High-grade Malignant Gliomas Research Articles

Abstract 4390: SVV-001 prolongs animal survival in PDOX adult GBM models

Abstract Background: Glioblastoma (GBM) is the most malignant and aggressive brain tumor, and survival of patients affected by GBM has remained virtually unchanged over numerous years. GBM is only minimally responsive to aggressive standard therapies including radical surgery and concurrent chemo-radiation treatment with temozolomide (TMZ). Seneca Valley virus (SVV-001) is a non-pathogenic oncolytic virus that can be systemically administered and can pass through the blood-brain barrier. In this study, we developed a new panel of patient derived orthotopic xenograft (PDOX) models to examine the therapeutic efficacy of SVV-001 combined with irradiation. In addition, we explored the mechanism of tumor cell infection with SVV-001 in malignant gliomas. Material and Methods: Surgical GBM tumor samples were obtained from 17 patients and directly implanted into the right cerebrum of NOD/SCID mice (1×105 cells suspended in 2 uL growth medium). Once tumor formation was confirmed, we performed H&E staining and IHC to determine the pathologic characteristics of the PDOX models over serial in vivo passages and compared with the matched patient tumors. In vitro antitumor activities of SVV-001 were examined in primary cultures, pre-formed neurospheres, and monolayer cells derived from PDOX models. In vivo therapeutic efficacy was examined by single I.V. injection of SVV-001 alone or administered in combination with radiation treatment of pre-formed xenograft tumors in permissive models. Results: 8 out from 17 samples had confirmed tumor formation in mouse brains; 4 of these samples have since been serially sub-transplanted for a total of 5 generations, while 4 intracerebral xenografts are in generation 2. The tumorigenicity of 8 additional samples is pending. These xenograft models precisely replicated histopathologic characteristics of their parental human tumors. SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, pre-formed neurospheres, and monolayer glioma cells derived from adult glioma xenograft models in vitro. A single I.V. injection of SVV-001 (1 ×1011 viral particles/kg) administered immediately after radiation or 1 week after radiation led to the infection of orthotopic xenografts without harming normal mouse brain cells and resulted in significantly prolonged survival in permissive mouse models. Additionally, SVV-001 injected immediately after radiation significantly improved the overall survival of animals compared to administration of the virus 1 week after radiation, indicating that dose timing was crucial for full efficacy of the combinatory therapy. Conclusion: Our results demonstrated that SVV-001 possesses potent anti-tumor activity against adult malignant high-grade gliomas. Because this study was performed in a panel of patient tumor-derived orthotopic xenograft models, it provides a pre-clinical rationale that supports the consideration of SVV-001 for clinical trials against adult gliomas. Citation Format: Huiyuan Zhang, Lin Qi, Yuchen Du, Mari Kogiso, Frank K. Braun, Sibo Zhao, Holly Lindsay, Nabil Ahmed, Akash J. Patel, Patricia A. Baxter, Jack M. Su, Xiao-nan Li. SVV-001 prolongs animal survival in PDOX adult GBM models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4390.

Antitumor Activity of Rat Mesenchymal Stem Cells during Direct or Indirect Co-Culturing with C6 Glioma Cells.

The tumor-suppressive effect of rat mesenchymal stem cells against low-differentiated rat C6 glioma cells during their direct and indirect co-culturing and during culturing of C6 glioma cells in the medium conditioned by mesenchymal stem cells was studied in an in vitro experiment. The most pronounced antitumor activity of mesenchymal stem cells was observed during direct co-culturing with C6 glioma cells. The number of live C6 glioma cells during indirect co-culturing and during culturing in conditioned medium was slightly higher than during direct co-culturing, but significantly differed from the control (C6 glioma cells cultured in medium conditioned by C6 glioma cells). The cytotoxic effect of medium conditioned by mesenchymal stem cells was not related to medium depletion by glioma cells during their growth. The medium conditioned by other "non-stem" cells (rat astrocytes and fibroblasts) produced no tumor-suppressive effect. Rat mesenchymal stem cells, similar to rat C6 glioma cells express connexin 43, the main astroglial gap junction protein. During co-culturing, mesenchymal stem cells and glioma C6 cells formed functionally active gap junctions. Gap junction blockade with connexon inhibitor carbenoxolone attenuated the antitumor effect observed during direct co-culturing of C6 glioma cells and mesenchymal stem cells to the level produced by conditioned medium. Cell-cell signaling mediated by gap junctions can be a mechanism of the tumor-suppressive effect of mesenchymal stem cells against C6 glioma cells. This phenomenon can be used for the development of new methods of cell therapy for high-grade malignant gliomas.

