The application of fluorescein sodium for the resection of medulloblastoma.

INTRODUCTION: Surgical resection of medulloblastoma (MB) remains a challenge. At present, a variety of tracers have been used for intraoperative tumor visualization. However, there are few reports on the intraoperative visualization of MB. Hence, we reported our experience of applying fluorescein sodium (FS) in MB surgery. METHODS: We retrospectively analyzed the clinical information of patients with MB confirmed by surgery and pathology from January 2016 to December 2020 from Sun Yat-sen University Cancer Center. A total of 62 patients were enrolled, of which 27 received intraoperative FS and 35 did not. The intraoperative dose of FS was 3 mg/kg. RESULTS: Among the 62 patients, 42 were males, and twenty were females. The age of onset in the FS group was 9.588 ± 7.322, which in the non-fluorescein sodium group was 13.469 ± 10.968, p = 0.198. We did not find significant differences in tumor location, tumor size, tumor resection, tumor histology, and preoperative symptoms (hydrocephalus, headache, vomit, balance disorder) between the groups. There was no significant difference in the postoperative symptoms (hydrocephalus, headache, vomiting, balance disorder, and cerebellar mutism). However, patients in the FS group had a relatively low incidence of balance disorder and cerebellar mutism. There was definite fluorescence of tumor in all cases of the FS group, and even the tiny metastatic lesion was visible. No case had side effects related to the use of FS. CONCLUSIONS: FS is safe and effective in MB surgery. Whether the application of FS for surgery can reduce complications remains to be studied in the future.

Assessment of circulating tumor DNA in cerebrospinal fluid by whole exome sequencing to detect genomic alterations of glioblastoma.

BACKGROUND: Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. METHODS: CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. RESULTS: Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF compared with the corresponding tumor tissue samples (3.56 ±â€Š0.75 vs. 2.22 ±â€Š0.32, P = 0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.1% ±â€Š6.0% vs. 73.8% ±â€Š6.0%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3 histone, family 3A (H3F3A) which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. CONCLUSION: Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

The utility of 3-dimensional-printed models for skull base meningioma surgery.

BACKGROUND: Skull base meningioma surgery is often difficult and complicated to perform. Therefore, this study aims to investigate the effectiveness of 3-dimensional (3D)-printed models of skull base meningioma in the representation of anatomical structures, the simulation of surgical plans, and patient education on surgical outcomes. METHODS: A retrospective study of 35 patients (3D group: 19 patients and non-3D group: 16 patients) with skull base meningioma was conducted. Mimics software was used to create 3D reconstructions (with the skull, blood vessels, nerves, and tumors set to different colors), and 3D solid models were printed to determine the surgical protocols and communication pathways with the patient. RESULTS: The 3D-printed model can visually display the relationship of different structures, including the skull, blood vessels, cranial nerves, and tumors. The surgeon should select the proper surgical approaches before surgery through the model and pay attention to protecting the important structures during the operation. According to the models, the surgeon should cut off the blood supply to the tumor to reduce intraoperative bleeding. For patients with skull base bone destruction, the skull base repair should be prepared in advance. Patients and their families should have a thorough understanding of the disease through the model, and there should be effective communication between doctors and patients. CONCLUSIONS: The 3D-printed model of a skull base meningioma can present the structures in a detailed manner and facilitate in helping the surgeon to develop a surgical plan. At the same time, it helps patients and their families to understand the condition and the surgical plan, which is conducive to better patient education.

Assessment of ctDNA in CSF may be a more rapid means of assessing surgical outcomes than plasma ctDNA in glioblastoma.

We aimed to develop a high-throughput deep DNA sequencing assay of cerebrospinal fluid (CSF) to identify clinically relevant oncogenic mutations that contribute to the development of glioblastoma (GBM) and serve as biomarkers to predict patients' responses to surgery. For this purpose, we recruited five patients diagnosed with highly suspicious GBM according to preoperative magnet resonance imaging. Subsequently, patients were histologically diagnosed with GBM. CSF was obtained through routine lumbar puncture, and plasma from peripheral blood was collected before surgery and 7 days after. Fresh tumor samples were collected using routine surgical procedures. Targeted deep sequencing was used to characterize the genomic landscape and identify mutational profile that differed between pre-surgical and post-surgical samples. Sequence analysis was designed to detect protein-coding exons, exon-intron boundaries, and the untranslated regions of 50 genes associated with cancers of the central nervous system. Circulating tumor DNAs (ctDNAs) were prepared from the CSF and plasma from peripheral blood. For comparison, DNA was isolated from fresh tumor tissues. Non-silent coding variants were detected in CSF and plasma ctDNAs, and the overall minor allele frequency (MAF) of the former corresponded to an earlier disease stage compared with that of plasma when the tumor burden was released (surgical removal). Gene mutation loads of GBMs significantly correlated with overall survival (OS, days) (Pearson correlation = -0.95, P = 0.01). We conclude that CSF ctDNAs better reflected the sequential mutational changes of driver genes compared with those of plasma ctDNAs. Deep sequencing of the CSF of patients with GBM may therefore serve as an alternative clinical assay to improve patients' outcomes.

