scholarly journals MN1 overexpression with varying tumor grade is a promising predictor of survival of glioma patients

2020 ◽  
Author(s):  
Masum Saini ◽  
Ajaya Nand Jha ◽  
Rajiv Tangri ◽  
M D Qudratullah ◽  
Sher Ali
Keyword(s):  
Copy Number ◽  
Copy Number Alteration ◽  
Incidence Rate Ratio ◽  
Prognostic Biomarker ◽  
Progression Free Survival ◽  
Tumor Grade ◽  
Low Grade ◽  
Free Survival ◽  
Expression Levels ◽  
Igf1 Expression

Abstract Gliomas have substantial mortality to incidence rate ratio and a dismal clinical course. Newer molecular insights, therefore, are imperative to refine glioma diagnosis, prognosis and therapy. Meningioma 1 (MN1) gene is a transcriptional co-regulator implicated in other malignancies, albeit its significance in glioma pathology remains to be explored. IGFBP5 is regulated transcriptionally by MN1 and IGF1, and is associated with higher glioma grade and shorter survival time, prompting us to ascertain their correlation in these tumors. We quantified MN1, IGFBP5 and IGF1 expression in 40 glioma samples and examined their interrelatedness. MN1 mRNA-protein inter-correlation and gene’s copy number were evaluated in these tumors. Publicly available TCGA datasets were used to examine the association of MN1 expression levels with patient survival and for validating our findings. We observed MN1 overexpression correlated with low grade (LGGs) and not high grade gliomas (HGGs), and is not determined by copy number alteration of the gene. Notably, gliomas with upregulated MN1 have better overall and progression-free survival. IGFBP5 expression inversely associated with MN1 expression levels in gliomas but correlated positively with IGF1 expression in only LGGs. This suggests a potential grade-specific interplay between repressive and activating roles of MN1 and IGF1, respectively in the regulation of IGFBP5. Thus, MN1 overexpression, a promising predictor of overall and progression-free survival in gliomas, may serve as a prognostic biomarker in clinical practice to categorize patients with survival advantage.

OUTCOME PREDICTORS FOR INTRACRANIAL EPENDYMOMA RADIOSURGERY

Neurosurgery ◽  
2009 ◽  
Vol 64 (2) ◽  
pp. 279-288 ◽  
Author(s):  
Hideyuki Kano ◽  
Ajay Niranjan ◽  
Douglas Kondziolka ◽  
John C. Flickinger ◽  
L. Dade Lunsford
Keyword(s):  
Radiation Therapy ◽  
Contrast Enhancement ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Tumor Grade ◽  
Tumor Control ◽  
Low Grade ◽  
Outcome Predictors ◽  
Free Survival ◽  
Imaging Characteristics

Abstract OBJECTIVE To develop outcome predictors after stereotactic radiosurgery (SRS) in patients with intracranial ependymomas who had received previous fractionated radiation therapy, we compared tumor control, survival, and complications with tumor grade, volume, age of patients, and imaging characteristics. METHODS We retrospectively reviewed records of 39 consecutive ependymoma patients who underwent SRS for 56 tumors. The median patient age was 22.8 years (range, 2.9–71.1 years). All patients had previous surgical resection of their ependymomas followed by radiotherapy, and 14 patients underwent previous chemotherapy. Twenty-five patients had low-grade ependymomas (34 tumors), and 14 patients had anaplastic ependymomas (22 tumors). The median radiosurgery target volume was 3.6 cm3 (range, 0.1–36.8 cm3), and the median margin dose was 15.0 Gy (range, 10–22 Gy). RESULTS At a median of 23.5 months after SRS (range, 6.1–155.2 months), 25 patients died as a result of metastases (12 patients) or disease progression (13 patients). The overall survival rates after SRS were 60.1, 36.1, and 32.1% at 1, 3, and 5 years, respectively. The progression-free survival rates after SRS at 1, 3, and 5 years were 81.6, 45.8, and 45.8%, respectively, for all grades of ependymomas. Lower histological tumor grade was not significantly associated with better progression-free survival (P = 0.725). Factors associated with an improved progression-free survival included smaller tumor volume and homogeneous tumor contrast enhancement in low-grade ependymomas. CONCLUSION SRS provides another management option for patients with residual or recurrent ependymomas that have failed surgery and radiation therapy. Predictors of response include smaller volume and homogeneous contrast enhancement.

scholarly journals A survival analysis of surgically treated incidental low-grade glioma patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lingcheng Zeng ◽  
Qi Mei ◽  
Hua Li ◽  
Changshu Ke ◽  
Jiasheng Yu ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Total Resection ◽  
Surgical Timing ◽  
Asymptomatic Group ◽  
Free Survival ◽  
Symptomatic Group ◽  
Significant Difference ◽  
Asymptomatic Phase

