Endoscopic endonasal surgery for non-invasive pituitary neuroendocrinology tumors with incomplete pseudocapsule.

Background: Pituitary neuroendocrinology tumors (PitNETs) with pseudocapsule can be effectively removed by the pseudocapsule-based extracapsular resection technique. In the areas without pseudocapsule, the tumor cells can spread into the adjacent tissues at the cellular level, which brings a great challenge to achieving total tumor resection. Methods: Our surgical strategy for PitNETs with an incomplete pseudocapsule is to combine the pseudocapsule-based extracapsular resection technique with the intensive excision technique for the removal of the tumor. Specifically, the pseudocapsule-based extracapsular resection technique is applied in the areas with pseudocapsule, while in the areas without pseudocapsule, the intensive excision technique bounded by adjacent normal structures is adopted. Moreover, a pathological examination was performed to determine the situations of pseudocapsule and tumor cell remnant. Results: All growth hormone-secreting PitNETs achieved biochemical remission after surgery. There was no deterioration of pituitary functions postoperatively, and the preoperative hypopituitarism had improved in all patients postoperatively. In total, two cases suffered a transient diabetes insipidus, and intraoperative cerebrospinal fluid leakage was observed in two cases but no postoperative cerebrospinal fluid leakage in all cases. There was no recurrence during the follow-up. The fragmental pseudocapsule and small tumor remnants were found in the majority of suspicious tissues by histological staining. Conclusion: The effectiveness and safety of the surgical strategy were preliminarily explored for removing PitNETs without incomplete pseudocapsules. In overview, the pseudocapsule-based extracapsular resection technique is applied in areas with pseudocapsule, while the intensive excision bounded by adjacent normal structures is adopted in other areas.

Early-start antiplatelet therapy after operation in patients with spontaneous intracerebral hemorrhage and high risk of ischemic events (E-start): Protocol for a multi-centered, prospective, open-label, blinded endpoint randomized controlled trial.

Background: For severe spontaneous intracerebral hemorrhage (sSICH) patients with high risk of ischemic events, the incidence of postoperative major cardiovascular/cerebrovascular and peripheral vascular events (MACCPE) is notable. Although antiplatelet therapy is a potential way to benefit these patients, the severe hemorrhagic complications, e.g., intracranial re-hemorrhage, is a barrier for early starting antiplatelet therapy. Objectives: This randomized controlled trial aims to identify the benefit and safety of early starting antiplatelet therapy after operation for sSICH patients with high risk of ischemic events. Methods: This study is a multicenter, prospective, randomized, open-label, blinded-endpoint trial. We will enroll 250 sSICH patients with a high risk of ischemic events (including cerebral infarcts, transient ischemic attack, myocardial infarction, pulmonary embolism, and deep venous thrombosis). The participants will be randomized in a 1:1 manner to early-start group (start antiplatelet therapy at 3 days after operation) and normal-start group (start antiplatelet therapy at 30 days after operation). The early-start group will receive aspirin 100 mg daily. The control group will not receive antithrombotic therapy until 30 days after operation. The efficacy endpoint is the incidence of MACCPE, and the safety endpoint is the incidence of intracranial re-hemorrhage. Discussion: The Early-Start antiplatelet therapy after operation in patients with spontaneous intracerebral hemorrhage trial (E-start) is the first randomized trial about early start antiplatelet therapy for operated sSICH patients with a high risk of ischemic events. This study will provide a new strategy and evidence for postoperative management in the future. Clinical trial registration: ClinicalTrials.gov, identifier NCT04820972; Available at: https://clinicaltrials.gov/ct2/show/NCT04820972?term=NCT04820972&draw=2&rank=1.Chinese Clinical Trial Registry, identifier ChiCTR2100044560; Available at: http://www.chictr.org.cn/showproj.aspx?proj=123277.

HIF1α/HIF2α induces glioma cell dedifferentiation into cancer stem cells through Sox2 under hypoxic conditions.

