The term malignant or high-grade glioma refers to tumors that are classified as:
● Grade 4 (glioblastoma multiforme)
Its annual incidence has risen over the last decades, particularly amongst elderly people. The actual standards of care allow for a 15-month median survival rate for WHO grade IV gliomas. As recurrence occurs in more than 85% of patients at the surgical margins, the initial resection extent is a cornerstone of disease control.
While there has been progress in understanding the molecular genetics of these tumors 4) , the cell type(s) of origin are still uncertain, and the molecular determinants of disease aggressiveness are not well understood. A better understanding of the cellular origin and molecular pathogenesis of these tumors may identify new targets for treatment of these neoplasms.
Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because HIF1A is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth.
Dissemination of high-grade gliomas (WHO grade IV) has been investigated poorly so far.
Usually, low grade gliomas show no increase in tumor rCBV, whereas high grade gliomas demonstrate high relative cerebral blood volume (rCBV) that in some cases even extends outside the contrast-enhancing portions of the tumor 5).
A 58-year-old male with slight left hemiparesis. The radiological evaluation with contrast administred magnetic resonance imaging (MRI) scan demonstrated a right temporo-parietal ring enhancing mass lesion surrounded by edema which was resembling a typical glioma.
The patient was operated on via a temporo-parietal craniotomy and an arteriovenous malformation surrounded by abnormal glial tissue was observed during the exposure. A nidus supplied by several branches arising from the middle cerebral artery (MCA) was obvious. The venous drainage of the malformation was to the superficial venous system. The observed arterial feeders and the draining vein were coagulated and the nidus was macroscopically totally excised. The frozen examination from surrounding glial tissue revealed a high grade glioma. The tumor was also macroscopically totally excised. Postoperatively, the cerebral angiogram demonstrated a right temporal arteriovenous malformation with a centrally excised nidus. The remaining major feeders involved the angular gyrus and the posterior temporal arteries. The venous drainage was to the straight and sigmoid sinuses.
The final histopathological examination of the specimen revealed an arteriovenous malformation surrounded by a high grade glioma.
The patient refused a second operation for total removal of the AVM. Postoperatively, he is doing well with improvement of his left hemiparesis 6).
The current neurosurgical goal for patients with malignant gliomas is maximal safe resection of the contrast-enhancing tumor. However, a complete resection of the contrast-enhancing tumor is achieved only in a minority of patients. One reason for this limitation is the difficulty in distinguishing viable tumor from normal adjacent brain during surgery at the tumor margin using conventional white-light microscopy. To overcome this limitation, 5 aminolevulinic acid fluorescence guided resection of high grade glioma has been introduced.
Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection.
Quantification of relative invasiveness assessed from routinely obtained pre-operative imaging provides a practical predictor of the benefit of gross total resection 7).
The primary obstacle in surgical treatment lies in differentiation between healthy and pathological tissue at the tumor margins, where current visualization methods reach their limits.
Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy 9).
The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles.
Despite advances in treatment, the median patient survival is 12 to 15 months 10).
Evidence have shown that a recombinant adenoviral vector expressing human wild-type p53, granulocyte-macrophage colony-stimulating factor (GM-CSF), and B7-1 genes (BB-102) may have antitumor effects in vitro. In this study, we investigated the effects of BB-102-based vaccine on glioma in vivo. An animal model using nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with human immune system was established. The mice were vaccinated with inactivated U251 glioma cells transduced with BB-102 or adenoviral vector expressing green fluorescence protein (Ad-GFP) as a control and followed by the challenge of live U251 glioma cells. Tumor growth and antitumor responses were measured. Data showed that mice vaccinated with BB-102 had significantly reduced local tumor growth compared to mice with Ad-GFP vaccination or the control group. Histopathological analysis displayed low tumor cell density and significant infiltration of human peripheral blood lymphocytes (HuPBLs) in the tumor tissues of mice transduced with BB-102. Immunohistochemical analysis showed that mutant p53 was not expressed in tumor tissues of mice with BB-102 vaccination, and the expression level of Ki67 was significantly lower in the tumor tissues of the BB-102 group than those in the Ad-GFP group or the control group. Further study demonstrated that mice with BB-102 vaccination had significantly increased total T cell numbers, total T cell proportion, CD4+ T cell proportion, and CD8+ T cell proportion in spleens, as well as higher value of IgG, IgA, and IgE in sera. These data suggest that the recombinant adenoviral vector expressing human wild-type p53, GM-CSF, and B7-1 genes could suppress glioma in NOD/SCID mice model and might be considered as a novel strategy for glioma therapy 11).
