One-and-a-half nostril versus binostril endoscopic transsphenoidal approach to the pituitary adenomas: A prospective randomized controlled trial.

Background: Binostril endoscopic transsphenoidal approach (BETA) is the most used approach for sellar lesions nowadays, while its damage to the nasal structures may cause nasal discomfort and affect nasal functions including respiration and olfaction. With the purpose to improve the post-operative sinonasal quality of life (QoL), we introduced the one-and-a-half nostril endoscopic transsphenoidal approach (OETA) in 2016 which preserved more natural structures and registered a prospective randomized controlled trial (ChiCTR-IOR-16008222) to compare the two approaches regarding the surgical outcomes and complications. Methods: Sixty patients with pituitary adenomas were recruited and randomly assigned to the OETA group and the BETA group between April 2016 and May 2017 in Jinling Hospital. The tumor resection rate, endocrinal and visual outcomes, and surgical complications between the OETA and BETA groups were analyzed. Besides, the questionnaire Anterior Skull Base Nasal Inventory-12 (ASK Nasal-12) was used to evaluate patients' sinonasal QoL at seven time points (pre-operative; 2-weeks, 1-month, 3-months, 6-months, 12-months, and long-term post-operatively). The Sniffin' Sticks were used to assess patients' olfactory function objectively in a long term. Each patient was followed for at least 12 months post-operatively. Results: There was no significant difference in tumor resection rate, hormonal and visual outcomes, and surgical complications between the two groups. Regarding the ASK Nasal-12, patients in the OETA group complained less about dried nasal material at 2 weeks after surgery (P = 0.017). One month after surgery, the OETA group had better olfaction function (P = 0.019) compared with the BETA group. However, there was no significant difference in early and long-term postoperative sinonasal QoL between the two approaches according to the entire ASK Nasal-12 metric. The results of the Sniffin' Sticks showed that the two groups had a similar olfactory performance at long-time follow-up. Conclusion: In this single tertiary center trial, the results showed that the OETA achieved the same surgical outcomes and post-operative sinonasal QoL as the BETA. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=13852, identifier: ChiCTR-IOR-16008222.

Evaluation of Surgical Freedom for One-and-a-Half Nostril, Mononostril, and Binostril Endoscopic Endonasal Transsphenoidal Approaches.

Objective This article determines which of the one-and-a-half nostril, mononostril, and binostril endoscopic endonasal transsphenoidal approaches provide a superior manipulation during surgery. Methods The three approaches were orderly performed on 10 silicon-injected cadaveric heads to quantitatively assess surgical freedom and attack angle for sella. Measurements were determined with a standardized method under neuronavigation system using data of computed tomography. Results The one-and-a-half nostril endoscopic transsphenoidal approach (OETA) offered superior exposed area than that of the mononostril approach (META), and similar to that of the binostril approach (BETA). For surgical freedom at anatomic targets, the OETA showed greater surgical flexibility at pituitary center, the right medial optic carotid recess (R-mOCR), the left mOCR, the medial intersection of the right cavernous internal carotid artery, and extension line of upper margin of the clivus (R-mICC) than those of the META, and similar to those of the BETA. For sagittal angle of attack to the R-mOCR, R-mICC, and L-mOCR, the OETA can provide better angular freedom for surgeon than that of the META, and similar to that of the BETA. The OETA had the same axial attack to the pituitary center with the BETA. The OETA and the META had limited surgical freedom at L-mICC, and both inferior to the BETA. Conclusion The OETA has similar exposed area, surgical freedom, and attack angle for most anatomic targets to the BETA without resecting contralateral nasal septal mucosa, and obviously superior to the META.

A Practical 3D-Printed Model for Training of Endoscopic and Exoscopic Intracerebral Hematoma Surgery with a Tubular Retractor.