Pretreatment neutrophil-to-lymphocyte ratio plus albumin-to-gamma-glutamyl transferase ratio predict the diagnosis of grade III glioma.

BACKGROUND: The present study explored the predictive value of systemic inflammatory indexes in diagnosing grade III gliomas of oligodendroglial origin. METHODS: A retrospective study of 154 patients with grade III gliomas was conducted. Systemic inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), albumin-to-gamma-glutamyl transferase ratio (AGR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, prognostic nutritional index, and fibrinogen-to-albumin ratio, were reviewed. The resulting predictive model was externally validated using a demographic-matched cohort of 49 grade III glioma patients. RESULTS: In the training set, gliomas of oligodendroglial origin tended to have a lower NLR (P=0.018) and a higher AGR (P=0.036) than those with tumors of astrocytic origin. Moreover, both NLR and AGR had predictive value for oligodendroglial tumors, when compared with astrocytic tumors. The best diagnostic value was obtained using NLR + AGR (AUC =64.9%, 95% CI: 55.5-74.3%, P=0.005). In the validation set, NLR + AGR satisfactorily predicted the presence of oligodendroglial tumors (AUC =66.5%, 95% CI: 50.6-82.4%, P<0.05) and co-deletion of 1p/19q (AUC =73.7%, 95% CI: 59.2-88.1%, P=0.005). Multivariate analysis further demonstrated NLR + AGR as an independent predictor for overall survival. CONCLUSIONS: Pretreatment NLR and AGR aid in prognosis and diagnosing grade III oligodendroglial gliomas.

Identification of P4HA1 as a prognostic biomarker for high-grade gliomas.

BACKGROUND: Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1) is the active catalytic component of prolyl 4-hydroxylase and plays a crucial role in modulating extracellular matrix hemostasis. P4HA1 has been reported to promote tumor progression by enhancing invasion and angiogenesis. Overexpression of P4HA1 is associated with decreased survival for patients with breast and prostate cancer. However, the prognostic significance of P4HA1 for glioma patients remains undefined. METHODS: The expression of P4HA1 in 290 gliomas (WHO grade II-IV) and 10 normal brain tissues was examined with TMA-based immunohistochemistry assay. The correlation between P4HA1 expression and clinicopathological parameters as well as the prognosis of glioma patients was investigated. RESULTS: Cytoplasmic expression of P4HA1 is high in 37.93% of all glioma cases, with 44.98% in high-grade gliomas and 19.75% in low-grade gliomas respectively. Increased P4HA1 level was correlated with advanced histological grade (p<0.01) and old age (p=0.01). Upregulation of P4HA1, as well as histological grade, was an independent risk factor for unfavorable prognosis. Subgroup analysis demonstrated that high P4HA1 expression was significantly associated with poor prognosis for high-grade gliomas (p<0.01) but not for low-grade gliomas. CONCLUSIONS: P4HA1 was upregulated in gliomas. High expression of P4HA1 was correlated with the malignancy of gliomas and could serve as a prognostic indicator for patients with high-grade gliomas.

Evaluation of cumulative prognostic score based on pretreatment plasma fibrinogen and serum albumin levels in patients with newly diagnosed high-grade gliomas.

This retrospective study was designed to determine the prognostic value of a cumulative score (FA score) based on pretreatment plasma fibrinogen and serum albumin levels for 326 patients newly diagnosed high-grade glioma (HGG). Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off values. Univariate and multivariate analysis were performed to evaluate the independent prognostic value of the FA scores associated with overall survival (OS) and progression-free survival (PFS). The optimal cut-off values were 2.815 g/L for fibrinogen and 43.65 g/L for albumin. PFS and OS were significantly worse for patients with higher FA scores. Patients with elevated fibrinogen level and decreased albumin levels had 3.00-fold higher risk of tumor progression and had a 3.23-fold higher risk of death compared with those with normal values. Multivariate analysis demonstrated FA score was an independent predictive factor for PFS and OS. Moreover, PFS and OS were better for the patients with lower FA score, either in patients with grade III or IV gliomas. These findings indicated that the pretreatment FA score could serve as a simple and noninvasive marker to predict the prognosis of patients with HGG.

