Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

A bis-boron boramino acid PET tracer for brain tumor diagnosis.

PURPOSE: Boramino acids are a class of amino acid biomimics that replace the carboxylate group with trifluoroborate and can achieve the 18F-labeled positron emission tomography (PET) and boron neutron capture therapy (BNCT) with identical chemical structure. METHODS: This study reports a trifluoroborate-derived boronophenylalanine (BBPA), a derived boronophenylalanine (BPA) for BNCT, as a promising PET tracer for tumor imaging. RESULTS: Competition inhibition assays in cancer cells suggested the cell accumulation of [18F]BBPA is through large neutral amino acid transporter type-1 (LAT-1). Of note, [18F]BBPA is a pan-cancer probe that shows notable tumor uptake in B16-F10 tumor-bearing mice. In the patients with gliomas and metastatic brain tumors, [18F]BBPA-PET shows good tumor uptake and notable tumor-to-normal brain ratio (T/N ratio, 18.7 ± 5.5, n = 11), higher than common amino acid PET tracers. The [18F]BBPA-PET quantitative parameters exhibited no difference in diverse contrast-enhanced status (P = 0.115-0.687) suggesting the [18F]BBPA uptake was independent from MRI contrast-enhancement. CONCLUSION: This study outlines a clinical trial with [18F]BBPA to achieve higher tumor-specific accumulation for PET, provides a potential technique for brain tumor diagnosis, and might facilitate the BNCT of brain tumors.

CT-based quantification of trachea shape to detect invasion by thyroid cancer.

OBJECTIVE: This study aims to develop a CT-based method for quantifying tracheal shape and evaluating its ability to distinguish between cases with or without tracheal invasion in patients with thyroid carcinoma. METHODS: A total of 116 quantitative shape features, including 56 geometric moments and 60 bounding shape features, were defined. The tracheal lumen was semi-automatically defined with a CT threshold of less than - 500 HU. Three contiguous slices with the 1st, 2nd, and 3rd smallest trachea lumen areas were contiguously selected, and the appropriate number of slices to be included was determined. Fifty-six patients with differentiated thyroid carcinoma (DTC) invading the trachea and 22 patients with DTC but without invasion were retrospectively included. A receiver operating characteristic (ROC) curve was applied to select the representative shape features and determine the optimal threshold. RESULTS: 23.3%, 25.9%, and 24.1% of the features displayed an area under the ROC curve (AUC) ≥ 0.800 when derived from 1, 2, and 3 slices, respectively. Calculating feature values from two slices with the 1st and 2nd smallest tracheal lumen area were considered appropriate. Six final features, including 3 geometric moments and 3 bounding shape features, were selected to determine the tracheal invasion status of DTC and displayed AUCs of 0.875-0.918, accuracies of 0.821-0.891, sensitivities of 0.813-0.893, and specificities of 0.818-0.932, outperforming the visual evaluation results. CONCLUSIONS: Geometric moments and bounding shape features can quantify the tracheal shape and are reliable for identifying DTC tracheal invasion. The selected features quantified the extent of tracheal deformity in DTC patients with and without tracheal invasion. CLINICAL RELEVANCE STATEMENT: Six geometric features provide a non-invasive, semi-automated evaluation of the tracheal invasion status of thyroid cancer. KEY POINTS: • A novel method for quantifying tracheal shape using 56 geometric moments and 60 bounding shape features was developed. • Six features identify tracheal invasion by thyroid carcinoma. • The selected features quantified the extent of tracheal deformity in differentiated thyroid carcinoma patients with and without tracheal invasion.

Kruppel-like factor 13 acts as a tumor suppressor in thyroid carcinoma by downregulating IFIT1.

