Association of Hormonal Contraception with Meningioma Location in Indonesian Patients.

BACKGROUND: Meningioma is the most common primary intracranial tumor. Previous studies have shown the possible association between hormonal contraceptive use and meningioma location. Therefore, this study aimed to analyze the association between the history of hormonal contraceptive use and the location of meningioma in the Indonesian population. METHODS: In total, 99 histologically confirmed female meningioma patients admitted to Dr. Sardjito General Hospital Yogyakarta, Indonesia, were included in this study. Data on hormonal contraception and other variables were collected from medical records. Meningioma locations were determined from brain Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) scan before surgery. RESULTS: Seventy-two (72.7%) patients had a history of hormonal contraceptive use. The subjects consist of 83 (83.8%) WHO grade I and 16 (16.2%) WHO grade II and III tumors. A total of 57 (57.6%) tumors were located in the spheno-orbital region. We found a significant association between hormonal contraceptive use and meningioma location in the spheno-orbital region (Odds ratio (OR) 2.573, p=0.038). This resulted in the patients in the hormonal contraception group having more visual impairment (p=0.044). CONCLUSION: The use of hormonal contraception is associated with the location of meningioma in the spheno-orbital region.

Diagnostic Accuracy of Immunohistochemistry in Detecting MGMT Methylation Status in Patients with Glioma.

BACKGROUND: The O6-methylguanine-DNA methyltransferase (MGMT) gene prevents mismatch in DNA replication and transcription by repairing mutagenic DNA lesions. MGMT is a predictor biomarker of chemotherapy in high-grade and low-grade gliomas based on high-risk clinical conditions. It also can be used for therapeutic decisions to predict hypermutation in recurrence in newly diagnosed low-grade gliomas. The gold standard  examination for the methylation is Polymerase Chain Reaction (PCR). However, this technique is not widely available in Indonesia for daily practice. Thus, an uncomplicated and simpler method such as immunohistochemistry (IHC) is needed as an alternative examination. This study aimed to predict the diagnostic accuracy of immunohistochemistry (IHC) in detecting the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) in glioma. METHODS: This research was a cross-sectional study using formalin-fixed paraffin embedded (FFPE) tissue samples of glioma patients, dating between October 2017 until March 2021. Diagnosis of glioma was established based on clinical, radiological, and histopathological findings. MGMT methylation status was investigated using the IHC and PCR techniques. Diagnostic value of IHC was analyzed, with PCR as a gold standard method. Optimum threshold to determine positivity of IHC was determined by the Area Under the Curve (AUC) on Receiver Operating Characteristics (ROC) curve and Youden index. RESULTS: Among 75 samples examined, 29 (38.7%) patients were methylated. IHC detected MGMT methylation with sensitivity of 86.2%, specificity of 63.0%, positive predictive value of 59.5%, negative predictive value of 87.9% and accuracy of 72.0%. The AUC was 0.746, indicating moderate diagnostic value. Optimum positivity threshold of the IHC examination based on Youden Index was 10%. CONCLUSION: IHC examination can be used to detect MGMT methylation status of glioma patients in limited resources setting, where PCR technique is not available.

Seizure in Indonesian Glioma Patients: Associated Risk Factors and Impact on Survival.

OBJECTIVE: Seizure is commonly found in patients with glioma. This study aimed to find risk factors for seizures in Indonesian patients with glioma. We also sought to determine the association between seizure and survival in this patient population. METHODS: Patients with glioma were enrolled from the Dr. Sardjito General Hospital and other hospitals in Yogyakarta Province, Indonesia. Detailed demographic and clinical data were collected from medical records. DNA extraction and polymerase chain reaction (PCR) were performed to detect IDH1 mutation. Tumor tissue samples were stained by hematoxylin-eosin and classified according to the 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Expression of Ki-67 was detected by immunohistochemistry staining. Survival data were also collected. RESULTS: In total, 107 patients were included in the analysis. Age, gender, history of smoking, tumor side, tumor grade, Ki-67 expression, and IDH1 mutation were not associated with seizure. Tumors involving the frontal lobe (p=0.037) and oligodendroglioma histology (p=0.031) were associated with the development of seizures in this study. However, multivariate analysis showed that only oligodendrogial histology was associated with seizure [p=0.032, odds ratio (OR) = 4.77, 95% confidence interval (CI) = 1.146-19.822]. Patients with seizures have significantly longer median overall survival than patients without seizures (69.3±25.01 vs. 10.6±6.14 months, respectively, p=0.04). CONCLUSION: This study showed that seizure in patients with glioma in Indonesia is associated with frontal lobe location and oligodendroglioma histology. Patients with seizures also have significantly longer overall survival. 
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Comparison of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, Immunohistochemistry, and DNA Sequencing for the Detection of IDH1 Mutations in Gliomas.

