Association of the combined stereotactic radiosurgery and embolization strategy and long-term outcomes in brain arteriovenous malformations with a volume >10 ml: A nationwide multicenter observational prospective cohort study.

BACKGROUND: To assess the long-term outcome of large brain arteriovenous malformations (AVMs) (volume > 10 ml) underwent combined embolization and stereotactic radiosurgery (E+SRS) versus SRS alone. METHODS: Patients were recruited from a nationwide multicenter prospective collaboration registry (MATCH study, August 2011-August 2021) and categorized into E+SRS and SRS alone cohorts. Propensity score-matched survival analysis was employed to control for potential confounding variables. The primary outcome was a composite event of non-fatal hemorrhagic stroke or death. Secondary outcomes were favorable patient outcomes, AVM obliteration, favorable neurological outcomes, seizure, worsened mRS score, radiation-induced changes (RIC), and embolization complications. Furthermore, the efficacy of distinct embolization strategies was evaluated. Hazard ratios (HRs) were computed utilizing Cox proportional hazard models. RESULTS: Among 1063 AVMs who underwent SRS with or without prior embolization, 176 patients met the enrollment criteria. Following propensity score matching, the final analysis encompassed 98 patients (49 pairs). Median (interquartile range) follow-up duration for primary outcomes spanned 5.4 (2.7-8.4) years. Overall, the E+SRS strategy demonstrated a trend toward reduced incidence of primary outcomes compared to the SRS alone strategy (1.44 vs 2.37 per 100 patient-years; HR, 0.58 [95 % CI, 0.17-1.93]). Regardless of embolization degree or strategy, stratified analyses further consistently revealed a similar trend, albeit without achieving statistical significance. Secondary outcomes generally exhibited equivalence, but the combined approach showed potential superiority in most measures. CONCLUSIONS: This study suggests a trend toward lower long-term non-fatal hemorrhagic stroke or death risks with the E+SRS strategy when compared to SRS alone in large AVMs (volume > 10 ml).

TLR agonists promote formation of Tertiary Lymphoid Structure and improve anti-glioma immunity.

BACKGROUND: Glioma, characterized by limited lymphocytic infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study aims to explore therapeutic strategies for inducing tertiary lymphoid structure (TLS) formation within the glioma microenvironment (GME) to transition it from an immune-resistant to an activated state. METHODS: TLS formation in GME was successfully induced by intracranial administration of Toll-like receptor (TLR) agonists (OK-432, TLR2/4/9 agonist) and glioma antigens (i.c. αTLR-mix). We employed staining analysis, antibody neutralization, single-cell RNA sequencing (scRNA-Seq), and BCR/TCR sequencing to investigate the underlying mechanisms of TLS formation and its role in anti-glioma immunity. Additionally, a preliminary translational clinical study was conducted. RESULTS: TLS formation correlated with increased lymphocyte infiltration in GME and led to improved prognosis in glioma-bearing mice. In the study of TLS induction mechanisms, certain macrophages/microglia and Th17 displayed markers of "LTo" and "LTi" cells, respectively, interaction through LTα/ß-LTßR promoted TLS induction. Post-TLS formation, CD4+ and CD8+ T cells but not CD19+ B cells contributed to anti-glioma immunity. Comparative analysis of B/T cells between brain and lymph node showed that brain B/T cells unveiled switch from naïve to mature, some B cells highlighted an enrichment of CSR-associated genes, V gene usage and clonotype bias were observed. In related clinical studies, i.c. αTLR-mix treatment exhibited tolerability, and chemokines/cytokines assay provided preliminary evidence supporting TLS formation in GME. CONCLUSION: TLS induction in GME enhanced anti-glioma immunity, improved the immune microenvironment, and controlled glioma growth, suggesting potential therapeutic avenues for treating glioma in the future.

A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness.