BACKGROUND: Kruppel-like factor 13 (KLF13) is a transcription factor and plays an important role in carcinogenesis. However, the significance of KLF13 in thyroid carcinoma (THCA) is underdetermined. In this study, we aimed to explore the clinical relevance and function of KLF13 in the progress of THCA. METHODS: The expression of KLF13 in thyroid carcinoma and normal tissue was investigated by qPCR and IHC assay. The expression of KLF13 and IFIT1 in cell samples was investigated with Western blot assay. Cell proliferation ability was detected with CCK8 and colony formation assay. Cell growth in vivo with or without KLF13 overexpression was evaluated on a xenograft model. Cell migration ability was measured with Transwell assay. Cell cycle was detected with flow cytometer. The downstream genes of KLF13 were screened using RNA-seq assay. Luciferase activity was employed to assess the transcriptional regulation of KLF13 on IFIT1 promoter. RESULTS: KLF13 expression was downregulated in THCA samples. KLF13 knockdown and overexpression promoted and inhibited the proliferation and migration of THCA cells, respectively. The RNA-seq, RT-qPCR and immunoblotting data showed that KLF13 knockdown significantly potentiated IFIT1 expression at both mRNA and protein levels. Luciferase assays showed that KLF13 suppressed the transcription activity of IFIT1 promoter. Besides, IFIT1 upregulation was critical for the proliferation and migration of THCA cell lines. Lastly, silencing of IFIT1 greatly reversed the proliferation and migration induced by KLF13 knockdown. CONCLUSIONS: In conclusion, KLF13 may function as an anti-tumor protein in THCA by regulating the expression of IFIT1 and offer a theoretical foundation for treating thyroid carcinoma.

The role of multifocality in predicting central lymph node metastasis in initially treated 18-55 years old female patients with unilateral papillary thyroid microcarcinoma.

Objective: To determine the predictive ability of multifocality for central lymph node metastasis in initially treated 18-55 years old female patients with unilateral papillary thyroid microcarcinoma. Study design: Retrospective review. Setting: Tertiary medical center. Methods: We retrospectively collected clinical data from initially treated papillary thyroid microcarcinoma (PTMC) patients at Cancer Hospital Chinese Academy of Medical and sciences between January 1st, 2018, and December 31st, 2018. Data from 975 initially treated 18-55 years old female patients with unilateral PTMC was collected. We also collected data from 340 initially treated 18-55 years old male patients with unilateral PTMC patients to compare the results between genders. Clinicopathological factors associated with central lymph node metastasis (CLNM) were investigated by univariate and multivariate analysis. Results: (1) In the female group, there were 196 (20.1%) cases that had tumor multifocality, including 126 (12.9%) with 2 foci and 70 (7.2%) with >2 foci. The risk of CLNM in patients with 2 foci was not significantly higher than patients with 1 focus (37.3% vs 38.6%, P=0.775). However, diagnosed with >2 foci were independently and positively correlated with CLNM (OR=2.708, 95%CI=1.592-4.607, P<0.001), as was tumor diameter >0.55cm (OR=2.047, 95%CI=1.535-2.730, P<0.001). (2) In the male group, the risk of CLNM with 2 foci was significantly higher than 1 focus (P=0.008). Compared to female patients, the risk of CLNM was significantly higher in patients with 1 focus (P<0.001) or 2 foci (P<0.001). Conclusion: In summary, the risk of CLNM in patients with 2 foci was not significantly higher than patients with 1 focus, while multifocality with over 2 foci was an independent risk factor of CLNM. Therefore, multifocality in this subgroup should not be simply defined as "more than 1 focus". Future models that include multifocality as a predictive factor for cervical lymph node metastasis could consider stratifying the cohort into smaller subgroups for more accurate conclusions.

Feasibility of evaluating the histologic and genetic subtypes of WHO grade II-IV gliomas by diffusion-weighted imaging.

BACKGROUND: To explore the feasibility of diffusion-weighted imaging (DWI) metrics to predict the histologic subtypes and genetic status of gliomas (e.g., IDH, MGMT, and TERT) noninvasively. METHODS: One hundred and eleven patients with pathologically confirmed WHO grade II-IV gliomas were recruited retrospectively. Apparent diffusion coefficient (ADC) values were measured in solid parts of gliomas on co-registered T2-weighted images and were compared with each other in terms of WHO grading and genotypes using t-tests. Receiver operating characteristic analysis was performed to assess the diagnostic performances of ADC. Subsequently, multiple linear regression was used to find independent variables, which can directly affect ADC values. RESULTS: The values of overall mean ADC (omADC) and normalized ADC (nADC) of high grade gliomas and IDH wildtype gliomas were lower than low grade gliomas and IDH mutated gliomas (P < 0.05). nADC values showed better diagnostic performance than omADC in identifying tumor grade (AUC: 0.787 vs. 0.750) and IDH status (AUC: 0.836 vs. 0.777). ADC values had limited abilities in distinguishing TERT status (AUC = 0.607 for nADC and 0.617 for omADC) and MGMT status (AUC = 0.651 for nADC). Only tumor grade and IDH status were tightly associated with ADC values. CONCLUSION: DWI metrics can predict glioma grading and IDH mutation noninvasively, but have limited use in detecting TERT mutation and MGMT methylation.

