World Health Organization Grade Research Articles

Postoperative Complications and Neurological Deficits After Petroclival Region Meningioma Resection: A Case Series.

Surgical management of meningiomas involving the petroclival junction remains a challenge because of nearby critical neurovascular structures. To describe surgical approach selection, outcomes, and factors associated with postoperative complications and neurological deficits in a series of patients undergoing resection of petroclival region meningiomas. Retrospective review of patients undergoing symptomatic petroclival region meningioma resection was performed. Logistic regression was performed to identify variables associated with postoperative complications and new neurological deficits. Sixty-five patients underwent 54 one-stage and 11 two-stage resections with median follow-up of 51 months. Most tumors were World Health Organization grade 1 (90.8%), and the median volume was 23.9 cm 3 . Posterior petrosectomy and anterior petrosectomy were performed in 67.1% and 6.6% of operations, respectively. The gross or near total resection rate was 15.4%, and 8 patients (12.3%) progressed on follow-up. The surgical complication rate was 26.2% with no perioperative mortalities. Postoperatively, 45.8% of patients had new, persistent neurological deficits, with cranial nerves VII palsy being most common. On multivariate analysis, higher body mass index (odds ratio [OR]: 1.1, P = .04) was associated with risk of surgical complications. Longer operative time (OR: 1.4, P = .004) and staged procedures (OR: 4.9, P = .04) were associated with risk of new neurological deficit on follow-up, likely reflecting more challenging tumors. Comparing early vs later career surgeries performed by the senior author, rates of severe complications and neurological deficits decreased 23.1% and 22.3%, respectively. Petroclival region meningiomas remain surgically challenging, but improved outcomes are seen with surgeon experience. These data help inform patients on perioperative morbidity risk and provide a guide for surgical approach selection.

Health-related quality-of-life results from the randomised phase II TAVAREC trial on temozolomide with or without bevacizumab in 1p/19q intact first-recurrence World Health Organization grade 2 and 3 glioma (European Organization for Research and Treatment of Cancer 26091)

BackgroundIn an international randomised controlled phase II study of temozolomide (TMZ) versus TMZ in combination with bevacizumab (BEV) in locally diagnosed non-1p/19q co-deleted World Health Organization grade 2 or 3 gliomas with a first and contrast-enhancing recurrence after initial radiotherapy, and overall survival at 12 months was not significantly different (61% in the TMZ arm and 55% in the TMZ + BEV arm). ObjectivesHealth-related quality of life (HRQoL) was a key secondary end-point in this trial, and the main objective of this study was to determine the impact of the addition of BEV to TMZ on HRQoL. MethodsHRQoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 (version 3) and QLQ-BN20 at baseline, and then every 12 weeks until disease progression. The pre-selected primary HRQoL end-point was the QLQ-C30 global health scale, with self-perceived cognitive functioning and pain selected as secondary HRQoL issues. Analysis was undertaken using linear mixed modelling and complemented with sensitivity analyses using summary statistics. A difference was considered clinically relevant with ≥10 points difference on a 100-point scale. ResultsBaseline compliance was high at 94% and remained above 60% until 72 weeks, limiting the analysis to 60 weeks. Compliance was similar in both arms. We found no statistically significant or clinically significant differences between the primary HRQoL end-point in both treatment arms (p = 0.2642). The sensitivity analyses confirmed this finding. The overall test for post-baseline differences between the two treatment arms also showed no statistically or clinically significant differences regarding the selected secondary end-point scales. InterpretationThe addition of BEV to TMZ in this patient group neither improves nor negatively impacts HRQoL.

Prognostic Factors in the Surgery of Clinoidal Meningiomas.

