scholarly journals Mitotic Index Thresholds Do Not Predict Clinical Outcome for IDH-Mutant Astrocytoma

2019 ◽  
Vol 78 (11) ◽  
pp. 1002-1010 ◽  
Author(s):  
Rebecca A Yoda ◽  
Troy Marxen ◽  
Lauren Longo ◽  
Chibawanye Ene ◽  
Hans-Georg Wirsching ◽  
...  
Keyword(s):  
Mitotic Activity ◽  
Cox Regression ◽  
Predictive Accuracy ◽  
Homozygous Deletion ◽  
World Health ◽  
Mitotic Figure ◽  
Lower Grade ◽  
Histological Grading ◽  
Who Grade ◽  
Diagnostic Uncertainty

Abstract Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while somatic copy number alterations are emerging as important prognostic biomarkers. One explanation for this relative underperformance of histological grading is that current criteria to distinguish World Health Organization (WHO) grade III anaplastic astrocytomas from lower-grade diffuse astrocytomas (WHO grade II) are vague (“increased mitotic activity”). This qualitative approach ensures diagnostic uncertainty and a broad “gray zone” where both diffuse and anaplastic designations can reasonably be assigned. Thus, we hypothesized that interobserver variability and lack of defined mitotic thresholds for IDH-mutant astrocytomas underlies poor predictive accuracy of current histologic grading approaches. To test this hypothesis, we quantified total mitotic figures and maximum mitotic activity per 10 high-powered fields in an institutional cohort of IDH-mutant astrocytomas. In our cohort, there was no mitotic activity threshold that was reflective of progression-free or overall survival (OS). Furthermore, in a multivariate Cox regression model consisting of mitotic activity, molecular markers, and clinical characteristics, only CDKN2A homozygous deletion was identified as a relevant variant for poor OS. We conclude that lack of defined mitotic figure thresholds may not contribute to underperformance of histological grading for IDH-mutant astrocytomas.

scholarly journals PATH-07. MITOTIC INDEX THRESHOLDS DO NOT PREDICT CLINICAL OUTCOME FOR IDH-MUTANT ASTROCYTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi144-vi144
Author(s):  
Rebecca Yoda ◽  
Troy Marxen ◽  
Lauren Longo ◽  
Chibawanye Ene ◽  
Hans-Georg Wirsching ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mitotic Activity ◽  
Cox Regression ◽  
Predictive Accuracy ◽  
World Health ◽  
Mitotic Figure ◽  
Lower Grade ◽  
Histological Grading ◽  
Poor Overall Survival ◽  
Who Grade

Abstract Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while somatic copy number alterations are emerging as important prognostic biomarkers. One explanation for this relative underperformance of histological grading is that current criteria to distinguish World Health Organization (WHO) grade III anaplastic astrocytomas from lower-grade diffuse astrocytomas (WHO grade II) are vague (‘increased mitotic activity’). This qualitative approach ensures diagnostic uncertainty and a broad ‘gray zone’ where both diffuse and anaplastic designations can reasonably be assigned. Thus, we hypothesized that interobserver variability and lack of defined mitotic thresholds for IDH-mutant astrocytomas underlies poor predictive accuracy of current histologic grading approaches. To test this hypothesis, we quantified total mitotic figures and maximum mitotic activity per ten high-powered fields in an institutional cohort of IDH-mutant astrocytomas. In our cohort, there was no mitotic activity threshold that was reflective of clinical progression-free or overall survival. Furthermore, in a multivariate Cox regression model consisting of mitotic activity, molecular markers, and clinical characteristics, only CDKN2A deletion was identified as a relevant variant for poor overall survival. We conclude that lack of defined mitotic figure thresholds may not contribute to underperformance of histological grading for IDH-mutant astrocytomas. This study supports the shift towards ‘molecular grading’ to replace traditional histological grading for IDH-mutant astrocytomas.

scholarly journals The Role of Extent of Resection in IDH1 Wild-Type or Mutant Low-Grade Gliomas

Neurosurgery ◽  
2017 ◽  
Vol 82 (6) ◽  
pp. 808-814 ◽  
Author(s):  
Toral Patel ◽  
Evan D Bander ◽  
Rachael A Venn ◽  
Tiffany Powell ◽  
Gustav Young-Min Cederquist ◽  
...  
Keyword(s):  
Cox Regression ◽  
Extent Of Resection ◽  
World Health ◽  
Low Grade ◽  
Wild Type ◽  
Who Grade ◽  
Cox Regression Analysis ◽  
Low Grade Gliomas ◽  
Grade Ii ◽  
The Impact