Prognostic Value of Choline and Other Metabolites Measured Using 1H-Magnetic Resonance Spectroscopy in Gliomas: A Meta-Analysis and Systemic Review.

Glioma is the most prevalent primary central nervous system malignant tumor, with high heterogeneity observed among different grades; therefore, non-invasive prediction of prognosis could improve the clinical management of patients with glioma. 1H-magnetic resonance spectroscopy (MRS) can estimate metabolite levels non-invasively. Multiple studies have investigated its prognostic value in gliomas; however, no consensus has been reached. PubMed and Embase databases were searched up to 20 October 2022 to identify studies investigating the prognostic value of metabolites using 1H-MRS in patients with glioma. Heterogeneity across studies was evaluated using the Q and I2 tests, and a fixed- or random-effects model was used to estimate the combined overall hazard ratio (HR). Funnel plots and Begg tests were used to assess publication bias. Higher choline levels were associated with shorter overall survival (HR = 2.69, 95% CI, 1.92−2.99; p < 0.001) and progression-free survival (HR = 2.20, 95% CI, 1.16−4.17; p = 0.02) in all patients; however, in pediatric gliomas, it showed no significant correlation with overall survival (HR = 1.60, 95% CI, 0.97−2.64; p = 0.06). The estimated choline level by 1H-MRS could be used to non-invasively predict the prognosis of patients with adult gliomas, and more studies are needed to evaluate the prognostic value of other metabolites.

The role of PET/CT in radiotherapy for nasopharyngeal carcinoma.

Radiotherapy has already been developed as the standard of care for patients with nasopharyngeal carcinoma (NPC), and precision staging, target volume delineation, prognosis prediction, and post-treatment surveillance are essential in the management of NPC. Positron emission tomography/computed tomography (PET/CT) is increasingly recognized as an imaging modality to guide precision radiotherapy in these areas. The feasibility and efficacy of 18F-FDG PET/CT have been confirmed in tumor diagnosis, treatment planning, prognosis, surveillance, and assessment. Coupled with the capability of revealing tumor metabolic information, 18F-FDG PET/CT is more accurate in identifying primary lesions and metastases of NPC than other conventional imaging methods including CT and MRI and shows the independently diagnostic and prognostic value for radiotherapy. However, 18F-FDG has limitations due to its physiological distribution in brain tissue and increasing uptake in post-radiation inflammation. Novel PET radiotracers including FAPI, NaF, CHO, and FLT are explored as alternatives with potential superiority for radiotherapy in NPC. In this review, we summarized the evolving role of PET/CT in the management of radiotherapy in NPC patients, aiming to facilitate precision radiotherapy from a molecular imaging aspect.

86Y-Labeled Albumin-Binding Fibroblast Activation Protein Inhibitor for Late-Time-Point Cancer Diagnosis.

Fibroblast activation protein inhibitor (FAPI) is a novel quinoline-based radiopharmaceutical that has theranostic potential, yet the limited tumor retention hinders late-time diagnosis and radionuclide treatment. This study synthesized four albumin-binding FAPIs (TE-FAPI-01 to 04) and evaluated their in vitro stability, binding affinity, in vivo biodistribution, and tumor uptake with 68Ga, 86Y, and 177Lu labeling, aiming to select the best molecule that has favorable pharmacokinetics to extend the blood circulation and tumor uptake in FAP-expressing tumors. All TE-FAPIs were stable in saline and plasma and displayed high FAP-binding affinity, with IC50 values ranging from 3.96 to 34.9 nmol/L. The capabilities of TE-FAPIs to be retained in circulation were higher than that of FAPI-04, and TE-FAPI-04 displayed minimum physiological uptake in major organs compared with other molecules. TE-FAPI-03 and TE-FAPI-04 exhibited persistent tumor accumulation, with tumor radioactivity 24 h after administration of 2.84 ± 1.19%ID/g and 3.86 ± 1.15%ID/g for 177Lu-TE-FAPI-03 and 177Lu-TE-FAPI-04, respectively, both of which outperformed 177Lu-FAPI-04 (0.34 ± 0.07%ID/g). TE-FAPI-04 was recognized as the albumin-binding FAPI with the most favorable pharmacokinetics and imaging performance. The enhanced circulation half-life and tumor uptake of TE-FAPI-04 aided the theranostics of malignant tumors and warrant further clinical investigations.