BACKGROUND: Due to the high mortality and disability rate of intracranial hemorrhage, headache is not the main focus of research on cerebral arteriovenous malformation (AVM), so research on headaches in AVM is still scarce, and the clinical understanding is shallow. This study aims to delineate the risk factors associated with headaches in AVM and to compare the effectiveness of various intervention treatments versus conservative treatment in alleviating headache symptoms. METHODS: This study conducted a retrospective analysis of AVMs who were treated in our institution from August 2011 to December 2021. Multivariable logistic regression analysis was employed to assess the risk factors for headaches in AVMs with unruptured, non-epileptic. Additionally, the effectiveness of different intervention treatments compared to conservative management in alleviating headaches was evaluated through propensity score matching (PSM). RESULTS: A total of 946 patients were included in the analysis of risk factors for headaches. Multivariate logistic regression analysis identified that female (OR 1.532, 95% CI 1.173-2.001, p = 0.002), supply artery dilatation (OR 1.423, 95% CI 1.082-1.872, p = 0.012), and occipital lobe (OR 1.785, 95% CI 1.307-2.439, p < 0.001) as independent risk factors for the occurrence of headaches. There were 443 AVMs with headache symptoms. After propensity score matching, the microsurgery group (OR 7.27, 95% CI 2.82-18.7 p < 0.001), stereotactic radiosurgery group(OR 9.46, 95% CI 2.26-39.6, p = 0.002), and multimodality treatment group (OR 8.34 95% CI 2.87-24.3, p < 0.001) demonstrate significant headache relief compared to the conservative group. However, there was no significant difference between the embolization group (OR 2.24 95% CI 0.88-5.69, p = 0.091) and the conservative group. CONCLUSIONS: This study identified potential risk factors for headaches in AVMs and found that microsurgery, stereotactic radiosurgery, and multimodal therapy had significant benefits in headache relief compared to conservative treatment. These findings provide important guidance for clinicians when developing treatment options that can help improve overall treatment outcomes and quality of life for patients.

Intratumoral calcification: not only a diagnostic but also a prognostic indicator in oligodendrogliomas.

OBJECTIVE: Calcification is a hallmark characteristic of oligodendroglioma (ODG) that may be used as a diagnostic factor, but its prognostic implications remain unclear. This study aimed to investigate the features of calcified ODGs and to evaluate the differences in survival between patients with calcified and noncalcified ODGs. METHODS: We retrospectively reviewed the records of 305 consecutive patients who were diagnosed with IDH-mutant, 1p/19q codeleted ODG at our institution from July 2009 to August 2020. Patients with intratumoral calcification were identified. The clinical, radiologic, and molecular features of the patients in the calcified group and noncalcified group were recorded. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Of the 305 patients, 112 (36.7%) were confirmed to have intratumoral calcification. Compared to ODGs without calcification, ODGs with calcifications had a larger tumor diameter; lower degree of resection; higher tumor grade; higher MGMT methylation level; higher Ki-67 index; and higher rates of midline crossing, enhancement, cyst, and 1q/19p copolysomy, and patients with calcification were more likely to receive chemoradiotherapy. ODGs with T2 hypointense calcification had a higher Hounsfield unit (HU) value on CT scans, and a lower degree of resection. Patients with T2 hypointense calcification ODGs had a shorter survival than those with non-hypointense calcification ODGs. ODGs with calcification and cysts showed a higher Ki-67 index, tumor grade, and enhanced rate, and the patients had an unfavorable overall survival (OS). Calcification was found to be a negative prognostic factor for both progression-free survival (PFS) and OS by univariate analysis, which was confirmed by the Cox proportional hazard model. CONCLUSIONS: Calcification is a useful negative prognostic factor for PFS and OS in patients with ODGs and could therefore be helpful in guiding personalized treatment and predicting patient prognosis. CLINICAL RELEVANCE STATEMENT: Calcification can serve as an independent prognostic factor for patients with oligodendroglioma and shows a vital role in guiding individualized treatment. KEY POINTS: • Intratumoral calcification is an independent negative prognostic risk factor for progression-free survival and overall survival in oligodendroglioma patients. • Calcifications in oligodendroglioma can be divided into hypointense and non-hypointense subtypes based on T2-weighted imaging, and patients with T2-hypointense calcification oligodendrogliomas have worse prognosis. • Calcification concurrent with cysts indicates a more aggressive phenotype of oligodendrogliomas and a significantly reduced survival rate.

Recurrence of Cerebral Arteriovenous Malformation Following Complete Obliteration Through Endovascular Embolization.

