World Health Organization Grade III-IV Research Articles

Analysis of DWI in the classification of glioma pathology and its therapeutic application in clinical surgery: a case-control study.

BackgroundGlioma is a common primary craniocerebral malignant tumor, due to the lack of specificity of imaging examination and clinical manifestations, its diagnostic accuracy is relatively low, which may result in misdiagnosis and missed diagnosis. The apparent diffusion coefficient (ADC) in magnetic resonance diffusion weighted imaging (DWI) can reflect the histological characteristics of gliomas, which can be widely applied to classify gliomas and evaluate the extent of metastasis of glioma. The present study aimed to assess the clinical value of magnetic resonance DWI in the pathological grading of glioma and its therapeutic application in clinical surgery.MethodsThis article retrospectively analyzed the clinical data of 41 patients with glioma confirmed by surgical pathology results from January 1, 2019 to March 31, 2020 in the People’s Hospital of Gaozhou. Among them, 16 patients had low-grade gliomas [World Health Organization (WHO) grade I–II] and 25 patients had high-grade gliomas (WHO grade III–IV). They were subjected to conventional T1WI and T2WI plain scans, along with DWI and enhanced scans before surgery. The ADC values of the glioma parenchyma, the peritumoral edema area, the surrounding white matter, and the contralateral normal white matter were measured. We selected some tumor tissues for pathological analysis as well, and conducted pathological grading according to WHO grading standards.ResultsWe compared and evaluated the ADC values of the observed areas for low-grade gliomas and high-grade gliomas. The ADC values of low-grade gliomas in the tumor parenchyma, peritumoral edema, and white matter around the edema area were significantly lower than those of high-grade gliomas, and the differences were statistically significant (P<0.05). The difference in ADC values of normal white matter between the two groups of patients was not statistically significant (P=0.125).ConclusionsDWI has prognostic predictive value in the preoperative differential diagnosis and pathological classification of gliomas. This advanced technology can verify the extent of glioma infiltration in the surrounding brain tissue. It can help clinicians formulate a safer and more effective therapeutic strategy by providing accurate information on prognostic evaluation before the successful surgical intervention of gliomas.

A diagnostic tree for differentiation of adult pilocytic astrocytomas from high-grade gliomas

BackgroundTo develop a diagnostic tree analysis (DTA) model based on demographical information and conventional MRI for differential diagnosis of adult pilocytic astrocytomas (PAs) and high-grade gliomas (HGGs; World Health Organization grade III-IV). MethodsA total of 357 adult patients with pathologically confirmed PA (n = 65) and HGGs (n = 292) who underwent conventional MRI were included. The patients were randomly divided into training (n = 250) and validation (n = 107) datasets to assess the diagnostic performance of the DTA model. The DTA model was created using a classification and regression tree algorithm on the basis of demographical and MRI findings. ResultsIn the DTA model, tumor location (on cerebellum, brainstem, hypothalamus, optic nerve, or ventricle), cystic mass with mural nodule appearance, presence of infiltrative growth, and major axis (cutoff value, 2.9 cm) were significant predictors for differential diagnosis of adult PAs and HGGs. The AUC, accuracy, sensitivity, and specificity were 0.94 (95% confidence interval 0.86–1.00), 96.2%, 89.5%, and 97.7%, respectively, in the test set. The accuracy of the DTA model was significantly higher than the no-information rate in the test (96.2 % vs 85.0%, P < 0.001) set. ConclusionThe DTA model based on MRI findings may be useful for differential diagnosis of adult PA and HGGs.

VEGF levels in patients with glioma: a systematic review and meta-analysis.

Vascular endothelial growth factor (VEGF) has a crucial role in the angiogenesis of various tumors, including glioma. As the levels of VEGF would change in patients with glioma, we conducted the current systematic review and meta-analysis to more clearly determine the VEGF level alterations in different grades of glioma. PubMed and Scopus databases were sensitively searched for all the possible keywords addressing glioma and VEGF. Case-control and cohort studies on human subjects, which measured VEGF levels were eligible to be included in the study. Out of a total number of 3,612 studies, 22 studies were included and 12 studies entered the meta-analysis. This review revealed that serum levels of VEGF in glioma patients were 1.56pg/dL higher compared to healthy controls (P=0.05). Besides, immunohistochemistry (IHC) measurement of VEGF in surgical biopsies indicated significant difference in these two groups as well (P=0.02). Yet, there was not a significant difference between patients with low-grade gliomas (World Health Organization (WHO) grades I-II, LGG) and those with high-grade gliomas (WHO grades III-IV, HGG) (P=0.43). The results of this systematic review and meta-analysis demonstrate that VEGF levels would significantly increase in glioma, and therefore, could be potentially considered as a biomarker for this cancer.