Clinoidal meningiomas are currently among the intracranial meningiomas with the greatest neurosurgical complexity, morbidity,and mortality associated with their resection. The worldwide literature has described tumor size (>4 cm3), patient age (>60 years), and invasion of the cavernous sinus as factors associated with a worse clinical outcome following surgery. We describe the series of cases of patients with clinoidal meningiomas who underwent microsurgical resection at our institution between January 2014 and March 2019. The intention was to analyze the multiple preoperative variables, such as the patient's demographic, tumor, and surgical characteristics, such as the Al-Mefty Classification to find a relationship with the patient's clinical outcome during their postoperative follow-up. Results: Death occurred in 4.8% of the cases. Postoperative morbidity was documented in 42.9%, the most frequent being ophthalmoparesis, followed by worsening of visual acuity, and new onset motor deficits. Radiological characteristics were assessed based on preoperative MRI. The maximum diameter, midline shift, invasion of the cavernous sinus, arterial encasement, and peritumoral edema were evaluated. Average intraoperative bleeding was 1.3 L. The most frequent histological grade was World Health Organization (WHO) grade 1 in 85.6% of the cases. Complete resection was obtained in 52.4% of the cases; 42.8% received fractionated stereotactic radiotherapy after surgery for disease control, and one received radiosurgery. Recurrence occurred in 33.3%. The average follow-up in months was 23.8. Conclusions:Demographic factors and tumor characteristics in clinoidal meningioma surgery are related to the subtype of meningioma according to the Al-Mefty Classification and impact directly the degree of resection, progression of the disease, and degree of postoperative complications. To achieve maximal resection while minimizing morbidity and mortality, these factors must be considered to decide on an appropriate approach and specific plan for each case.

Long-Term Outcomes of Stereotactic Radiosurgery for Postoperative World Health Organization Grade I Skull Base Meningioma: Utility of Ki-67 Labeling Index as a Prognostic Indicator.

Gross total resection, without causing neurological deficits, is challenging in skull base meningioma (SBM). Therefore, stereotactic radiosurgery (SRS) is an important approach for SBMs; however, it is difficult to predict the long-term prognosis. To identify the predictive factors for tumor progression after SRS for World Health Organization (WHO) grade I SBMs, focusing on the Ki-67 labeling index (LI). In this single-center retrospective study, factors affecting progression-free survival rates (PFSs) and neurological outcomes in patients undergoing SRS for postoperative SBMs were evaluated. Based on the Ki-67 LI, patients were classified into 3 groups: low (<4%), intermediate (4%-6%), and high LI (>6%). In the 112 patients enrolled, the cumulative 5- and 10-year PFSs were 93% and 83%, respectively. The PFSs were significantly higher in the low LI group (95% at 10 years) compared with the other groups (intermediate LI, 60% at 10 years, P = .007; high LI, 20% at 10 years, P = .001). Multivariable Cox proportional hazard analysis demonstrated that the Ki-67 LI was significantly associated with the PFSs (low vs intermediate LI; hazard ratio, 6.00; 95% CI, 1.41-25.54; P = .015; low vs high LI; hazard ratio, 31.90; 95% CI, 5.59-181.77; P = .001). Ki-67 LI may be a useful predictor of long-term prognosis in SRS for postoperative WHO grade I SBM. SRS provides excellent long- and mid-term PFSs in SBMs with Ki-67 LIs <4% or 4% to 6%, with a low risk of radiation-induced adverse events.

Spinal meningiomas.

Spinal meningiomas (SM) are lesions with a mostly favorable oncological and surgical prognosis and a low incidence of tumor recurrence. SM account for approximately 1.2-12.7% of all meningiomas and 25% of all spinal cord tumors. Typically, SM are located in the intradural extramedullary space. SM grow slowly and spread laterally into the subarachnoid space, stretching and sometimes incorporating the surrounding arachnoid but rarely the pia. Standard treatment is surgery with the primary aims of achieving complete tumor resection as well as improving and recovering neurologic function. Radiotherapy may be considered in case of tumor recurrence, for challenging surgical cases, and for patients with higher-grade lesions (World Health Organization grade 2 or 3); however, radiotherapy is mostly used as an adjuvant therapy for SM. New molecular and genetic profiling increases the understanding of SM and may uncover additional treatment options.

AhR and HIF-1α Signaling Pathways in Benign Meningioma under Hypoxia.

