Publications by authors named "Qinghui Zhu"

7 Publications

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

Cancer Sci 2021 Jun 11. Epub 2021 Jun 11.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

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.
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http://dx.doi.org/10.1111/cas.15024DOI Listing
June 2021

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

Front Oncol 2021 19;11:700599. Epub 2021 May 19.

Department of Neurosurgery, National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

[This corrects the article DOI: 10.3389/fonc.2021.627325.].
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http://dx.doi.org/10.3389/fonc.2021.700599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171117PMC
May 2021

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

Front Oncol 2021 13;11:632663. Epub 2021 May 13.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

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 (=0.006), a higher KPS score (=0.011), higher rates of cystic change (=0.037), O-methylguanine-DNA methyltransferase (MGMT) promoter methylation (=0.007), and IDH mutation (=0.049), and more likely to have undergone gross total resection (<0.001). Survival analysis demonstrated that LTS with wildtype IDH conferred a longer progression-free survival (66.0 27.0 months, =0.04), but a shorter post-progression survival (46.5 months not reached, =0.0001) than those of LTS with mutant IDH. LTS with mutant IDH showed a trend towards increased survival after receiving re-operation (=0.155) and reirradiation (=0.127), while this clinical benefit disappeared in the subset of LTS with wildtype IDH (>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.
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http://dx.doi.org/10.3389/fonc.2021.632663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155513PMC
May 2021

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

Front Immunol 2021 7;12:632547. Epub 2021 May 7.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

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 (<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.
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http://dx.doi.org/10.3389/fimmu.2021.632547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138184PMC
May 2021

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

Front Oncol 2021 20;11:627325. Epub 2021 Apr 20.

Department of Neurosurgery, National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

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 isocitrate dehydrogenase (IDH) wild-type GBM patients. 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). 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 (: 2.161, = 0.026), gross total removal (GTR) of the tumor (: 6.571, < 001), located in the frontal lobe (: 2.561, = 0.008), non-subventricular zone (SVZ) infringement (: 10.937, < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (: 9.737, < 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. 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.
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http://dx.doi.org/10.3389/fonc.2021.627325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093388PMC
April 2021

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

Scand J Gastroenterol 2011 Apr 6;46(4):436-45. Epub 2010 Dec 6.

Experimental Center for Medical Science Research of Teaching Hospital of Jiangsu University, Shanghai People's Hospital of Putuo District, Shanghai, PR China.

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.
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http://dx.doi.org/10.3109/00365521.2010.537682DOI Listing
April 2011

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

Mol Med Rep 2009 Mar-Apr;2(2):283-9

Teaching Hospital of Jiangsu University, Shanghai People's Hospital of Putuo District, Shanghai 200060, P.R. China.

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.
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http://dx.doi.org/10.3892/mmr_00000097DOI Listing
October 2012