BACKGROUND: IDH1 mutation shows diagnostic, prognostic, and predictive value in gliomas. Direct Sanger sequencing is considered the gold standard to detect IDH1 mutation. However, this technology is not available in most neuropathological centers in developing countries such as Indonesia. Immunohistochemistry (IHC) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) have also been used to detect IDH1 mutation. This study aimed to compare DNA sequencing, IHC, and PCR-RFLP in detecting IDH1 mutations in gliomas. METHODS: Research subjects were recruited from Dr. Sardjito Hospital. Genomic DNA was extracted from fresh or formalin-fixed paraffin-embedded samples of tumor tissue. DNA sequencing, PCR-RFLP and IHC were performed to detect IDH1 mutation. Sensitivity, specificity, and accuracy of PCR-RFLP and IHC were calculated by comparing them to DNA sequencing as the gold standard. RESULTS: Among 61 recruited patients, 13 (21.3%) of them carried a mutation in codon 132 of the IDH1 gene, as shown by DNA sequencing. PCR-RFLP and DNA sequencing have a concordance value of 100%. Meanwhile, the concordance value between IDH1 R132H IHC and DNA sequencing was 96.7%. The sensitivity, specificity, positive predictive values, negative predictive values, and accuracy for PCR-RFLP were all 100%. On the other hand, the sensitivity, specificity, and accuracy of IHC were 92.3%, 97.9%, and 96.7%, respectively. CONCLUSION: This study showed that both PCR-RFLP and IHC have high accuracy in detecting IDH1 mutation. We recommend a combination of PCR-RFLP and IHC to detect IDH1 mutation in resource-limited settings.
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Clinicopathological Features and Prognosis of Indonesian Patients with Gliomas with IDH Mutation: Insights into Its Significance in a Southeast Asian Population.

BACKGROUND: Gliomas remain one of the most common primary brain tumors. Mutations in the isocitrate dehydrogenase (IDH) gene are associated with a distinct set of clinicopathological profiles. However, the distribution and significance of these mutations have never been studied in the Indonesian population. This study aimed to elucidate the association between IDH mutations and clinicopathological as well as prognostic profiles of Indonesian patients with gliomas. METHODS: In total, 106 patients with gliomas were recruited from a tertiary academic medical center in Yogyakarta, Indonesia. Formalin-fixed paraffin-embedded and fresh tissue specimens were obtained and sectioned for hematoxylin-eosin staining and immunohistochemical examinations. Genomic DNA was isolated and analyzed for the presence of IDH mutations using standard polymerase chain reaction and nucleotide sequencing methods. Clinicopathological data were collected from medical records. RESULTS: Although no IDH2 mutation was identified, IDH1 mutations were found in 23 (21.7%) of the patients. Patients with IDH1 mutations tended to have a history of smoking and a shorter interval between onset of symptoms and initial surgical interventions. Frontal lobe involvement, oligodendroglial histology, lower Ki67 expression, WHO grades II and III gliomas, and methylated O6-methylguanine-DNA methyltransferase (MGMT) promoters were significantly associated with the presence of IDH1 mutations. Compared with patients with IDH1-wild-type, patients with IDH1 mutation were observed to have a longer overall survival. CONCLUSIONS: IDH1 mutations are associated with certain clinicopathological and prognostic profiles in Indonesian patients with gliomas. This finding demonstrates the importance of identifying IDH mutations as part of the management of patients with glioma in Indonesia. 
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Association between Ki-67 Labeling index and Histopathological Grading of Glioma in Indonesian Population.

BACKGROUND: Gliomas are the most frequent primary brain tumors. According to World Health Organization guidelines, gliomas are graded into four groups (Group I-IV). This histological grading will determine prognosis and treatment of the patient. Morphological criteria are not always accurate. Tumor proliferation index is a potent quantitative marker for tumor behavior and prognosis, also it's the basis of gliomagenesis. Ki-67 immunohistochemistry examination for determining proliferation index has been suggested as an ancillary marker in deciding the definitive grading of glioma. OBJECTIVE: To analyze the correlation between Ki-67 labeling index and histopathological grading of glioma in Indonesian population. METHODS: One hundred and six formalin fixed-paraffin embedded tissue of glioma patients were collected from 4 different hospitals. Expression of Ki-67 was detected using immunohistochemistry staining and the labeling index was counted. The association between Ki-67 labeling index and histopathological grading was analyzed. RESULTS: Age range of patient were 1-73-years old, with male predominance (55.70%). Glioblastoma was the most common diagnosis accounting for 41.51% of all samples. Ki-67 labeling index cut point of 6.35% was obtained and significantly sensitive and specific for determining low- or high-grade glioma (p<0.001). CONCLUSION: A significant association between Ki-67 labeling index and histopathological grading in Indonesian glioma patients has been revealed. The result of this study may be used to improve diagnostic and grading accuracy of glioma cases in Indonesia, especially in small biopsy specimens.
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