The role of hypoxia in benign meningiomas is less clear than that in the malignant meningiomas. Hypoxia-induced transcription factor 1 subunit alpha (HIF-1α) and its downstream signaling pathways play a central role in the mechanism of hypoxia. HIF-1α forms a complex with the aryl hydrocarbon receptor nuclear translocator (ARNT) protein and can compete for ARNT with aryl hydrocarbon receptor (AhR). In this work, the status of HIF-1α- and AhR-dependent signaling pathways was investigated in World Health Organization (WHO) grade 1 meningioma and patient-derived tumor primary cell culture under hypoxic conditions. mRNA levels of HIF-1α, AhR, and of their target genes as well as of ARNT and nuclear receptor coactivator NCOA2 were determined in tumor tissues from patients in whom the tumor was promptly removed either with or without prior endovascular embolization. Using the patient-derived nonembolized tumor primary cell culture, the effects of a hypoxia mimetic cobalt chloride (CoCl2) and an activator of the AhR signaling pathway benzo(α)pyrene (B[a]P) on mRNA levels of HIF-1α, AhR, and their target genes were investigated. Our findings show active functioning of AhR signaling in meningioma tissue of patients with tumor embolization and crosstalk between HIF-1α and AhR signaling in meningeal cells under hypoxia.

A phase 2 study of sirolimus in combination with metronomic chemotherapy (CHOAnome) in children with recurrent and/or refractory solid and CNS tumors.

10024 Background: Multiple low-dose, anti-angiogenic (metronomic) chemotherapy regimens have demonstrated activity in pediatric solid and central nervous system (CNS) tumors. The mTOR pathway is activated in many human cancers and provides an attractive therapeutic target. We previously conducted a phase 1 trial establishing the dose (2 mg/m2), safety and tolerability of sirolimus in combination with metronomic chemotherapy. In the current study, we conducted a prospective, multi-institutional phase 2 trial to determine the objective response rate (ORR) in pediatric patients with recurrent and/or refractory (R/R) solid and CNS tumors treated with this regimen (NCT02574728); herein we report the results of the CNS tumor stratum. Methods: Patients aged 12 months to 30 years with R/R CNS tumors of all world health organization (WHO) grades were eligible. After completion of the trial’s first stage, patients with diffuse intrinsic pontine glioma (DIPG) were excluded due to lack of efficacy. Patients were required to have measurable disease and no known curative therapeutic options. Treatment consisted of continuous sirolimus (2 mg/m2/dose PO daily), celecoxib (100 mg PO BID), and oral etoposide (50 mg/m2/day; max dose: 100 mg) alternating every 21 days with oral cyclophosphamide (2.5 mg/kg/day; max dose: 100 mg) in 42-day cycles. Sirolimus was dose-adjusted to maintain a serum trough concentration of 10-15 ng/ml. Response was determined using a modified Response Assessment in Neuro-Oncology (RANO) criteria. Enrollment proceeded using a Fleming’s two-stage design based on best overall response (BOR), which required two objective disease status determinations. Results: Twenty-two CNS tumor patients were enrolled; 20/22 were evaluable for response. Median age was 11.2 years (range: 5.9 – 18.1); 6 (30%) were female. Diagnoses included DIPG (N = 5), medulloblastoma (N = 3), high-grade (HG) glioma (N = 5), HG/malignant neuroepithelial tumor (N = 3) and one each of diffuse midline glioma, atypical teratoid/rhabdoid tumor (ATRT), choroid plexus carcinoma, and pineoblastoma. Median number of cycles was 2 (range: 1-6). Best response after any cycle was partial response (PR) in 4 [medulloblastoma (N = 3); pineoblastoma (N = 1)], stable disease (SD) in 4, and progressive disease (PD) in 12 for an ORR of 20%; all patients with DIPG had PD at or before their first disease evaluation. BOR was PR in 3 (15%), SD in 2 (10%), PD in 14 (70%), and unknown in 1 (5%). Four patients had SD or response for ≥ 6 months [medulloblastoma (n = 1), pineoblastoma (N = 1), and HG glioma (N = 2)]. Conclusions: The combination of sirolimus with metronomic chemotherapy showed activity in pediatric patients with some R/R CNS tumors, producing objective responses in medulloblastoma and pineoblastoma. Patients with DIPG did not benefit from this regimen and should be offered alternative treatments. Clinical trial information: NCT02574728 .