Arteriovenous malformation (AVM) recurrence after embolization was rarely reported. This study aimed to explore the potential risk factors of recurrence in angiographically obliterated AVMs treated with endovascular embolization. This study reviewed AVMs treated with embolization only in a prospective multicenter registry from August 2011 to December 2021, and ultimately included 92 AVMs who had achieved angiographic obliteration. Recurrence was assessed by follow-up digital subtraction angiography (DSA) or magnetic resonance imaging (MRI). Hazard ratios (HRs) with 95% confidence intervals were calculated using Cox proportional hazards regression models. Nineteen AVMs exhibited recurrence on follow-up imaging. The recurrence rates after complete obliteration at 6 months, 1 year, and 2 years were 4.35%, 9.78%, and 13.0%, respectively. Multivariate Cox regression analysis identified diffuse nidus (HR 3.208, 95% CI 1.030-9.997, p=0.044) as an independent risk factor for recurrence. Kaplan-Meier analysis confirmed a higher cumulative risk of recurrence with diffuse nidus (log-rank, p=0.016). Further, in the exploratory analysis of the effect of embolization timing after AVM rupture on recurrence after the complete obliteration, embolization within 7 days of the hemorrhage was found as an independent risk factor (HR 4.797, 95% CI 1.379-16.689, p=0.014). Kaplan-Meier analysis confirmed that embolization within 7 days of the hemorrhage was associated with a higher cumulative risk of recurrence in ruptured AVMs (log-rank, p<0.0001). This study highlights the significance of diffuse nidus as an independent risk factor for recurrence after complete embolization of AVMs. In addition, we identified a potential recurrent risk associated with early embolization in ruptured AVMs.

Characterization and clinical implications of different malignant transformation patterns in diffuse low-grade gliomas.

Malignant transformation (MT) of low-grade gliomas (LGGs) to a higher-grade variant seems inevitable, yet it remains unclear which LGG patients will progress to grade 3 or even directly to grade 4 after receiving a long course of treatment. To elucidate this, we conducted a retrospective cohort study based on 229 adults with recurrent LGG. Our study aimed to disclose the characteristics of different MT patterns and to build predictive models for patients with LGG. Patients were allocated into group 2-2 (n = 81, 35.4%), group 2-3 (n = 91, 39.7%), and group 2-4 (n = 57, 24.9%), based on their MT patterns. Patients who underwent MT showed lower Karnofsky performance scale (KPS) scores, larger tumor sizes, smaller extents of resection (EOR), higher Ki-67 indices, lower rates of 1p/19q codeletion, but higher rates of subventricular involvement, radiotherapy, chemotherapy, astrocytoma, and post-progression enhancement (PPE) compared with those in group 2-2 (p < 0.01). On multivariate logistic regression, 1p/19q codeletion, Ki-67 index, radiotherapy, EOR, and KPS score were independently associated with MT (p < 0.05). Survival analyses demonstrated that patients in group 2-2 had the longest survival, followed by group 2-3 and then group 2-4 (p < 0.0001). Based on these independent parameters, we constructed a nomogram model that exhibited superior potential (sensitivity: 0.864, specificity: 0.814, and accuracy: 0.843) compared with PPE in early prediction of MT. Combining the factors of 1p/19q codeletion, Ki-67 index, radiotherapy, EOR, and KPS score that were presented at initial diagnosis could precisely forecast the subsequent MT patterns of patients with LGG.

The sinuous, wave-like intratumoral-wall sign is a sensitive and specific radiological biomarker for oligodendrogliomas.

OBJECTIVES: The purpose of this study was to investigate the clinical utility of the sinuous, wave-like intratumoral-wall (SWITW) sign on T2WI in diagnosing isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted (IDHmut-Codel) oligodendrogliomas, for which a relatively conservative resection strategy might be sufficient due to a better response to chemoradiotherapy and favorable prognosis. METHODS: Imaging data from consecutive adult patients with diffuse lower-grade gliomas (LGGs, histological grades 2-3) in Beijing Tiantan Hospital (December 1, 2013, to October 31, 2021, BTH set, n = 711) and the Cancer Imaging Archive (TCIA) LGGs set (n = 117) were used to develop and validate our findings. Two independent observers assessed the SWITW sign and some well-reported discriminative radiological features to establish a practical diagnostic strategy. RESULTS: The SWITW sign showed satisfying sensitivity (0.684 and 0.722 for BTH and TCIA sets) and specificity (0.938 and 0.914 for BTH and TCIA sets) in defining IDHmut-Codels, and the interobserver agreement was substantial (κ 0.718 and 0.756 for BTH and TCIA sets). Compared to calcification, the SWITW sign improved the sensitivity by 0.28 (0.404 to 0.684) in the BTH set, and 81.0% (277/342) of IDHmut-Codel cases demonstrated SWITW and/ or calcification positivity. Combining the SWITW sign, calcification, low ADC values, and other discriminative features, we established a concise and reliable diagnostic protocol for IDHmut-Codels. CONCLUSIONS: The SWITW sign was a sensitive and specific imaging biomarker for IDHmut-Codels. The integrated protocol provided an explicable, efficient, and reproducible method for precise preoperative diagnosis, which was essential to guide individualized surgical plan-making. KEY POINTS: • The SWITW sign was a sensitive and specific imaging biomarker for IDHmut-Codel oligodendrogliomas. • The SWITW sign was more sensitive than calcification and an integrated strategy could improve diagnostic sensitivity for IDHmut-Codel oligodendrogliomas. • Combining SWITW, calcification, low ADC values, and other discriminative features could make a precise preoperative diagnosis for IDHmut-Codel oligodendrogliomas.

