Sensitizing chemotherapy for glioma with fisetin mediated by a microenvironment-responsive nano-drug delivery system.

Drug resistance has become an obstacle to successful cancer chemotherapies, with therapeutic agents effectively traversing the blood-brain barrier (BBB) remaining a great challenge. A microenvironment responsive and active targeting nanoparticle was constructed to enhance the penetration of drugs, leading to improved therapeutic effects. Dynamic light scattering demonstrated that the prepared nanoparticle had a uniform size. The cRGD modification renders the nanoparticle with active targeting capabilities to traverse the BBB for chemotherapy. The disulfide-bond-containing nanoparticle can be disintegrated in response to a high concentration of endogenous glutathione (GSH) within the tumor microenvironment (TME) for tumor-specific drug release, resulting in more effective accumulation. Notably, the released fisetin further increased the uptake of doxorubicin by glioma cells and exerted synergistic effects to promote apoptosis, induce cellular G2/M cycle arrest, and inhibit cell proliferation and migration in vitro. Moreover, the nanoparticle showed favorable anti-glioma effects in vivo. Our study provides a new strategy to overcome drug resistance by utilizing a natural product to sensitize conventional chemotherapeutics with well-designed targeted nanodelivery systems for cancer treatment.

Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy.

Bromodomain-Containing Protein 4 (BRD4) is a member of the BET family of bromodomains, which participates in gene transcription process and is closely related to tumor progression. We observed the up-regulated expression of BRD4 in colorectal cancer (CRC) after doxorubicin (DOX) treatment, which might be a potential mechanism for DOX resistance. This study constructed the tumor-targeting (cyclo (Arg-Gly-Asp-D-Phe-Lys)-poly(ethylene glycol)-poly(ε-caprolactone)) (cRGD-PEG-PCL) copolymer for co-delivery of DOX and BRD4 PROTAC degrader ARV-825 (ARV-DOX/cRGD-P) for CRC treatment. The ARV-DOX/cRGD-P complexes elicited synergistic anti-tumor effect via cell cycle arrest and the increased cell apoptosis, and mechanism studies implicated the regulation of proliferation- and apoptosis-related pathways in vitro. Moreover, the administration of ARV-DOX/cRGD-P significantly improved anti-tumor activity in subcutaneous colorectal tumors and colorectal intraperitoneal disseminated tumor models in mice by promoting tumor apoptosis, suppressing tumor proliferation and angiogenesis. Taken together, these data reveal that ARV-825 can heighten DOX sensitivity in CRC treatment and BRD4 is a potential therapeutic target for DOX-resistant CRC. The ARV-DOX/cRGD-P preparations have outstanding anti-cancer effects and may be used for clinical treatment of colorectal cancer in the future.

Enhanced anti-glioma efficacy of doxorubicin with BRD4 PROTAC degrader using targeted nanoparticles.

Current treatment of glioma is hampered due to the physical blood-brain barrier (BBB) and the resistance to traditional chemotherapeutic agents. Herein, we proposed a combined treatment strategy based on Cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfk) peptides-modified nanoparticle named cRGD-P in a self-assembly method for the co-delivery of doxorubicin (DOX) and BRD4 PROTAC degrader ARV-825 (ARV). Molecular dynamics simulations showed that cRGD-P could change its conformation to provide interaction sites for perfectly co-loading DOX and ARV. The cRGD-P/ARV-DOX exhibited an average size of 39.95 â€‹nm and a zeta potential of -0.25 â€‹mV. Increased expression of BRD4 in glioma cells was observed after being stimulated by cRGD-P/DOX, confirming one of the possible mechanisms of DOX resistance and the synergistic tumor inhibition effect of BRD4 degrading ARV combined with DOX. In the study, the combination of DOX and ARV in the cRGD-P nanoparticle system exhibited synergistic suppression of tumor growth in glioma cells on account of cell cycle arrest in the G2/M phase and the activation of tumor cells apoptosis-related pathways including triggering caspase cascade and downregulating Bcl-2 as well as upregulating Bax. The cRGD-P/ARV-DOX system could effectively suppress the heterotopic and orthotopic growth of glioma by increasing tumor apoptosis, inhibiting tumor proliferation, and decreasing tumor angiogenesis in vivo. Therefore, the cRGD-modified nanoparticle to co-deliver DOX and ARV provides a potential platform for exploiting a more effective and safer combination therapy for glioma.

