IDH wild-type lower-grade gliomas with glioblastoma molecular features: a systematic review and meta-analysis

Brain Tumor Pathology - The WHO 2021 classification defines IDH wild type (IDHw) histologically lower-grade glioma (hLGG) as molecular glioblastoma (mGBM) if TERT promoter mutation (pTERTm), EGFR...     

Volumetric analysis of IDH-mutant lower-grade glioma: a natural history study of tumor growth rates before and after treatment

BackgroundLower-grade gliomas (LGGs) with isocitrate dehydrogenase 1 and/or 2 (IDH1/2) mutations have long survival times, making evaluation of treatment efficacy difficult. We investigated the volumetric growth rate of IDH mutant gliomas before and after treatment with established glioma therapies to determine whether a significant change in growth rate could be documented and perhaps be used in the future to evaluate treatment response to investigational agents in LGG trials.MethodsIn this multicenter retrospective study, 230 adult patients with IDH1/2 mutated LGGs (World Health Organization grade II or III) undergoing surgery, radiation, or chemotherapy for progressive non-enhancing tumor were identified. Subjects were required to have 3 MRI scans containing T2/fluid attenuated inversion recovery imaging spanning a minimum of 6 months prior to treatment. A mixed-effect model was used to estimate tumor growth prior to treatment. A subset of 95 patients who received chemotherapy, radiotherapy, or chemoradiotherapy and had 2 posttreatment imaging time points available were evaluated for change in pre- and posttreatment volumetric growth rates using a piecewise mixed model.ResultsThe pretreatment volumetric growth rate across all 230 patients was 27.37%/180 days (95% CI: [23.36%, 31.51%]). In the 95 patients with both pre- and posttreatment scans available, there was a significant difference in volumetric growth rates before (26.63%/180 days, 95% CI: [19.31%, 34.40%]) and after treatment (−15.24% /180 days, 95% CI: [−21.37%, −8.62%]) (P < 0.0001). The growth rates for patient subgroup with 1p/19q codeletion (N = 118) was significantly slower than the rate of the 1p/19q non-codeleted group (N = 68) (22.84% vs 35.49%, P = 0.0108).ConclusionIn this study, we evaluated the growth rates of IDH mutant gliomas before and after standard therapy. Further study is needed to establish whether a change in growth rate is associated with patient survival and its use as a surrogate endpoint in clinical trials for IDH mutant LGGs.     

CDKN2A exon-wise deletion status and novel somatic mutations in Indian glioma patients

Over the years, deletions of CDKN2A (p16) tumor suppressor gene has been studied using FISH and multiplex PCR, with major focus on exon 2 in various cancers, and the frequency of mutation is found to be varied in different studies. In this study, we analyzed the deletion status of all three exons of p16 and frequency of exon 2 somatic point mutations in glioma from the Indian population and its clinical implications. Multiplex PCR was carried out in order to check deletion of all 3 exons in 50 glioma samples. Nonconventional PCR-SSCP analysis and sequencing was done to identify mutations in 48 cases. Deletion of at least one of the three exons of p16 INK4A was observed in ten cases (20 %). The frequencies of exon-wise deletions were 10 % for exon 1, 4 % for exon 2, and 8 % for exon 3. Two out of 48 samples were positive for mutations in p16 exon 2. One sample had a transition of G to C on position 147 with a codon change TGG to TGC which does not contribute to the protein structure. Another sample had a transversion of A to G on the position 154 with a codon change ATG to GTG with change in amino acid methionine to valine in 52nd position. Deletion pattern was found to be varied in three exons. Frequency of p16 gene mutation was less in the Indian population (4.2 %), and this mutation does not contribute to any remarkable change in protein structure.     

The rate of homozygous CDKN2A/p16 deletions in glioma cell lines and in primary tumors.

