus and hippocampus were evaluated. Extracellular vesicle micro-RNA (miRNA) from the peripheral blood was extracted and analyzed. RESULTS: hNSC transplantation reduced the remaining infarcted lesion volume of cynomolgus monkeys with ischemic stroke without remarkable side effects. Proteomic analyses indicated that hNSC transplantation promoted GABAergic and glutamatergic neurogenesis, and restored the mitochondrial electron transport chain function in the ischemic infarcted left precentral gyrus or hippocampus. Immunohistochemical staining and qRT-PCT confirmed the promoting effects on neurogenesis and revealed that hNSCs attenuated post-infarct inflammatory responses by suppressing resident glia activation and mediating peripheral immune cell infiltration. Consistently, miRNA-sequencing revealed the miRNAs which were related to these pathways were down-regulated after hNSC transplantation. CONCLUSIONS: This study indicates that hNSCs can be effectively and safely used to treat ischemic stroke by promoting neurogenesis, regulating post-infarct inflammatory responses, and restoring mitochondrial function in both the infarct region and hippocampus.

Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Phenotype Transformation of PitNETs.

Phenotype transformation in pituitary neuroendocrine tumors is a little-known and unpredictable clinical phenomenon. Previous studies have not clearly defined and systematically concluded on the causes of this rare phenomenon. Additionally, the mechanisms of phenotype transformation are not well known. We reviewed cases reported in the literature with the aim of defining phenotype transformation in pituitary neuroendocrine tumors. We present an overview of the wide spectrum of phenotype transformation and its clinical features. We also discuss findings on the potential mechanism of this rare transformation, which may be related to PC1/3, the bioactivity of secretory hormones, gene mutations and the plasticity of pituitary neuroendocrine tumors. Clinicians should be aware of this rare phenomenon and more studies on the underlying mechanisms are required.

Considering Context-Specific microRNAs in Ischemic Stroke with Three "W": Where, When, and What.

MicroRNAs are short non-coding RNA molecules that function as critical regulators of various biological processes through negative regulation of gene expression post-transcriptionally. Recent studies have indicated that microRNAs are potential biomarkers for ischemic stroke. In this review, we first illustrate the pathogenesis of ischemic stroke and demonstrate the biogenesis and transportation of microRNAs from cells. We then discuss several promising microRNA biomarkers in ischemic stroke in a context-specific manner from three dimensions: biofluids selection for microRNA extraction (Where), the timing of sample collection after ischemic stroke onset (When), and the clinical application of the differential-expressed microRNAs during stroke pathophysiology (What). We show that microRNAs have the utilities in ischemic stroke diagnosis, risk stratification, subtype classification, prognosis prediction, and treatment response monitoring. However, there are also obstacles in microRNA biomarker research, and this review will discuss the possible ways to improve microRNA biomarkers. Overall, microRNAs have the potential to assist clinical treatment, and developing microRNA panels for clinical application is worthwhile.

The advantages of multi-level omics research on stem cell-based therapies for ischemic stroke.

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.

Human neural stem cells.

'Human neural stem cells' jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research, is the first guideline for human neural stem cells (hNSCs) in China. This standard specifies the technical requirements, test methods, test regulations, instructions for use, labelling requirements, packaging requirements, storage requirements, transportation requirements and waste disposal requirements for hNSCs, which is applicable to the quality control for hNSCs. It was originally released by the China Society for Cell Biology on 30 August 2022. We hope that publication of the guideline will facilitate institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardization of hNSCs for clinical development and therapeutic applications.

Integrating network pharmacology and transcriptomic omics reveals that akebia saponin D attenuates neutrophil extracellular traps-induced neuroinflammation via NTSR1/PKAc/PAD4 pathway after intracerebral hemorrhage.