Larger 18F-fluoroboronotyrosine (FBY) active volume beyond MRI contrast enhancement in diffuse gliomas than in circumscribed brain tumors.

BACKGROUND: To investigate the relationship between 18F-fluoroboronotyrosine (FBY) positron emission tomography (PET)- and magnetic resonance imaging (MRI)-defined tumor volumes in contrast-enhanced diffuse gliomas and circumscribed brain tumors. METHODS: A total of 16 diffuse gliomas and 7 circumscribed brain tumors were included, and two types of three-dimensional regions of interest (ROIs), namely, MRI-based ROI (ROIMRI) and FBY-based ROI (ROIFBY), were semiautomatically defined. The overlap volume and DICE score were calculated to reveal the spatial relationship between the ROIMRI and ROIFBY. RESULTS: The ROIMRI was smaller than the ROIFBY and was mostly contained by the ROIFBY with an overlap volume of 0.995 ± 0.006 in the whole population. A significant difference in the DICE score was observed between circumscribed tumors and diffuse tumors (0.886 ± 0.026 vs. 0.684 ± 0.165, p = 0.004), and for the regions that have increased FBY metabolism but not MRI contrast enhancement, diffuse tumors and circumscribed tumors showed similar SUVmean values (0.630 ± 0.19 vs. 0.671 ± 0.18, p = 0.625). CONCLUSION: FBY uptake beyond contrast enhancement is more significant in diffuse tumors than in circumscribed tumors, which may aid the delineation of active tumor areas and facilitate boron neutron capture therapy.

Metabolic characteristics of [18F]fluoroboronotyrosine (FBY) PET in malignant brain tumors.

OBJECTIVE: [18F]fluoroboronotyrosine (FBY) is a large neutral amino acid transporter 1 (LAT-1) dependent boron-derived tyrosine which has diagnostic and therapeutic potentiality. This study aimed to investigate the imaging characteristics of FBY positron emission tomography (PET) in malignant brain tumors. METHODS: A total of 35 patients with 36 lesions were prospectively enrolled for FBY positron emission tomography (PET) and magnetic resonance imaging (MRI). Three-dimensional region of interest was semiautomatically defined on MRI and coregistered to FBY PET images. Five quantitative parameters, namely, standardized uptake value (SUV) maximum (SUVmax), SUVmean, metabolic tumor volume (MTV), total lesion activity (TLA) and tumor-to-normal ratio (T/N ratio), were calculated. The mean and standard deviation values of the parameters in different circumstances were calculated, and the Wilcoxon rank-sum test was applied to reveal the differences of FBY parameters. RESULTS: The maximum and mean standardized uptake value (SUV) of the normal brain were 0.119 ± 0.030 and 0.038 ± 0.017 in the study cohort. Majority of the neoplastic lesions displayed elevated FBY uptake, with SUVmax of 0.26 ± 0.14, 3.00 ± 0.61, 2.30 ± 0.51, 2.62 ± 0.36, and T/N ratio of 2.2 ± 1.3, 22.6 ± 6.6, 23.7 ± 8.3, 20.2 ± 3.8 for primary lower grade glioma (LGG), primary glioblastoma (GBM), recurrent diffuse glioma and metastatic brain tumor, respectively. Primary GBM showed significantly higher SUVmax, SUVmean and T/N ratio than primary LGG (p = 0.015-0.032). Meanwhile, 1 gliosis and 1 stable disease were also included and exhibited minimum FBY activity, with SUVmax of 0.17 and 0.33, T/N ratio of 1.04 and 2.58, respectively. CONCLUSION: Elevated FBY activity can be seen in most malignant brain tumors, and primary GBM, recurrent glioma and metastatic brain tumor displayed significant tumor to background ratio, which may facilitate the malignancy stratification and future boron neutron capture therapy.

Effects of oncolytic viruses and viral vectors on immunity in glioblastoma.

