MGMT protein expression is a reliable predictive biomarker for temozolomide-containing chemotherapy in osteosarcoma.

The prognosis of patients with osteosarcoma who experience recurrence or progression (R/P) is extremely poor, and more effective and less toxic therapies are needed. In the current study, the clinical data of osteosarcoma patients who experienced R/P were retrospectively analyzed to verify the reliability of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression or MGMT promoter methylation for predicting the response to off-label temozolomide (TMZ)-containing chemotherapy. Of the 30 evaluable patients, 9 (30%) showed no/low MGMT protein expression, whereas all 16 evaluable patients had unmethylated MGMT promoter irrespective of MGMT protein expression levels. Twenty-three patients received TMZ-containing chemotherapy for measurable lesions (n = 14) or as adjuvant therapy following resection of recurrent lesions (n = 9). Among 14 patients with radiologically measurable lesions, the objective response rate was higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group with borderline significance (0%, p = 0.066). The 6-month progression-free survival (PFS) rate in patients with radiologically measurable lesions was significantly higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group (0%, p = 0.036). In the multivariate analysis of the 23 patients receiving TMZ-containing chemotherapy, MGMT expression and disease status before TMZ-containing chemotherapy were significantly associated with PFS. No severe adverse effects were observed during TMZ-containing chemotherapy. MGMT protein expression, but not MGMT promoter methylation, could predict a favorable outcome in patients receiving TMZ-containing chemotherapy.

Combined Lanreotide Autogel and Temozolomide Treatment of Progressive Pancreatic and Intestinal Neuroendocrine Tumors: The Phase II SONNET Study.

BACKGROUND: In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. MATERIALS AND METHODS: SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. RESULTS: Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. CONCLUSIONS: LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile.

Quality assessment of the MRI-radiomics studies for MGMT promoter methylation prediction in glioma: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the methodological quality and diagnostic accuracy of MRI-based radiomic studies predicting O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in gliomas. METHODS: PubMed Medline, EMBASE, and Web of Science were searched to identify MRI-based radiomic studies on MGMT methylation in gliomas published until December 31, 2022. Three raters evaluated the study methodological quality with Radiomics Quality Score (RQS, 16 components) and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis Or Diagnosis (TRIPOD, 22 items) scales. Risk of bias and applicability concerns were assessed with QUADAS-2 tool. A meta-analysis was performed to estimate the pooled area under the curve (AUC) and to assess inter-study heterogeneity. RESULTS: We included 26 studies, published from 2016. The median RQS total score was 8 out of 36 (22%, range 8-44%). Thirteen studies performed external validation. All studies reported AUC or accuracy, but only 4 (15%) performed calibration and decision curve analysis. No studies performed phantom analysis, cost-effectiveness analysis, and prospective validation. The overall TRIPOD adherence score was between 50% and 70% in 16 studies and below 50% in 10 studies. The pooled AUC was 0.78 (95% CI, 0.73-0.83, I2 = 94.1%) with a high inter-study heterogeneity. Studies with external validation and including only WHO-grade IV gliomas had significantly lower AUC values (0.65; 95% CI, 0.57-0.73, p < 0.01). CONCLUSIONS: Study RQS and adherence to TRIPOD guidelines was generally low. Radiomic prediction of MGMT methylation status showed great heterogeneity of results and lower performances in grade IV gliomas, which hinders its current implementation in clinical practice. CLINICAL RELEVANCE STATEMENT: MGMT promoter methylation status appears to be variably correlated with MRI radiomic features; radiomic models are not sufficiently robust to be integrated into clinical practice to accurately predict MGMT promoter methylation status in patients with glioma before surgery. KEY POINTS: • Adherence to the indications of TRIPOD guidelines was generally low, as was RQS total score. • MGMT promoter methylation status prediction with MRI radiomic features provided heterogeneous diagnostic accuracy results across studies. • Studies that included grade IV glioma only and performed external validation had significantly lower diagnostic accuracy than others.

Prediction of O(6)-methylguanine-DNA methyltransferase promoter methylation status in IDH-wildtype glioblastoma using MRI histogram analysis.