Nonhematogenic circulating aneuploid cells confer inferior prognosis and therapeutic resistance in gliomas.

Aneuploidy is the hallmark of malignancy. Our previous study successfully detected nonhematogenic circulating aneuploidy cells (CACs) in types of gliomas. The current prospective clinical study aims to further precisely subcategorize aneuploid CACs, including CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells, and thoroughly investigate the clinical utilities of these different subtypes of cells. Co-detection and analysis of CTCs and circulating tumor-derived endothelial cells (CTECs) expressing CD133, glial fibrillary acidic protein (GFAP), or epidermal growth factor receptor variant III (EGFR vIII) were performed by integrated subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) in 111 preoperative primary diffuse glioma patients. Aneuploid CACs could be detected in most de novo glioma patients. Among detected CACs, 45.6% were CD31- /CD45- aneuploid CTCs and the remaining 54.4% were CD31+ /CD45- aneuploid CTECs. Positive detection of CTECs significantly correlated with disruption of the blood-brain barrier. The median number of large CTCs (L CTCs, >5 µm, 2) in low-grade glioma (WHO grade 2) was less than high-grade glioma (WHO grades 3 and 4) (3, p = 0.044), but this difference was not observed in small CTCs (S CTCs, ≤5 µm), CTECs or CACs (CTCs + CTECs). The numbers of CTCs, CTECs, or CACs in patients with contrast-enhancing (CE) lesions considerably exceeded that of non-CE lesions (p < 0.05). Receiver operating characteristic curves demonstrated that CD31+ CTECs, especially L CTECs, exhibited a close positive relationship with CE lesions. Survival analysis revealed that the high number of CD31- CTCs could be an adverse factor for compromised progression-free survival and overall survival. Longitudinal surveillance of CD31- CTCs was suitable for evaluating the therapeutic response and for monitoring potential emerging treatment resistance.

Orelabrutinib Combined With Lenalidomide and Immunochemotherapy for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Retrospective Analysis of Case Series.

Background: Relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL) is an intractable situation without sound treatment. Bruton's tyrosine kinase (BTK) represents an attractive drug target in PCNSL. Orelabrutinib is a new-generation BTK inhibitor with high cerebrospinal fluid (CSF) concentration. This study aimed to evaluate the efficacy and safety of orelabrutinib-containing combination therapy in patients with r/r PCNSL. Methods: We retrospectively analyzed r/r PCNSL patients who received combination therapy with rituximab, high-dose methotrexate, temozolomide, orelabrutinib and lenalidomide, and further explored the relationship between the efficacy and genetic characteristics. Results: A total of fifteen patients were included in this retrospective study. The overall response rate (ORR) was 86.7%, the complete remission (CR) rate was 73.3% and the disease control rate (DCR) was 93.3%. Among 13 responders, 9 patients are still receiving oral orelabrutinib and lenalidomide. The most common adverse event (AEs) was transaminase increase (66.7%). No grade 4 AE or drug-related death was reported. Genomic sequencing showed that patients who responded to orelabrutinib had abnormal NF-κB activation, while those who had no response were mainly enriched with transcriptional misregulation. Patients who had mutations in TLR, BCR, or NF-κB pathway achieved complete or partial response to the orelabrutinib-containing therapy. Moreover, the blood and cerebrospinal fluid circulating tumor DNA (ctDNA) were closely associated with tumor recurrence and treatment response and sustained tumor responses correlated with the clearance of ctDNA. Conclusion: Orelabrutinib-containing regimen was effective and well-tolerated in patients with r/r PCNSL. Genome sequencing of tumor samples could help to screen patients who may respond to the orelabrutinib-containing regimen, and liquid biopsy may contribute to tracing tumor burden and monitoring treatment response.