A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization.

Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood‒brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

Individualized management of giant anterior meningoceles-case series.

RATIONALE: Anterior spinal meningoceles are rare neuroanatomic abnormality formed by protrusion of the spinal meninges through a defect in the vertebral column. Presently, therapeutic options for anterior spinal meningoceles are still controversial. The objective of this study is to discuss the individualized management of giant anterior spinal meningoceles. PATIENT CONCERNS AND DIAGNOSES: We analyzed 4 patients with anterior spinal meningoceles between 2007 and 2014 in our department by retrospective chart review, two of whom were anterior sacral meningoceles (ASMs), and another2 were intrathoracic meningoceles (ITMs). INTERVENTIONS AND OUTCOMES: Patients mainly presented with compressive symptoms including rectal irritation, dyspnea (patient 3) and fixed neurologic deficits (patient 4). Three out of 4 patients received surgical treatment, one of which underwent reoperation. After surgery, meningoceles in 1 patient completely disappeared. Two patients acquired the stability of the size of the meningoceles. LESSONS: Management of anterior spinal meningoceles often requires precise treatment based on the different conditions of each patient. Surgical intervention has been proposed for the treatment of symptomatic anterior spinal meningoceles. The goal of surgery is to safely disconnect the linkage between the cyst and CSF from subarachnoid space to prevent further enlargement of the cyst or reaccumulating of cystic fluid.

Anti-Glioma Effect with Targeting Therapy Using Folate Modified Nano-Micelles Delivery Curcumin.

Targeted drug delivery systems have currently demonstrated considerable potential clinical benefits in cancer treatment. Curcumin has become a candidate anti-tumor drug for the therapy of glioblastoma multiforme (GBM) by increasing cell apoptosis and suppressing cell proliferation. In current research, we explored a novel targeted drug delivery system with a self-assembly measure by curcumin, MPEG-PLA and Fa-PEG-PLA. Compared with free curcumin and Cur/MPEG-PLA, Cur/Fa-PEG-PLA can remarkably suppress the growth of GL261 cells and promote apoptotic rate. Moreover, after the procession of tumor-bearing mice with curcumin/Fa-PEG-PLA complex, tumor growth in subcutaneous and intracranial tumor models were repressed via suppressing angiogenesis and facilitating apoptosis in vivo. The Curcumin/Fa-PEG-PLA nanoparticle may be a novel drug for the therapy of GBM.

Delivery luteolin with folacin-modified nanoparticle for glioma therapy.

BACKGROUND: Glioblastoma mutliforme is the most common and has the poorest prognosis of any malignant tumor of the central nervous system. Luteolin, the most abundant xanthone extracted from vegetables and medicinal plants, has been shown to have treatment effects in various cancer cell types. Luteolin is however, hydrophobic and has poor biocompatibility, which leads to low bioavailability. PATIENTS AND METHODS: In this study, folic acid modifiedpoly(ethylene glycol)-poly(e-caprolactone) (Fa-PEG-PCL) nano-micelles was used to encapsulate the luteolin, creating luteolin loaded PEG-PCL (Lut/Fa-PEG-PCL) micelles to treat glioma both in vitro and in vivo. RESULTS: When compared with the free luteolin and Lut/MPEG-PCL, Lut/Fa-PEG-PCL induced a significant cell growth inhibition and more apoptosis of GL261 cells both in vitro and in vivo. The safety assessment also showed no obvious side effects were observed in mice which were administrated with free luteolin or Lut/MPEG-PCL and Lut/Fa-PEG-PCL. CONCLUSION: These results suggested Lut/Fa-PEG-PCL may be used as an excellent intravenously injectable formulation for the treatment and chemoprevention.