Neutrophils and their production of neutrophil extracellular traps (NETs) significantly contribute to neuroinflammation and brain damage after intracerebral hemorrhage (ICH). Although Akebia saponin D (ASD) demonstrates strong anti-inflammatory activities and blood-brain barrier permeability, its role in regulating NETs formation and neuroinflammation following ICH is uncharted. Our research focused on unraveling the influence of ASD on neuroinflammation mediated by NETs and the mechanisms involved. We found that increased levels of peripheral blood neutrophils post-ICH are correlated with worse prognostic outcomes. Through network pharmacology, we identified ASD as a promising therapeutic target for ICH. ASD administration significantly improved neurobehavioral performance and decreased NETs production in neutrophils. Furthermore, ASD was shown to upregulate the membrane protein NTSR1 and activate the cAMP signaling pathway, confirmed through transcriptome sequencing, western blot, and immunofluorescence. Interestingly, the NTSR1 inhibitor SR48692 significantly nullified ASD's anti-NETs effects and dampened cAMP pathway activation. Mechanistically, suppression of PKAc via H89 negated ASD's anti-NETs effects but did not affect NTSR1. Our study suggests that ASD may reduce NETs formation and neuroinflammation, potentially involving the NTSR1/PKAc/PAD4 pathway post-ICH, underlining the potential of ASD in mitigating neuroinflammation through its anti-NETs properties.

Resting-state functional connectivity in a non-human primate model of cortical ischemic stroke in area F1.

BACKGROUND: The application of functional MRI to non-human primates after stroke has not yet been undertaken. This is the first study to explore the functional connectivity changes in non-human primate models during acute stages after stroke onset. METHODS: Nineteen healthy male cynomolgus monkeys (4-5 years) were used in this study. The photothrombosis model was employed to induce focal ischemic stroke in F1 area in the monkey's left hemisphere. T1-weighted structural images and resting-state functional magnetic resonance imaging (rs-fMRI) of all subjects were obtained using a 3.0 Tesla MRI system on the third day following stroke. Based on the D99 atlas, the structural and functional changes of bilateral F1 areas in monkeys were analyzed using region of interest (ROI)-based functional connectivity (FC). The bilateral F1 areas were selected as the seed regions due to their crucial role in motor control and their potential to unveil the comprehensive functional reorganization of the motor system at a whole-brain level following stroke. RESULTS: Ischemic lesions were observed after the stroke, with larger lesion volumes associated with poorer neurological dysfunction. Compared with baseline condition, left area F1 demonstrated decreased FC with the left cerebellum, left ventral pons and left 5_(PEa). When the ROI was located in the right area F1, ischemic monkeys showed decreased FC in left ventral pons, left cerebellum, left primary visual cortex and left 5_(PEa), accompanied by increased FC in the right orbitofrontal cortex. Importantly, the degree of altered FC between left area F1 and left cerebellum was associated with upper limb tone. CONCLUSIONS: These results provide valuable insights into the early-stage functional connectivity changes in the F1 areas of monkeys under ischemic conditions, highlighting the potential involvement of specific brain regions in the pathophysiology of ischemic injury.

Preoperative and postoperative blood testosterone levels in patients with acromegaly: a prospective study.

Purpose: To investigate the prevalence of low blood testosterone level (LTL) and its determinant factors among active male acromegaly patients, as well as the effect of surgery on LTL in male acromegaly patients. Methods: A retrospective, single-center study focused on 252 male acromegaly patients aged 18 years-60 years diagnosed in the Peking Union Medical College Hospital from January 2015 to December 2018 was carried out. The measurements of preoperative and postoperative testosterone levels, serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and other clinical data were analyzed. Results: Forty per cent of subjects included were diagnosed with LTL pre surgery. Patients were divided into normal testosterone level (NTL) and LTL groups based on their testosterone level. There were significant differences (p < 0.01) between groups in the presence of macroadenomas, invasion of the cavernous sinus, compression of the optic chiasm, and serum GH and prolactin levels pre surgery. Invasion of the cavernous sinus [odds ratio (OR) = 4.299; p = 0.000] and serum prolactin level (OR = 1.023, p = 0.001) were independent predictors of LTLs in male patients before surgical intervention. A total of 67.9% of LTL patients recovered during the follow-up, with a new-onset rate of 3.4%. Body mass index, invasion of the cavernous sinus, GH, IGF-1, and prolactin levels, the presence of a prolactin-secreting tumor, and recovery from acromegaly were significantly different (p < 0.05) in the NTL group and in the LTL group during the follow-up. The presence of a prolactin-secreting tumor (OR = 0.224; p = 0.001) and recovery from acromegaly (OR = 0.168; p = 0.006) were independent predictors of LTLs in male acromegaly patients during the follow-up. Conclusion: The invasiveness of tumor and levels of blood prolactin are independent factors for LTLs before surgery, whereas GH and IGF-1 levels are not. Most male patients can recover from LTL after tumor restriction surgery: those who recover from acromegaly have a better chance of recovering from LTL.