To evaluate the utility of magnetic resonance imaging (MRI) histogram parameters in predicting O(6)-methylguanine-DNA methyltransferase promoter (pMGMT) methylation status in IDH-wildtype glioblastoma (GBM). From November 2021 to July 2023, forty-six IDH-wildtype GBM patients with known pMGMT methylation status (25 unmethylated and 21 methylated) were enrolled in this retrospective study. Conventional MRI signs (including location, across the midline, margin, necrosis/cystic changes, hemorrhage, and enhancement pattern) were assessed and recorded. Histogram parameters were extracted and calculated by Firevoxel software based on contrast-enhanced T1-weighted images (CET1). Differences and diagnostic performance of conventional MRI signs and histogram parameters between the pMGMT-unmethylated and pMGMT-methylated groups were analyzed and compared. No differences were observed in the conventional MRI signs between pMGMT-unmethylated and pMGMT-methylated groups (all p > 0.05). Compared with the pMGMT-methylated group, pMGMT-unmethylated showed a higher minimum, mean, Perc.01, Perc.05, Perc.10, Perc.25, Perc.50, and coefficient of variation (CV) (all p < 0.05). Among all significant CET1 histogram parameters, minimum achieved the best distinguishing performance, with an area under the curve of 0.836. CET1 histogram parameters could provide additional value in predicting pMGMT methylation status in patients with IDH-wildtype GBM, with minimum being the most promising parameter.

Apparent Diffusion Coefficient as Imaging Biomarker for Identifying IDH Mutation, 1p19q Codeletion, and MGMT Promoter Methylation Status in Patients With Glioma.

BACKGROUND: Glioma genotypes are of importance for clinical decision-making. This data can only be acquired through histopathological analysis based on resection or biopsy. Consequently, there is a need for alternative biomarkers that noninvasively provide reliable information for preoperatively identifying molecular characteristics. PURPOSE: To investigate apparent diffusion coefficient (ADC) as imaging biomarker for preoperatively identifying glioma genotypes based on the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. STUDY TYPE: Retrospective. SUBJECTS: One hundred and fifty-nine patients (47.6 ± 14.4 years) diagnosed with WHO grade 2-4 glioma including 93 males and 66 females. FIELD STRENGTH/SEQUENCE: A 3 T/spin echo echo planner imaging. ASSESSMENT: The ADC measurements were assessed by two neuroradiologists (both with 6 years of experience). Three different lowest portions inside the tumors without overlap were manually drawn on the ADC maps as regions of interest (ROIs). The mean ADC value of the three ROIs was defined as the minimum ADC value (ADCmin ). An ROI was placed in the contralateral normal appearing white matter (NAWM) to obtain the ADC value (ADCNAWM ). The ADCmin to ADCNAWM ratio (ADCratio ) was calculated. Genetics results were retrospectively recorded from pathologic and genetic test reports. STATISTICAL TESTS: Two-sample independent t-tests, receiver operating characteristic curve analysis, and intraclass correlation coefficient analysis were used. Statistical significance was set at P < 0.05. RESULTS: Isocitrate dehydrogenase (IDH)-mutated glioma showed higher ADCmin and ADCratio than IDH wild-type glioma. Among IDH-mutated glioma, higher ADCmin and ADCratio were found in 1p19q intact glioma than in 1p19q codeletion glioma. ADC parameters enabled differentiation of IDH mutation status with area under the curve (AUC) of 0.84 and 0.86. DATA CONCLUSION: ADC has potential discriminative value for IDH mutation and 1p19q codeletion status. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Brain Tumor Radiogenomic Classification of O6-Methylguanine-DNA Methyltransferase Promoter Methylation in Malignant Gliomas-Based Transfer Learning.