Novel Chemically Synthesized, Alpha-Mangostin-Loaded Nano-Particles, Enhanced Cell Death Through Multiple Pathways Against Malignant Glioma.

Mangostin is a hydrophobic agent with potential anticancer activity. Molecular dynamics computer simulation indicated methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and α-mangostin (α-M) have good compatibility. The α-M-loaded nano-particles acting as an anticancer agents against growth of glioma cells were prepared by self-assembly methods. In this study, the effects of α-M-loaded nano-particles, α-M/MPEG-PLA with drug loading of 15% and a mean particle size of 32 nm, on the growth of glioma cells were examined both in vitro and in vivo. The occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death and glioma xenograft models (i.e., zebra fish, subcutaneous-mouse and orthotopic-mouse) growth following the administration of α-M/MPEG-PLA were investigated. The novel α-M/MPEG-PLA inhibited the growth of malignant glioma cells, induced cells apoptosis with cleaved caspases expression and DNA fragmentation, along with down-regulation of anti-apoptotic molecules and up-regulation of apoptotic molecules. Furthermore, decreased proliferation as well as vascularization of the tumor in vivo models were significantly achieved. A dramatic induction of programmed cell death was found in malignant glioma cells after treatment with synthetic α-M/MPEG-PLA. These results suggest that synthetic α-M/MPEG-PLA could be a promising novel anticancer agent for performing chemotherapy against malignant glioma.

Systemic lupus erythematosus flare up as acute spinal subarachnoid hemorrhage with bilateral lower limb paralysis.

Subarachnoid hemorrhage (SAH) is an uncommon complication of systemic lupus erythematosus (SLE). Solitary association of fatal spinal SAH as a complication of SLE, has not been encountered much in literature although coexisting acute cerebral and spinal SAH have been associated with SLE. We present a 39-year old female with initial diagnosis of SLE eight years ago who suddenly developed a productive cough, acute abdomen and paralysis of the lower limbs. Magnetic resonance imaging of the spine revealed thoracic spinal SAH with varying degrees of thoracic spinal cord compression. The hemorrhage was total evacuated via surgery. She regained normal function of her lower limbers after the operation with no further neurological complications. One of the rare but fatal complications of SLE is solitary spinal SAH without cranial involvement. The best and most appropriate management of this kind of presentation is surgical decompression of the hematoma with total hemostasis. The cause of hemorrhage should be identified intra-operatively and treated appropriately.

Spinal extradural angiolipoma: a report of two cases and review of literature.

Spinal extradural angiolipomas (SEALs) are extremely extraordinary benign extradural lesions. They are infrequently encountered in normal clinical practice although several authors have report single cases or case series. We present two cases of SEAL which we successfully surgical resected with no further neurological deficits. Our cases comprise of a male and a female with ages ranging from 30 to 60 years. Their principal presenting complains were numbness and pain at the lower extremity with associated fecal and urinary incontinence. In all our cases, MRI revealed extradural spinal lesions that exerted compressive effect on the spinal cord. The male patient had an infiltrating type while the female had non-infiltrating type. We attained total resection in both cases without any further neurological complication. The diagnosis of SEALs initially can be challenging radiologically since they may mimic other spinal lesions. The gold standard treatment modality should always be surgery although total resection may not be achievable in some cases.

Tumor-associated hemorrhage in patients with vestibular schwannoma.