Efficacy and Safety of Bone Marrow Derived Stem Cell Therapy for Ischemic Stroke: Evidence from Network Meta-analysis.

BACKGROUND: Several types of stem cells are available for the treatment of stroke patients. However, the optimal type of stem cell remains unclear. OBJECTIVE: To analyze the effects of bone marrow-derived stem cell therapy in patients with ischemic stroke by integrating all available direct and indirect evidence in network meta-analyses. METHODS: We searched several databases to identify randomized clinical trials comparing clinical outcomes of bone marrow-derived stem cell therapy vs. conventional treatment in stroke patients. Pooled relative risks (RRs) and mean differences (MDs) were reported. The surface under the cumulative ranking (SUCRA) was used to rank the probabilities of each agent regarding different outcomes. RESULTS: Overall, 11 trials with 576 patients were eligible for analysis. Three different therapies, including mesenchymal stem cells (MSCs), mononuclear stem cells (MNCs), and multipotent adult progenitor cells (MAPCs), were assessed. The direct analysis demonstrated that stem cell therapy was associated with significantly reduced all-cause mortality rates (RR 0.55, 95% CI 0.33 to 0.93; I2=0%). Network analysis demonstrated MSCs ranked first in reducing mortality (RR 0.42, 95% CrI 0.15 to 0.86) and improving modified Rankin Scale score (MD -0.59 95% CI -1.09 to -0.09), with SUCRA values 80%, and 98%, respectively. Subgroup analysis showed intravenous transplantation was superior to conventional therapy in reducing all-cause mortality (RR 0.53, 95% CrI 0.29 to 0.88). CONCLUSION: Using stem cell transplantation was associated with reduced risk of death and improved functional outcomes in patients with ischemic stroke. Additional large trials are warranted to provide more conclusive evidence.

Exosomal RNAs in the development and treatment of pituitary adenomas.

Exosomes are small extracellular vesicles that carry various bioactive molecules including various RNAs that modulate the activities of recipient cells. It has drawn considerable attention as means of cell communication and drug delivery. Exosome plays important role in various tumors, but it is rarely summarized in pituitary adenoma (PA). PA is the second most common primary central nervous system tumor, and its recurrence and persistent postoperative hormone hypersecretion lead to compromised quality of life. How exactly exosomes impact tumor development and hormone secretion is important for the development of this tumor diagnosis and treatment. In this review, we discuss how exosomal RNAs impact PAs and their potential as future clinical therapies. In our literature review, first, we found that exosomal microRNA hsa-miR-1180-3p is a potential early biomarker for NFPAs. Since NFPAs are typically difficult to diagnose, this is an especially important finding. Second, exosomal protein transcripts are potential invasive biomarker, such as MMP1, N-cadherin, CDK6, RHOU, INSM1, and RASSF10. Third, exosomal contents such as hsa-miR-21-5p promote distant bone formation of GHPA patients. Fourth, tumor suppressors in the exosome constitute novel therapeutic application of exosome, including long noncoding RNA (lncRNA) H19, miR-149-5p, miR-99a-3p, and miR-423-5p. This review discusses the possible mechanisms of exosome and their contents in PA and promotes the use of exosomes in both clinical diagnosis and treatment of this tumor.

Impact of Penicillin Allergy-Based Alternative Antibiotics on the Risk of Postoperative Central Nervous System Infection: A Retrospective Cohort Study.