AbstractTo evaluate the surgical effect on survival in patients with incidental low-grade glioma (LGG) through comparison between asymptomatic and symptomatic patients. The medical records of surgically treated adult cerebral incidental LGG (iLGG) patients in our department between January 2008 and December 2015 were retrospectively reviewed. The survival of patients was calculated starting from the initial imaging diagnosis. Factors related to progression-free survival (PFS), overall survival (OS) and malignant progression-free survival (MPFS) were statistically analyzed. Seventy-five iLGG patients underwent surgery: 49 in the asymptomatic group, who underwent surgery in the asymptomatic period, and 26 in the symptomatic group, who underwent surgery after the tumor had grown and the patients had developed tumor-related symptoms. Significantly more tumors were initially located adjacent to the functional area in the symptomatic group than in the asymptomatic group (P < 0.05), but there was no significant difference in the total resection rate between the two groups. The incidence of postoperative complications (15.4%) and postoperative epilepsy (23.1%) was higher in the symptomatic group than in the asymptomatic group (4.1% and 10.2%, respectively). Multivariate analysis showed that surgical timing, namely, surgery performed before or after symptom occurrence, had no significant effect on PFS, OS or MPFS, while total resection significantly prolonged PFS, OS and MPFS, and the pathology of oligodendroglioma was positively correlated with PFS and OS (P < 0.05). Surgical timing for iLGGs should facilitate total resection. If total resection can be achieved, even after symptom occurrence, patients can achieve comparable survival benefits to those treated with surgery in the asymptomatic phase.

scholarly journals RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Ingo Mellinghoff ◽  
Martin van den Bent ◽  
Jennifer Clarke ◽  
Elizabeth Maher ◽  
Katherine Peters ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Escalation ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Low Grade ◽  
Who Grade ◽  
Free Survival ◽  
Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

scholarly journals IMG-14. DEVELOPING A PREDICTIVE GRADING MODEL FOR CHILDREN WITH GLIOMAS BASED ON DIFFUSION KURTOSIS IMAGING METRICS: ACCURACY AND CLINICAL CORRELATIONS WITH SURVIVAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii357-iii358
Author(s):  
Ioan Paul Voicu ◽  
Antonio Napolitano ◽  
Alessia Carboni ◽  
Lorenzo Lattavo ◽  
Andrea Carai ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
High Grade Glioma ◽  
Diffusion Kurtosis Imaging ◽  
Low Grade ◽  
Free Survival ◽  
Kaplan Meier ◽  
Model Predictions ◽  
Probability Prediction ◽  
Grading Model ◽  
Diffusion Kurtosis

Abstract PURPOSE To develop a predictive grading model based on diffusion kurtosis imaging (DKI) metrics in children affected by gliomas, and to investigate the clinical impact of the model via correlations with overall survival and progression-free survival. MATERIALS AND METHODS We retrospectively studied 59 children (33M, 26F, median age 7.2 years) affected by gliomas on a 3T magnet. Patients with tumor locations other than infratentorial midline were included. Conventional and DKI sequences were obtained. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps were obtained. Whole tumor volumes (VOIs) were segmented semiautomatically. Mean DKI values were calculated for each metric. The quantitative values from DKI-derived metrics were used to develop a predictive grading model with penalized logistic regression (glmnet package, R). Elasticnet regularization was used to avoid model overfitting. Fitted model coefficients from each metric were used to develop a probability prediction of a high-grade glioma (HGG). Grading accuracy of the resulting probabilities was tested with ROC analysis. Finally, model predictions were correlated to progression-free survival (PFS) with a Kaplan-Meier analysis. RESULTS The cohort included 46 patients with low-grade gliomas (LGG) and 13 patients with HGG. The developed model predictions yielded an AUC of 0.946 (95%CI: 0.890–1). Model predictions were significantly correlated with PFS (23.1 months for HGG vs 34.7 months for LGG, p&lt;0.004). CONCLUSION In our cohort, a DKI-based predictive model was highly accurate for pediatric glioma grading. DKI-based model predictions were significantly correlated with progression-free survival.

scholarly journals P04.16 TP53 mutations in codon 273 is predictive of overall survival in astrocytoma patients

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii32-iii32
Author(s):  
H Noor ◽  
R Rapkins ◽  
K McDonald
Keyword(s):  
Overall Survival ◽  
Tp53 Mutation ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Wild Type ◽  
Mutation Status ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Fresh Frozen