Budding uninhibited by benzimidazoles 1 promotes cell proliferation, invasion, and epithelial-mesenchymal transition via the Wnt/β-catenin signaling in glioblastoma

The pathogenesis and progression of GBM (glioblastoma), as one of the most frequently occurring malignancies of the central nervous system, are regulated by several genes. BUB1 (budding uninhibited by benzimidazoles 1) is a mitotic checkpoint that plays an important role in chromosome segregation as well as in various tumors. However, its role in glioma is unknown. The current study discovered prominently elevated BUB1 in glioma and a significant relationship between BUB1 expression, a high World Health Organization grade, and a poor prognosis in glioma patients. Moreover, BUB1 triggered EMT (epithelial-mesenchymal transition) apart from promoting glioma cell proliferation, migration, and infiltration. Besides, BUB1 promoted EMT by activating the Wnt/β-catenin axis. As implied by our study, BUB1 probably has the potential as a target for GBM management.

Predictors of Progression-Free Survival in Patients With Spinal Intramedullary Ependymoma: A Multicenter Retrospective Study by the Neurospinal Society of Japan.

Ependymoma is the most common spinal intramedullary tumor. Although clinical outcomes have been described in the literature, most of the reports were based on limited numbers of cases or been confined to institutional experience. The objective of this study was to analyze more detailed characteristics of spinal intramedullary ependymoma (SIE) and provide clinical factors associated with progression-free survival (PFS). This retrospective observational multicenter study included consecutive patients with SIE in the cervical or thoracic spine treated surgically at a total of 58 institutions between 2009 and 2020. The results of pathological diagnosis at each institute were confirmed, and patients with myxopapillary ependymoma, subependymoma, or unverified histopathology were strictly excluded from this study. Outcome measures included surgical data, surgery-related complications, postoperative systemic adverse events, postoperative adjuvant treatment, postoperative functional condition, and presence of recurrence. This study included 324 cases of World Health Organization grade II (96.4%) and 12 cases of World Health Organization grade III (3.6%). Gross total resection (GTR) was achieved in 76.5% of cases. Radiation therapy (RT) was applied after surgery in 16 cases (4.8%), all of which received local RT and 5 of which underwent chemotherapy in combination. Functional outcomes were significantly affected by preoperative neurological symptoms, tumor location, extent of tumor resection, and recurrence. Multivariate regression analysis suggested that limited extent of tumor resection or recurrence resulted in poor functional outcomes. Multiple comparisons among the groups undergoing GTR, subtotal resection and biopsy, or partial resection of the tumor showed that the probability of PFS differed significantly between GTR and other extents of resection. When GTR can be safely obtained in the surgery for SIE, functional maintenance and longer PFS can be expected.

Research Progress on the Mechanism and Treatment of Pyroptosis in Brain Glioma

Glioma is the most common fatal primary malignant brain tumor in the central nervous system (CNS). Currently, the main standard treatment is the combination of tumor resection, chemotherapy and radiotherapy. The World Health Organization (WHO) classifies glioma into four grades. Glioblastoma (GBM, WHO Grade 4) is the most aggressive type of glioma, characterized by cell heterogeneity, high proliferation rate, diffuse infiltration ability, and high resistance to chemotherapy drugs. Since the five-year survival rate is extremely low and the recurrence rate is high, some new effective treatment strategies are expected. Pyroptosis is an inflammatory programmed cell death mode. Compared with apoptosis, pyroptosis occurs faster and is accompanied by the release of a large number of pro-inflammatory factors. A large amount of evidence shows that pyrodeath can affect the development of tumor, and has both promoting and inhibiting effects on the development of glioma. In order to further understand the influence of pyroptosis on the glioma, this paper discussed the related studies of pyroptosis and glioma, in order to provide potential tumor treatment strategies based on pyroptosis for glioma patients.