BACKGROUND: Central nervous system (CNS) infection is one of the most serious complications after neurosurgery. This study aimed to analyze the effect of penicillin allergy (PA) and alternative prophylactic antibiotics on risk of postoperative CNS infection in patients undergoing neurosurgery. METHODS: Data of patients who underwent neurosurgical procedures from January 2015 to December 2021 were analyzed retrospectively. Patients with PA were compared with patients without PA in a 1:1 ratio. A multivariate logistic regression model was used to examine whether PA was a risk factor for postoperative CNS infection. RESULTS: Overall, 15,049 eligible neurosurgical records were reviewed, from which 578 surgical records of 556 patients with PA were matched to 578 records of 570 patients without PA. Patients with PA showed significantly lower probability to receive prophylactic cephalosporins (55.9% vs. 98.8%, P < 0.01), but significantly higher probability to receive clindamycin (41.86% vs. 1.03%, P < 0.01), than patients without PA. Multivariate analysis revealed that patients with PA were more likely to experience postoperative CNS infection than patients without PA (odds ratio = 2.03; 95% confidence interval, 1.15-3.56; P = 0.014). The incidence of postoperative CNS infection returned to a level comparable to that in general population when patients with suspected PA received prophylactic cephalosporins. CONCLUSIONS: PA is associated with higher risk of postoperative CNS infection in patients undergoing neurosurgery. This may be attributed to the use of alternative prophylactic antibiotics other than cephalosporins, especially clindamycin.

Neural Stem Cells in the Treatment of Alzheimer's Disease: Current Status, Challenges, and Future Prospects.

Alzheimer's disease (AD), a progressive dementia, is one of the world's most dangerous and debilitating diseases. Clinical trial results of amyloid-ß (Aß) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Further understanding of the mechanisms underlying AD and the development of novel therapeutic options are critical. Neurogenesis is impaired in AD, which contributes to memory deficits. Transplanted neural stem cells (NSCs) can regenerate degraded cholinergic neurons, and new neurons derived from NSCs can form synaptic connections with neighboring neurons. In theory, employing NSCs to replace and restore damaged cholinergic neurons and brain connections may offer new treatment options for AD. However there remain barriers to surmount before NSC-based therapy can be used clinically. The objective of this article is to describe recent advances in the treatment of AD models and clinical trials involving NSCs. In addition, we discuss the challenges and prospects associated with cell transplant therapy for AD.

The Clinical and Pathological Characteristics of Refractory Pituitary Adenomas: A Single Center Experience.

Background: Most of pituitary adenomas (PAs) are slow-growing benign tumors which can be cured or controlled by conventional therapies, including surgery, medical treatment or radiotherapy. A small set of PAs, usually known as aggressive PAs or refractory PAs, present with more aggressive behavior and lead to poorer prognosis than classical PAs. Methods: We retrospectively analyzed the clinical and pathological characteristics of 44 patients who were diagnosed with refractory PAs by a multidisciplinary team (MDT). All the patients' demographic characteristics, radiological findings, Knosp grade, treatment details and clinical outcomes were abstracted from the medical records. Additionally, 44 patients with nonrefractory PAs (NRPAs) matched for age and gender were selected to serve as the control group. Results: Despite using all combined treatments including surgery, radiotherapy and conventional medical treatments, all the refractory PAs showed tumor progression or hormone hypersecretion which caused increased morbidity and mortality and remained challenging to management. Compared with those of the non-refractory PAs, the tumor size, invasive rate and tumor growth rate (TGR) were significantly higher in the refractory PAs. TGR >2.2% per month may be considered as a preoperative indicator of refractoriness. The Ki-67 index in the refractory PAs were all ≥3%. EGFR, but not MMP2 or MMP9, was significantly overexpressed in refractory PAs compared with the corresponding levels in nonrefractory PAs. Conclusion: Refractory PAs are unresponsive to surgery, radiotherapy and conventional medical treatments with a poor prognosis. Moreover, a TGR ≥2.2% per month, Ki-67 index ≥3% and EGFR overexpression may be independent predictors of clinical refractoriness.