Artificial Intelligence (AI) is the subject of a challenge and attention in the field of oncology and raises many promises for preventive diagnosis, but also fears, some of which are based on highly speculative visions for the classification and detection of tumors. A brain tumor that is malignant is a life-threatening disorder. Glioblastoma is the most prevalent kind of adult brain cancer and the 1 with the poorest prognosis, with a median survival time of less than a year. The presence of O6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation, a particular genetic sequence seen in tumors, has been proven to be a positive prognostic indicator and a significant predictor of recurrence.This strong revival of interest in AI is modeled in particular to major technological advances which have significantly increased the performance of the predicted model for medical decision support. Establishing reliable forecasts remains a significant challenge for electronic health records (EHRs). By enhancing clinical practice, precision medicine promises to improve healthcare delivery. The goal is to produce improved prognosis, diagnosis, and therapy through evidence-based sub stratification of patients, transforming established clinical pathways to optimize care for each patient's individual requirements. The abundance of today's healthcare data, dubbed "big data," provides great resources for new knowledge discovery, potentially advancing precision treatment. The latter necessitates multidisciplinary initiatives that will use the knowledge, skills, and medical data of newly established organizations with diverse backgrounds and expertise.The aim of this paper is to use magnetic resonance imaging (MRI) images to train and evaluate your model to detect the presence of MGMT promoter methylation in this competition to predict the genetic subtype of glioblastoma based transfer learning. Our objective is to emphasize the basic problems in the developing disciplines of radiomics and radiogenomics, as well as to illustrate the computational challenges from the perspective of big data analytics.

Late-line treatment with bevacizumab alone or in combination with chemotherapy in recurrent high-grade gliomas.

PURPOSE: Bevacizumab's use in recurrent high-grade glioma is controversial. This study evaluates outcomes in recurrent high-grade glioma patients receiving bevacizumab alone or combined with chemotherapy as a late-line treatment. METHODS: We retrospectively analyzed patients treated with bevacizumab alone or combined with chemotherapy for high-grade gliomas who showed tumor progression after multiple treatment attempts. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier curves. Predictors of PFS according to prognostic variables were assessed with regression analysis. RESULTS: Between 2010 and 2022, 31 consecutive patients received bevacizumab alone or combined with chemotherapy as a late-line treatment for recurrent high-grade gliomas. Of these patients, 14 (45.2%) were responders according to RANO criteria, and 17 (54.8%) showed progressive or stable disease. OS at 3, 6, and 12 months was 80.3%, 62.1%, and 43.5. PFS was 48.4%, 34.3%, and 21.8%, respectively. In the multivariate survival analysis, the only factor independently associated with PFS was smaller 2D tumor size in post-contrast T1-weighted MRI at bevacizumab initiation (p = 0.02). Median time-to-progression was 3 months (95%CI: 1-4) in the unmethylated MGMT promoter group and 6 (95%CI: 1-11) in the methylated MGMT promoter group. This difference was not statistically significant (p = 0.37). CONCLUSIONS: Bevacizumab alone or in combination with chemotherapy could be beneficial as a late-line therapy in a subset of patients with recurrent high-grade glioma. Small 2D tumor size in post-contrast T1 weighted MRI at bevacizumab initiation was independently associated with prolonged time to progression.

Long-term survival in patients with IDH-wildtype glioblastoma: clinical and molecular characteristics.

BACKG ROUND: Glioblastoma is an aggressive tumor that has a dismal prognosis even with multimodal treatment. However, some patients survive longer than expected. The objective of this study was to revisit patients diagnosed with glioblastoma according to the 2021 WHO classification and analyze clinical and molecular characteristics associated with long-term survival (LTS). METHODS: We retrospectively analyzed 120 IDH-wildtype glioblastomas operated on at our institution between 2013 and 2018. We divided them into LTS patients, surviving more than 3 years, and non-LTS patients, and then compared their features. Additionally, we performed DNA methylation-based brain tumor classification in LTS patients. RESULTS: Sixteen patients were long-term survivors. Age < 70 years, MGMT promoter methylation, extent of resection ≥ 95%, and administration of radiochemotherapy were associated with LTS (P = 0.005, P < 0.001, P = 0.048, and P = 0.008, respectively). In addition, when these factors were combined, the probability of LTS was 74% (95% CI: 62--84). The methylome analysis confirmed the diagnosis of glioblastoma in the majority of the tested LTS patients. Regarding subtypes, 29% of cases were mesenchymal (MES), 43% were RTK1, and 29% were RTK2. Interestingly, RTK1 and RTK2 cases tended to have longer overall survival than MES cases (P = 0.057). Moreover, the only tested LTS patient with an unmethylated MGMT promoter had an "adult-type diffuse high-grade glioma, IDH-wildtype, subtype E" rather than a glioblastoma. This tumor was characterized by multinucleated giant cells and a somatic mutation in POLE. CONCLUSIONS: We suggest that glioblastoma patients with a combination of favorable prognostic factors can achieve LTS in 74% of cases. In addition, methylome analysis is important to ascertain the type of glioma in LTS patients, especially when the MGMT promoter is unmethylated.