Cross-domain heterogeneous residual network for single image super-resolution.

Single image super-resolution is an ill-posed problem, whose purpose is to acquire a high-resolution image from its degraded observation. Existing deep learning-based methods are compromised on their performance and speed due to the heavy design (i.e., huge model size) of networks. In this paper, we propose a novel high-performance cross-domain heterogeneous residual network for super-resolved image reconstruction. Our network models heterogeneous residuals between different feature layers by hierarchical residual learning. In outer residual learning, dual-domain enhancement modules extract the frequency-domain information to reinforce the space-domain features of network mapping. In middle residual learning, wide-activated residual-in-residual dense blocks are constructed by concatenating the outputs from previous blocks as the inputs into all subsequent blocks for better parameter efficacy. In inner residual learning, wide-activated residual attention blocks are introduced to capture direction- and location-aware feature maps. The proposed method was evaluated on four benchmark datasets, indicating that it can construct the high-quality super-resolved images and achieve the state-of-the-art performance. Code and pre-trained models are available at https://github.com/zhangyongqin/HRN.

Combining hyperintense FLAIR rim and radiological features in identifying IDH mutant 1p/19q non-codeleted lower-grade glioma.

OBJECTIVES: Even very small residual tumors of IDH mutant 1p/19q non-codeleted (IDHmut-Noncodel) astrocytoma could have a significantly negative impact on survival; thus, accurate preoperative diagnosis is of utmost importance to guide aggressive tumor resection strategy for this subtype. This study aimed to diagnose IDHmut-Noncodel from IDH mutant 1p/19q codeleted (IDHmut-Codel) and IDH wild-type gliomas by preoperative MRI and CT to guide surgical plan-making. METHODS: Consecutive adult patients diagnosed with diffuse lower-grade glioma (LGG, histological grade 2-3) from December 1, 2013 to December 31, 2020, were retrospectively included in this study. Clinical and radiological features were recorded and analyzed. Patients were divided into cohort A and cohort B for training and validation based on the operation date (2:1). RESULTS: A total of 585 patients were included in this study (cohort A, 390; cohort B, 195). The hyperintense FLAIR rim with hypointense core (hyperFLAIRrim) was a more sensitive sign than T2-FLAIR mismatch (T2FM) in defining IDHmut-Noncodel astrocytoma (sensitivity in cohort A: 0.713, 0.539, respectively; in cohort B: 0.713, 0.489, respectively) without compromised specificity (all 1.00). The hyperFLAIRrim, higher rADC, homogenous pattern on T2WI, non-calcification, and younger age were the most important factors associated with IDHmut-Noncodel astrocytoma. Combining these factors, the random forest model showed the best predictive ability. CONCLUSION: The hyperFLAIRrim sign was a specific and more sensitive sign in diagnosing IDHmut-Noncodel astrocytoma. Combining hyperFLAIRrim, higher rADC, homogenous pattern, non-calcification, and younger age could precisely predict glioma subtype for subsequent surgical plan-making. KEY POINTS: • A single hyperintense FLAIR rim (hyperFLAIRrim) sign with a hypointense core, regardless of T2 appearance, was more sensitive than T2FM in diagnosing IDHmut-Noncodel astrocytoma with high specificity. • The higher rADC value, homogenous pattern on T2WI, non-calcification, and younger age have a close relationship with IDHmut-Noncodel astrocytoma. • Neurosurgeons should perform a more aggressive resection strategy to prolong survival for radiologically indicated IDHmut-Noncodel astrocytoma. Our study provided a usable, practicable, and reliable protocol for neurosurgeons to make an individualized surgical strategy.

A prognostic estimation model based on mRNA-sequence data for patients with oligodendroglioma.

