Endocrine Outcomes and Associated Predictive Factors for Somatotrophin Pituitary Adenoma after Endoscopic Endonasal Transsphenoidal Surgery: 10 Years of Experience in a Single Institute.

Objective Biochemical remission rates of endoscopic endonasal transsphenoidal surgery (EETS) and its associated predictive factors were evaluated in patients with somatotrophin pituitary adenomas. Methods The patients who underwent EETS in Jinling Hospital were identified between 2011 and 2020. The surgeons' experience, preoperative insulin-like growth factor 1 (IGF-1), basal growth hormone (GH) levels, nadir GH levels, and the tumor characteristics were analyzed for their relationships with endocrine outcomes. Total 98 patients were included for single factor analysis and regression analysis. They were divided into three groups according to the admission chronologic order. Results The overall remission rate of the patients was 57% (56/98) for all the patients over 10 years. In the single factor analysis, we found that the tumor size, cavernous invasion, and sellar invasion were valuable to predict the endocrine outcome after surgery. As for the suprasellar invasion, no significant difference was found between the noninvasive group and the invasive group. The preoperative IGF-1 level ( p = 0.166), basal GH level ( p = 0.001), and nadir GH level ( p = 0.004) were also different between the remission group and the nonremission group in the single factor analysis. The logistic regression analysis indicated that the preoperative nadir GH (odds ratio = 0.930, 95% confidence interval = 0.891-0.972, p = 0.001) was a significant predictor for the endocrine outcomes after surgery. Conclusion The surgeons' experience is an important factor that can affect the patients' endocrine outcomes after surgery. The macroadenomas with lateral invasion are more difficult to cure. Patients with higher preoperative nadir GH levels are less likely to achieve remission.

A Preoperative Nomogram for Prediction of Postoperative Hypocortisolism in Patients with Pituitary Adenomas: A Single-Center Retrospective Cohort Study.

BACKGROUND: Patients with pituitary adenomas (PAs) are at an increased risk preoperatively and postoperatively for hypopituitarism. Postoperative hypocortisolism is associated with increased mortality and morbidity as well as poor quality of life. However, research about the risk factors for postoperative hypocortisolism is limited, and a predictive nomogram for postoperative hypocortisolism has not yet been developed. We aimed to investigate the predictive factors for postoperative hypocortisolism and construct a dynamic online nomogram. METHODS: Our database included 438 consecutive PA patients who were hospitalized and treated with transsphenoidal surgery by experienced neurosurgeons from the different medical teams in the Neurosurgery Department, Jinling Hospital, between January 2018 and October 2020. The final study group included 238 eligible patients. Data on possible predictors, including age, sex, treatment history of PAs, preoperative signs and symptoms, primary recurrence subtype, and clinical subtypes, were collected. Univariable and multivariable logistic regression analyses were applied to identify independent predictors, which were included in constructing the nomogram model. The calibration curve and receiver operating characteristic curve were computed to evaluate the predictive performance of the nomogram model. RESULTS: The incidence of postoperative hypocortisolism was 12.08%. Three preoperative predictors were identified to construct the nomogram: surgical type (microscopic or endoscopic, with endoscopic surgery proven to be the protective factor) (odds ratio, 0.24; 95% confidence interval [CI], 0.093-0.610; P = 0.003), prothrombin time (odds ratio, 2.40; 95% CI, 1.332-4.326; P = 0.004), and basophil cell count (odds ratio, 5.25; 95% CI, 1.270-21.816; P = 0.022,). The area under the curve of receiver operating characteristic curve for the constructed nomogram was 0.749 (95% CI, 0.640-0.763); a well-fixed calibration curve was generated for the nomogram model. An interactive web-based dynamic nomogram application was also constructed. CONCLUSIONS: In this study, surgical type, prothrombin time, and basophil cell count were the most relevant predictive factors for postoperative hypocortisolism. A predictive nomogram that can preoperatively assess the risk of hypocortisolism after surgical treatment of PAs was developed. This nomogram could be helpful in identifying high-risk patients who require close monitoring of serum cortisol levels and initiating clinical procedures for patients requiring cortisol administration therapy as a lifesaving strategy.

Predictors and dynamic online nomogram for postoperative delayed hyponatremia after endoscopic transsphenoidal surgery for pituitary adenomas: a single-center, retrospective, observational cohort study with external validation.