Objective: Our previous study showed that glioma stem-like cells could be induced to undergo dedifferentiation under hypoxic conditions, but the mechanism requires further study. HIF1α and HIF2α are the main molecules involved in the response to hypoxia, and Sox2, as a retroelement, plays an important role in the formation of induced pluripotent stem cells, especially in hypoxic microenvironments. Therefore, we performed a series of experiments to verify whether HIF1α, HIF2α and Sox2 regulated glioma cell dedifferentiation under hypoxic conditions. Materials and methods: Sphere formation by single glioma cells was observed, and CD133 and CD15 expression was compared between the normoxic and hypoxic groups. HIF1α, HIF2α, and Sox2 expression was detected using the CGGA database, and the correlation among HIF1α, HIF2α and Sox2 levels was analyzed. We knocked out HIF1α, HIF2α and Sox2 in glioma cells and cultured them under hypoxic conditions to detect CD133 and CD15 expression. The above cells were implanted into mouse brains to analyze tumor volume and survival time. Results: New spheres were formed from single glioma cells in 1% O2, but no spheres were formed in 21% O2. The cells cultured in 1% O2 highly expressed CD133 and CD15 and had a lower apoptosis rate. The CGGA database showed HIF1α and HIF2α expression in glioma. Knocking out HIF1α or HIF2α led to a decrease in CD133 and CD15 expression and inhibited sphere formation under hypoxic conditions. Moreover, tumor volume and weight decreased after HIF1α or HIF2α knockout with the same temozolomide treatment. Sox2 was also highly expressed in glioma, and there was a positive correlation between the HIF1α/HIF2α and Sox2 expression levels. Sox2 was expressed at lower levels after HIF1α or HIF2α was knocked out. Then, Sox2 was knocked out, and we found that CD133 and CD15 expression was decreased. Moreover, a lower sphere formation rate, higher apoptosis rate, lower tumor formation rate and longer survival time after temozolomide treatment were detected in the Sox2 knockout cells. Conclusion: In a hypoxic microenvironment, the HIF1α/HIF2α-Sox2 network induced the formation of glioma stem cells through the dedifferentiation of differentiated glioma cells, thus promoting glioma cell chemoresistance. This study demonstrates that both HIF1α and HIF2α, as genes upstream of Sox2, regulate the malignant progression of glioma through dedifferentiation.

Case report: Fully endoscopic microvascular decompression for trigeminal neuralgia.

Microvascular decompression is safe, effective, and micro-invasive. Due to these advantages, it has become the mainstream treatment for trigeminal neuralgia, glossopharyngeal neuralgia, and hemifacial spasm. Initially, microvascular decompression was performed under a microscope, which limited the light source and visualization capabilities. With the development of endoscopic technology, the endoscope has been used in microvascular decompression, which further improved the visualization range and light source properties. The purpose of the present study was to investigate the efficacy of fully endoscopic microvascular decompression for the treatment of trigeminal neuralgia. In total, three patients with trigeminal neuralgia who underwent fully endoscopic microvascular decompression were evaluated. After surgery, the facial pain of all patients was significantly relieved. In addition, there were no obvious postoperative complications and no recurrence after 6 months of follow-up. These excellent surgical outcomes indicate that fully endoscopic microvascular decompression is an effective and safe method for the treatment of trigeminal neuralgia. Furthermore, it also shows that the endoscope presents advantages for use in microvascular decompression.

Hyperbaric oxygen promotes not only glioblastoma proliferation but also chemosensitization by inhibiting HIF1α/HIF2α-Sox2.