Background: The diagnosis of oligodendroglioma based on the latest World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS 5) criteria requires the codeletion of chromosome arms 1p and 19q and isocitrate dehydrogenase gene (IDH) mutation (mut). Previously identified prognostic indicators may not be completely suitable for patients with oligodendroglioma based on the new diagnostic criteria. To find potential prognostic indicators for oligodendroglioma, we analyzed the expression of mRNAs of oligodendrogliomas in Chinese Glioma Genome Atlas (CGGA). Methods: We collected 165 CGGA oligodendroglioma mRNA-sequence datasets and divided them into two cohorts. Patients in the two cohorts were further classified into long-survival and short-survival subgroups. The most predictive mRNAs were filtered out of differentially expressed mRNAs (DE mRNAs) between long-survival and short-survival patients in the training cohort by least absolute shrinkage and selection operator (LASSO), and risk scores of patients were calculated. Univariate and multivariate analyses were performed to screen factors associated with survival and establish the prognostic model. qRT-PCR was used to validate the expression differences of mRNAs. Results: A total of 88 DE mRNAs were identified between the long-survival and the short-survival groups in the training cohort. Seven RNAs were selected to calculate risk scores. Univariate analysis showed that risk level, age, and primary-or-recurrent status (PRS) type were statistically correlated with survival and were used as factors to establish a prognostic model for patients with oligodendroglioma. The model showed an optimal predictive accuracy with a C-index of 0.912 (95% CI, 0.679-0.981) and harbored a good agreement between the predictions and observations in both training and validation cohorts. Conclusion: We established a prognostic model based on mRNA-sequence data for patients with oligodendroglioma. The predictive ability of this model was validated in a validation cohort, which demonstrated optimal accuracy. The 7 mRNAs included in the model would help predict the prognosis of patients and guide personalized treatment.

Nomograms for predicting cancer-specific survival in patients with primary central nervous system lymphoma: a population-based analysis.

BACKGROUND: This study identified the risk factors for survival in patients with primary central nervous system lymphoma (PCNSL). Nomograms were developed and validated to predict individualized overall survival (OS) and cancer-specific survival (CSS) in this particular cohort. METHODS: Patients diagnosed with PCNSL between 1975 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database for this study. The Cox regression model, the Fine and Grey's model, and the backward method were applied to determine the risk factors for OS and CSS. Nomograms were established accordingly. Internal and external validation was performed in an Asian population to examine the accuracy of the nomograms. RESULTS: A total of 5,900 patients with PCNSL were identified from the SEER database. A further 163 patients with PCNSL from the Beijing Tiantan Hospital between 2004 and 2018 were included. Age at diagnosis, tumor site, pathological subtype, surgery, chemotherapy, coexisting malignancies, and HIV infection were independent risk factors of CSS. In addition to the risk factors of CSS, gender, marital status, and radiation were also independent factors of OS. Nomograms were developed to estimate the 1-, 3-, and 5-year OS and CSS. The discrimination and calibration of the nomograms performed well. The C-indexes of the nomograms for OS and CSS prediction were 0.728 [95% confidence interval (CI): 0.703-0.753] and 0.726 (95% CI: 0.696-0.756), respectively. In addition, compared with previously published OS nomograms, the newly established nomograms displayed superior prediction for OS. CONCLUSIONS: Nomograms predicting the 1-, 3- and 5-year OS and CSS of patients with PCNSL were established in this study. The validated nomograms showed relatively good performance and may be used clinically to evaluate patients' individualized risk and prognosis with PCNSL. Free software for individualized survival prediction is provided at http://www.pcnsl-survivalprediction.cn.

Corrigendum: Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological and Molecular Features.

[This corrects the article DOI: 10.3389/fonc.2021.627325.].

Combining MGMT promoter pyrosequencing and protein expression to optimize prognosis stratification in glioblastoma.

Pyrosequencing (PSQ) represents the golden standard for MGMT promoter status determination. Binary interpretation of results based on the threshold from the average of several CpGs tested would neglect the existence of the "gray zone". How to define the gray zone and reclassify patients in this subgroup remains to be elucidated. A consecutive cohort of 312 primary glioblastoma patients were enrolled. CpGs 74-81 in the promoter region of MGMT were tested by PSQ and the protein expression was assessed by immunohistochemistry (IHC). Receiver operating characteristic curves were constructed to calculate the area under the curves (AUC). Kaplan-Meier plots were used to estimate the survival rate of patients compared by the log-rank test. The optimal threshold of each individual CpG differed from 5% to 11%. Patients could be separated into the hypomethylated subgroup (all CpGs tested below the corresponding optimal thresholds, n = 126, 40.4%), hypermethylated subgroup (all CpGs tested above the corresponding optimal thresholds, n = 108, 34.6%), and the gray zone subgroup (remaining patients, n = 78, 25.0%). Patients in the gray zone harbored an intermediate prognosis. The IHC score instead of the average methylation levels could successfully predict the prognosis for the gray zone (AUC for overall survival, 0.653 and 0.519, respectively). Combining PSQ and IHC significantly improved the efficiency of survival prediction (AUC: 0.662, 0.648, and 0.720 for PSQ, IHC, and combined, respectively). Immunohistochemistry is a robust method to predict prognosis for patients in the gray zone defined by PSQ. Combining PSQ and IHC could significantly improve the predictive ability for clinical outcomes.

Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological, and Molecular Features.

Background: Pseudoprogression (PsP) mimics true early progression (TeP) in conventional imaging, which poses a diagnostic challenge in glioblastoma (GBM) patients who undergo standard concurrent chemoradiation (CCRT). This study aimed to investigate whether perioperative markers could distinguish and predict PsP from TeP in de novo isocitrate dehydrogenase (IDH) wild-type GBM patients. Methods: New or progressive gadolinium-enhancing lesions that emerged within 12 weeks after CCRT were defined as early progression. Lesions that remained stable or spontaneously regressed were classified as PsP, otherwise persistently enlarged as TeP. Clinical, radiological, and molecular information were collected for further analysis. Patients in the early progression subgroup were divided into derivation and validation sets (7:3, according to operation date). Results: Among 234 consecutive cases enrolled in this retrospective study, the incidences of PsP, TeP, and neither patterns of progression (nP) were 26.1% (61/234), 37.6% (88/234), and 36.3% (85/234), respectively. In the early progression subgroup, univariate analysis demonstrated female (OR: 2.161, P = 0.026), gross total removal (GTR) of the tumor (OR: 6.571, P < 001), located in the frontal lobe (OR: 2.561, P = 0.008), non-subventricular zone (SVZ) infringement (OR: 10.937, P < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (OR: 9.737, P < 0.001) were correlated with PsP, while GTR, non-SVZ infringement, and mMGMTp were further validated in multivariate analysis. Integrating quantitative MGMTp methylation levels from pyrosequencing, GTR, and non-SVZ infringement showed the best discriminative ability in the random forest model for derivation and validation set (AUC: 0.937, 0.911, respectively). Furthermore, a nomogram could effectively evaluate the importance of those markers in developing PsP (C-index: 0.916) and had a well-fitted calibration curve. Conclusion: Integrating those clinical, radiological, and molecular features provided a novel and robust method to distinguish PsP from TeP, which was crucial for subsequent clinical decision making, clinical trial enrollment, and prognostic assessment. By in-depth interrogation of perioperative markers, clinicians could distinguish PsP from TeP independent from advanced imaging.

Differential Predictors and Clinical Implications Associated With Long-Term Survivors in IDH Wildtype and Mutant Glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most aggressive intracranial tumor which can be divided into two subtypes based on status of isocitrate dehydrogenase (IDH). A small fraction of patients after receiving standard treatment can be long-term survivors (LTS). This study was designed to disclose the predictors and clinical implications associated with LTS in IDH wildtype and mutant GBM. METHODS: Patients who survived beyond five years after diagnosis of GBM were defined as LTS, while those with a survival less than one year were defined as short-term survivors (STS). A total of 211 patients with diagnosis of GBM in Beijing Tiantan Hospital from January 2007 to January 2015 were enrolled, including 44 (20.9%) LTS and 167 (79.1%) STS. The clinical, radiological and molecular features between groups were systematically compared. RESULTS: Compared with STS, LTS were a subgroup of patients with a younger age at diagnosis (P=0.006), a higher KPS score (P=0.011), higher rates of cystic change (P=0.037), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (P=0.007), and IDH mutation (P=0.049), and more likely to have undergone gross total resection (P<0.001). Survival analysis demonstrated that LTS with wildtype IDH conferred a longer progression-free survival (66.0 vs. 27.0 months, P=0.04), but a shorter post-progression survival (46.5 months vs. not reached, P=0.0001) than those of LTS with mutant IDH. LTS with mutant IDH showed a trend towards increased survival after receiving re-operation (P=0.155) and reirradiation (P=0.127), while this clinical benefit disappeared in the subset of LTS with wildtype IDH (P>0.05). CONCLUSION: The prognostic value and therapeutic implications associated with LTS in GBM population significantly differed on the basis of IDH status. Our findings provide a new approach for physicians to better understand the two subtypes of GBM, which may assist in making more tailored treatment decisions for patients.