BACKGROUND: Postoperative delayed hyponatremia (PDH) is a major cause of readmission after endoscopic transsphenoidal surgery (eTSS) for pituitary adenomas (PAs). However, the risk factors associated with PDH have not been well established, and the development of a dynamic online nomogram for predicting PDH is yet to be realized. We aimed to investigate the predictive factors for PDH and construct a dynamic online nomogram to aid in its prediction. METHODS: We analyzed the data of 226 consecutive patients who underwent eTSS for PAs at the Department of Neurosurgery in Jinling Hospital between January 2018 and October 2020. An additional 97 external patients were included for external validation. PDH was defined as a serum sodium level below 137 mmol/L, occurring on the third postoperative day (POD) or later. RESULTS: Hyponatremia on POD 1-2 (OR = 2.64, P = 0.033), prothrombin time (PT) (OR = 1.78, P = 0.008), and percentage of monocytes (OR = 1.22, P = 0.047) were identified as predictive factors for PDH via multivariable logistic regression analysis. Based on these predictors, a nomogram was constructed with great discrimination in internal validation (adjusted AUC: 0.613-0.688) and external validation (AUC: 0.594-0.617). Furthermore, the nomogram demonstrated good performance in calibration plot, Brier Score, and decision curve analysis. Subgroup analysis revealed robust predictive performance in patients with various clinical subtypes and mild to moderate PDH. CONCLUSIONS: Preoperative PT and the percentage of monocytes were, for the first time, identified as predictive factors for PDH. The dynamic nomogram proved to be a valuable tool for predicting PDH after eTSS for PAs and demonstrated good generalizability. Patients could benefit from early identification of PDH and optimized treatment decisions.

Expression of RUNX2/LAPTM5 in the Induction of MC3T3-e1 Mineralization and Its Possible Relationship with Autophagy.

BACKGROUND: The study aims to correlate osteogenesis with autophagy during the mineralization induction of MC3T3-e1 through exploring the expression of runt-related transcription factor 2 (RUNX2)/lysosomal-associated transmembrane protein 5 (LAMPT5). METHODS: The induction of mineralization in MC3T3-e1 was followed by detecting the expressions of osteogenesis-related indexes such as RUNX2, alkaline phosphatase (ALP), osteocalcin (OCN), and LAPTM5 using RT-qPCR and Western blot from 0 to 14 days. Transmission electron microscope was utilised in visualizing the alterations of autophagosomes, which was followed by immunofluorescence detecting the subcellular localization of autophagy-related index sequestosome 1 (P62) and microtubule-associated protein 1 light 3 (LC3) protein and scrutinising the expression of P62 mRNA and P62 and LC3 proteins. RESULTS: Induction of MC3T3-e1 mineralization demonstrated an increased expression of osteogenesis-related indicators such as RUNX2, ALP, OCN, and LAPTM5 (p < 0.05), as evident from the results of RT-qPCR and Western blot. Meanwhile, the expression of autophagosomes increased one day after mineralization induction and then experienced a gradual decline, and enhanced expression of LC3 protein was noted on days 1-2 of mineralization induction but was then followed by a corresponding reduce. In contrast, a continuous increase was reported in the expression of P62 mRNA and protein, respectively (p < 0.05). Up- and down-regulating RUNX2/LAPTM5 expression alone confirmed the aforementioned results. CONCLUSION: It was therefore proposed that RUNX2 may be responsible for an early increase and then a gradual decrease in LAPTM5-mediated autophagy through the regulation of its high expression. Meanwhile, increased LAPTM5 expression in osteogenic mineralization presumed that RUNX2/LAPTM5 promoted autophagy and osteogenic expression, which may play a bridging role in the regulation of autophagy and osteogenesis.

Roles of the m6A Modification of RNA in the Glioblastoma Microenvironment as Revealed by Single-Cell Analyses.

Purpose: Glioblastoma multiforme (GBM) is a common and aggressive form of brain tumor. The N6-methyladenosine (m6A) mRNA modification plays multiple roles in many biological processes and disease states. However, the relationship between m6A modifications and the tumor microenvironment in GBM remains unclear, especially at the single-cell level. Experimental Design: Single-cell and bulk RNA-sequencing data were acquired from the GEO and TCGA databases, respectively. We used bioinformatics and statistical tools to analyze associations between m6A regulators and multiple factors. Results: HNRNPA2B1 and HNRNPC were extensively expressed in the GBM microenvironment. m6A regulators promoted the stemness state in GBM cancer cells. Immune-related BP terms were enriched in modules of m6A-related genes. Cell communication analysis identified genes in the GALECTIN signaling network in GBM samples, and expression of these genes (LGALS9, CD44, CD45, and HAVCR2) correlated with that of m6A regulators. Validation experiments revealed that MDK in MK signaling network promoted migration and immunosuppressive polarization of macrophage. Expression of m6A regulators correlated with ICPs in GBM cancer cells, M2 macrophages and T/NK cells. Bulk RNA-seq analysis identified two expression patterns (low m6A/high ICP and high m6A/low ICP) with different predicted immune infiltration and responses to ICP inhibitors. A predictive nomogram model to distinguish these 2 clusters was constructed and validated with excellent performance. Conclusion: At the single-cell level, m6A modification facilitates the stemness state in GBM cancer cells and promotes an immunosuppressive microenvironment through ICPs and the GALECTIN signaling pathway network. And we also identified two m6A-ICP expression patterns. These findings could lead to novel treatment strategies for GBM patients.