Sex as a prognostic factor in adult-type diffuse gliomas: an integrated clinical and molecular analysis according to the 2021 WHO classification.

PURPOSE: To investigate whether type-specific sex differences in survival exist independently of clinical and molecular factors in adult-type diffuse gliomas according to the 2021 World Health Organization (WHO) classification. METHODS: A retrospective chart and imaging review of 1325 patients (mean age, 54 ± 15 years; 569 females) with adult-type diffuse gliomas (oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, n = 183; astrocytoma, IDH-mutant, n = 211; glioblastoma, IDH-wildtype, n = 800; IDH-wildtype diffuse glioma, NOS, n = 131) was performed. The demographic information, extent of resection, imaging data, and molecular data including O6-methylguanine-methyltransferase promoter methylation (MGMT) promotor methylation were collected. Sex differences in survival were analyzed using Cox analysis. RESULTS: In patients with glioblastoma, IDH-wildtype, female sex remained as an independent predictor of better overall survival (hazard ratio = 0.91, P = 0.031), along with age, histological grade 4, MGMT promoter methylation status, and gross total resection. Female sex showed a higher prevalence of MGMT promoter methylation (40.2% vs 32.0%, P = 0.017) but there was no interaction effect between female sex and MGMT promoter methylation status (P-interaction = 0.194), indicating independent role of female sex. The median OS for females were 19.2 months (12.3-35.0) and 16.2 months (10.5-30.6) for males. No sex difference in survival was seen in other types of adult-type diffuse gliomas. CONCLUSION: There was a female survival advantage in glioblastoma, IDH-wildtype, independently of clinical data or MGMT promoter methylation status. There was no sex difference in survival in other types of adult-type diffuse gliomas, suggesting type-specific sex effects solely in glioblastoma, IDH-wildtype.

NMDA receptor signaling induces the chemoresistance of temozolomide via upregulation of MGMT expression in glioblastoma cells.

PURPOSE: The alkylating agent temozolomide (TMZ) has a significant impact on the prognosis of glioblastoma (GBM) patients. Therefore, maximizing TMZ efficacy is important for GBM treatment. Many reports have shown that glutamate signaling promotes GBM progression via glutamate receptors, including N-methyl-D-aspartate receptors (NMDARs). Although NMDARs promote cell migration and invasion of GBM cells, their role in TMZ resistance remains unclear. Therefore, we focused on NMDAR signaling and investigated its effects on TMZ resistance. METHODS: We investigated the effect of NMDAR signaling on O6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme that induces chemoresistance to TMZ, using quantitative real-time polymerase chain reaction and western blotting in human GBM T98G cells. In addition, we used memantine (MEM), an NMDAR antagonist, to investigate the cytotoxic effect of TMZ/MEM combination and its detailed mechanism. RESULTS: Activation of NMDAR by N-methyl-D-aspartate (NMDA) elevated MGMT expression and suppressed the effect of TMZ in T98G cells. In contrast, knockdown of NMDAR by NMDAR1 shRNA decreased MGMT expression and enhanced the effect of TMZ in T98G cells. The cytotoxic effect of TMZ was enhanced by MEM in T98G cells. Inhibition of NMDAR by MEM decreased MGMT expression and increased DNA alkylation by TMZ. CONCLUSION: NMDAR signaling induced chemoresistance of TMZ via the upregulation of MGMT expression in GBM cells. Furthermore, MEM inhibited TMZ-induced MGMT upregulation and increased the cytotoxic effect of TMZ on MGMT-positive cells. This study demonstrates that the combination of TMZ and MEM could be a new therapeutic strategy for MGMT-positive GBM. Overview of this study. NMDAR signaling controls the expression of MGMT and the cytotoxic effect of TMZ.

Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin.

Glioblastoma is the most frequent and lethal primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40-50% of all primary malignant brain tumors, with an annual incidence of 3-6 cases per 100,000 population. Despite maximum treatment, patients only have a median survival time of 15 months. Metformin is a biguanide drug utilized as the first-line medication in treating type 2 diabetes. Recently, researchers have noticed that metformin can contribute to antineoplastic activity. The objective of this study is to investigate the mechanism of metformin as a potential adjuvant treatment drug in glioblastoma. Glioblastoma cell lines U87MG, LNZ308, and LN229 were treated with metformin, and several cellular functions and metabolic states were evaluated. First, the proliferation capability was investigated using the MTS assay and BrdU assay, while cell apoptosis was evaluated using the annexin V assay. Next, a wound-healing assay and mesenchymal biomarkers (N-cadherin, vimentin, and Twist) were used to detect the cell migration ability and epithelial-mesenchymal transition (EMT) status of tumor cells. Gene set enrichment analysis (GSEA) was applied to the transcriptome of the metformin-treated glioblastoma cell line. Then, DCFH-DA and MitoSOX Red dyes were used to quantify reactive oxygen species (ROS) in the cytosol and mitochondria. JC-1 dye and Western blotting analysis were used to evaluate mitochondrial membrane potential and biogenesis. In addition, the combinatory effect of temozolomide (TMZ) with metformin treatment was assessed by combination index analysis. Metformin could decrease cell viability, proliferation, and migration, increase cell apoptosis, and disrupt EMT in all three glioblastoma cell lines. The GSEA study highlighted increased ROS and hypoxia in the metformin-treated glioblastoma cells. Metformin increased ROS production, impaired mitochondrial membrane potential, and reduced mitochondrial biogenesis. The combined treatment of metformin and TMZ had U87 as synergistic, LNZ308 as antagonistic, and LN229 as additive. Metformin alone or combined with TMZ could suppress mitochondrial transcription factor A, Twist, and O6-methylguanine-DNA methyltransferase (MGMT) proteins in TMZ-resistant LN229 cells. In conclusion, our study showed that metformin decreased metabolic activity, proliferation, migration, mitochondrial biogenesis, and mitochondrial membrane potential and increased apoptosis and ROS in some glioblastoma cells. The sensitivity of the TMZ-resistant glioblastoma cell line to metformin might be mediated via the suppression of mitochondrial biogenesis, EMT, and MGMT expression. Our work provides new insights into the choice of adjuvant agents in TMZ-resistant GBM therapy.

siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model.

Temozolomide (TMZ) is the standard of care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug resistance mediated by a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here we report the development of an iron oxide nanoparticle (NP) system for targeted delivery of siRNAs to suppress the TMZ-resistance gene (MGMT). We show that our NP is able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially-passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ resulted in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly-prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.

Automated machine learning to predict the co-occurrence of isocitrate dehydrogenase mutations and O6 -methylguanine-DNA methyltransferase promoter methylation in patients with gliomas.