The rate of homozygous deletions of CDKN2A/p16 is variable between different tumor entities, and in addition it is higher in established cell lines in comparison with primary tumors. Such incongruencies may reflect statistical sampling errors, true differences depending on tissue derivatisation and CDKN2A/p16 loss under selective pressure in tissue culture. Clarification of these issues is warranted in the context of defining tumor suppressor genes such as CDKN2A/p16 as targets for gene replacement therapies. We therefore compared established cell lines derived from human glioblastomas and their corresponding primary tumors by multiplex PCR methodology. Archival early passages were included to determine the time point at which the p16 status of a cell line changes if it is different from the original tumor. It was found that in 2 of 11 cases (18%) the primary tumor had no p16 alteration whereas the corresponding cell lines had a homozygous p16 deletion. Tracking the in vitro evolution of these two cell lines we found that CDKN2A/p16 was lost already in the earliest passages. This suggests a clonal outgrowth advantage of a subpopulation of p16 deleted tumor cells rather than instability of the CDKN2A/p16 genotype in vitro. Including 20 additional glioblastoma-derived cell lines we detected that in 19 of the total 31 lines at least one exon was lost bringing the rate of p16 loss in the whole panel to 61%. This compares to a rate of 49% which was found in original glioma tissue from 47 unselected other patients. It is concluded, that in cell culture selective pressure favours the outgrowth of pre-existing CDKN2A/p16 negative clones, which account for the difference of CDKN2A/p16 status between cell lines and tumors. In no case did we see a change of the CDKN2A/p16 status during prolonged tissue culture periods of up to 8 years.     

Expression and prognostic value of microRNAs in lower-grade glioma depends on IDH1/2 status

Histological and genomic characteristics are widely used in glioma management and research. This study investigated their relationship to the expression and prognostic value of microRNAs (miRNAs) in lower-grade glioma (LGG). A total of 447 LGG samples with available clinical and genomic information from The Cancer Genome Atlas database were reviewed. Samples with isocitrate dehydrogenase (IDH) 1/2 mutations (n?=?366) were randomly divided into training and validation sets to establish and confirm a four-miRNA-based risk classifier. We found that IDH1/2 mutation status had greater impact than histological and other genomic features on miRNA expression patterns; 361/487 (74%) of miRNAs were differentially expressed according to IDH1/2 mutation status. Importantly, there were no miRNAs with the same prognostic significance among groups with different IDH1/2 mutation status. For IDH1/2-mut LGG, a four-miRNA risk classifier (miR-10b, miR-130b, miR-1304, and miR-302b) was established that could independently distinguish cases as high or low risk of poor prognosis in both training and validation sets. The risk classifier outperformed individual miRNAs and traditional prognostic factors in terms of sensitivity and specificity. Bioinformatic analyses indicated that high-risk samples were more mitotically active than low-risk samples. Taken together, IDH1/2 mutation status had a significant influence on miRNA expression and prognostication in LGG. The four-miRNA-based risk classifier can be used for risk stratification of IDH1/2-mut LGG.     

Exercise in patients with lymphedema: a systematic review of the contemporary literature

Background  

Controversy exists regarding the role of exercise in cancer patients with or at risk for lymphedema, particularly breast. We conducted a systematic review of the contemporary literature to distill the weight of the evidence and provide recommendations for exercise and lymphedema care in breast cancer survivors.     

Life beyond a diagnosis of glioblastoma: a systematic review of the literature

Background

The median survival of glioblastoma is 12–14 months with less than 10% of patients surviving at least 2 years from diagnosis. Patients diagnosed with glioblastoma face poor prognosis, significant symptom burden, and high care needs. The aim of this study is to undertake a literature review to document the issues encountered by long-term survivors of glioblastoma, a small but important subset of patients.

Methods

MEDLINE, PsychInfo, and EMBASE were searched with core concepts: (1) glioblastoma, (2) survivor, and (3) terms pertaining to survivorship issues. A thematic analysis was undertaken of the three included studies.

Results

Long-term survivors of glioblastoma encounter neurologic deficits, impairment in cognition, psychological distress, reduced social function, and future uncertainty. These issues result in the inability to return to work and financial difficulties. Independence in activities of daily living, working memory, and overall quality of life appears to be preserved.

Conclusions

Long-term survivors of glioblastoma continue to have significant symptom burden and care needs. There is currently a paucity of literature surrounding this topic. Further research is required to accurately describe these issues in order for improved supportive care to be implemented in the community and the outpatient setting.