Abstract BACKGROUND Maximizing extent of resection (EOR) improves outcomes in adults with World Health Organization (WHO) grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. OBJECTIVE To assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS) in mtIDH and wtIDH LGGs. METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing resection at a single institution. EOR was assessed with quantitative 3-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan–Meier method. RESULTS Fifty-two (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median preoperative tumor volume was 37.4 cm3; median EOR of 57.6% was achieved. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, stratifying by IDH status demonstrates that greater EOR independently prolonged MPFS and OS for wtIDH patients (hazard ratio [HR] = 0.002 [95% confidence interval {CI} 0.000-0.074] and HR = 0.001 [95% CI 0.00-0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17-4.13] and HR = 2.99 [95% CI 0.15-61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wtLGGs, but the impact on IDH1 mtLGGs requires further study.

scholarly journals Prognostic Significance and Gene Co-Expression Network of PLAU and PLAUR in Gliomas

2022 ◽  
Vol 11 ◽  
Author(s):  
Junhong Li ◽  
Huanhuan Fan ◽  
Xingwang Zhou ◽  
Yufan Xiang ◽  
Yanhui Liu
Keyword(s):  
Cox Regression ◽  
Prognostic Significance ◽  
High Expression ◽  
Lower Grade ◽  
Tumor Type ◽  
Who Grade ◽  
Cox Regression Analysis ◽  
Online Databases ◽  
Type Plasminogen Activator ◽  
Primary Glioma

The urokinase-type plasminogen activator(PLAU) and its receptor PLAUR participate in a series of cell physiological activities on the extracellular surface. Abnormal expression of PLAU and PLAUR is associated with tumorigenesis. This study aims to evaluate the prognostic value of PLAU/PLAUR transcription expression in glioma and to explore how they affect the generation and progression of glioma. In this study, online databases are applied, such as Oncomine, GEPIA, CGGA, cBioPortal, and LinkedOmics. Overexpression of PLAU/PLAUR was found to be significantly associated with clinical variables including age, tumor type, WHO grade, histology, IDH-1 mutation, and 1p19q status. PLAU and PLAUR had a high correlation in transcriptional expression levels. High expression of PLAU and PLAUR predicted a poor prognosis in primary glioma and recurrent glioma patients, especially in lower grade gliomas. Cox regression analysis indicated that high expression of PLAU and PLAUR were independent prognostic factors for shorter overall survival in glioma patients. In gene co-expression network analysis PLAU and PLAUR and their co-expression genes were found to be involved in inflammatory activities and tumor-related signaling pathways. In conclusion, PLAU and PLAUR could be promising prognostic biomarkers and potential therapeutic targets of glioma patients.

scholarly journals Analysis of Prognostic Factors of World Health Organization Grade Ⅲ Meningiomas

2020 ◽  
Vol 10 ◽  
Author(s):  
Weidong Tian ◽  
Jingdian Liu ◽  
Kai Zhao ◽  
Junwen Wang ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Cox Regression ◽  
Postoperative Radiotherapy ◽  
World Health ◽  
Low Grade ◽  
Ki 67 ◽  
Who Grade ◽  
Who Grade Iii ◽  
Grade Iii

ObjectiveWHO grade III meningiomas are highly aggressive and lethal. However, there is a paucity of clinical information because of a low incidence rate, and little is known for prognostic factors. The aim of this work is to analyze clinical characteristics and prognosis in patients diagnosed as WHO grade III meningiomas.Methods36 patients with WHO grade III meningiomas were enrolled in this study. Data on gender, age, clinical presentation, preoperative Karnofsky Performance Status (KPS), histopathologic features, tumor size, location, radiologic findings, postoperative radiotherapy (RT), surgical treatment, and prognosis were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. Univariate and multivariate analysis were conducted by the Cox regression model.ResultsMedian PFS is 20 months and median OS is 36 months in 36 patients with WHO grade III meningiomas. Patients with secondary tumors which transformed from low grade meningomas had lower PFS (p=0.0014) compared with primary group. Multivariate analysis revealed that tumors location (PFS, p=0.016; OS, p=0.013), Ki-67 index (PFS, p=0.004; OS, p<0.001) and postoperative radiotherapy (PFS, p=0.006; OS, p<0.001) were associated with prognosis.ConclusionWHO grade III meningiomas which progressed from low grade meningiomas were more prone to have recurrences or progression. Tumors location and Ki-67 index can be employed to predict patient outcomes. Adjuvant radiotherapy after surgery can significantly improve patient prognosis.