OBJECTIVE: To present a three-dimensional (3D)-printed model that simulates endoscopic and exoscopic intracerebral hematoma (ICH) surgery with a tubular retractor. METHODS: We used 3D printing technology to develop the model that consisted of the skull frame and a replaceable inserted module. Edible gelatin and animal blood were placed into the module to mimic brain tissue and the hematoma. Twenty neurosurgeons were recruited to participate in our training program that required the use of an endoscope and an exoscope to aspirate the hematoma with a tubular retractor. Five postgraduates were asked to complete the entire training with the endoscope five times. Questionnaires were distributed for feedback after the training program. RESULTS: The more experienced surgeons obviously performed better than the rather inexperienced surgeons, verifying that our model could reflect the ability of the trainees. As the training progressed, the scores of the postgraduates increased, and the average score of the fifth training was obviously higher than the first score. No significant differences were observed in the trainees' performance with the endoscope and the exoscope. The feedback questionnaires showed the average score for value of the simulator as a training tool was a 3.65 (on a 4-point scale). Our model received better comments regarding the bone texture (mean: 3.20), the brain tissue texture (mean: 3.20), and the experience in aspirating the hematoma (mean: 3.10). The surgical position (mean: 2.95), surgical approach (mean: 2.90), and simulated brain tissue (mean: 2.85) should be improved. CONCLUSION: Our model was practical for endoscopic and exoscopic ICH surgery training. The results of our program showed that prior surgical experience benefited the mastery of both the endoscopic and the exoscopic ICH surgery in the 3D-printed model. Our model could make mastering basic skills more efficient.

Bromocriptine and cabergoline induce cell death in prolactinoma cells via the ERK/EGR1 and AKT/mTOR pathway respectively.

The treatment of hyperprolactinemia is based on the use of dopamine agonists, mainly bromocriptine (BRC) and cabergoline (CAB). They reduce tumour size effectively and restore gonadal function. However, there is a difference in drug sensitivity between CAB and BRC in patients with prolactinoma, although the underlying mechanisms are still unknown. Thus, we investigated whether there are differences in tumour sensitivity to CAB and BRC and their possible differential mechanisms in two prolactinoma cell lines. In our study, we found that GH3 cells are more sensitive to BRC and that MMQ cells are more sensitive to CAB. Moreover, BRC and CAB elicited cell death via different pathways; BRC induced prolactinoma cell death mainly through the apoptosis pathway, and CAB induced pituitary prolactinoma cell death mainly via the autophagic cell death pathway. Using gene microarray analysis, we found that BRC induces the apoptosis of prolactinoma cells through the ERK/EGR1 signalling pathway, whereas CAB induces autophagic death by inhibiting the AKT/mTOR signalling pathway. Our study showed the difference in tumour sensitivity and differential mechanisms in BRC- and CAB-treated prolactinoma cells, which provides a theoretical basis for the accurate treatment of prolactinoma.

Unexpected Intracranial Hemorrhage and Death After Cranioplasty in a Patient With Massive Hemispheric Infarction.

The benefits and common complications of cranioplasty are often mentioned, but fatal complications are rarely documented. Here, the authors report a patient of intracranial hemorrhage and death after cranioplasty and discussed the possible mechanism. A 42-year-old man was admitted with the diagnosis of massive cerebral infarction in left fronto-temporo- parietal lobe, emergency surgery for decompressive large craniotomy and Encephalo-Myo-Synangiosis were performed. One year after surgery, cranioplasty was performed using a titanium mesh plate. Intraoperative cerebrospinal fluid leakage was occurred and dura mater was repaired using pieces of silk. During the postoperative anesthesia emergence, the patient had epileptic seizures and did not wake after surgery. The authors also observed about 150 mL bloody cerebrospinal fluid (CSF) in the subcutaneous vacuum drainage system within 2 hours. Emergency computed tomography of the brain showed epidural, subdural, subarachnoid hemorrhages in the postischemic area, the middle line left, and the brain stem swelling. The patient's family refused to immediately remove the titanium mesh plate. Finally, nonoperative treatment is invalid and the patient's neurological condition did not recover and he died 3 days after the surgery. In the authors' mind, patients with previous massive cerebral infarction and Encephalo-Myo-Synangiosis undergoing cranioplasty might be at heightened risk of a fatal event than other cranioplasty. Therefore, the patients should be paid more attention to prevent and treat the fatal complications.

MEG3 is associated with gsp oncogene regulation of growth hormone hypersecretion, proliferation and invasiveness of human GH-secreting adenomas.