Application Value of 3.0-T Multivoxel 1H-MR Spectroscopy in the Peritumoral Tissue of Brain Astrocytic Tumors.

This study aimed to explore metabolic features in the peritumoral tissue of different-rank brain astrocytic tumors using multivoxel proton magnetic resonance spectroscopy (1H-MRS) and to estimate its application value in the MRS quantitative ratio of brain astrocytic tumors. A total of 82 patients with brain astrocytic tumors, confirmed by postoperative pathological evaluation, were divided into low-grade astrocytic tumors [World Health Organization (WHO) grade I-II; 32 cases] and high-grade astrocytic tumors (WHO grade III-IV; 50 cases). The semi-quantitative and relative quantitative metabolite ratios of the parenchyma area, peritumoral tissue area, and normal area were measured. The P value was set as <0.05. The relative quantitative ratios of choline (Cho)/creatine (Cr) and Cho/N-acetyl aspartate (NAA) significantly differed in the peritumoral tissues of the high-grade astrocytic tumors and low-grade astrocytic tumors (P < 0.05), but NAA/Cr showed no significant difference. The changes in the metabolite ratio of the peritumoral tissue area in brain astrocytic tumors reflect the biological behavior of different tumors. They have a significant clinical value in classifying brain astrocytic tumors and indicating the scope of invasion.

Health status, health-related quality of life, and socioeconomic outcome in childhood brain tumor survivors: a German cohort study.

With rising numbers of childhood cancer survivors, somatic and socioeconomic outcome as well as health-related quality of life (QoL) gain increasing relevance. Based on the first nationwide German Survey on Life Situation, State of Health, and Quality of Life of Childhood Cancer Survivors, the VIVE survey, we report the outcome of survivors of childhood brain tumors localized in the posterior fossa. Two hundred seventy participants with a median follow-up period of 21.9 years completed a questionnaire on socioeconomic and somatic late effects as well as a standardized QoL questionnaire (European Organisation for Research and Treatment of Cancer QLQ-C30). Comparisons were performed between World Health Organization (WHO) grades I-II, WHO grades III-IV brain tumor survivors (BTS), and the general population adjusting for potential confounders. The socioeconomic and QoL results of WHO grades I-II BTS were largely comparable to the general population, while grades III-IV BTS were at higher risk for significantly worse outcomes. Of WHO grades III-IV BTS, 36.8% were still living with their parents or in assisted living facilities compared with 16.1% of grades I-II BTS and 7.8% of the age-adjusted general population. Of grades III-IV BTS, 60.8% achieved at least an intermediate school degree in comparison to 80.5% of grades I-II BTS and 75.6% of the general population. Grades III-IV BTS developed up to 2 times more somatic late effects than survivors of grades I-II tumors. Derived from a large and homogeneous cohort, these results stress the importance of an appropriate follow-up period focusing not only on physical aspects but encompassing the entire living situation to allow patient-tailored support.

Abnormal expression of circulating and tumor-infiltrating carcinoembryonic antigen-related cell adhesion molecule 1 in patients with glioma

Glioma, the most prevalent primary tumor of the central nervous system, is known to evade immune surveillance and escape immune attacks by inducing immunosuppression. The homophilic interactions of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) serve a critical function in immunoregulation. In the present study, the expression levels of CEACAM1 in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes (TILs) from patients with gliomas were assessed. Furthermore, associations between CEACAM1 expression and multiple clinicopathological characteristics in patients with gliomas were analyzed. The results of the present study suggested that the expression of CEACAM1 in circulating T cells was markedly increased in patients with gliomas compared with control subjects, and was further increased in TILs. Patients with high-grade gliomas [World Health Organization (WHO) grade III–IV] demonstrated a significantly increased expression of CEACAM1 on T cells compared with those with low-grade gliomas (WHO grade I–II). Furthermore, the expression of CEACAM1 on T cells was negatively correlated with the Karnofsky score and the plasma level of interferon-γ in patients with gliomas. Immunohistochemical analysis revealed that the expression levels of CEACAM1 in high-grade glioma tissues (WHO grade III–IV) were increased compared with the expression levels in the controls, and were associated with the expression of CEACAM1 in TILs. In summary, the results of the present study indicate that homophilic interactions of CEACAM1 may participate in the progression and development of gliomas through their negative regulatory effects on T cells. Thus, CEACAM1 may be a promising candidate for targeted glioma immunotherapy.

Impact of [18F]-fluoro-ethyl-tyrosine PET imaging on target definition for radiation therapy of high-grade glioma.