Meningioma Grading beyond Histopathology: Relevance of Epigenetic and Genetic Features to Predict Clinical Outcome.

Meningiomas are common tumors of the central nervous system. The grading system established by the World Health Organization (WHO) has recently included pTERT mutations and CDKN2A/B homozygous deletions as criteria for grade 3, owing to their association with increased recurrence risk. However, these alterations identify only a portion of meningiomas that are devoid of histopathological malignancy and are prone to recurrence. Over the last few years, the integration of epigenetic, genetic, transcriptomic, and proteomic profiling has led to the identification of three main groups of meningiomas with distinct clinical outcomes and peculiar genetic features. Meningiomas in the first group have the best prognosis, are distinguished by the lack of NF2 alterations and chromosomal instability, and may be responsive to cytotoxic drugs. Meningiomas in the second group have an intermediate prognosis and are characterized by NF2 alterations, mild chromosomal instability, and enrichment in immune cells. Meningiomas in the third group had the worst prognosis, displayed NF2 alterations coupled with high chromosomal instability, and were resistant to cytotoxic treatment. Classification into these three groups predicts the recurrence risk of meningiomas more accurately than WHO grading and could be applicable in routine practice, owing to the possibility of distinguishing the different groups by specific immunostaining.

The Association of Fibulin-2 Expression with Histopathological Grade and Fibrotic Tumor Vessel in Meningioma

Background&#x0D; Meningiomas are the most common primary tumors of the central nervous system. About one-fifth of meningiomas tend to recur. The World Health Organization (WHO) histopathological grade was the most useful morphological predictor of recurrence. Fibrotic tumor vessels (FTV) were detected in nearly half of WHO grade I meningiomas and correlated with vascular density and increased risk of recurrence. Fibulin-2 is an extracellular matrix glycoprotein whose expression increases in traumatic central nervous system injuries and can be used as a marker to differentiate the histopathological grade of meningiomas. This study aimed to determine the association of fibulin-2 expression with histopathological grade and FTV in meningiomas.&#x0D; &#x0D; Methods&#x0D; This research was an observational cross-sectional study. The study sample was 36 cases of meningioma in three Anatomical Pathology laboratories in West Sumatra on period January 2019 to December 2020. Samples obtained from resected meningioma cases were then reevaluated on Hematoxylin Eosin (HE) slides to determine the histopathological grade and FTV. Van-Gieson staining was performed to confirm FTV. Fibulin-2 expression in tumor cells was analyzed using immunohistochemical staining. Bivariate statistical analysis using the Chi-Square test with p&lt;0.05 was considered significant.&#x0D; &#x0D; Result&#x0D; High-risk meningiomas (WHO grade II and III) showed high fibulin-2 expression (62.5%), whereas low-risk meningiomas (WHO grade I) were more abundant with low fibulin-2 expression (75%). The presence of FTV at low fibulin-2 expression was 58.3%. Statistical analysis showed no significant association between fibulin-2 expression with histopathological grade (p=0.077) and FTV (p=1,000).&#x0D; &#x0D; Conclusion&#x0D; In summary, the study showed that fibulin-2 expression was not associated to histopathological grade nor to FTV in meningiomas.

Metastatic secondary gliosarcoma: patient series.

Gliosarcoma is a rare and highly malignant cancer of the central nervous system with the ability to metastasize. Secondary gliosarcoma, or the evolution of a spindle cell-predominant tumor after the diagnosis of a World Health Organization grade IV glioblastoma, has also been shown to metastasize. There is little information on metastatic secondary gliosarcoma. The authors present a series of 7 patients with previously diagnosed glioblastoma presenting with recurrent tumor and associated metastases with repeat tissue diagnosis consistent with gliosarcoma. The authors describe the clinical, imaging, and pathological characteristics in addition to carrying out a systematic review on metastases in secondary gliosarcoma. The present institutional series and the systematic review of the literature show that metastatic secondary gliosarcoma is a highly aggressive disease with a poor prognosis.