Application of fluorescein sodium in the resection of vermis pilocytic astrocytomas.

BACKGROUND: Pilocytic astrocytomas (PAs) are slow growing neoplasms and usually located at the cerebellum. There has been certainty regarding the truthful benefit of surgical resection for patients with PA. Gross total resection (GTR) of PAs, especially those being situated in deep regions, remains a surgical challenge. Generally, they are considered as benign and usually develop in young patients. PAs, belonging to WHO I can be cured by radical resection. The patients with PA have excellent prognosis if complete resection can be conducted. The use of fluorescein in vermis PA surgery has not been yet reported. Our data presents fluorescein facilitates surgical resection of vermis PA. METHODS: Five milligrams per kilogram of fluorescein sodium was intravenously injected directly before general anesthesia for the three patients with PA. The yellow 560 filter was employed for microsurgical tumor resection. Surgical outcomes were assessed concerning the extent of resection. RESULTS: Most portion of PA in the three cases was found to be highly fluorescent after intravenous fluorescein sodium injection, which markedly enhanced tumor visibility. Gross total resection in all of the patients was achieved without further neurological deficits. No adverse effects and complications resulting from fluorescein sodium were observed over the postoperative course. CONCLUSIONS: Intraoperative guidance by fluorescein sodium as a new, simple, safe, and practical procedure can enhance the fidelity of tumor tissue and increase the possibility of completely resecting PAs.

Langerhans cell histiocytosis of skull: a retrospective study of 18 cases.

BACKGROUND: The present study presents 18 cases of Chinese patients harboring a Langerhans cell histiocytosis (LCH) of the skull. METHODS: Eighteen consecutive patients were diagnosed as LCH of the skull and confirmed pathologically between March 2002 and February 2014. In the present study, the patients of LCH without skull involvement were excluded. According to disease extent at diagnosis, the 18 LCH patients with skull involvement were divided into three groups: (I) unifocal-monosystem group, including ten cases with solitary skull lesion; (II) multifocal-monosystem group, including two cases with multiple bone lesions and no extra-skeletal involvement; (III) multisystem group, including six cases with LCH lesions involving both skeletal and extra-skeletal system. In unifocal-monosystem group, excision of the skull lesion was performed in eight of ten cases, a low dosage of local radiotherapy and a purposeful observation was accept by the remaining two cases of this group after biopsy respectively. In multifocal-monosystem group, both of the two cases were received chemotherapy. In multi-system group, all the six cases were managed with systemic chemotherapy, after their diagnoses of LCH were confirmed. RESULTS: The mean age at the time of diagnosis was 9.4 years. There was a male predominance in this disease male/female ratio was 3.5:1. In our cases, a skull mass with or without tenderness was the most common chief complaint (13 cases, 72.2%), and frontal bone was the most frequent affected locations of skull (6 cases, 33.3%). In unifocal-monosystem group, nine of ten remained free from LCH, the remain one lesion recurred 22 months after his surgical excision. In multifocal-monosystem group, a complete response (CR) was obtained in one of them, and a stable disease (SD) of multiple osseous lesions was obtained in another one. In the multi-system group, a CR in four cases and a partial response (PR) in one case were obtained, and a progressive disease (PD) was observed in the remaining one. CONCLUSIONS: The unifocal-monosystem of LCH of the skull is a clinicopathological entity with a good outcome, and resection, irradiation or purposeful observation are also can be been utilized as the choice of treatment. For the multifocal bone lesions and multisystem lesions of LCH, chemotherapy is an effective treatment as a systemic therapy. There is no enough publication literature to determine guidelines or indications for managing this disease.

Transforaminal Resection of Cervical Dumbbell Schwannomas in Patients with Additional Tumors.

BACKGROUND: It is rare for 2 primary tumors to occur simultaneously in a patient. Management of cervical dumbbell schwannomas (CDSs) with concurrent tumors (CTs) requires a specific neurosurgical strategy. The primary objective of this study is to investigate surgical strategies for CDSs with CTs while preserving as much of the mechanically relevant bone structures as possible. METHODS: Twelve patients with concurrent CTs and CDSs were identified from 3 medical centers. Surgical strategies for CDSs were based on accurate preoperative images and subsequent treatment considerations for CTs. All patients received surgical treatment for CDSs and CTs. Clinical features, surgical considerations for a transforaminal approach (TA), and ultimate outcome were studied retrospectively. RESULTS: Gross total resection of CDSs was achieved with endoscopic and microscopic assistance in 9 cases, and subtotal resection was achieved in 3 cases after the head and neck surgeons exposed and removed the extraforaminal anatomy. One patient required an additional hemilaminectomy for the resection of the intraspinal segment. After wound healing, patients were transferred to the appropriate surgical department for surgery on CTs with cervical spine stabilization after a transforaminal approach. CONCLUSIONS: In most patients, the stability of the cervical spine can be preserved with low invasive microsurgical or endoscopic transforaminal resection. CTs could be surgically treated sequentially after microscopic- and endoscopic-assisted resection of CDSs.