Glioblastoma (GBM) is regarded as an incurable disease due to its poor prognosis and limited treatment options. Virotherapies were once utilized on cancers for their oncolytic effects. And they are being revived on GBM treatment, as accumulating evidence presents the immunogenic effects of virotherapies in remodeling immunosuppressive GBM microenvironment. In this review, we focus on the immune responses induced by oncolytic virotherapies and viral vectors in GBM. The current developments of GBM virotherapies are briefly summarized, followed by a detailed depiction of their immune response. Limitations and lessons inferred from earlier experiments and trials are discussed. Moreover, we highlight the importance of engaging the immune responses induced by virotherapies into the multidisciplinary management of GBM.

Imposing Phase II and Phase III Clinical Trials of Targeted Drugs for Glioblastoma: Current Status and Progress.

The most common primary intracranial tumor is glioma, among which glioblastoma (GBM) has the worst prognosis. Because of the high degree of malignancy of GBM and frequent recurrence after surgery, postoperative therapy, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, is particularly important. A wide variety of targeted drugs have undergone phase III clinical trials for patients with GBM, but these drugs do not work for all patients, and few patients in these trials have prolonged overall survival. In this review, some imposing phase III clinical trials of targeted drugs for glioma are introduced, and some prospective phase II clinical trials that have been completed or are in progress are summarized. In addition, the mechanisms of these drugs are briefly introduced, and deficiencies of these clinical trials are analyzed. This review aims to provide a comprehensive overview of current research on targeted drugs for glioma to clarify future research directions.

Comprehensive ability evaluation and trend analysis of patients with malignant intracranial tumors in the perisurgery period.

INTRODUCTION: Prognostic situations differ in patients with malignant intracranial tumors. We focused on the quality of life, ability of daily living, and cognitive function of patients in the perisurgery period and investigated the correlation between them and the prognosis of patients. MATERIALS AND METHODS: Patients with malignant intracranial tumors admitted to Peking Union Medical College Hospital from May 2018 to August 2020 for surgery were included. The evaluations were performed 6 times in the perisurgery period. The questionnaires for assessment included QLQ-C30, ADL, and so forth. RESULTS: A total of 165 patients were included (115 glioma and 50 brain metastases). Patients had their worst performance at the 7-day postsurgical assessment (EORTC QLQ-C30, ADL, HAD-D, Frail Scale, MMSE, MoCA, CSHA-FI, and NANO) and recovered at the 1-month postsurgical assessment (p < .05). Patients with left-sided tumors had significantly worse cognitive function than patients with right-sided tumors before surgery and at 7 days, 1 month, and 6 months after surgery (p < .05). The scores of QLQ-C30 and QLQ-BN20 at 1 month, 3 months, 6 months, and 1 year after surgery were used to reflect the prognosis, and the preoperative MoCA, NANO, CCI, CSHA-FI, and HAD score might predict the quality of life and nutrition status after operation. CONCLUSION: The quality of life and daily living ability of patients with malignant intracranial tumors decreased significantly 7 days after the surgery but recovered 1 month after the surgery. Patients with left hemisphere lesions had a worse cognitive function, while the ADL is associated with short-term prognosis. The comprehensive evaluation of the perisurgical period can indicate the prognosis of patients and further guide clinical decision-making.

Current evidence and challenges of systematic therapies for adult recurrent glioblastoma: Results from clinical trials.

Recurrence is a major concern for adult patients with glioblastomas (GBMs), and the prognosis remains poor. Although several therapies have been assessed, most of them have not achieved satisfactory results. Therefore, there is currently no standard treatment for adult recurrent GBM (rGBM). Here, we review the results of clinical trials for the systematic therapy of rGBM. Regorafenib, rindopepimut and neoadjuvant programmed death 1 (PD-1) inhibitors are promising agents for rGBM, while regorafenib is effective in both O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated patients. Temozolomide rechallenge and alkylating agents combined with bevacizumab can be useful for patients with MGMT methylation, and patients with isocitrate dehydrogenase (IDH) mutations or second recurrence can benefit from vocimagene amiretrorepvec (Toca 511). Some phase I trials on targeted therapy and immunotherapy have shown positive results, and results from further studies are expected. In addition to the analysis of existing clinical trial results, forthcoming trials should be well designed, and patients are encouraged to participate in appropriate clinical trials.

Oncogenesis, Microenvironment Modulation and Clinical Potentiality of FAP in Glioblastoma: Lessons Learned from Other Solid Tumors.