Combination of Immunotherapy and Radiotherapy for Recurrent Malignant Gliomas: Results From a Prospective Study.

Background: World Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients. Methods: This study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545. Results: Thirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (P<0.05). Conclusion: The combination of immunotherapy and radiotherapy is well tolerated and may provide clinical benefit for patients with recurrent WHO grade IV glioma. A prospective phase II study is needed to further validate the efficacy of our therapeutic regimen.

Impact of MTHFR gene C677T polymorphism on Bcl-2 gene methylation and protein expression in colorectal cancer.

OBJECTIVE: To investigate the impact of MTHFR C677T polymorphism on Bcl-2 gene promoter CpG island (CGI) methylation and Bcl-2 protein expression. MATERIAL AND METHODS: MTHFR polymorphisms of 86 sporadic colorectal cancer (CRC) patients and 100 healthy volunteers were analyzed by PCR-based restriction fragment length polymorphism, and Bcl-2 promoter CGI methylation in 86 CRC tissues and 86 paired nonneoplastic adjacent tissues was determined by methylation-specific PCR. Bcl-2 oncoprotein expression in 70 CRC tissues and paired nonneoplastic adjacent tissues was detected by immunohistochemistry. RESULTS: The frequency of MTHFR 677 T allele and combined variant genotypes (677CT + TT) in CRC patients was significantly higher than that in healthy controls (p = 0.023 and p = 0.035, respectively), and there is a significant association between 677TT or 677(CT + TT) genotypes and CRC (OR = 2.534, p = 0.045 and OR = 1.888, p = 0.035, respectively). The frequency of methylated Bcl-2 promoter CGI in tumor tissues was significantly lower than that in nonneoplastic adjacent tissues (p = 0.014). The frequency of methylated Bcl-2 promoter CGI in CRC tissues of the individuals with CC genotype was significantly higher than that of those with CT/TT genotypes (p = 0.018), there was significant distribution difference of C and T alleles between individuals with methylated and unmethylated Bcl-2 promoter CGI in colorectal cancer tissues (p = 0.023). Bcl-2 promoter hypomethylation was significantly correlated with Bcl-2 oncoprotein expression in colorectal cancer tissues (r = 0.558, p < 0.001). CONCLUSION: Bcl-2 promoter is hypomethylated in colorectal cancer tissue, and there is a significant correlation between MTHFR 677 TT or CT/TT genotypes and CRC or Bcl-2 promoter CGI methylation/oncoprotein expression in CRC.

Effect of the methylenetetrahydrofolate reductase gene C677T polymorphism on C-erbB-2 methylation status and its association with cancer.

Methylation abnormalities of cancer-related genes are recognized to play an important role in carcinogenesis. Methylenetetrahydrofolate reductase (MTHFR) regulates DNA methylation by affecting synthesis of S-adenosylmethionine, which is a universal methyl donor for methylation reactions. MTHFR gene polymorphisms that affect enzymatic activity may be associated with DNA methylation and cancer susceptibility. In the present study, we investigated the MTHFR C677T polymorphism in 247 cancer patients and 100 healthy subjects using PCR-RFLP, as well as the methylation status of the CpG island in the promoter region of the C-erbB-2 oncogene in 247 tumor and matched adjacent tissue samples using methylation-specific PCR. The results revealed that the methylation rate of the C-erbB-2 gene was significantly lower in the tumor tissues than in the matched adjacent tissues (43.3 vs. 69.2%, P=0.000). No correlation was observed between the methylation patterns of C-erbB-2 in tumor tissues and the clinicopathological characteristics of the patients. The frequency of the MTHFR gene 677 T allele was significantly higher in cancer patients than in the healthy subjects, and the combined variant genotypes (677CT+TT) significantly increased the risk of developing cancer (OR=1.619, 95% CI 1.012-2.588, P=0.043). Among the cancer patients, the methylation rate of the C-erbB-2 gene was higher in indi-viduals with the CC genotype than in those with the CT/TT genotype (50.0 vs. 39.4%). This difference was not significant (P=0.103). However, a significant difference was found in patients with breast cancer (P=0.008). In conclusion, the C-erbB-2 promoter CpG island was hypomethylated in cancer patients, and the MTHFR 677 CT/TT genotype increased the risk of developing the disease. Moreover, in breast cancer patients, the MTHFR gene C677T polymorphism had an effect on the methylation status of the C-erbB-2 gene.