Modified Le Fort I interpositional grafting of the severe atrophied maxilla-a retrospective study of 106 patients over 10 years.

OBJECTIVES: The objective of this study was to evaluate a modified Le Fort I interpositional grafting followed by dental implants for the rehabilitation of edentulous atrophied maxillae (Cawood classes IV and V). The surgical modification was a bilateral sinus floor augmentation prior to the osteotomy. This generated a closed recipient bed which allowed the use of particulated bone grafts (xenogenic bone mineral) and a reduced amount of autologous iliac bone grafts. MATERIALS AND METHODS: A total of 106 patients with maxillary interpositional bone grafts were included in this retrospective analysis between 2006 and 2020. The panoramic radiographs and lateral cephalograms were analyzed to assess the gain and stability of the maxillary bone and the peri-implant bone loss. In addition, the observational period of up to 14 years implant survival and success was evaluated. RESULTS: A stable vertical bone height with mean 0.63 ± 1.41 mm resorption over 5 years after implant loading was observed. A mean of 0.20 ± 0.37 mm marginal bone loss was noted after 5 years. The implant survival was 96.4% after 5 years and implant success can be rated 91.7% in a mean follow-up period of 93 months and 168 months maximal observation time. Perioperative complications included sinus membrane perforation (59.43%), wound healing disturbances (25.47%), and transient primary complications (13.78%). All receded apart from two subtotal graft losses (1.8%). CONCLUSIONS: The modified Le Fort I osteotomy with interpositional bone grafts is a predictable procedure in terms of bone and implant stability. Patients with atrophic maxillae who are fit for surgery should be informed about risks and benefits of this treatment alternative.

Prefabricated 3D-Printed Tissue-Engineered Bone for Mandibular Reconstruction: A Preclinical Translational Study in Primate.

The advent of three dimensionally (3D) printed customized bone grafts using different biomaterials has enabled repairs of complex bone defects in various in vivo models. However, studies related to their clinical translations are truly limited. Herein, 3D printed poly(lactic-co-glycolic acid)/ß-tricalcium phosphate (PLGA/TCP) and TCP scaffolds with or without recombinant bone morphogenetic protein -2 (rhBMP-2) coating were utilized to repair primate's large-volume mandibular defects and compared efficacy of prefabricated tissue-engineered bone (PTEB) over direct implantation (without prefabrication). 18F-FDG PET/CT was explored for real-time monitoring of bone regeneration and vascularization. After 3-month's prefabrication, the original 3D-architecture of the PLGA/TCP-BMP scaffold was found to be completely lost, while it was properly maintained in TCP-BMP scaffolds. Besides, there was a remarkable decrease in the PLGA/TCP-BMP scaffold density and increase in TCP-BMP scaffolds density during ectopic (within latissimus dorsi muscle) and orthotopic (within mandibular defect) implantation, indicating regular bone formation with TCP-BMP scaffolds. Notably, PTEB based on TCP-BMP scaffold was successfully fabricated with pronounced effects on bone regeneration and vascularization based on radiographic, 18F-FDG PET/CT, and histological evaluation, suggesting a promising approach toward clinical translation.

Accuracy of Implant Placement Guided with Surgical Template: An In Vitro and In Vivo Study.

This study evaluated the accuracy of implant placement with surgical-template guidance both in vitro and in vivo. Virtual surgical planning was performed based on the data from CBCT scans and an intraoral scanner. Surgical templates were designed according to the planned implants and manufactured with stereolithography. In vitro, 60 implants were placed in 15 resin models. In vivo, 74 implants were placed in 54 patients. The implants were scanned with CBCT postoperatively. Implant accuracy was evaluated by measuring the following parameters: central deviation at the apex and shoulder, horizontal deviation at the apex and shoulder, vertical deviation at the apex and shoulder, and angular deviation. There were statistically significant in vitro and in vivo deviations for all parameters, and the implant deviations in vivo were significantly greater than those in vitro. When using a mucosa-supported template, horizontal deviations at the apex were significantly greater than when a teeth-supported template was used. Within the limitation of the study design, inaccuracy existed in implant placement guided with a surgical template. More studies are needed to investigate the value of the procedure in future.