Currently, glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults. Fibroblast activation protein (FAP) is a member of the dipeptidyl peptidase family, which has catalytic activity and is engaged in protein recruitment and scaffolds. Recent studies have found that FAP expression in different types of cells within the GBM microenvironment is typically upregulated compared with that in lower grade glioma and is most pronounced in the mesenchymal subtype of GBM. As a marker of cancer-associated fibroblasts (CAFs) with tumorigenic activity, FAP has been proven to promote tumor growth and invasion via hydrolysis of molecules such as brevican in the extracellular matrix and targeting of downstream pathways and substrates, such as fibroblast growth factor 21 (FGF21). In addition, based on its ability to suppress antitumor immunity in GBM and induce temozolomide resistance, FAP may be a potential target for immunotherapy and reversing temozolomide resistance; however, current studies on therapies targeting FAP are still limited. In this review, we summarized recent progress in FAP expression profiling and the understanding of the biological function of FAP in GBM and raised the possibility of FAP as an imaging biomarker and therapeutic target.

Prognostic Prediction Model for Glioblastoma: A Metabolic Gene Signature and Independent External Validation.

Background: Glioblastoma (GBM) is the most common primary malignant intracranial tumor and closely related to metabolic alteration. However, few accepted prognostic models are currently available, especially models based on metabolic genes. Methods: The transcriptome data were obtained for all of the patients diagnosed with GBM from the Gene Expression Omnibus (GEO) (training cohort, n=369) and The Cancer Genome Atlas (TCGA) (validation cohort, n=152) with the following variables: age at diagnosis, sex, follow-up and overall survival (OS). Metabolic genes according to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were contracted, and a Lasso regression model was constructed. Survival was assessed by univariate or multivariate Cox proportional hazards regression and Kaplan-Meier analysis, and an independent external validation was also conducted to examine the model. Results: There were 341 metabolic genes showed significant differences between normal brain and GBM tissues in both the training and validation cohorts, among which 56 genes were dramatically correlated to the OS of patients. Lasso regression revealed that the metabolic prognostic model was composed of 18 genes, including COX10, COMT, and GPX2 with protective effects, as well as OCRL and RRM2 with unfavorable effects. Patients classified as high-risk by the risk score from this model had markedly shorter OS than low-risk patients (P<0.0001), and this significant result was also observed in independent external validation (P<0.001). Conclusions: The prognosis of GBM was dramatically related to metabolic pathways, and our metabolic prognostic model had high accuracy and application value in predicting the OS of GBM patients.

Role of traditional CHO PET parameters in distinguishing IDH, TERT and MGMT alterations in primary diffuse gliomas.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status are diagnostic, prognostic, predictive and therapeutic biomarkers for primary diffuse gliomas, and this study aimed to explore the relationship between choline (CHO) positron emission tomography (PET) parameters and these molecular alterations. METHODS: Twenty-eight patients who were histopathologically diagnosed with primary diffuse glioma and underwent presurgical CHO PET/CT were retrospectively analyzed, and IDH, TERT and MGMT alterations were examined. The volume of interest (VOI) was semiautomatically defined based on standardized uptake value (SUV) thresholds, and 5 traditional CHO parameters, namely, SUVmax, SUVmean, metabolic tumor volume (MTV), total lesion CHO uptake (TLC) and tumor-to-normal contralateral cortex activity ratio (T/N ratio), were calculated. Wilcoxon rank-sum tests and receiver operating characteristic (ROC) curves were applied to evaluate the differences and performances of the CHO parameters, and their capability to stratify patient prognosis was also evaluated. RESULTS: All 5 parameters were significantly higher in IDH-wildtype gliomas than in IDH-mutant gliomas (p = 0.0001-0.037), and SUVmax, SUVmean, TLC and the T/N ratio exhibited good performances in distinguishing the IDH status (areas under the ROC curve (AUCs) 0.856-0.918, accuracies 0.857-0.893) as well as stratifying patient prognosis. Although the differences and performances of the traditional parameters in distinguishing diverse TERT and MGMT statuses were moderate in the whole population, the T/N ratio and TLC displayed certain predictive value in discriminating the TERT status in the IDH-mutant and IDH-wildtype subgroups (p = 0.028-0.048, AUCs 0.857-0.860, accuracies 0.800-0.917, respectively). CONCLUSIONS: Traditional CHO PET parameters are capable of distinguishing IDH but not TERT or MGMT alterations in the whole population. In accordance with the clinical understanding of TERT promoter mutations, the T/N ratio and TLC can also discriminate the TERT status in IDH subgroups.