Implications for Cancer Survivors

Understanding the issues faced by long-term survivor of glioblastoma will provide insight into the care needs of patients as well as support networks required for patients and their carers.

     

EN2在胶质母细胞瘤中的表达及其预后价值

目的:探讨EN2在胶质母细胞瘤中的表达及其预后价值。方法:利用Oncomine 数据库及GEPIA数据库分析EN2 在胶质母细胞瘤组织中的表达情况;检索GEPIA数据库，分析EN2 在胶质母细胞瘤组织中的表达与预后的相关性。结果:在胶质母细胞瘤组织中EN2的mRNA表达显著高于正常对照组(P＜0.05）；EN2的mRNA表达量与胶质母细胞瘤总生存期存在相关性，即低表达EN2的患者预后较好，高表达EN2的患者预后较差(P=0.015)。结论:EN2基因在胶质母细胞瘤组织中呈高表达，其表达水平对预测胶质母细胞瘤患者的预后具有重要意义。     

The BIM deletion polymorphism is a prognostic biomarker of EGFR-TKIs response in NSCLC: A systematic review and meta-analysis

The prognostic value of Bcl-2-like protein 11 (BIM) deletion polymorphism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC) were reported. However, the results remained controversial. Thus, we did this systematic review and meta-analysis to address this issue. Databases including PubMed, Embase, and the Cochrane Register of Controlled Trials were searched to find relevant studies. The primary outcome was progression-free survival (PFS). Five retrospective cohort studies were included. All of the studies were conducted in Asian population (n = 951). The methodological quality of all included studies was high. Compared with BIM wild type, BIM deletion polymorphism was predictive of shorter PFS in NSCLC patients who were treated with EGFR-TKIs (adjusted HR = 2.38, 95% CI 1.66–2.41, P < 0.001). In conclusion, the BIM deletion polymorphism was associated with poor response in NSCLC patients who received EGFR-TKIs treatment.     

Spectroscopic imaging of D-2-hydroxyglutarate and other metabolites in pre-surgical patients with IDH-mutant lower-grade gliomas

Journal of Neuro-Oncology - Prognostically favorable IDH-mutant gliomas are known to produce oncometabolite D-2-hydroxyglutarate (2HG). In this study, we investigated metabolite-based features of...     

Prognostic awareness and communication of prognostic information in malignant glioma: a systematic review

Malignant glioma (MG) is a devastating neurological disease with a uniformly poor prognosis and a clinical course characterized by progressive functional and cognitive impairment. A small body of literature addresses patients’ and caregivers’ prognostic awareness (PA), or understanding of prognosis in patients with cancer. Studies that examine PA and desire for prognostic information among patients with MG are limited. We sought to review the existing literature on PA and communication of prognostic information to patients with MG. Fourteen studies examining PA or experience and preferences regarding communication of prognostic information were included. The definition and measurement of PA across studies varied, and the prevalence of accurate PA ranged from 25 to 100 % of participants. There is likely a subset of patients who do not desire accurate prognostic information, although the patient and disease characteristics that predict this preference are currently unknown. This review suggests that patients with MG desire prognostic information communicated in a manner that preserves hope. Systematic investigation to define communication needs for prognostic information in the unique clinical setting of MG is needed.     

The prognostic significance of perineural invasion in prostatic cancer biopsies: a systematic review

Men with clinically localized prostate cancer are faced with a wide range of treatment options, and only Gleason grading is universally used as a histopathological prognostic factor for this disease. The significance of perineural invasion in diagnostic biopsies is controversial. Opinion about whether or not it should influence treatment decisions is currently almost equally divided. To address this, the authors performed a systematic review of studies that examine the association between perineural invasion and prostate cancer recurrence. MEDLINE, Embase, and the Web of Knowledge were searched from January 1990 to December 2005. Outcomes analyzed were the development of biochemical or clinical recurrence. Twenty-one articles on the association of perineural invasion in biopsies and prostate cancer recurrence after radical prostatectomy (n = 10) or radiotherapy (n = 11) were found but none on its significance in the context of watchful waiting. Structured data extraction was performed to allow comparisons between articles and to identify sources of heterogeneity to explain discrepancies in results. The considerable variation in study design, execution, and reporting precluded meta-analysis and quantitative risk estimation, but the weight of evidence suggested that perineural invasion in biopsies was a significant prognostic indicator, particularly in specific patient groups defined by presenting serum prostate-specific antigen levels and biopsy Gleason scores. Immediate treatment rather than watchful waiting may be more appropriate for patients with localized prostatic cancer and perineural invasion. However, the data are limited, and well-designed studies that use predefined stringent protocols are required to provide robust estimates of risk to aid in treatment planning.     