We sought to assess the impact of amino-acid (18)F-fluoro-ethyl-tyrosine (FET) positron emission tomography (PET) on the volumetric target definition for radiation therapy of high-grade glioma versus the current standard using MRI alone. Specifically, we investigated the influence of tumor grade, MR-defined tumor volume, and the extent of surgical resection on PET positivity. Fifty-four consecutive high-grade glioma patients (World Health Organization grades III-IV) with confirmed histology were scanned using FET-PET/CT and T1 and T2/fluid attenuated inversion recovery MRI. Gross tumor volume and clinical target volumes (CTVs) were defined in a blinded fashion based on MRI and subsequently PET, and volumetric analysis was performed. The extent of the surgical resection was reviewed using postoperative MRI. Overall, for ∼ 90% of the patients, the PET-positive volumes were encompassed by T1 MRI with contrast-defined tumor plus a 20-mm margin. The tumor volume defined by PET was larger for glioma grade IV (P < .001) and smaller for patients with more extensive surgical resection (P = .004). The margin required to be added to the MRI-defined tumor in order to fully encompass the FET-PET positive volume tended to be larger for grade IV tumors (P = .018). With an unchanged CTV margin and by including FET-PET for gross tumor volume definition, the CTV will increase moderately for most patients, and quite substantially for a minority of patients. Patients with grade IV glioma were found to be the primary candidates for PET-guided radiation therapy planning.

Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma.

α-(11)C-methyl-L-tryptophan (AMT) PET allows evaluation of brain serotonin synthesis and can also track upregulation of the immunosuppressive kynurenine pathway in tumor tissue. Increased AMT uptake is a hallmark of World Health Organization grade III-IV gliomas. Our recent study also suggested decreased frontal cortical AMT uptake in glioma patients contralateral to the tumor. The clinical significance of extratumoral tryptophan metabolism has not been established. In the present study, we investigated clinical correlates of tryptophan metabolic abnormalities in the nontumoral hemisphere of glioma patients. Standardized AMT uptake values (SUVs) and the uptake rate constant of AMT (K [mL/g/min], a measure proportional to serotonin synthesis in nontumoral gray matter) were quantified in the frontal and temporal cortex and thalamus in the nontumoral hemisphere in 77 AMT PET scans of 66 patients (41 men, 25 women; mean age ± SD, 55 ± 15 y) with grade III-IV gliomas. These AMT values were determined before treatment in 35 and after treatment in 42 patients and were correlated with clinical variables and survival. AMT uptake in the thalamus showed a moderate age-related increase before treatment (SUV, r = 0.39, P = 0.02) but decrease after treatment (K, r = -0.33, P = 0.057). Women had higher thalamic SUVs before treatment (P = 0.037) and higher thalamic (P = 0.013) and frontal cortical K values (P = 0.023) after treatment. In the posttreatment glioma group, high thalamic SUVs and high thalamocortical SUV ratios were associated with short survival in Cox regression analysis. The thalamocortical ratio remained strongly prognostic (P < 0.01) when clinical predictors, including age, glioma grade, and time since radiotherapy, were entered in the regression model. Long interval between radiotherapy and posttreatment AMT PET as well as high radiation dose affecting the thalamus were associated with lower contralateral thalamic or cortical AMT uptake values. These observations provide evidence for altered tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system. Low thalamic tryptophan uptake appears to be a strong, independent predictor of long survival in patients with previous glioma treatment.

Increased tryptophan uptake on PET has strong independent prognostic value in patients with a previously treated high-grade glioma

Previously, we demonstrated the high accuracy of alpha-[(11)C]methyl-L-tryptophan (AMT) PET for differentiating recurrent gliomas from radiation injury. The present study evaluated the prognostic value of increased AMT uptake in patients with previously treated high-grade glioma. AMT-PET was performed in 39 patients with suspected recurrence of World Health Organization grades III-IV glioma following surgical resection, radiation, and chemotherapy. Mean and maximum standardized uptake values (SUVs) and unidirectional AMT uptake (K) were measured in brain regions suspicious for tumor and compared with the contralateral cortex (ie, background). Optimal cutoff thresholds for 1-year survival prediction were determined for each AMT parameter and used for calculating the prognostic value of high (above threshold) versus low (below threshold) values for post-PET overall survival (OS). In univariate analyses, 1-year survival was strongly associated with 3 AMT parameters (SUVmax, SUVmean, and tumor-to-background K-ratio; odds ratios: 21.3-25.6; P ≤ .001) and with recent change in MRI contrast enhancement (odds ratio: 14.7; P = .02). Median OS was 876 days in the low- versus 177 days in the high-AMT groups (log-rank P < .001). In multivariate analyses, all 3 AMT parameters remained strong predictors of survival: high AMT values were associated with unfavorable 1-year survival (binary regression P ≤ .003) and shorter overall survival in the whole group (Cox regression hazard ratios: 5.3-10.0) and in patients with recent enhancement change on MRI as well (hazard ratios: 7.0-9.3; P ≤ .001). Increased AMT uptake on PET is highly prognostic for 1-year and overall survival, independent of MRI contrast enhancement and other prognostic factors in patients with a previously treated high-grade glioma.

Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI

Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97% of all relapses occurred in the brain and 3% were isolated to the spine. Relapse was identified in 226 (8%) brain and 48 (4%) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care.

MRI patterns of T1 enhancing radiation necrosis versus tumour recurrence in high‐grade gliomas

Despite the emergence of new imaging technologies, the differentiation of treatment-related changes from recurrent tumour in patients with high-grade gliomas remains a difficult challenge. We evaluated whether specific MRI (magnetic resonance imaging) T1 post-contrast enhancement patterns can help to distinguish between radiation necrosis and tumour recurrence. This study was approved by local institutional review board. Fifty-one patients with World Health Organization grade III-IV glioma underwent reoperation after prior chemoradiation. The percentage of radiation necrosis versus recurrent tumour in reoperation specimens was estimated by an experienced neuropathologist. Enhancement patterns on T1 post-contrast sequences from the MRIs obtained prior to reoperation were evaluated according to pathology. T1 contrast enhancement patterns correlating with recurrent tumour included focal solid nodules and solid uniform enhancement with distinct margins. Eighty-five per cent (17/20) of patients with ≥70% recurrent tumour at reoperation demonstrated one of these patterns on preoperative MRI. Enhancement patterns correlating with radiation necrosis included a hazy mesh-like diffuse enhancement and rim enhancement with feathery indistinct margins. Ninety-four per cent (17/18) of patients with ≥70% radiation necrosis demonstrated one of these two patterns. Thirteen cases had more mixed pathology (>30% of tumour/necrosis) and demonstrated patterns associated with recurrence and/or necrosis. Compared to MR spectroscopy performed in 10 patients, enhancement patterns on MRI were just as accurate in predicting pathologic diagnosis. Identifying distinct patterns of contrast enhancement on MRI may help to differentiate between radiation necrosis and tumour recurrence in high-grade gliomas.

TP53 mutations in astrocytic gliomas: an association with histological grade, TP53 codon 72 polymorphism and p53 expression

TP53 mutations and polymorphisms have been widely related to many cancers as long as these alterations may impair its capacity to induce cell cycle arrest, DNA repair mechanisms, and apoptosis. Although TP53 alterations have been studied in astrocytic tumors, there is a lack of analysis considering specific TP53 mutations and their associations with p53 immunostainning, polymorphisms and their significance among the histological grades. Thus, we analyzed TP53 alterations in exons 2-11, including the codon 72 polymorphism, using DNA sequencing in 96 astrocytic gliomas (18 grade I, 20 grade II, 14 grade III, and 44 grade IV). Also, immunohistochemistry was assessed to evaluate the p53 protein expression. In this study, we found that the higher histological grades were statistically associated with TP53 mutations. Some of these mutations, such as TP53 P98T and TP53 G244S, seemed to be a specific marker for the higher grades, and the TP53 E286K mutation appears to be a World Health Organization grade III-IV progression marker. Also, the TP53 P98T mutation, in exon 4, is very likely to be important on the stabilization of the p53 protein, leading to its immunopositivity and it is potentially associated with the TP53 72Pro/Pro genotype.

Radiotherapy-Associated Neutropenia and Thrombocytopenia: Analysis of Risk Factors and Development of a Predictive Model

AbstractRisk factors for unscheduled interruptions in radiotherapy courses completed between June 1989 and August 1995, lasting ≥2 days, and associated with World Health Organization grade III-IV neutropenia or thrombocytopenia were studied retrospectively. A group of controls was randomly selected. Potential risk factors for myelosuppression were analyzed using univariate and multivariate analyses. The most important risk factors for treatment interruption with thrombocytopenia were concurrent chemotherapy (odds ratio [OR], 45.5; P < .001), increasing percentage of marrow irradiated (OR, 4.1 for each 20%; P < .001), and brain metastases (OR, 7.3; P = .01). Other significant (P < .05) factors were leukemia/lymphoma, bone or bone marrow metastases, and prior chemotherapy. The most important risk factors for treatment interruptions with neutropenia were concurrent chemotherapy (OR, 42.1; P < .001) and increasing percentage of marrow irradiated (OR, 3.3 for each 20%; P < .001). Similarly, the most important risk factors for treatment interruptions with both thrombocytopenia and neutropenia were concurrent chemotherapy (OR, 48.6; P < .001) and increasing percentage of marrow irradiated (OR, 3.9 for each 20%; P < .001). Other significant (P < .05) factors in these groups were bone marrow or brain metastases and previous chemotherapy. These data were used to create a model, assigning patients to groups at high, intermediate, or low risk for treatment interruption with thrombocytopenia. High-risk patients may be candidates for clinical trials of a platelet growth factor.