Comparison of the accuracy of dental implant placement using static and dynamic computer-assisted systems: an in vitro study.

OBJECTIVES: The study aimed to compare the accuracy of implant placement between static and dynamic computer-assisted systems (CAS) in a partially edentulous mandible model. MATERIALS & METHODS: A total of 80 implants was placed in mandible models. The implants were placed using either static or dynamic computer-assisted system. Deviations of implant hex, apex and angulation were measured between preoperative planning and postoperative CBCT in planning software. RESULTS: The mean deviations of implant hex, apex and angulation in static CAS group were 1.15 ± 0.34 mm, 1.37 ± 0.38 mm and 2.60 ± 1.11 degree, while in dynamic CAS group were 0.40 ± 0.41 mm, 0.34 ± 0.33 mm and 0.97 ± 1.21 degree, respectively. Implant placement with dynamic CAS showed less deviations of shoulder, apex and angulation than with static CAS significantly. CONCLUSIONS: The implant accuracy using CAS system could be influenced by the guiding technique.

Dental implant location via surface scanner: a pilot study.

PURPOSE: Implant location is performed after placement to verify that the safety of neighboring anatomic structure and the realizability of prosthetic plan. Routine postoperative location is based on radiological scanning and raises the concerns on radiation exposure and inconveniency in practice. In the present study a location method based on surface scanning was introduced and the accuracy of this method was assessed in vitro. MATERIAL AND METHODS: A total of 40 implants were placed in 10 resin mandible models. The models were scanned with intraoral scanner (IS group) and extraoral scanner (ES group). The implant position was located with fusing the images of surface scanning and cone beam computerized tomography (CBCT) after implant placement. Deviations were measured between positions located by surface scanner and postoperative CBCT with the parameters: central deviation at apex (cda), central deviation at hex (cdh), horizontal deviation at apex (hda), horizontal deviation at hex (hdh), vertical deviation at apex (vda), vertical deviation at hex (vdh) and angular deviation (ad). RESULTS: In IS group, the mean value of cda, cdh, hda, hdh, vda, vdh and ad was 0.27 mm, 0.23 mm, 0.12 mm, 0.10 mm, 0.21 mm, 0.19 mm and 0.72°, respectively. In ES group, the mean value of cda, cdh, hda, hdh, vda, vdh and ad was 0.28 mm, 0.25 mm 0.14 mm, 0.11 mm, 0.22 mm, 0.20 mm and 0.68°, respectively. The implant deviations in IS and ES groups were of no significant difference for any of the measurements. CONCLUSIONS: Dental implant can be located via surface scanner with acceptable accuracy for postoperative verification. Further clinical investigation is needed to assess the feasibility of the method.

A novel method to improve the osteogenesis capacity of hUCMSCs with dual-directional pre-induction under screened co-culture conditions.

OBJECTIVES: Mesenchymal stem cells (MSCs) based therapy for bone regeneration has been regarded as a promising method in the clinic. However, hBMSCs with invasive harvesting process and undesirable proliferation rate hinder the extensive usage. HUCMSCs of easier access and excellent performances provide an alternative for the fabrication of tissue-engineered bone construct. Evidence suggested the osteogenesis ability of hUCMSCs was weaker than that of hBMSCs. To address this issue, a co-culture strategy of osteogenically and angiogenically induced hUCMSCs has been proposed since thorough vascularization facilitates the blood-borne nutrition and oxygen to transport in the scaffold, synergistically expediting the process of ossification. MATERIALS AND METHODS: Herein, we used osteogenic- and angiogenic-differentiated hUCMSCs for co-culture in screened culture medium to elevate the osteogenic capacity with in vitro studies and finally coupled with 3D TCP scaffold to repair rat's critical-sized calvarial bone defect. By dual-directional induction, hUCMSCs could differentiate into osteoblasts and endothelial cells, respectively. To optimize the co-culture condition, gradient ratios of dual-directional differentiated hUCMSCs co-cultured under different medium were studied to determine the appropriate condition. RESULTS: It revealed that the osteogenic- and angiogenic-induced hUCMSCs mixed with the ratio of 3:1 co-cultured in the mixed medium of osteogenic induction medium to endothelial cell induction medium of 3:1 possessed more mineralization nodules. Similarly, ALP and osteogenesis/angiogenesis-related genes expressions were relatively higher. Further evidence of bone defect repair with 3D printed TCP of 3:1 group exhibited better restoration outcomes. CONCLUSIONS: Our work demonstrated a favourable and convenient approach of dual-directional differentiated hUCMSCs co-culture to improve the osteogenesis, establishing a novel way to fabricate tissue-engineered bone graft with 3D TCP for large bone defect augmentation.