OBJECT: Intratumoral hemorrhage (ITH) associated with vestibular schwannomas (VS) is very rare. We retrospectively analyzed VS patients presenting with ITH in our department to further gain a better understanding of this uncommon clinical presentation. METHODS: We treated seven patients who had VS presenting with ITH between January 2012 and June 2017. All the patients had preoperative computed tomography (CT), computed tomography angiography (CTA), and magnetic resonance imaging(MRI) done which aided in the radiological diagnosis as well as postoperative MRI to confirm the resection extent of the VS. Continuous electrophysiological monitoring of cranial nerves was carried out during surgery. RESULTS: Of the seven patients, three were male and four were female. Their ages ranged from 42 to 71 years (average age, 57.4 years). Two patients reported a history of hypertension. Sudden onset or rapid worsening of clinical symptoms occurred in five patients at time of hemorrhage. The mean diameter of the lesions was 4.1 cm (range, 3.0-5.0 cm). No patient had a pretreatment of stereotactic radiosurgery. Gross total resection was achieved in four cases and subtotal resection in three cases. There were no surgery-related neurological deficits but one patient died 18 days after surgery. Follow-up visits were scheduled at 6 months postoperatively and two patients had tumor recurrence and received stereotactic radiosurgery again. CONCLUSIONS: The incidence of ITH in VS is relatively rare and hypertension may highly correlate with ITH in VS. In comparison with peritumoral adhesion caused by chronic inflammation in multicystic VS with microhemorrhage,ITH caused by acute massive hemorrhage will not increase the extent of peritumoral adhesion immediately. The prognosis of surgery for patients with acute hemorrhagic VS may be better than that for microhemorrhage in multicystic VS. Besides, timely microsurgical treatment is also important to relieve symptoms.

Invasive intramedullary melanotic schwannoma: case report and review of the literature.

PURPOSE: Melanotic schwannoma (MS) is rare, accounting for less than 1% of primary peripheral nerve sheath tumors, and most often occurs in the paraspinal nerve roots. Intramedullary MS is exceedingly rare, and to the best of our knowledge, only nine cases have been reported in literature. METHODS AND RESULTS: We present a 47-year-old male, who underwent excision of thoracic intraspinal space-occupying lesion 6 years ago, as the 10th known case to date of intradural intramedullary MS that had a more invasive growth pattern than those reported before, and we review the diagnosis, clinicopathologic features, treatment and prognosis of intramedullary MS. CONCLUSIONS: Intramedullary MS' behavior is unpredictable and can have an aggressive clinical course such as recurrence and metastasis.

Chiari type I malformation with cervicothoracic syringomyelia subterfuge as flail arm syndrome.

Chiari type I malformation with cervicothoracic syringomyelia although very common in clinical practice usually in children can progress slowly and mimic muscular dystrophies in adulthood. We present a rare adult case of Chiari type I malformation with cervicothoracic syringomyelia subterfuge as Flail arm syndrome. A 44-year-old man was diagnosed with congenital type I Chiari malformation with cervicothoracic syringomyelia about 21 years ago without surgery. His health status deteriorated over the years until 21 days prior to presentation when he had severe pain in the right knee. In his upper limbs, he had bilateral corresponding severe weakness of 0/5 proximal strength and 0/5 strength in his distal muscles. Magnetic resonance imaging (MRI) revealed an enlargement of the spinal cord from C1-C4 level with a mass that appeared hypo-dense on T1 and hyperdense on T2. Syringomyelia is a potentially serious neurologic condition that can mimic other neuromuscular disorders. Early detection and diagnosis with MRI is crucial to avoid irreversible neurological complications. We suggest that whether asymptomatic or symptomatic, decompressive surgery should be carried out to allow for free flow of cerebrospinal fluid thereby improving the quality of life for the patient.

Application of luteolin nanomicelles anti-glioma effect with improvement in vitro and in vivo.

Glioblastoma multiforme (GBM) is one of the most common and malignant tumor. Luteolin, a polyphenolic compound, has been proposed to have anti-tumor activity against various cancers. However, the greatest obstacle in the administration of luteolin is its hydrophobicity as well as the low oral bioavailability. In this study, we formulated luteolin-loaded MPEG-PCL (Luteolin/MPEG-PCL) micelles aiming to improve its solubility in aqueous solution and investigate the anti-tumor effect on glioma in vitro and in vivo. The spherical Luteolin/MPEG-PCL micelles were completely dispersible in normal saline and could release luteolin in a sustained manner in vitro. We demonstrated that Luteolin/MPEG-PCL micelles had stronger cytotoxicity and induced a higher percentage of apoptosis in C6 and U87 cells than free luteolin in vitro. The immunohistochemical study revealed that Luteolin/MPEG-PCL micelles induced more glioma cell apoptosis than free luteolin and inhibited neovascularization in tumor tissues. The Pro-caspase9 and Bcl-2 down-regulation and cleaved-caspase9 and Bax up-regulation suggested that luteolin induced apoptosis via the mitochondrial pathway in vitro. What is more, we found the drug could cumulated much more in the nano-drug group than free drug group through imaging in vivo. In conclusion, the Luteolin/MPEG-PCL micelles have the potential clinical application in glioma chemotherapy.