Combining isocitrate dehydrogenase mutation (IDHmut) with O6 -methylguanine-DNA methyltransferase promoter methylation (MGMTmet) has been identified as a critical prognostic molecular marker for gliomas. The aim of this study was to determine the ability of glioma radiomics features from magnetic resonance imaging (MRI) to predict the co-occurrence of IDHmut and MGMTmet by applying the tree-based pipeline optimization tool (TPOT), an automated machine learning (autoML) approach. This was a retrospective study, in which 162 patients with gliomas were evaluated, including 58 patients with co-occurrence of IDHmut and MGMTmet and 104 patients with other status comprising: IDH wildtype and MGMT unmethylated (n = 67), IDH wildtype and MGMTmet (n = 36), and IDHmut and MGMT unmethylated (n = 1). Three-dimensional (3D) T1-weighted images, gadolinium-enhanced 3D T1-weighted images (Gd-3DT1WI), T2-weighted images, and fluid-attenuated inversion recovery (FLAIR) images acquired at 3.0 T were used. Radiomics features were extracted from FLAIR and Gd-3DT1WI images. The TPOT was employed to generate the best machine learning pipeline, which contains both feature selector and classifier, based on input feature sets. A 4-fold cross-validation was used to evaluate the performance of automatically generated models. For each iteration, the training set included 121 subjects, while the test set included 41 subjects. Student's t-test or a chi-square test was applied on different clinical characteristics between two groups. Sensitivity, specificity, accuracy, kappa score, and AUC were used to evaluate the performance of TPOT-generated models. Finally, we compared the above metrics of TPOT-generated models to identify the best-performing model. Patients' ages and grades between two groups were significantly different (p = 0.002 and p = 0.000, respectively). The 4-fold cross-validation showed that gradient boosting classifier trained on shape and textual features from the Laplacian-of-Gaussian-filtered Gd-3DT1 achieved the best performance (average sensitivity = 81.1%, average specificity = 94%, average accuracy = 89.4%, average kappa score = 0.76, average AUC = 0.951). Using autoML based on radiomics features from MRI, a high discriminatory accuracy was achieved for predicting co-occurrence of IDHmut and MGMTmet in gliomas. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 3.

Noninvasive Assessment of O(6)-Methylguanine-DNA Methyltransferase Promoter Methylation Status in World Health Organization Grade II-IV Glioma Using Histogram Analysis of Inflow-Based Vascular-Space-Occupancy Combined with Structural Magnetic Resonance Imaging.

BACKGROUND: O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation is an important prognostic factor for gliomas and is associated with tumor angiogenesis. Arteriolar cerebral blood volume (CBVa) obtained from inflow-based vascular-space-occupancy (iVASO) magnetic resonance imaging (MRI) is assumed to be an indicator of tumor microvasculature. Its preoperative predictive ability for MGMT promoter methylation remains unclear. PURPOSE: To investigate the role of iVASO-CBVa histogram features in determining MGMT promoter methylation status of grade II-IV gliomas. STUDY TYPE: Retrospective SUBJECTS: Forty-six patients consisting of 20 MGMT methylated and 26 unmethylated gliomas. FIELD STRENGTH/SEQUENCE: 3.0 T magnetic resonance images containing iVASO MRI, T1 -weighted image (T1 WI), T2 -weighted image, T2 -weighted fluid attenuated inversion recovery image images, and enhanced T1 WI. ASSESSMENT: Sixteen structural imaging features were visually evaluated on structural MRI and 14 CBVa histogram features were extracted from iVASO-CBVa maps. STATISTICAL TESTS: Imaging features were screened and ranked using Fisher's exact test, Mann-Whitney U-test, and randomforest algorithm. Features with higher importance were selected to develop logistic regression models to determine MGMT methylation status. Receiver operating characteristics (ROC) curve with the area under the curve (AUC) and leave-one-out cross-validation (LOOCV) were used to assess effectiveness and stability. RESULTS: The top two CBVa histogram features were root mean squared (RMS) and variance. The top two structural imaging features were contrast-enhancing component of the tumor (CET) location and tumor location. Both the CBVa model of RMS and variance (ROC, AUC = 0.867; LOOCV, AUC = 0.819) and the model of structural features (ROC, AUC = 0.882; LOOCV, AUC = 0.802) accurately identified MGMT methylation. The fusion model of CBVa RMS and CET location improved diagnostic performance (ROC, AUC = 0.931; LOOCV, AUC =0.906). DATA CONCLUSION: iVASO-CBVa has potential in evaluating MGMT methylation status in grade II-IV gliomas. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Stereotactic radiosurgery for IDH wild type glioblastoma: an international, multicenter study.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutation status is recommended used for diagnosis and prognostication of glioblastoma patients. We studied efficacy and safety of stereotactic radiosurgery (SRS) for patients with recurrent IDH-wt glioblastoma. METHODS: Consecutive patients treated with SRS for IDH-wt glioblastoma were pooled for this retrospective observational international multi-institutional study from institutions participating in the International Radiosurgery Research Foundation. RESULTS: Sixty patients (median age 61 years) underwent SRS (median dose 15 Gy and median treatment volume: 7.01 cm3) for IDH-wt glioblastoma. All patients had histories of surgery and chemotherapy with temozolomide, and 98% underwent fractionated radiation therapy. MGMT status was available for 42 patients, of which half of patients had MGMT mutant glioblastomas. During median post-SRS imaging follow-up of 6 months, 52% of patients experienced tumor progression. Median post-SRS progression free survival was 4 months. SRS prescription dose of > 14 Gy predicted longer progression free survival [HR 0.357 95% (0.164-0.777) p = 0.009]. Fifty-percent of patients died during post-SRS clinical follow-up that ranged from 1 to 33 months. SRS treatment volume of > 5 cc emerged as an independent predictor of shorter post-SRS overall survival [HR 2.802 95% CI (1.219-6.444) p = 0.02]. Adverse radiation events (ARE) suggestive of radiation necrosis were diagnosed in 6/55 (10%) patients and were managed conservatively in the majority of patients. CONCLUSIONS: SRS prescription dose of > 14 Gy is associated with longer progression free survival while tumor volume of > 5 cc is associated with shorter overall survival after SRS for IDH-wt glioblastomas. AREs are rare and are typically managed conservatively.