scholarly journals Somatostatin Receptors in Human Meningiomas—Clinicopathological Aspects

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5704
Author(s):  
Sofie Eline Tollefsen ◽  
Anders H. Jarmund ◽  
Borgny Ytterhus ◽  
Øyvind Salvesen ◽  
Patricia Mjønes ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Cox Regression ◽  
Somatostatin Receptors ◽  
World Health ◽  
Recurrence Rates ◽  
Who Grade ◽  
Tissue Samples ◽  
Increased Risk ◽  
Staining Index ◽  
Human Meningiomas

Meningiomas have high recurrence rates despite frequently benign histopathological appearances. Somatostatin receptors (SSTRs) may be reliable biomarkers that could identify patients with increased risk of recurrence. Even though SSTRs are previously detected in meningiomas, their associations to clinicopathological features remain unclear. The aim of this study was to investigate the diagnostic and prognostic value of SSTRs in a large series of human meningiomas with long follow-up data. Immunohistochemistry was used to measure the expression of SSTR1-SSTR5 in tissue samples from 162 patients diagnosed with intracranial meningiomas of World Health Organization (WHO) grade 1 or 2. Digital scoring and a manual staining index were applied to assess immunoreactivity. All SSTRs, except SSTR4, were upregulated in our series of meningiomas. SSTR1 (p = 0.036), SSTR2 (p = 0.036) and SSTR5 (p = 0.029) were associated with a higher malignancy grade. SSTR2 presented as the most reliable marker. Only SSTR2 was associated with time to recurrence (TTR) in univariate Cox regression analyses. Manual staining index was strongly correlated with digital scoring for all SSTRs (r > 0.65, p < 0.001). SSTRs, and especially SSTR2, are useful in the diagnostics of meningiomas, even though their prognostic value appears limited. Digital scoring is valuable to ensure reproducibility.

scholarly journals Identification and validation of a five-lncRNA prognostic signature related to Glioma using bioinformatics analysis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chunyu Zhang ◽  
Haitao Liu ◽  
Pengfei Xu ◽  
Yinqiu Tan ◽  
Yang Xu ◽  
...  
Keyword(s):  
Network Analysis ◽  
Cox Regression ◽  
Predictive Accuracy ◽  
Characteristic Curve ◽  
Prognostic Indicator ◽  
High Risk Group ◽  
Survival Prediction ◽  
Prognostic Signature ◽  
Who Grade ◽  
Cox Analysis

Abstract Background To accurately predict the prognosis of glioma patients. Methods A total of 541 samples from the TCGA cohort, 181 observations from the CGGA database and 91 samples from our cohort were included in our study. Long non-coding RNAs (LncRNAs) associated with glioma WHO grade were evaluated by weighted gene co-expression network analysis (WGCNA). Five lncRNA features were selected out to construct prognostic signatures based on the Cox regression model. Results By weighted gene co-expression network analysis (WGCNA), 14 lncRNAs related to glioma grade were identified. Using univariate and multivariate Cox analysis, five lncRNAs (CYTOR, MIR155HG, LINC00641, AC120036.4 and PWAR6) were selected to develop the prognostic signature. The Kaplan-Meier curve depicted that the patients in high risk group had poor prognosis in all cohorts. The areas under the receiver operating characteristic curve of the signature in predicting the survival of glioma patients at 1, 3, and 5 years were 0.84, 0.92, 0.90 in the CGGA cohort; 0.8, 0.85 and 0.77 in the TCGA set and 0.72, 0.90 and 0.86 in our own cohort. Multivariate Cox analysis demonstrated that the five-lncRNA signature was an independent prognostic indicator in the three sets (CGGA set: HR = 2.002, p < 0.001; TCGA set: HR = 1.243, p = 0.007; Our cohort: HR = 4.457, p = 0.008, respectively). A nomogram including the lncRNAs signature and clinical covariates was constructed and demonstrated high predictive accuracy in predicting 1-, 3- and 5-year survival probability of glioma patients. Conclusion We established a five-lncRNA signature as a potentially reliable tool for survival prediction of glioma patients.