Abstract BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C>T and c.818 G>A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p<0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p<0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p<0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

scholarly journals Low-grade astrocytoma: surgical outcomes in eloquent versus non-eloquent brain areas

2013 ◽  
Vol 71 (1) ◽  
pp. 31-34 ◽  
Author(s):  
André de Macedo Bianco ◽  
Flavio Key Miura ◽  
Carlos Clara ◽  
Jose Reynaldo W. Almeida ◽  
Clemar Correa da Silva ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Subtotal Resection ◽  
Low Grade ◽  
Brain Areas ◽  
Free Survival ◽  
Eloquent Areas ◽  
Eloquent Area ◽  
Extent Of Surgical Resection

A retrospective study of 81 patients with low-grade astrocytoma (LGA) comparing the efficacy of aggressive versus less aggressive surgery in eloquent and non-eloquent brain areas was conducted. Extent of surgical resection was analyzed to assess overall survival (OS) and progression- free survival (PFS). Degree of tumor resection was classified as gross total resection (GTR), subtotal resection (STR) or biopsy. GTR, STR and biopsy in patients with tumors in non-eloquent areas were performed in 31, 48 and 21% subjects, whereas in patients with tumors in eloquent areas resections were 22.5, 35 and 42.5%. Overall survival was 4.7 and 1.9 years in patients with tumors in non-eloquent brain areas submitted to GTR/STR and biopsy (p=0.013), whereas overall survival among patients with tumors in eloquent area was 4.5 and 2.1 years (p=0.33). Improved outcome for adult patients with LGA is predicted by more aggressive surgery in both eloquent and non-eloquent brain areas.

scholarly journals Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas

1997 ◽  
Vol 2 (3) ◽  
pp. E1
Author(s):  
Roger J. Packer ◽  
Joanne Ater ◽  
Jeffrey Allen ◽  
Peter Phillips ◽  
Russell Geyer ◽  
...  
Keyword(s):  
Objective Response ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Low Grade ◽  
Significant Prognostic Factor ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Low Grade Gliomas ◽  
Response To Chemotherapy

The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided. There has been increased interest in the use of chemotherapy for young children, but little information concerning the long-term efficacy of such treatment. Seventy-eight children with a mean age of 3 years (range 3 months-16 years) who had newly diagnosed, progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy. The patients were followed for a median of 30 months from diagnosis, with 31 patients followed for more than 3 years. Fifty-eight children had diencephalic tumors, 12 had brainstem gliomas, and three had diffuse leptomeningeal gliomas. Forty-four (56%) of 78 patients showed an objective response to treatment. Progression-free survival rates were 75 ± 6% at 2 years and 68 ± 7% at 3 years. There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year, progression-free survival 79 ± 11% vs. 75 ± 6%, respectively). The histological subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. The only significant prognostic factor was age: children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 ± 7% compared with a rate of 39 ± 21% in older children (p < 0.01). Treatment with carboplatin and vincristine is effective, especially in younger children, in controlling newly diagnosed progressive low-grade gliomas.

scholarly journals Genome-Wide Scan for Copy Number Alteration Association with Relapse-Free Survival in Colorectal Cancer with Liver Metastasis Patients

2018 ◽  
Vol 7 (11) ◽  
pp. 446 ◽  
Author(s):  
Po-Sheng Yang ◽  
Hsi-Hsien Hsu ◽  
Tzu-Chi Hsu ◽  
Ming-Jen Chen ◽  
Cin-Di Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Gene Signature ◽  
Comparative Genomic ◽  
Relapse Free Survival ◽  
Cgh Array ◽  
Free Survival

Predicting a patient’s risk of recurrence after the resection of liver metastases from colorectal cancer is critical for evaluating and selecting therapeutic approaches. Clinical and pathologic parameters have shown limited accuracy thus far. Therefore, we combined the clinical status with a genomic approach to stratify relapse-free survival in colorectal cancer liver metastases patients. To identify new molecular and genetic signatures specific to colorectal cancer with liver metastasis (CRCLM) patients, we conducted DNA copy number profiling on a cohort of 21 Taiwanese CRCLM patients using a comparative genomic hybridization (CGH) array. We identified a three-gene signature based on differential copy number alteration between patients with different statuses of (1) recurrence and (2) synchronous metastasis. In relapse hotspot regions, only three genes (S100PBP, CSMD2, and TGFBI) were significantly associated with the synchronous liver metastasis factor. A final set of three genes—S100PBP, CSMD2, TGFBI—significantly predicted relapse-free survival in our cohort (p = 0.04) and another CRCLM cohort (p = 0.02). This three-gene signature is the first genomic signature validated for relapse-free survival in post-hepatectomy CRCLM patients. Our three-gene signature was developed using a whole-genome CGH array and has a good prognostic position for the relapse-free survival of CRCLM patients after hepatectomy.