An online survival predictor in glioma patients using machine learning based on WHO CNS5 data.

The World Health Organization (WHO) CNS5 classification system highlights the significance of molecular biomarkers in providing meaningful prognostic and therapeutic information for gliomas. However, predicting individual patient survival remains challenging due to the lack of integrated quantitative assessment tools. In this study, we aimed to design a WHO CNS5-related risk signature to predict the overall survival (OS) rate of glioma patients using machine learning algorithms. We extracted data from patients who underwent an operation for histopathologically confirmed glioma from our hospital database (2011-2022) and split them into a training and hold-out test set in a 7/3 ratio. We used biological markers related to WHO CNS5, clinical data (age, sex, and WHO grade), and prognosis follow-up information to identify prognostic factors and construct a predictive dynamic nomograph to predict the survival rate of glioma patients using 4 kinds machine learning algorithms (RF, SVM, XGB, and GLM). A total of 198 patients with complete WHO5 molecular data and follow-up information were included in the study. The median OS time of all patients was 29.77 [95% confidence interval (CI): 21.19-38.34] months. Age, FGFR2, IDH1, CDK4, CDK6, KIT, and CDKN2A were considered vital indicators related to the prognosis and OS time of glioma. To better predict the prognosis of glioma patients, we constructed a WHO5-related risk signature and nomogram. The AUC values of the ROC curves of the nomogram for predicting the 1, 3, and 5-year OS were 0.849, 0.835, and 0.821 in training set, and, 0.844, 0.943, and 0.959 in validation set. The calibration plot confirmed the reliability of the nomogram, and the c-index was 0.742 in training set and 0.775 in validation set. Additionally, our nomogram showed a superior net benefit across a broader scale of threshold probabilities in decision curve analysis. Therefore, we selected it as the backend for the online survival prediction tool (Glioma Survival Calculator, https://who5pumch.shinyapps.io/DynNomapp/), which can calculate the survival probability for a specific time of the patients. An online prognosis predictor based on WHO5-related biomarkers was constructed. This therapeutically promising tool may increase the precision of forecast therapy outcomes and assess prognosis.

Hemorrhagic Complications After Brain Tumor Biopsy: Risk-Reduction Strategies Based on Safer Biopsy Targets and Techniques

Brain tumor biopsies are essential for pathologic diagnosis. However, hemorrhagic complications after biopsies may occur, leading to suboptimal outcomes. This study aimed to evaluate the associated factors of hemorrhagic complications after brain tumor biopsies and propose countermeasures. We retrospectively collected data on 208 consecutive patients with brain tumors (malignant lymphoma or glioma) who underwent a biopsy from 2011-2020. We evaluated factors and microbleeds (MBs) in the tumor plus relative cerebral/tumoral blood flow (rCBF) at the biopsy site on preoperative magnetic resonance imaging (MRI). Postoperative all and symptomatic hemorrhage occurred in 21.6% and 9.6% of patients. In univariate analysis, a needle biopsy was significantly associated with the risk of all and symptomatic hemorrhages compared to techniques that allow adequate hemostatic manipulation (i.e., open and endoscopic biopsies). Multivariate analyses revealed that a needle biopsy and gliomas of World Health Organization (WHO) grade III/IV were significantly associated with postoperative all and symptomatic hemorrhages. Multiple lesions were also an independent risk factor for symptomatic hemorrhages. On preoperative MRI, abundant MBs in the tumor and MBs at the biopsy sites, in addition to high rCBF, were significantly associated with postoperative all and symptomatic hemorrhages. We recommend the following measures to prevent hemorrhagic complications: consider biopsy techniques that allow adequate hemostatic manipulation preferentially; perform more careful hemostasis in cases of suspected gliomas of WHO grade III/IV, multiple lesions, and abundant MBs in the tumors; and, if there are multiple candidate biopsy sites, select areas with lower rCBF and no MBs as a biopsy target.