scholarly journals Classification of Adverse Events Following Surgery in Patients With Diffuse Lower-Grade Gliomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Tomás Gómez Vecchio ◽  
Alba Corell ◽  
Dongni Buvarp ◽  
Isabelle Rydén ◽  
Anja Smits ◽  
...  
Keyword(s):  
Adverse Events ◽  
Neurological Deficit ◽  
Patient Reported Outcomes ◽  
Higher Order ◽  
World Health ◽  
Lower Grade ◽  
Who Grade ◽  
Patient Reported ◽  
New Onset

BackgroundRecently, the Therapy-Disability-Neurology (TDN) was introduced as a multidimensional reporting system to detect adverse events in neurosurgery. The aim of this study was to compare the novel TDN score with the Landriel–Ibanez classification (LIC) grade in a large cohort of patients with diffuse lower-grade glioma (dLGG). Since the TDN score lacks validation against patient-reported outcomes, we described health-related quality of life (HRQoL) change in relation to TDN scores in a subset of patients.MethodsWe screened adult patients with a surgically treated dLGG World Health Organization (WHO) grade 2 and 3 between 2010 and 2020. Up until 2017, it consists of a retrospective cohort (n = 158). From 2017 and onwards, HRQoL was registered using EuroQoL-5-dimension, three levels of response (EQ-5D 3L) questionnaire at baseline and 3 months follow-up, in a prospectively recruited cohort (n = 102). Both the LIC grade and TDN score were used to classify adverse events.ResultsIn total, 231 patients were included. In 110/231 (47.6%) of the surgical procedures, a postoperative complication was registered. When comparing the TDN score to LIC grades, only a minor shift towards complications of higher order could be observed. EQ-5D 3L was reported for 45 patients. Patients with complications related to surgery had pre- to postoperative changes in EQ-5D 3L index values (n = 27; mean 0.03, 95% CI −0.06 to 0.11) that were comparable to patients without complications (n = 18; mean −0.06, 95% CI −0.21 to 0.08). In contrast, patients with new-onset neurological deficit had a deterioration in HRQoL at follow-up, with a mean change in the EQ-5D 3L index value of 0.11 (n = 13, 95% CI 0.0 to 0.22) compared to −0.06 (n = 32, 95% CI −0.15 to 0.03) for all other patients.ConclusionsIn patients with dLGG, TDN scores compared to the standard LIC tend to capture more adverse events of higher order. There was no clear relation between TDN severity and HRQoL. However, new-onset neurological deficit caused impairment in HRQoL. For the TDN score to better align with patient-reported outcomes, more emphasis on neurological deficit and function should be considered.

scholarly journals Predicting prognosis and IDH mutation status for patients with lower-grade gliomas using whole slide images

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shuai Jiang ◽  
George J. Zanazzi ◽  
Saeed Hassanpour
Keyword(s):  
Performance Metrics ◽  
Small Sample Size ◽  
Small Sample ◽  
The Cancer Genome Atlas ◽  
World Health ◽  
Lower Grade ◽  
Who Grade ◽  
Mutation Status ◽  
Idh Mutations ◽  
Whole Slide Images

AbstractWe developed end-to-end deep learning models using whole slide images of adults diagnosed with diffusely infiltrating, World Health Organization (WHO) grade 2 gliomas to predict prognosis and the mutation status of a somatic biomarker, isocitrate dehydrogenase (IDH) 1/2. The models, which utilize ResNet-18 as a backbone, were developed and validated on 296 patients from The Cancer Genome Atlas (TCGA) database. To account for the small sample size, repeated random train/test splits were performed for hyperparameter tuning, and the out-of-sample predictions were pooled for evaluation. Our models achieved a concordance- (C-) index of 0.715 (95% CI: 0.569, 0.830) for predicting prognosis and an area under the curve (AUC) of 0.667 (0.532, 0.784) for predicting IDH mutations. When combined with additional clinical information, the performance metrics increased to 0.784 (95% CI: 0.655, 0.880) and 0.739 (95% CI: 0.613, 0.856), respectively. When evaluated on the WHO grade 3 gliomas from the TCGA dataset, which were not used for training, our models predicted survival with a C-index of 0.654 (95% CI: 0.537, 0.768) and IDH mutations with an AUC of 0.814 (95% CI: 0.721, 0.897). If validated in a prospective study, our method could potentially assist clinicians in managing and treating patients with diffusely infiltrating gliomas.