Overactivation of the Gs-mediated pathway by mutations of the G-protein α subunit (Gsα), a gsp oncogene, results in increased growth hormone (GH) hypersecretion and reduced tumor volume in patients with GH-secreting pituitary tumors. However, the mechanism underlying the clinical characteristics of gsp oncogene requires further investigation. Cyclic adenosine monophosphate-responsive element binding (CREB), as a downstream target gene of gsp oncogene, is implicated in activating maternally expressed gene 3 (MEG3). The present study proposes that gsp oncogene mediates MEG3-regulating GH hypersecretion, resulting in the small tumor size of GH-secreting tumors. Therefore, the present study detected Gsα mutations by polymerase chain reaction in GH-secreting tumors, and revealed that Gsα mutations were observed in 7/25 (28%) GH-secreting tumors. Gsp-positive tumors indicated significantly increased levels of phosphorylated p-CREB (P<0.0001) and MEG3 (P=0.039), compared with gsp-negative tumors. The results indicated that MEG3 levels were positively correlated with GH and IGF-1 levels, and negatively correlated with the tumor volume of GH-secreting tumors. The group with gsp-positive or with high MEG3 expression indicated a significantly reduced proportion of invasiveness and lower Ki-67 index, compared with the gsp-negative or low MEG3 expression group. In conclusion, gsp oncogene may mediate MEG3 by promoting GH hypersecretion, resulting in smaller tumors, as well as suppressing proliferation and invasiveness of GH-secreting pituitary tumors.

Universal Sellar Anatomical Reconstruction Using the Sellar Floor Flap after Endoscopic Pituitary Adenoma Surgery.

Postoperative cerebrospinal fluid (CSF) leaks still occur in patients without intraoperative CSF leaks after endoscopic endonasal pituitary adenoma surgery. We propose a reconstructive technique, the sellar floor flap (SFF), for universal sellar anatomical reconstruction. A total of 113 patients without intraoperative CSF leaks after endoscopic endonasal pituitary adenoma surgery from July 2013 to June 2016 were reviewed: 43 underwent sellar reconstruction with the SFF (the SFF group) and 70 underwent sellar packing only (the nonreconstruction group). No case of postoperative CSF leak was reported in the SFF group, whereas 7 cases were reported in the nonreconstruction group ( P < .05). The SFF is suitable for universal reconstruction after endoscopic endonasal pituitary adenoma surgery and may decrease postoperative CSF leak.

Neuroprotection by quercetin via mitochondrial function adaptation in traumatic brain injury: PGC-1α pathway as a potential mechanism.

The aim of this study was to investigate the neuroprotective effects of quercetin in mouse models of traumatic brain injury (TBI) and the potential role of the PGC-1α pathway in putative neuroprotection. Wild-type mice were randomly assigned to four groups: the sham group, the TBI group, the TBI+vehicle group and the TBI+quercetin group. Quercetin, a dietary flavonoid used as a food supplement, significantly reduced TBI-induced neuronal apoptosis and ameliorated mitochondrial lesions. It significantly accelerated the translocation of PGC-1α protein from the cytoplasm to the nucleus. In addition, quercetin restored the level of cytochrome c, malondialdehyde and superoxide dismutase in mitochondria. Therefore, quercetin administration can potentially attenuate brain injury in a TBI model by increasing the activities of mitochondrial biogenesis via the mediation of the PGC-1α pathway.

The Mechanism and Pathways of Dopamine and Dopamine Agonists in Prolactinomas.

Dopamine agonists such as bromocriptine and cabergoline are the predominant treatment drugs for prolactinoma by inhibiting prolactin secretion and shrinking tumor size. However, the pathways of either dopamine or its agonists that lead to the death of cells are incompletely understood and some are even conflicting conclusions. The main aim of this paper is to review the different pathways of dopamine and its agonists in prolactinomas to help to gain a better understanding of their functions and drug resistance mechanisms.

Serum AGR2 as a useful biomarker for pituitary adenomas.

OBJECTIVE: This study aims to evaluate whether the serum Anterior Gradient-2 (AGR2) can be used as a potential biomarker screening in the diagnosis of Pituitary adenomas(PAs). PATIENTS AND METHODS: The serum AGR2 protein levels were preoperatively measured in 163 PA patients, 43 patients with other sellar lesions excluding PAs, 7 patients with prostate cancer as a positive control and 20 normal people(10 female and 10 male) using Enzyme-Linked ImmunoSorbent Assay (ELISA). Differences in the serum AGR2 level between different groups were analyzed for statistical significance with a Mann-Whitney U test. RESULTS: The data showed that serum AGR2 level was significantly higher in the serum of PA patients (250.10±79.14ng/ml) than the patients with other sellar lesions (220.84±79.62ng/ml, P=0.017) and normal people (163.67±50.38ng/ml, P <0.001). Receiver operating characteristic (ROC) curve analysis was used. The detected area under the curve (AUC) was 0.835. The calculated optimal cut-off point for AGR2 level in serum samples was 158.63ng/ml (Youden index=0.564). The sensitivity was 91.4% and the specificity was 65.0%. Despite the variety of PA clinical features, the serum level of AGR2 are definite in PAs, although there may be a difference between male or female patients. CONCLUSION: Our data suggests AGR2 as a potential biomarker for the diagnosis of PAs.

Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension.

Venous hypertension(VH) plays an important role in the pathogenesis of cerebral arteriovenous malformations (AVMs) and is closely associated with the HIF-1α/VEGF signaling pathway. Nuclear factor erythroid 2-related factor 2(Nrf2) significantly influences angiogenesis; however, the interplay between Nrf2 and VEGF under VH in brain AVMs remains unclear. Therefore, our study aimed to investigate the interplay between Nrf2 and VEGF due to VH in brain AVMs. Immunohistochemistry indicated that Nrf2 and VEGF were highly expressed in human brain AVM tissues. In vivo, we established a VH model in both wild-type (WT) and siRNA-mediated Nrf2 knockdown rats. VH significantly increased the expression of Nrf2 and VEGF. Loss of Nrf2 markedly inhibited the upregulation of VEGF, as determined by Western blot analysis and qRT-PCR. In vitro, primary brain microvascular endothelial cells (BMECs) were isolated from WT and Nrf2-/- mice, and a VEGF-Nrf2 positive feed-back loop was observed in BMECs. By trans well assay and angiogenesis assay, Nrf2 knockout significantly inhibited the migration and vascular tube formation of BMECs. These findings suggest that the interplay between Nrf2 and VEGF can contribute to VH-induced angiogenesis in brain AVMs pathogenesis.

One-and-a-half nostril endoscopic transsphenoidal approach for pituitary adenomas-a technical report.

BACKGROUND: Binostril endoscopic transsphenoidal approach (BETA) provides sufficient manipulation space and wide endoscopic vision, although it increases the trauma of nose. Mononostril endoscopic transsphenoidal approach (META) has minimal trauma of nose, at the expense of space within the operation. We describe a one-and-a-half nostril endoscopic transsphenoidal approach (OETA) that combines the advantages of BETA and META. METHODS: We introduced OETA for pituitary adenomas with a detailed technical description. A retrospective analysis was also performed on 57 consecutive patients who underwent one-and-a-half nostril endoscopic transsphenoidal surgery between March 2014 and June 2015 at Jinling hospital. RESULTS: The gross total resection rate was 79%. The gross complete resection rate of Knosp grade 3 tumors were 63.6, and 27.3% in grade 4 tumors. Postoperative hormone remission was achieved in 14 out of 18 (77.8%) patients with secreting adenomas. Postoperative abnormal visual function improvement was achieved in 23 out of 32 patients (73%) with preoperative visual dysfunction. The overall intra-operative CSF leak was 17.5%, with the postoperative CSF leak decreased to 3.5% after the sellar reconstruction with the unilateral "rescue" nasoseptal flap procedure. The main sinonasal complaints 2 weeks after surgery were: loss of sense of smell (28%), decrease in sense of taste (4%), trouble breathing during the day (18%), thick nasal discharge (36%), post nasal discharge (8%), dried nasal material (6%), and headache (6%). Three months after surgery, there were no reports of decrease of taste, post nasal discharge, or dried nasal material. Other complaints were decreased significantly. Six months after surgery, the main complaints of sinonasal quality of life were negligible, and overall health status was near complete recovery to preoperative status. CONCLUSIONS: The one-and-a-half nostril endoscopic transsphenoidal approach for pituitary adenomas is a simple and reliable technique. It provides not only a sufficient surgical corridor for a 2-surgeon/4 or 3-hands technique, but also ensures minimal invasion of the nasal canal.

Protective Effects of Quercetin on Mitochondrial Biogenesis in Experimental Traumatic Brain Injury via the Nrf2 Signaling Pathway.

The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in mitochondrial biogenesis. Recently, quercetin has been proved to have a protective effect against mitochondria damage after traumatic brain injury (TBI). However, its precise role and underlying mechanisms in traumatic brain injury are not yet fully understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism of these effects in a weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administrated 30 min after TBI. In this experiment, ICR mice were divided into four groups: A sham group, TBI group, TBI + vehicle group, and TBI + quercetin group. Brain samples were collected 24 h later for analysis. Quercetin treatment resulted in an upregulation of Nrf2 expression and cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD) levels were restored by quercetin treatment. Quercetin markedly promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus. These observations suggest that quercetin improves mitochondrial function in TBI models, possibly by activating the Nrf2 pathway.