Epidural Cystic Spinal Meningioma: A Case Report.

Cystic spinal meningioma (CSM) is an uncommon meningioma variant. Extradural CSMs are particularly rare and difficult to distinguish from other intraaxial tumors. This study presents a case of a 36-year-old woman with intraspinal extradual CSM at the thoracolumbar spine. She experienced persistent weakness, progressive numbness, and sensory disturbance in the right lower limb. Magnetic resonance imaging (MRI) of the patient revealed an irregular cystic mass at the thoracic 11 to lumbar 3 levels dorsally. This case was misdiagnosed as other neoplasms prior to surgery because of the atypical radiographic features and location of the tumor. Extradural CSMs should be considered in the differential diagnosis of intraspinal extradural cystic neoplasms. Complete removal of cystic wall provides an optimal outcome, rendering the lesion curable.

Safety evaluation of high-dose BCNU-loaded biodegradable implants in Chinese patients with recurrent malignant gliomas.

OBJECTIVES: Malignant gliomas are common primary brain tumors with dismal prognosis. The blood-brain barrier and unacceptable systemic toxicity limit the employment of chemotherapeutic agents. BCNU-impregnated biodegradable polymers (Gliadel®) have been demonstrated to prolong the survival of patients with malignant gliomas. Until now, no biodegradable drug delivery system has been commercially available in China. In the present study, we evaluated the safety of implants with high-dose BCNU in Chinese patients with recurrent malignant gliomas. PATIENTS AND METHODS: Adults with supratentorial recurrent malignant glioma were eligible. High-dose BCNU-loaded PLGA implants (20mg of BCNU in each implant) were placed in the debulking cavity. The implants were investigated by a classical 3+3 design. Four levels of BCNU, up to 12 implants, were evaluated. Pharmacokinetic sampling was performed. The toxicity of the implants and the survival of patients were recorded. RESULTS: Fifteen recurrent patients were enrolled with 12 glioblastomas and 3 anaplastic gliomas. Among 15 patients, 3 were treated with 3 implants (60 mg of BCNU), 3 with 6 implants (120 mg), 3 with 9 implants (180 mg) and 6 with 12 implants (240 mg). No dose-limiting toxicity was observed in the cohort of patients. Subgaleal effusion was the most common adverse event, presenting in 7 patients (46.7%). The median overall survival (OS) was 322 days (95% CI, 173-471 days). The 6-month, 1-year and 2-year survival rates were 66.7%, 40% and 13.3%, respectively. CONCLUSIONS: The high-dose BCNU-loaded PLGA implants were safe for Chinese patients with recurrent malignant gliomas and further investigation for efficacy is warranted.

Brain ischemia induces regeneration of interneurons but not projection neurons.

PURPOSE: How injured long-distance neural tracts are reestablished following ischemic brain injury remains unclear. Theories surrounding reconnection include the growth of newly formed axons from newborn neurons, modification of local circuits and a beneficial influence from neurotrophic factors. This research aimed to find the developing new born neurons and the neurotrophic factors they secreted in a middle cerebral artery occlusion (MCAO) rat model to explain the roles of neural progenitor cells in post-ischemic neurogenesis. METHODS: Fifty-three male Sprague-Dawley rats underwent the MCAO procedure or sham operation. Double labeling of specific neuron markers (calbindin and N-200) and a dividing cell marker (BrdU) were used to identify newly formed neurons. Neurotrophic factors were examined in the cerebrospinal fluid in post-ischemic rats using enzyme-linked immunosorbent assay. RESULTS: Ischemic injury induced activation of neurogenesis. The newborn neurons differentiated into calbindin-positive interneurons, but not N-200 positive projection neurons. The concentration of neurotrophic factors was elevated and was in accordance with the neurogenesis seen in ischemic animal models. CONCLUSION: Our research indicates that the recovery of neural function is not ascribed to the reestablishment of damaged projection tracts, but to the modulation of local circuits and beneficial effects of neurotrophins produced by neural progenitor cells.