Multi-Omics Investigations Revealed Underlying Molecular Mechanisms Associated With Tumor Stiffness and Identified Sunitinib as a Potential Therapy for Reducing Stiffness in Pituitary Adenomas.

Purpose: Pituitary adenomas (PAs) are the second most common intracranial neoplasms. Total surgical resection was extremely important for curing PAs, whereas tumor stiffness has gradually become the most critical factor affecting the resection rate in PAs. We aimed to investigate the molecular mechanisms of tumor stiffening and explore novel medications to reduce stiffness for improving surgical remission rates in PA patients. Methods: RNA sequencing, whole-genome bisulfite sequencing, and whole exome sequencing were applied to identify transcriptomic, epigenomic, and genomic underpinnings among 11 soft and 11 stiff PA samples surgically resected from patients at Peking Union Medical College Hospital (PUMCH). GH3 cell line and xenograft PA model was used to demonstrate therapeutic effect of sunitinib, and atomic force microscopy (AFM) was used to detect the stiffness of tumors. Results: Tumor microenvironment analyses and immunofluorescence staining indicated endothelial cells (ECs) and cancer-associated fibroblasts (CAFs) were more abundant in stiff PAs. Weighted gene coexpression network analysis identified the most critical stiffness-related gene (SRG) module, which was highly correlated with stiff phenotype, ECs and CAFs. Functional annotations suggested SRGs might regulate PA stiffness by regulating the development, differentiation, and apoptosis of ECs and CAFs and related molecular pathways. Aberrant DNA methylation and m6A RNA modifications were investigated to play crucial roles in regulating PA stiffness. Somatic mutation analysis revealed increased intratumoral heterogeneity and decreased response to immunotherapy in stiff tumors. Connectivity Map analysis of SRGs and pRRophetic algorithm based on drug sensitivity data of cancer cell lines finally determine sunitinib as a promising agent targeting stiff tumors. Sunitinib inhibited PA growth in vitro and in vivo, and also reduced tumor stiffness in xenograft PA models detected by AFM. Conclusion: This is the first study investigating the underlying mechanisms contributing to the stiffening of PAs, and providing novel insights into medication therapy for stiff PAs.

Transsphenoidal Surgery of Corticotroph Adenomas With Cavernous Sinus Invasion: Results in a Series of 86 Consecutive Patients.

OBJECTIVE: Transsphenoidal surgery (TSS) is the first-line treatment for corticotroph adenomas. Although most corticotroph adenomas are noninvasive microadenomas, a small subset of them invading cavernous sinus (CS) is notoriously difficult to manage. The aim of this study was to evaluate the surgical outcome of corticotroph adenomas with CSI from a single center. PATIENTS AND METHODS: The clinical features and outcomes of CD patients who underwent TSS between January 2000 and September 2019 at Peking Union Medical College Hospital were collected from medical records. The clinical, endocrinological, radiological, histopathological, and surgical outcomes, and a minimum 12-month follow-up of patients with corticotroph adenomas invading CS were retrospectively reviewed. RESULTS: Eighty-six patients with corticotroph adenomas invading CS were included in the study. The average age at TSS was 37.7 years (range, 12 to 67 years), with a female-to-male ratio of 3.1:1 (65/21). The median duration of symptoms was 52.6 months (range, 1.0 to 264 months). The average of maximum diameter of tumor was 17.6 mm (range, 4.5-70 mm). All included 86 patients underwent TSS using a microscopic or an endoscopic approach. Gross total resection was achieved in 63 patients (73.3%), subtotal resection was attained in 18 (20.9%), and partial resection was achieved in 5 (5.8%). After surgery, the overall postoperative immediate remission rate was 48.8% (42/86); 51.2% (44/86) of patients maintained persistent hypercortisolism. In 42 patients with initial remission, 16.7% (7/42) experienced a recurrence. In these patients with persistent disease and recurrent CD, data about further treatment were available for 30 patients. Radiotherapy was used for 15 patients, and 4 (26.7%) of them achieved biochemical remission. Repeat TSS was performed in 5 patients, and none achieved remission. Medication was administered in 4 patients, and one of them obtained disease control. Adrenalectomy was performed in 6 patients, and 5 (83.3%) achieved biochemical remission. At the last follow-up, 10 of 30 patients (33.3%) were in remission, and 20 patients still had persistent disease.The remission rate in corticotroph adenomas with cavernous sinus invasion (CSI) that underwent gross total resection and first TSS was significantly higher than that in patients undergoing subtotal resection, partial resection, and a second TSS (all p < 0.05). However, there was no significant difference in the remission rate between patients with different tumor sizes, Knosp grades, and surgical approaches (p > 0.05). CONCLUSION: The management of corticotroph adenomas with CSI remain a therapeutic challenge due to incomplete resection of invasive and/or a large adenoma. With the application of multiple techniques, approximately half of the patients could achieve gross total resection and biochemical remission via TSS by experienced neurosurgeons. The extent of tumor resection and the number of operations were associated with surgical remission rate in corticotroph adenomas with CSI. If the remission was not achieved by surgery, other treatments including radiotherapy, medical therapy, and even bilateral adrenalectomy are required.