Quercetin induces mitochondrial biogenesis in experimental traumatic brain injury via the PGC-1α signaling pathway.

Quercetin, a dietary flavonoid used as a food supplement, has been found to have protective effect against mitochondria damage after traumatic brain injury (TBI) in mice. However, the mechanisms underlying these effects are still not well understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism mediating these effects in the weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administration 30 min after TBI. Brain samples were collected 24 h later for analysis. Quercetin treatment upregulated the expression of PGC-1α and restored the level of cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD). These results demonstrate that quercetin improves mitochondrial function in mice by improving the level of PGC-1α following TBI.

Mononostril versus Binostril Endoscopic Transsphenoidal Approach for Pituitary Adenomas: A Systematic Review and Meta-Analysis.

BACKGROUND: Over the past several decades, the endoscopic endonasal transsphenoidal approach (EETA) has gradually become a preferred option of pituitary adenomas surgery because of its minimal invasiveness and high efficiency. However, some EETA operations were performed through one nostril (mononostril), while other EETA operations were performed through both nostrils (binostril). Therefore, we conducted this study to compare the pros and cons of these two methods in an attempted to confirm which method is more effective. METHODS: We executed a systematic literature search of PubMed, the Cochrane Library, and the Web of Science and Medline (1992-2015). The language is limited to English and all studies should meet the inclusion criteria. Comparisons were made for postoperative outcomes, complications, and other relevant parameters between the mononostril and the binostril group. Statistical analyses of categorical variables were undertaken by the use of Stata 12.0 and SPASS 19.0. RESULTS: Thirty studies, involving 4805 patients, were included. The two groups had similar results in GTR rate (included GTR rate of macroadenomas), hormonal remission rate, improvement in visual function, postoperative CSF leak, permanent diabetes insipidus, meningitis, and sinusitis. The binostril group had less temporary diabetes insipidus (2.9% vs. 5.3%, p = 0.022), less anterior pituitary insufficiency (2.3% vs. 6.4%, p = 0.000) and few hospitalization days (3.2 days vs. 4.4 days, p<0.05) than the mononostril group. However, the mononostril group had less rate of epistaxis (0.4% vs. 1.5%, p = 0.008) than the binostril group. For invasive macroadenomas, the binostril group seem to demonstrate a tendency towards better outcomes though there was no subgroup analysis between the two groups. CONCLUSION: The binostril approach had less temporary diabetes insipidus, anterior pituitary insufficiency, and a shorter length of hospital stay, although they demonstrated a higher rate of epistaxis than the mononstril group. Additionally, the binostril group seemed to suggest a tendency towards better outcomes for invasive macroadenomas.

A practical 3D printed simulator for endoscopic endonasal transsphenoidal surgery to improve basic operational skills.

PURPOSE: We aimed to present a practical three-dimensional (3D) printed simulator to comprehensively and effectively accelerate the learning curve of endoscopic endonasal transsphenoidal surgery (EETS). METHODS: The 3D printed simulator consists of three parts: (1) skull frame, (2) the nasal passage and the nasal alar of the face, and (3) a modified sella turcica. We aimed to improve three basic operational skills of surgeons: drilling, curetting, and aspirating. Eighteen neurosurgeons and five post-graduates were recruited and consented for the training. RESULTS: For trainees, (1) as the training progressed, the scores increased gradually, (2) a significant increase in the average scores was observed in the tenth training compared to the first training, and (3) there is a significant decrease in trainee variability in the shortening of the gap. The 18 neurosurgeons were divided into three groups: experts, assistants, and observers. For all three basic operations, (1) the average score of experts was obviously higher than that of the assistants, observers, and trainees' tenth training and (2) the average scores of assistants and observers were obviously higher than that of trainees' first training. A significant high in the average score between the assistants and the observers was seen for aspirating, but not for drilling or curetting. For curetting and aspirating, the tenth training average score of trainees was obviously higher than that of assistants and observers. CONCLUSION: This 3D printed simulator allows different endoscopic basic operations to be simulated and improves the EETS techniques of surgeons. We believed it to be a practical, simple, and low-cost simulator.