Efficacy of Preoperative Biopsy in Predicting the Newly Proposed Histologic Grade of Resected Lung Adenocarcinoma

A novel histologic grading system for invasive lung adenocarcinomas (LUAD) has been newly proposed and adopted by the World Health Organization (WHO) classification. We aimed to evaluate the concordance of newly established grades between preoperative biopsy and surgically resected LUAD samples. Additionally, factors affecting the concordance rate and its prognostic impact were also analyzed. In this study, surgically resected specimens of 222 patients with invasive LUAD and their preoperative biopsies collected between January 2013 and December 2020 were used. We determined the histologic subtypes of preoperative biopsy and surgically resected specimens and classified them separately according to the novel WHO grading system. The overall concordance rate of the novel WHO grades between preoperative biopsy and surgically resected samples was 81.5%, which was higher than that of the predominant subtype. When stratified by grades, the concordance rate of grades 1 (well-differentiated, 84.2%) and 3 (poorly differentiated, 89.1%) was found to be superior compared to grade 2 (moderately differentiated, 66.2%). Overall, the concordance rate was not significantly different from biopsy characteristics, including the number of biopsy samples, biopsy sample size, and tumor area size. On the other hand, the concordance rate of grades 1 and 2 was significantly higher in tumors with smaller invasive diameters, and that of grade 3 was significantly higher in tumors with larger invasive diameters. Preoperative biopsy specimens can predict the novel WHO grades, especially grades 1 and 3 of surgically resected specimens, more accurately than the former grading system, regardless of preoperative biopsy or clinicopathologic characteristics.

Combination of multi-modal MRI radiomics and liquid biopsy technique for preoperatively non-invasive diagnosis of glioma based on deep learning: protocol for a double-center, ambispective, diagnostical observational study.

2021 World Health Organization (WHO) Central Nervous System (CNS) tumor classification increasingly emphasizes the important role of molecular markers in glioma diagnoses. Preoperatively non-invasive "integrated diagnosis" will bring great benefits to the treatment and prognosis of these patients with special tumor locations that cannot receive craniotomy or needle biopsy. Magnetic resonance imaging (MRI) radiomics and liquid biopsy (LB) have great potential for non-invasive diagnosis of molecular markers and grading since they are both easy to perform. This study aims to build a novel multi-task deep learning (DL) radiomic model to achieve preoperative non-invasive "integrated diagnosis" of glioma based on the 2021 WHO-CNS classification and explore whether the DL model with LB parameters can improve the performance of glioma diagnosis. This is a double-center, ambispective, diagnostical observational study. One public database named the 2019 Brain Tumor Segmentation challenge dataset (BraTS) and two original datasets, including the Second Affiliated Hospital of Nanchang University, and Renmin Hospital of Wuhan University, will be used to develop the multi-task DL radiomic model. As one of the LB techniques, circulating tumor cell (CTC) parameters will be additionally applied in the DL radiomic model for assisting the "integrated diagnosis" of glioma. The segmentation model will be evaluated with the Dice index, and the performance of the DL model for WHO grading and all molecular subtype will be evaluated with the indicators of accuracy, precision, and recall. Simply relying on radiomics features to find the correlation with the molecular subtypes of gliomas can no longer meet the need for "precisely integrated prediction." CTC features are a promising biomarker that may provide new directions in the exploration of "precision integrated prediction" based on the radiomics, and this is the first original study that combination of radiomics and LB technology for glioma diagnosis. We firmly believe that this innovative work will surely lay a good foundation for the "precisely integrated prediction" of glioma and point out further directions for future research. This study was registered on ClinicalTrails.gov on 09/10/2022 with Identifier NCT05536024.

Epigenetic Regulation in Primary CNS Tumors: An Opportunity to Bridge Old and New WHO Classifications.