Determinants of immediate and long-term remission after initial transsphenoidal surgery for acromegaly and outcome patterns during follow-up: a longitudinal study on 659 patients.

OBJECTIVE: Treatment outcomes following initial transsphenoidal surgery (TSS) for acromegaly are erratic. Identifying outcome patterns can assist in informing patients about possible treatment outcomes and planning for individualized adjuvant treatments in advance. In this study, the authors aimed to investigate the immediate and long-term endocrine remission rates following initial TSS for acromegaly, identify clinical determinants of treatment outcomes, and explore outcome patterns during a long-term follow-up and the pattern-specific patient features. METHODS: This prospective, single-center, longitudinal cohort study enrolled patients with acromegaly who underwent TSS in the period from 2015 to 2018 at the authors' institution. Immediate remission, assessed on the 2nd postoperative morning, and long-term remission, assessed at least 18 months after TSS, were evaluated according to the strict 2010 consensus criteria (random growth hormone [GH] < 1 ng/ml or GH nadir < 0.4 ng/ml after oral glucose tolerance test, and age- and sex-normalized insulin-like growth factor 1). Univariate and bivariate regression analyses were used to identify determinants of remission. RESULTS: A total of 659 patients with acromegaly (average age 42 years, 44% males) underwent TSS for pituitary adenomas (macroadenomas, 85%; invasive tumors, 35%) and were followed up during a median of 51 months. Immediate and long-term remission rates after initial TSS were 37% and 69%, respectively. Older age at diagnosis (OR 1.7), male sex (OR 1.6), smaller tumors (OR 2.0), noninvasive tumors (OR 4.8), and tumors positive for follicle-stimulating hormone/luteinizing hormone (OR 1.5) were predictors of immediate surgical remission. In addition to the above predictors, lower preoperative GH (OR 2.4), absence of preoperative central hypothyroidism (OR 2.6), and endoscopic TSS (OR 10.6) were predictors of long-term remission. Regression analyses revealed that endoscopic TSS (OR 2.8, 95% CI 1.524-5.291, p = 0.001), absence of cavernous sinus invasion (OR 4.1, 95% CI 2.522-6.613, p < 0.001), older age (OR 1.03, 95% CI 1.006-1.048, p = 0.013), and male sex (OR 2.0, 95% CI 1.224-3.247, p = 0.006) were independent determinants of long-term remission. Five outcome patterns were identified based on the changes in hormonal results during follow-up, including continuous remission (34%), refractory acromegaly (28%), delayed remission (21%), remission after adjuvant therapy (14%), and recurrence after initial remission (3%). The clinical characteristics of each subgroup were identified. CONCLUSIONS: Cavernous sinus invasion, age at diagnosis, and sex are the best determinants of immediate and long-term remission after initial TSS for acromegaly. Endoscopic TSS predicts a higher long-term remission rate than that with microscopic TSS. The authors identified five outcome patterns in acromegaly and group-specific patient characteristics for clinical decision-making.