There exists a consensus that combining hyperbaric oxygen (HBO) and chemotherapy promotes chemotherapy sensitivity in GBM cells. However, few studies have explored the mechanism involved. HIF1α and HIF2α are the two main molecules that contribute to GBM malignant progression by inhibiting apoptosis or maintaining stemness under hypoxic conditions. Moreover, Sox2, a marker of stemness, also contributes to GBM malignant progression through stemness maintenance or cell cycle arrest. Briefly, HIF1α, HIF2α and Sox2 are highly expressed under hypoxia and contribute to GBM growth and chemoresistance. However, after exposure to HBO for GBM, whether the expression of the above factors is decreased, resulting in chemosensitization, remains unknown. Therefore, we performed a series of studies and determined that the expression of HIF1α, HIF2α and Sox2 was decreased after HBO and that HBO promoted GBM cell proliferation through cell cycle progression, albeit with a decrease in stemness, thus contributing to chemosensitization via the inhibition of HIF1α/HIF2α-Sox2.

HIF1α/HIF2α-Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR-PI3K/AKT signalling pathway with positive feedback under hypoxia.

Previous studies have suggested that hypoxic responses are regulated by hypoxia-inducible factors (HIFs), which in turn promote the malignant progression of glioblastoma (GBM) by inhibiting apoptosis and increasing proliferation; these events lead to a poor prognosis of GBM patients. However, there are still no HIF-targeted therapies for the treatment of GBM. We have conducted series of experiments and discovered that GBM cells exhibit features indicative of malignant progression and are present in a hypoxic environment. Knocking out HIF1α or HIF2α alone resulted in no significant change in cell proliferation and cell cycle progression in response to acute hypoxia, but cells showed inhibition of stemness expression and chemosensitization to temozolomide (TMZ) treatment. However, simultaneously knocking out HIF1α and HIF2α inhibited cell cycle arrest and promoted proliferation with decreased stemness, making GBM cells more sensitive to chemotherapy, which could improve patient prognosis. Thus, HIF1α and HIF2α regulate each other with negative feedback. In addition, HIF1α and HIF2α are upstream regulators of epidermal growth factor (EGF), which controls the malignant development of GBM through the EGFR-PI3K/AKT-mTOR-HIF1α signalling pathway. In brief, the HIF1α/HIF2α-EGF/EGFR-PI3K/AKT-mTOR-HIF1α signalling axis contributes to the growth of GBM through a positive feedback mechanism. Finally, HIF1α and HIF2α regulate Sox2 and Klf4, contributing to stemness expression and inducing cell cycle arrest, thus increasing malignancy in GBM. In summary, HIF1α and HIF2α regulate glioblastoma malignant progression through the EGFR-PI3K/AKT pathway via a positive feedback mechanism under the effects of Sox2 and Klf4, which provides a new tumour development model and strategy for glioblastoma treatment.

The HIF1α/HIF2α-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions.

Hypoxia-inducible factor 1α (HIF1α) promotes the malignant progression of glioblastoma under hypoxic conditions, leading to a poor prognosis for patients with glioblastoma; however, none of the therapies targeting HIF1α in glioblastoma have successfully eradicated the tumour. Therefore, we focused on the reason and found that treatments targeting HIF1α and HIF2α simultaneously increased tumour volume, but the combination of HIF1α/HIF2α-targeted therapies with temozolomide (TMZ) reduced tumourigenesis and significantly improved chemosensitization. Moreover, miR-210-3p induced HIF1α expression but inhibited HIF2α expression, suggesting that miR-210-3p regulates HIF1α/HIF2α expression. Epidermal growth factor (EGF) has been shown to upregulate HIF1α expression under hypoxic conditions. However, in the present study, in addition to the signalling pathways mentioned above, the upstream proteins HIF1α and HIF2α have been shown to induce EGF expression by binding to the sequences AGGCGTGG and GGGCGTGG. Briefly, in a hypoxic microenvironment the HIF1α/HIF2α-miR210-3p network promotes the malignant progression of glioblastoma through a positive feedback loop with EGF. Additionally, differentiated glioblastoma cells underwent dedifferentiation to produce glioma stem cells under hypoxic conditions, and simultaneous knockout of HIF1α and HIF2α inhibited cell cycle arrest but promoted proliferation with decreased stemness, promoting glioblastoma cell chemosensitization. In summary, both HIF1α and HIF2α regulate glioblastoma cell proliferation, dedifferentiation and chemoresistance through a specific pathway, which is important for glioblastoma treatments.