Originally approved in 1979, a specific grading classification for central nervous system (CNS) tumors was devised by the World Health Organization (WHO) in an effort to guide cancer treatment and better understand prognosis. These "blue books" have since undergone several iterations based on tumor location, advancements in histopathology, and most recently, diagnostic molecular pathology in its fifth edition. As new research methods have evolved to elucidate complex molecular mechanisms of tumorigenesis, a need to update and integrate these findings into the WHO grading scheme has become apparent. Epigenetic tools represent an area of burgeoning interest that encompasses all non-Mendelian inherited genetic features affecting gene expression, including but not limited to chromatin remodeling complexes, DNA methylation, and histone regulating enzymes. The SWItch/Sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is the largest mammalian family of chromatin remodeling proteins and is estimated to be altered in 20-25% of all human malignancies; however, the ways in which it contributes to tumorigenesis are not fully understood. We recently discovered that CNS tumors with SWI/SNF mutations have revealed an oncogenic role for endogenous retroviruses (ERVs), remnants of exogenous retroviruses that integrated into the germline and are inherited like Mendelian genes, several of which retain open reading frames for proteins whose expression putatively contributes to tumor formation. Herein, we analyzed the latest WHO classification scheme for all CNS tumors with documented SWI/SNF mutations and/or aberrant ERV expression, and we summarize this information to highlight potential research opportunities that could be integrated into the grading scheme to better delineate diagnostic criteria and therapeutic targets.

Immunohistochemical study of CD147 and matrix metalloproteases in meningiomas

Background/Aim: Expression of extracellular matrix proteins and metalloproteases (MMPs) has been implicated in neoplasm recurrence. Some recent studies have suggested a correlation between matrix modifier proteins and recurrence or invasion of meningiomas. Based on previous data, the aim of this study was to find a correlation between the immunohistochemical (IHC) expression patterns of a group of matrix modifier proteins, including CD147, Matrix Metalloprotease 2 and 9 (MMP2 and 9, respectively), Epithelial Cadherin (ECAD), and Galectin-3 (GAL3) with World Health Organization (WHO)-defined grade, brain invasion, recurrence, and other clinicopathological features. Methods: This study was a cohort study. All patients with meningioma who underwent resection over a 10-year period were identified from the electronic pathology archives. Tissue microarrays (TMAs) were created for IHC studies, and IHC staining was performed using standard methodology. Results: A total of 231 cases fulfilled the study criteria. Histological review identified 198 grade 1 tumors (85.3%), 28 grade 2 tumors (12.6%), and five grade 3 tumors (2.2%). CD147 was determined to be positively correlated with WHO-defined grade (P=0.009). ECAD, MMP2, MMP9, GAL3 were not found to be correlated with brain invasion, recurrence, or WHO grade. Conclusion: The study results demonstrated that CD147 could be a target for diagnosis, prognosis, and treatment of meningiomas.

Clinical Efficacy of Adjuvant Radiotherapy for World Health Organization Grade II Intracranial Meningioma

Maximal surgical resection remains the treatment of choice for grade II meningiomas, and for some authors it is sufficient to guarantee a long indolent course even without postsurgical radiotherapy (RT), but there is no consensus on the use of RT in this patient population. We retrospectively compared clinical and radiologic outcomes between World Health Organization grade I (group A) and grade II (group B) surgically treated meningiomas, focusing on the role of adjuvant RT. We registered clinical, surgical, and radiologic data to detect differences in survival and functional outcome between the 2 groups. The final cohort consisted of 284 patients for group A and 94 patients for group B. Group B showed a higher risk of developing recurrence independently of the extent of resection (7.75% for Group A vs. 27.7% for Group B, P= 0.01). Patients who did not undergo adjuvant RT documented recurrence in 50% of cases, compared with 19% of patients who underwent RT (P= 0.024). There is a weak difference in the risk of developing postoperative seizures in the group submitted to radiotherapy (P= 0.08). Performance status remained stable for both groups, but for Group B it tended to decrease significantly after 1 year with regard to extent of resection and RT. Recurrence is more frequent for grade II meningiomas, even though there are no significant differences in terms of complications and functional outcome. Radiotherapy in grade II meningiomas does indeed lead to better control of recurrence but leads to an increased risk of seizures and reduced performance status.