scholarly journals Management of low-grade glioma: a systematic review and meta-analysis

2018 ◽  
Vol 6 (4) ◽  
pp. 249-258 ◽  
Author(s):  
Timothy J Brown ◽  
Daniela A Bota ◽  
Martin J van Den Bent ◽  
Paul D Brown ◽  
Elizabeth Maher ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
World Health ◽  
Subtotal Resection ◽  
Low Grade ◽  
Evidence Based ◽  
Free Survival ◽  
Low Grade Gliomas

Abstract Background Optimum management of low-grade gliomas remains controversial, and widespread practice variation exists. This evidence-based meta-analysis evaluates the association of extent of resection, radiation, and chemotherapy with mortality and progression-free survival at 2, 5, and 10 years in patients with low-grade glioma. Methods A quantitative systematic review was performed. Inclusion criteria included controlled trials of newly diagnosed low-grade (World Health Organization Grades I and II) gliomas in adults. Eligible studies were identified, assigned a level of evidence for every endpoint considered, and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality and of progression at 2, 5, and 10 years was calculated for patients undergoing resection (gross total, subtotal, or biopsy), radiation, or chemotherapy. Results Gross total resection was significantly associated with decreased mortality and likelihood of progression at all time points compared to subtotal resection. Early radiation was not associated with decreased mortality; however, progression-free survival was better at 5 years compared to patients receiving delayed or no radiation. Chemotherapy was associated with decreased mortality at 5 and 10 years in the high-quality literature. Progression-free survival was better at 5 and 10 years compared to patients who did not receive chemotherapy. In patients with isocitrate dehydrogenase 1 gene (IDH1) R132H mutations receiving chemotherapy, progression-free survival was better at 2 and 5 years than in patients with IDH1 wild-type gliomas. Conclusions Results from this review, the first to quantify differences in outcome associated with surgery, radiation, and chemotherapy in patients with low-grade gliomas, can be used to inform evidence-based management and future clinical trials.

scholarly journals Treatment of Residual, Recurrent, or Metastatic Intracranial Hemangiopericytomas With Stereotactic Radiotherapy Using CyberKnife

2021 ◽  
Vol 11 ◽  
Author(s):  
Lichao Huang ◽  
Jingmin Bai ◽  
Yanyang Zhang ◽  
Zhiqiang Cui ◽  
Zhizhong Zhang ◽  
...  
Keyword(s):  
Stereotactic Radiotherapy ◽  
Progression Free Survival ◽  
Tumor Grade ◽  
Tumor Control ◽  
Intracranial Metastasis ◽  
Free Survival ◽  
The Mean ◽  
Aggressive Tumors

PurposeHemangiopericytomas are aggressive tumors known for their recurrence. The purpose of this study was to evaluate the management of residual, recurrent, and metastatic intracranial hemangiopericytomas using CyberKnife (CK) stereotactic radiotherapy (SRT).Materials and MethodsData were collected from 15 patients (28 tumors; eight men and seven women; 32–58 years) with residual, recurrent, or metastatic intracranial hemangiopericytomas, who were treated with stereotactic radiotherapy using CyberKnife between January 2014 and August 2019. All patients had previously been treated with surgical resection. Initial tumor volumes ranged from 0.84 to 67.2 cm3, with a mean volume of 13.06 cm3. The mean marginal and maximum radiosurgical doses to the tumors were 21.1 and 28.76 Gy, respectively. The mean follow-up time for tumors was 34.5 months, ranging from 13 to 77 months.Results15 patients were alive after treatment; the mean post-diagnosis survival at censoring was 45.6 months (range 13–77 months). The volumes of the 28 tumors in the 15 followed patients were calculated after treatment. Postoperative magnetic resonance imaging revealed a mean tumor volume of 6.72 cm3 and a range of 0–67.2 cm3, with the volumes being significantly lower than pretreatment values. Follow-up imaging studies demonstrated tumor disappearance in seven (25%) of 28 tumors, reduction in 14 (50%), stability in one (3.57%), and recurrence in six (21.4%). Total tumor control was achieved in 22 (78.5%) of 28 tumors. The tumor grade and fraction time were not significantly associated with progression-free survival. Intracranial metastasis occurred in three patients, and extraneural metastasis in one patient.ConclusionsOn the basis of the current results, stereotactic radiotherapy using CyberKnife is an effective and safe option for residual, recurrent, and metastatic intracranial hemangiopericytomas. Long-term close clinical and imaging follow-up is also necessary.

Sign in / Sign up

Export Citation Format

Share Document