HIF1α regulates glioma chemosensitivity through the transformation between differentiation and dedifferentiation in various oxygen levels.

Chemotherapy plays a significant role in glioma treatment; however, it has limited effectiveness in extending the life expectancies of glioma patients. Traditional studies have attributed this lack of efficacy to glioma stem cells (GSCs) and their high resistance to chemotherapy, and hypoxia worsens this issue. In contrast, hyperoxia effectively alleviates hypoxia in glioma and sensitizes glioma cells to chemotherapy. In a summary of traditional studies, the majority of researchers overlooked the influence of hypoxia on differentiated cells because they only focused on the maintenance of GSCs stemness, which thus resulted in chemoresistance. Because of this background, we hypothesized that GSCs may be induced through dedifferentiation under hypoxic conditions, and hypoxia maintains GSCs stemness, which thus leads to resistance to chemotherapy. In contrast, hyperoxia inhibits the dedifferentiation process and promotes GSCs differentiation, which increases the sensitization of glioma cells to chemotherapy. Hypoxia-inducible factor-1α (HIF1α) contributes substantially to the stemness maintenance of GSCs and resistance of glioma to chemotherapy; thus, we investigated whether HIF1α regulates the resistance or sensitization of glioma cells to chemotherapy in different oxygen levels. It highlights a novel viewpoint on glioma chemosensitivity from the transformation between dedifferentiation and differentiation in different oxygen levels.

HIF1α regulates single differentiated glioma cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential under hypoxia.

The standard treatment for Glioblastoma multiforme (GBM) is surgical resection and subsequent radiotherapy and chemotherapy. Surgical resection of GBM is typically restricted because of its invasive growth, which results in residual tumor cells including glioma stem cells (GSCs) and differentiated cells. Recurrence has been previously thought to occur as a result of these GSCs, and hypoxic microenvironment maintains the GSCs stemness also plays an important role. Summarizing traditional studies and we find many researchers ignored the influence of hypoxia on differentiated cells. We hypothesized that the residual differentiated cells may be dedifferentiated to GSC-like cells under hypoxia and play a crucial role in the rapid, high-frequency recurrence of GBM. Therefore, isolated CD133-CD15-NESTIN- cells were prepared as single-cell culture and treated with hypoxia. More than 95% of the surviving single differentiated CD133-CD15-NESTIN- cell dedifferentiated into tumorigenic CD133+CD15+NESTIN+ GSCs, and this process was regulated by hypoxia inducible factor-1α. Moreover, the serum also played an important role in this dedifferentiation. These findings challenge the traditional glioma cell heterogeneity model, cell division model and glioma malignancy development model. Our study also highlights the mechanism of GBM recurrence and the importance of anti-hypoxia therapy. In addition to GSCs, residual differentiated tumor cells also substantially contribute to treatment resistance and the rapid, high recurrence of GBM.

Clinical evaluation of Crosstrees pod kyphoplasty in the treatment of osteoporotic vertebral compression fractures.

Although percutaneous vertebroplasty and balloon kyphoplasty have improved the management of osteoporotic vertebral compression fractures (OVCFs), these techniques still suffer from inherent disadvantages and complications, such as cement leakage. This prospective pilot study evaluated the clinical outcomes of 15 OVCF patients treated with a new technique, the Crosstrees pod kyphoplasty (C-pod kyphoplasty). This is in fact a balloon kyphoplasty, where the balloon is filled with cement, then opened and removed. The VAS for back pain decreased significantly from 8.9 +/- 1.4 preoperatively to 2.1 +/- 13 at 24hrs postoperatively, and to 2.2 +/-1.5 at final followup (p = 0.001). Likewise, the ODI score decreased significantly from 86.1 +/- 8.7 preoperatively to 30.5+/-7.5 at 24 h, and to 32.8 +/- 8.3 at final follow up (p = 0.001). The average vertebral height increased significantly from 14.50 1.34 mm preoperatively to 23.20 1.12 mm 24 h postoperatively and to 22.82 +/- 0.85 mm at final follow-up (p = 0.002). The kyphotic angle decreased significantly from preoperatively (28.50 +/-1.85 degrees) to 24 h postoperatively (11.30 +/-1.40 degrees) and to final follow-up (12.48 +/- 0.70 degrees) (p = 0.005). Cement leakage, infection, pulmonary embolism or nerve injury were not seen. The C-pod kyphoplasty may be an effective minimally invasive procedure to treat OVCFs, with a decreased complication rate compared with vertebroplasty and balloon kyphoplasty.