Preibisch et al. performed a study in 12 patients with high-grade glioma, where they directly compared the two currently most promising techniques, namely the MR-based relative oxygen extraction fraction (MR-rOEF) and the PET hypoxia marker H-1-(3-[18 F]-fluoro-2-hydroxypropyl)-2-nitroimidazole ([18 F]-FMISO). MR-rOEF was determined from separate measurements of T2 , T2 * and relative cerebral blood volume (rCBV) employing a multi-parametric approach for quantification of the blood-oxygenation-level-dependent (BOLD) effect. With respect to [18 F]-FMISO-PET, besides the commonly used late uptake between 120 and 130 min ([18 F]-FMISO120-130 min ), we also analyzed the hypoxia specific uptake rate [18 F]-FMISO-k3 , as obtained by pharmacokinetic modeling of dynamic uptake data. Since pharmacokinetic modeling of partially acquired dynamic [18 F]-FMISO data was sensitive to a low signal-to-noise-ratio, analysis was restricted to high-uptake tumor regions. Individual spatial analyses of deoxygenation and hypoxia-related parameter maps revealed that high MR-rOEF values clustered in (edematous) peritumoral tissue, while areas with high [18 F]-FMISO120-130 min concentrated in and around active tumor with disrupted blood-brain barrier, i.e. contrast enhancement in T1 -weighted MRI. Volume-of-interest-based correlations between MR-rOEF and [18 F]-FMISO120-130 min as well as [18 F]-FMISO-k3 , and voxel-wise analyses in individual patients, yielded limited correlations, supporting the notion that [18 F]-FMISO uptake, even after 2 h, might still be influenced by perfusion while [18 F]-FMISO-k3 was severely hampered by noise. According to these results, vascular deoxygenation, as measured by MR-rOEF, and severe tissue hypoxia, as measured by [18 F]-FMISO, show a poor spatial correspondence. Overall, the two methods appear to rather provide complementary than redundant information about high-grade glioma biology 12).
Data of 47 consecutive patients with HGG have been collected in our study (25 males, 22 females; mean age: 60.3 years, range: 27-86 years). Fluorescein (5 mg/kg of body weight) was injected intravenously right after the induction of general anesthesia. A YELLOW 560 filter was used on an OPMI Pentero 900 microscope (Carl Zeiss Meditec, Oberkochen, Germany) to complete a microsurgical tumor removal. Glioma resection and quality of life were evaluated preoperative and postoperatively.
Gross total resection (GTR) was achieved in 53.2% (n = 25) of patients. A subtotal resection (STR) (>95%) was achieved in 29.8% (n = 14), while a partial resection (PR) (<95%) was obtained in 17% (n = 8) of patients. Overall, in 83% (n = 39) of patients who underwent fluorescence-guided surgery the resection rate achieved was >95%. No adverse effects correlated to fluorescein have been recorded.
Fluorescein seems to be safe and effective in the resection of HGGs, allowing a high rate of gross total removal of contrast enhanced areas 13).
A retrospective study of 125 HGG patients used three different classification standards of age-groups (≤50 and >50years old, ≤60 and >60years old, ≤45 and 45-65 and ≥65years old) to evaluate the impact of age on prognosis. The primary end-point was overall survival (OS). The Kaplan Meier method was applied for univariate analysis and Cox proportional hazards model for multivariate analysis. Univariate analysis showed a significant correlation between OS and all three classification standards of age-groups as well as between OS and pathological grade, gender, location of glioma, and regular chemotherapy and radiotherapy treatment. Multivariate analysis showed that the only independent predictors of OS were classification standard of age-groups ≤50 and >50years old, pathological grade and regular chemotherapy. In summary, the most appropriate classification standard of age-groups as an independent prognostic factor was ≤50 and >50years old. Pathological grade and chemotherapy were also independent predictors of OS in post-operative HGG patients 14).
Malignant glioma, ie, anaplastic astrocytoma and glioblastoma, is the most common type of primary malignant brain tumor in the People's Republic of China, and is particularly aggressive.
The median survival of patients with newly diagnosed glioblastoma is only 12-14 months despite advanced therapeutic strategies.
Treatment of malignant glioma consists mainly of surgical resection followed by adjuvant radiation and chemotherapy. Temozolomide (TMZ), a second-generation oral alkylating agent, is playing an increasingly important role in the treatment of malignant glioma in Chinese patients. Since the publication of a study by Stupp et al in 2005, which used a protocol of conventional fractionated irradiation with concomitant TMZ followed by standard TMZ for six cycles, many clinical studies in the People's Republic of China have demonstrated that such a treatment strategy has significantly improved efficacy with limited side effects for newly diagnosed glioblastoma after surgery as compared with strategies that do not contain TMZ. However, as a relatively new agent, the history and development of TMZ for malignant glioma is not well documented in Chinese patients. Multicenter, randomized controlled trials including appropriately sized patient populations investigating multiple aspects of TMZ therapy and related combination therapies are warranted in patients with malignant glioma 15).
The Nationwide Inpatient Sample (NIS) database was queried from 2002 to 2011. All adult patients who underwent elective brain surgery for a malignant brain tumor were included. Surgical complications included wrong side surgery, retention of a foreign object, iatrogenic stroke, meningitis, hemorrhage/hematoma complicating a procedure, and neurological complications. A regression model was conducted to estimate the odds ratios (OR) with their 95% confidence intervals (95% CI) of in-hospital mortality for each surgical complication.
A total of 16,530 admissions were analyzed, with 601 (36.2 events per 1000 cases) surgical complications occurring in 567 patients. Over the examined 10-year period, the overall incidence of surgical complications did not change (P=0.061) except for iatrogenic strokes, which increased in incidence from 14.1 to 19.8 events per 1000 between 2002 and 2011 (P=0.023). Patients who developed a surgical complication had significantly longer lengths of stay, total hospital costs, and higher rates of other complications. Patients who experienced an iatrogenic stroke had a significantly increased risk of mortality (OR 9.6; 95% 6.3-14.8) and so were patients with a hemorrhage/hematoma (OR 3.3; 95% CI 1.6-6.6).
In this study of an administrative database, patients undergoing surgery for a malignant brain tumor who suffered from a surgical complication had significantly longer lengths of stay, total hospital charges, and complication rates. Having a surgical complication was also an independent risk factor for in-hospital mortality. Nonetheless, it is unclear whether all surgical complications were clinically relevant, and further research is encouraged 16).
Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown.
Zhou et al. document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas 17).