Combination chemotherapy versus temozolomide for patients with methylated MGMT (m-MGMT) glioblastoma: results of computational biological modeling to predict the magnitude of treatment benefit.

BACKGROUND: A randomized trial in glioblastoma patients with methylated-MGMT (m-MGMT) found an improvement in median survival of 16.7 months for combination therapy with temozolomide (TMZ) and lomustine, however the approach remains controversial and relatively under-utilized. Therefore, we sought to determine whether comprehensive genomic analysis can predict which patients would derive large, intermediate, or negligible benefits from the combination compared to single agent chemotherapy. METHODS: Comprehensive genomic information from 274 newly diagnosed patients with methylated-MGMT glioblastoma (GBM) was downloaded from TCGA. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotypes representing hallmark behavior of cancers. In silico responses to TMZ, lomustine, and combination treatment were biosimulated. Efficacy scores representing the effect of treatment for each treatment strategy were generated and compared to each other to ascertain the differential benefit in drug response. RESULTS: Differential benefits for each drug were identified, including strong, modest-intermediate, negligible, and deleterious (harmful) effects for subgroups of patients. Similarly, the benefits of combination therapy ranged from synergy, little or negligible benefit, and deleterious effects compared to single agent approaches. CONCLUSIONS: The benefit of combination chemotherapy is predicted to vary widely in the population. Biosimulation appears to be a useful tool to address the disease heterogeneity, drug response, and the relevance of particular clinical trials observations to individual patients. Biosimulation has potential to spare some patients the experience of over-treatment while identifying patients uniquely situated to benefit from combination treatment. Validation of this new artificial intelligence tool is needed.

MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas.