The prognostic value of CDKN2A hypermethylation in colorectal cancer: a meta-analysis

Background:

The prognostic value of CDKN2A promoter hypermethylation in colorectal cancer remains controversial. We systematically reviewed the evidence for assessment of CDKN2A methylation in colorectal cancer to elucidate this issue.

Methods:

Pubmed, Embase and ISI web of knowledge were searched to identify eligible studies to evaluate the association of CDKN2A hypermethylation and overall survival and clinicopathological features of colorectal cancer patients. Combined hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were pooled using a random-effects model.

Results:

A total of 11 studies encompassing 3440 patients were included in the meta-analysis. CDKN2A hypermethylation had an unfavourable impact on OS of patients with colorectal cancer (HR 1.65, 95% CI 1.29–2.11). Subgroup analysis indicated that CDKN2A hypermethylation was significantly correlated with OS in Europe (HR 1.49; 95% CI 1.28–1.74) and Asia (HR 3.30; 95% CI 1.68–6.46). Furthermore, there was a significant association between CDKN2A hypermethylation and lymphovascular invasion (OR 1.68, 95% CI 1.15–2.47), lymph node metastasis (OR 1.68, 95% CI 1.09–2.59) and proximal tumour location (OR 2.09, 95% CI 1.34–3.26) of colorectal cancer.

Conclusion:

This meta-analysis indicated that CDKN2A hypermethylation might be a predictive factor for unfavourable prognosis of colorectal cancer patients.     

癌性胸水p16基因纯合性缺失检测的临床意义

研究癌性胸水Ｐ１６基因纯合性缺失检测的临床意义。方法：应用ＰＣＲ技术检测胸水Ｐ１６基因第一、二外显子纯合性缺失，并结合胸水脱落细胞学检测分析其在临床诊断中的意义。结果表明所检３１例肺癌所致癌性胸水标本中均无出现Ｐ１６基因第一外显子纯合性缺失，１２例有Ｐ１６基因第二外显子纯合性缺失，阳性率为３８．７１％。     

Detection of Homozygous Deletions and Mutations in the CDKN2A Gene in Hydatidiform Moles

OBJECTIVE To investigate homozygous deletions and mutations in the CDKN2A gene(p16 INK4a and p14 ARF gene)in hydatidiform moles. METHODS A total of 38 hydatidiform mole samples and 30 villi samples were examined for homozygous deletions in the CDKN2A gene by PCR and for mutations by DHPLC. RESULTS i)Among 38 hydatidiform mole samples, homozygous deletions in the p16 INK4a exon 1 were identified in 5 cases(13.2%),while no homozygous deletions were found in the p16I NK4aexon 1 of 30 early-pregnancy samples.The rates of those deletions in hydatidiform compared to early-pregnancy villi samples was statistically significant(P=0.036).ii)No homozygous deletions in the p14 ARF exon 1 or p16 INK4a exon 2 were found in any of the hydatidiform moles or early-preganancy samples.iii) In all hydatidiform moles and early-pregnancy villi samples,no mutations were detected by DHPLC. CONCLUSION We suggest there may be a close correlation between homozygous deletions in the CDKN2A gene and occurrence of hydatidiform moles variation in the CDKN2A gene is mainly caused by homozygous deletions,while mutations may be not a major cause.     