Surgical treatment of severe scoliosis and kyphoscoliosis by stages.

BACKGROUND: Although previous reports had reported the use of temporary internal distraction as an aid to correct severe scoliosis, two-stage surgery strategy (less invasive internal distraction followed by posterior correction and instrumentation) has never been reported in the treatment of patients with severe spinal deformity. This study aimed to report the results of the surgical treatment of severe scoliosis and kyphoscoliosis by two-stage and analyse the safety and efficacy of this surgical strategy in the treatment of severe spinal deformities. METHODS: A total of 15 patients with severe scoliosis, kyphoscoliosis or kyphosis who underwent two-stage surgeries (less invasive internal distraction followed by posterior correction and instrumentation) were studied based on hospital records. Pretreatment radiographs and radiographs taken after first surgery (internal distraction by two small incisions), before second surgery (posterior correction, instrumentation and fusion), one week after second surgery and final follow-up were measured. Subjects were analyzed by age, gender, major coronal curve magnitude, flexibility of major curve, major sagittal curve magnitude before first surgery, after first surgery, before second surgery, after second surgery and at final follow-up. Complications related to two-stage surgeries were noted in each case. RESULTS: The average major curve magnitude was 129.4° (range, 95° to 175°), reduced 58.9° or 45.4% after first stage surgery and reduced 30.6° or 24.6% after second stage surgery. The loss of correction during the interval between two surgeries was 7.1%. The total major coronal curve correction was 81.4° or 62.9%. At the final follow up, the average loss of correction of major coronal curve was 3.9° and the final average correction rate was 59.7%. The average major sagittal curve magnitude was 80.3° (range, 30° to 170°), and the total major sagittal curve correction was 48.2°. Loss of correction averaged 4.0° for major sagittal curve and the final correction averaged 42.2°. Clinical complications were noted in the peri-operative and long-term periods. CONCLUSIONS: Two-stage surgery was a safe and effective surgical strategy in this difficult population. Using two-small-incision technique, the first stage surgery was less invasive. No permanent neurologic deficit was noted in this series.

Two-stage posterior-only procedures for correction of severe spinal deformities.

PURPOSE: To review the outcomes of surgical treatment for severe spinal deformities via a two-stage posterior-only approach. METHODS: A total of 18 patients with large and rigid spinal deformities were studied based on clinical and radiographic data. All of them received a two-stage posterior-only approach: first on the concave side by internal distraction of pedicle screws and rods through intramuscular tunnels, followed by respiratory function exercise and improving nutritional status during the intervening period, and finally by posterior additional correction, ultimate instrumentation and spinal fusion in the second operation. RESULTS: The mean major coronal curve was corrected by 46% after the first operation and by 60.4% after the second operation. The mean thoracic kyphosis was corrected by 50.9% after the first operation and by 64.8% after the second operation. The loss of correction mean was 3.3° for the major coronal curve and 2.6° for the thoracic kyphosis at a mean of 31.5 months follow-up. The mean operation time for the first and second operation was 186.2 and 300.6 min, and the mean intraoperative blood loss was 211.1 and 1,597.2 mL, respectively. No severe complication was noticed in this series. CONCLUSIONS: The two-stage posterior-only procedures permitting stepwise correction for the treatment of severe spinal deformities provide safe and satisfactory outcomes in this patient population.