scholarly journals Behavior-Oriented Nomogram for the Stratification of Lower-Grade Gliomas to Improve Individualized Treatment

2020 ◽  
Vol 10 ◽  
Author(s):  
Ruo-Lun Wei ◽  
Li-Wei Zhang ◽  
Jian-Guo Li ◽  
Feng-Dong Yang ◽  
Ya-Ke Xue ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Predictive Performance ◽  
Individualized Treatment ◽  
World Health ◽  
Low Grade ◽  
Lower Grade ◽  
Validation Group ◽  
Who Grade ◽  
Health Organization ◽  
Cortical Involvement

Secondary glioblastomas (sGBM) are derived from previously lower-grade [World Health Organization (WHO) grades II or III] gliomas. Lower-grade benign-behaving gliomas may retain their former grade following recurrence, or may become malignant higher-grade glioblastomas. Prediction of tumor behavior in lower-grade gliomas is critical for individualized glioma therapy. A total of 89 patients were included between January 2000 and January 2019 in the present study to establish a nomogram via univariate and multivariate logistic regression analyses. Nomogram predictive performance was tested in the validation group. We then analyzed 36 O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated lower-grade gliomas from patients seen at West China Hospital of Sichuan University. Survival statistics were calculated with the Kaplan-Meier method. Two clinical factors (molecular diagnosis and WHO grade), five radiological factors (location, cortical involvement, multicentricity, uniformity, and margin enhancement), one biomarker (1p19q codeletion), and a combination of three biomarkers (IDH+/ATRX-/TP53-) were associated with glioma upgrading. Nomograms positive for these prognostic factors had an AUC of 0.880 in the derivation group and 0.857 in the validation group. The calibration and score-stratified survival curves for the derivation group and validation group were good. An operational nomogram was published at https://warrenwrl.shinyapps.io/DynNomapp/. The overall survival of secondary gliomas in the MGMT-unmethylated cohort were influenced independently by the use of temozolomide during the treatment of formerly low-grade gliomas (p=0.00096). Clinical and radiological factors and biomarker-based behavior-oriented nomograms may offer a feasible identification tool for the detection of sGBM precursors. This method may further assist neurosurgeons with the stratification of lower-grade glioma cases and thus the development of better, more individualized treatment plans.

scholarly journals TMOD-01. A PROGNOSTIC NOMOGRAM MODEL AND ONLINE SOFTWARE FOR PATIENTS WITH NEWLY DIAGNOSED LOWER-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i35-i35
Author(s):  
Mingzhi Han
Keyword(s):  
Cox Regression ◽  
Molecular Subtype ◽  
Age At Diagnosis ◽  
Calibration Plot ◽  
Low Grade ◽  
Lower Grade ◽  
Newly Diagnosed ◽  
Who Grade ◽  
Cox Regression Analysis ◽  
Survival Probabilities

Abstract The nomogram represents a statistical model that incorporates multiple risk factors to estimate individualized survival probabilities. In this study, we developed a nomogram which provides an important tool for individulized survival predicition for newly diagnosed low-grade gliomas (LGG). A total number of 582 newly diagnosed LGG patients were included; the median age was 39.93 years and 42% were female. Cox regression analysis showed that younger age at diagnosis, WHO grade II vs. III, the IDHmut-codel vs. the IDHwt, and the IDHmut-non-codel vs. the IDHwt were significantly associated with better prognosis. The adjuvant treatment following surgery showed a trend towards improved survival. Subsequently, the nomogram to estimate 60-, 90-, and 120-month survival probabilities was established. Our data showed that the age at diagnosis was the largest contributor to patient survival, followed by molecular subtype, WHO grade, treatment and gender. The calibration plot showed that the observed and the nomogram predicted OS curves were well-aligned. In addition, we also validated our nomogram for LGG patients who received postsurgical adjuvant therapy through cross-validation and the calibration plot. Finally, we developed a free online tool for this nomogram (softwarewebsite:https://rrlnnomogram.shinyapps.io/LGG_Nom_Asian/). Overall, this model should be a useful tool for counseling patients in clinical practice including treatment decisions, follow-up, and prognosis.

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