Survivin and EPR-1 expression in acute leukemias: prognostic significance and review of the literature

The aim of this study is to detect the biologic and/or prognostic significance of survivin (S) and effector protease receptor 1: EPR-1 (E) expression in acute leukemias (34 ALL and 40 AML) by using RT-PCR. S and E expressions were found in 83.8 and 20.3% of the cases, respectively. S was detected in 90%, 76.5% and E was detected in 17.5%, 23.5% of the cases with AML and ALL, respectively. There was a significant correlation between S and E (r=0.30 p=0.01). Mortality rate was higher in E(-) cases than E(+) cases (83.1 % versus 66.7%) (p=0.04). The median DFS and OS rates were shorter in S(+) and E(-) cases. In subgroup analysis, there was not a significant difference for OS between S(-) and S(+) cases and E(-) and E(+) cases in ALL group. The median OS rate was significantly longer in S(-) cases than S(+) cases, and longer in E(+) cases than E(-) in AML groups (p=0.04, 0.001, respectively). OS and DFS rates were longest in S(-) E(+) cases and shortest in S(+) E(-) cases (p=0.04 and 0.03, respectively). In multivariate analyses EPR1 negativity was found to be an independent poor risk factor for survival (OR: 2.4, p=0.02). In conclusion S expression is a bad prognostic indicator in cases with acute leukemia especially in AML. S negativity and E positivity show good clinical outcome in acute leukemias. E expression is important due to its property of the possible natural anti-sense of the S.     

Glucocorticoids promote a glioma stem cell‐like phenotype and resistance to chemotherapy in human glioblastoma primary cells: Biological and prognostic significance

Glioma stem cells (GSCs) are glioblastoma (GBM) cells that are resistant to therapy and can give rise to recurrent tumors. The identification of patient‐related factors that support GSCs is thus necessary to design effective therapies for GBM patients. Glucocorticoids (GCs) are used to treat GBM‐associated edema. However, glucocorticoids participate in the physiological response to psychosocial stress, which has been linked to poor cancer prognosis. This raises concern that glucocorticoids affect the tumor and GSCs. Here, we treated primary human GBM cells with dexamethasone and evaluated GC‐driven changes in cell morphology, proliferation, migration, gene expression, secretory activity and growth as neurospheres. Dexamethasone treatment of GBM cells appeared to promote the development of a GSC‐like phenotype and conferred resistance to physiological stress and chemotherapy. We also analyzed a potential correlation between GC treatment and tumor recurrence after surgical excision in a population‐based consecutive cohort of 48 GBM patients, adjusted for differences in known prognostic factors concerning baseline and treatment characteristics. In this cohort, we found a negative correlation between GC intake and progression‐free survival, regardless of the MGMT methylation status. In conclusion, our findings raise concern that treatment of GBM with GCs may compromise the efficacy of chemotherapy and may support a GSC population, which could contribute to tumor recurrence and the poor prognosis of the disease.     

MDM2/MDM4 amplification and CDKN2A deletion in metastatic melanoma and glioblastoma multiforme may have implications for targeted therapeutics and immunotherapy

Metastatic melanoma has a five-year survival of ~10%, with a paucity of biomarkers predicting metastasis to specific anatomic sites or targeted therapies for metastases. We analyzed 1015 primary and 358 metastatic melanomas and found metastatic disease is enriched for MDM2 and MDM4 amplifications compared to primary disease, and amplifications are associated with lower overall survival. MDM2/4 amplifications are associated with a higher rate of metastasis to the brain and liver. Two negative regulators of p53, USP7 and PPM1D, are also altered in metastatic melanoma compared to primary disease. These findings suggest that patients with metastatic melanoma have a dysregulated TP53 pathway compared to primary disease. We propose that patients with metastatic melanoma and wild-type TP53 may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors. Patients with MDM2/4 amplification display deep deletions in CDKN2A, alterations also associated with a higher rate of metastasis to the brain. Patients with a CDKN2A deletion have a higher rate of alterations in TTN, MUC16, LRP1B, and NF1, alterations previously associated with favorable response to immune-checkpoint inhibitors in melanoma. We propose CDKN2A alteration as a potential biomarker to predict response to immunotherapy in melanoma. We found that GBM displays the highest rate of MDM4 amplifications (9.63%) and CDKN2A deletions (54.39%) across all cancer types. In 592 GBM samples we found that 8.45% display MDM2 amplification. We suggest that patients with melanoma or GBM and amplifications in MDM2/4 and CDKN2A alterations may benefit from combinations of targeted inhibitors of MDM2/4 and CDK4/6, as well as immunotherapy.