LAPTM5 is transactivated by RUNX2 and involved in RANKL trafficking in osteoblastic cells.

The present study aimed to investigate the role of lysosomal­associated transmembrane protein 5 (LAPTM5) in osteoclast differentiation induced by osteoblasts. The results demonstrated that the expression levels of LAPTM5 were downregulated following runt­related transcription factor 2 (RUNX2) silencing and upregulated following RUNX2 overexpression in ST2 cells. Chromatin immunoprecipitation analysis identified the binding of RUNX2 to the LAPTM5 promoter at the ­1176 to ­1171 position. Dual­luciferase reporter assays confirmed that RUNX2 directly activated the LAPTM5 gene. The concentration of receptor activator of nuclear factor­κB ligand (RANKL) protein in the cytoplasm and in the media was significantly increased following LAPTM5 knockdown. LAPTM5 silencing in ST2 cells enhanced osteoclastic differentiation of co­cultured RAW264.7 cells. The present study indicated that expression of LAPTM5 was regulated by the interaction of RUNX2 with its promoter region and that LAPTM5 was involved in the trafficking of RANKL. These findings suggested a possible coupling mechanism between osteogenesis and osteoclastogenesis in which RUNX2 may be involved in osteoclast differentiation through the regulation of the lysosome­associated genes that modulate RANKL expression.

Sandwich osteotomy in atrophic mandibles: A retrospective study with a 2- to 144-month follow-up.

OBJECTIVES: The aim of the present retrospective study was to assess the long-term clinical outcome of sandwich osteotomy in pre-implant augmentation of atrophic mandible. MATERIALS AND METHODS: Sandwich osteotomies were performed in partially and fully edentulous mandibles of 63 consecutive patients in the present study. The vertical bone gain, graft stability, and marginal bone loss were measured radiographically. Implant survival and success rates were estimated in the follow-up ranged from 2 to 144 months (mean, 58 months). RESULTS: A total of 75 procedures were reviewed. After an average healing time of 148 days, 220 implants were placed in 74 procedures. Perioperative complications included intraoperative fracture (1/75), transient paresthesia (18/75), wound healing disturbance (18/75), and keratinized tissue deficiency (14/75). The average vertical bone gain was 5.4 mm at the time of implant placement. Significant marginal bone loss occurred during the first 6 months, after which the resorption remained stable. The implant survival rate was estimated as 96.7%, and the success rate was 95.3%. Implant survival and success showed no significant correlation with higher age, anticoagulation therapy, cardiovascular disease, or thyroid disorder. Smoking was correlated with significant lower success rate. CONCLUSION: Sandwich osteotomy is a suitable augmentation procedure for atrophic mandible, allowing for implant placement with promising outcome.

Particulate Coral Hydroxyapatite Sheltered by Titanium Mesh for Localized Alveolar Rehabilitation After Onlay Graft Failure: A Case Report.

Reconstruction of bone loss in the alveolar ridge has long been challenging. Autologous bone grafts are considered as the "golden standard," while little research has focused on how to repair pronounced alveolar bone defects after autologous bone graft failure. The aim of this study was to detail a method based on the titanium mesh technique coupled with particulate coral hydroxyapatite to solve the onlay graft failure. With bone deficiency in the No. 11 and No. 24-25 regions, we harvested 2 autologous bone blocks for reconstruction. Two weeks after transplantation, the graft in the No. 11 region had healed uneventfully, while the graft in the anterior mandible became infected because of soft tissue dehiscence. After removal of the failed autologous bone block, pure coral hydroxyapatite stabilized within titanium mesh was used for alveolar rehabilitation. Six months later, the width of the local alveolar bone was evaluated. After the titanium mesh was removed, a biopsy was performed to study bone regeneration by micro computerized tomography and histology, following by a standard Straumann implant insertion. Although there was wound dehiscence 14 days after bone augmentation, repeated local rinsing and anti-inflammation therapy controlled the inflammatory reaction. The total horizontal bone gain was 4.2 ± 0.5 mm. Micro computerized tomography revealed that the closer the coral hydroxyapatite was to the host bone, the more was resorbed and the more bone regenerated. Histology showed mature lamellar bone structures, with evident residual coral hydroxyapatite. A 3-year follow-up revealed stable bone around the dental implant and successful function of the implant-born prosthesis. This study proposes that the method of particulate coral hydroxyapatite sheltered by titanium mesh is a promising solution in handling alveolar bone augmentation failure. More cases are needed for further research to form an efficient treatment procedure.