Efficacy of Closed Continuous Lumbar Drainage on the Treatment of Postcraniotomy Meningitis: A Retrospective Analysis of 1062 Cases.

BACKGROUND: Postcraniotomy meningitis is a severe complication in neurosurgery, and can result in high morbidity and mortality. Closed continuous lumbar drainage (CCLD) as an adjuvant method for treating postcraniotomy meningitis in adults is rarely assessed. This study aimed to evaluate the efficacy of CCLD in the treatment of postcraniotomy meningitis. METHODS: A total of 1062 patients older than 16 years with postcraniotomy meningitis were included, between January 2000 and December 2015. Of these, 474 received intravenous antibiotic therapy, steroid administration and adjuvant CCLD (experimental Group). The remaining 588 patients only received intravenous antibiotic and steroid therapies (control Group). Data were extracted from medical records. RESULTS: In the experimental group, meningitis-related mortality was 2.7%, and 77.4% individuals achieved a Glasgow Outcome Scale of 4-5. In the control group, meningitis-related mortality reached 11.6%, with only 61.1% of patients achieving a GOS of 4-5. The time to negative cerebrospinal fluid laboratory test and the duration of meningitis-related symptoms were significantly shorter in the experimental group compared with controls (P < 0.05). CONCLUSIONS: Intravenous antibiotic and steroid therapies, assisted by CCLD, can lead to lower mortality and improved Glasgow Outcome Scale score in patients with meningitis after craniotomy. Laboratory results negative for cerebrospinal fluid leak and meningitis-related symptom relief occurred faster in the experimental group. Intravenous antibiotic and steroid therapies combined with CCLD appear to be an effective and safe treatment for postcraniotomy meningitis.

Primary Spinal Cord Glioblastoma Multiforme: A Retrospective Study of Patients at a Single Institution.

BACKGROUND AND OBJECTIVE: Primary spinal cord (PSC) glioblastoma multiforme (GBM) is extremely rare and accounts for only 1.5% of all spinal cord tumors. Therefore, its treatment is still ill defined. To elucidate prognostic factors, we performed a single-institutional retrospective review of the largest series to date of patients with PSC GBM who underwent surgical resection in West China Hospital between 2008 and 2014. A total of 14 patients with PSC GBM were reviewed. METHODS: Demographic, operative, and postoperative factors were recorded. Overall survival (OS) and progression-free survival (PFS) were calculated and compared with the Kaplan-Meier method. RESULTS: Eight males (57%) and 6 females (43%) were involved in the study. Their median age was 28 years (range, 14-56 years). Median Karnofsky Performance Status score was 60 (range, 20-90). Four patients (28.6%) received gross total resection, 5 (35.7%) partial resection, and the remaining 5 (35.7%) biopsy only. Nine patients (64.3%) received postoperative radiotherapy and chemotherapy, 3 (21.4%) chemotherapy only, and 2 (14.3%) neither. Median follow-up period was 15 months (range, 5-26 months). One-year and 2-year survival was 78.5% (11/14) and 7.1% (1/14), respectively. Median OS was 15 months, and median PFS 8 months. Univariate log-rank analysis showed that OS and PFS were significantly associated with patients' age (P = 0.007 and P = 0.04, respectively) and postoperative radiotherapy (P = 0.001 and P = 0.002, respectively). However, preoperative Karnofsky Performance Status score affected only OS and did not affect PFS (P = 0.033 and P = 0.106, respectively). CONCLUSIONS: According to our study, the combination of postoperative radiotherapy and temozolomide chemotherapy can improve prognosis and may serve as a feasible postoperative adjuvant treatment of PSC GBM.