OBJECTIVES: To assess the combined role of tumor vascularity, estimated from perfusion MRI, and MGMT methylation status on overall survival (OS) in patients with glioblastoma. METHODS: A multicentric international dataset including 96 patients from NCT03439332 clinical study were used to study the prognostic relationships between MGMT and perfusion markers. Relative cerebral blood volume (rCBV) in the most vascularized tumor regions was automatically obtained from preoperative MRIs using ONCOhabitats online analysis service. Cox survival regression models and stratification strategies were conducted to define a subpopulation that is particularly favored by MGMT methylation in terms of OS. RESULTS: rCBV distributions did not differ significantly (p > 0.05) in the methylated and the non-methylated subpopulations. In patients with moderately vascularized tumors (rCBV < 10.73), MGMT methylation was a positive predictive factor for OS (HR = 2.73, p = 0.003, AUC = 0.70). In patients with highly vascularized tumors (rCBV > 10.73), however, there was no significant effect of MGMT methylation (HR = 1.72, p = 0.10, AUC = 0.56). CONCLUSIONS: Our results indicate the existence of complementary prognostic information provided by MGMT methylation and rCBV. Perfusion markers could identify a subpopulation of patients who will benefit the most from MGMT methylation. Not considering this information may lead to bias in the interpretation of clinical studies. KEY POINTS: • MRI perfusion provides complementary prognostic information to MGMT methylation. • MGMT methylation improves prognosis in glioblastoma patients with moderate vascular profile. • Failure to consider these relations may lead to bias in the interpretation of clinical studies.

Correlation between dynamic susceptibility contrast perfusion MRI and genomic alterations in glioblastoma.

PURPOSE: To determine if dynamic susceptibility contrast perfusion MR imaging (DSC-pMRI) can predict significant genomic alterations in glioblastoma (GB). METHODS: A total of 47 patients with treatment-naive GB (M/F: 23/24, mean age: 54 years, age range: 20-90 years) having DSC-pMRI with leakage correction and genomic analysis were reviewed. Mean relative cerebral blood volume (rCBV), maximum rCBV, relative percent signal recovery (rPSR), and relative peak height (rPH) were derived from T2* signal intensity-time curves by ROI analysis. Major genomic alterations of IDH1-132H, MGMT, p53, EGFR, ATRX, and PTEN status were correlated with DSC-pMRI-derived GB parameters. Statistical analysis was performed utilizing the independent-samples t-test, ROC (receiver operating characteristic) curve analysis, and multivariable stepwise regression model. RESULTS: rCBVmean and rCBVmax were significantly different in relation to the IDH1, MGMT, p53, and PTEN mutation status (all p < 0.05). The rPH of the p53 mutation-positive GBs (mean 5.8 ± 2.8) was significantly higher than those of the p53 mutation-negative GBs (mean 4.0 ± 1.5) (p = 0.022). Multivariable stepwise regression analysis revealed that the presence of IDH-1 mutation (B = - 2.81, p = 0.005) was associated with decreased rCBVmean; PTEN mutation (B = - 1.21, p = 0.003) and MGMT methylation (B = - 1.47, p = 0.038) were associated with decreased rCBVmax; and ATRX loss (B = - 1.05, p = 0.008) was associated with decreased rPH. CONCLUSION: Significant associations were identified between DSC-pMRI-derived parameters and major genomic alterations, including IDH-1 mutation, MGMT methylation, ATRX loss, and PTEN mutation status in GB.

O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms.

BACKGROUND: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. METHODS: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). RESULTS: In GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = - 0.4570; MGMT score: P = 0.0064, ρ = - 0.4399; H-score: P = 0.0110, ρ = - 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. CONCLUSION: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.

Temozolomide and etoposide combination for the treatment of relapsed osteosarcoma.

The prognosis of patients with relapsed osteosarcoma is extremely poor and the optimal treatment remains to be identified. Here, we retrospectively analysed the clinical outcomes of nine patients with relapsed osteosarcoma treated with temozolomide/etoposide. Of the two patients who received temozolomide/etoposide as palliative therapy for unresectable tumours, one remained alive with stable disease for >4 years. The remaining seven patients received temozolomide/etoposide as adjuvant therapy following resection of relapsed metastatic disease; of these, one was free from disease for 41 months. Potentially beneficial effects were observed in two of three O6-methylguanine-DNA methyltransferase protein-negative patients, whereas all five O6-methylguanine-DNA methyltransferase-positive patients experienced subsequent relapse. None of the patients experienced severe adverse effects requiring hospitalization. Temozolomide/etoposide is a feasible candidate as salvage therapy for relapsed osteosarcoma. Further studies are needed to verify the utility of O6-methylguanine-DNA methyltransferase protein expression as a biomarker for predicting the response to this treatment.