Bevacizumab plus irinotecan in patients with recurrent high grade malignant gliomas.

e13057 Background: Recurrent high grade malignant gliomas (MGs) have a short survival. Initial standard therapy is based on surgery followed by concurrent radiotherapy with Temozolomide (TMZ) and s...

Essential competencies in palliative medicine for neuro-oncologists.

Palliative care is an approach to practicing medicine that addresses symptom management, alleviation of pain, assessment of psychosocial and spiritual distress or suffering, and practical support for patients and their caregivers with a goal of improving quality of life for patients with serious and life-threatening illnesses. Although palliative care has gained acceptance as an important part of comprehensive cancer care at the end of life, early integration of palliative care is less common. Patients with high-grade malignant gliomas have an invariably poor prognosis and high morbidity. With short survival times and complex neurological and systemic symptoms, these patients require palliative care from the time of diagnosis. In this review, we highlight the palliative care needs of neuro-oncology patients at diagnosis, during treatment, and at the end of life. We identify some of the barriers to incorporation of palliative care in standard neuro-oncology practice and equate competency in neuro-oncology with competency in the basic tenets of palliative medicine.

CDKN2A (p16) mRNA decreased expression is a marker of poor prognosis in malignant high-grade glioma.

Human high-grade glioma is heterogeneous in nature based on pathological and genetic profiling. Various tumour suppressor gene alterations are considered as prognostic markers in high-grade glioma. Gene expression of CDKN2A (p16) is used in various cancers as a prognostic biomarker along with methylation and deletion status of this gene. Expression levels of p16 mRNA were not studied as a biomarker in gliomas before. In this study, we have performed mRNA quantification analysis on 48 high-grade glioma tissues and checked for a possible prognostic role. The decreased expression of p16 mRNA in majority of the tumour tissues (57.1 %) was observed when compared to control tissues (P = 0.02). mRNA expression level was correlated with clinical variables also. p16 deletion status and BMI1 mRNA expression were also considered for comparison. p16 mRNA was negatively correlated with the BMI1 mRNA (P = <0.0001) but not with p16 deletion. p16 mRNA expression, midline shift in MRI and tumour type were able to predict patient survival in overall survival (OS) and progression-free survival (PFS). p16 mRNA could independently predict prognosis of OS (P = 0.0146) and PFS (P = 0.0305) in multivariate analysis. We have shown that p16 mRNA expression can act as an independent prognostic biomarker in high-grade glioma.

Predicting distress among people who care for patients living longer with high-grade malignant glioma.

Caregivers of patients living longer with high-grade malignant glioma (HGG) have the unique challenge of caring for a person who may have cognitive impairment, along with cancer-related issues over a prolonged period of time. This study aims to detail the psychosocial profile of long-term caregivers, to describe their perceptions of the patient's quality of life and to examine predictors of their psychological distress. Sixty-nine caregivers (48%) of eligible patients with HGG surviving over 2 years were recruited from two Australian metropolitan tertiary hospitals. Caregivers completed cross-sectional measures of psychological distress (GHQ-12), caregiver impact (FACQ-PC) and patient functional well-being (FACT-Br TOI). Correlational analyses identified factors related to caregiver psychological distress. Those of significance (p ≤ .01) were examined using multiple regression models to determine their predictive value. Caregivers were mostly female (73%), spouses (67%), cohabiting (78%) and were caring for patients surviving a median of 5.9 years since diagnosis. Whilst caregivers overall reported minimal psychological distress, 28% endorsed moderate to severe psychological distress, warranting clinical attention. Caregiver strain and low patient functional well-being both significantly predicted caregiver psychological distress (adjusted R(2) = .35, F(4, 60) = 17.7, p < .001), accounting for a moderate amount (35%) of variance. Other typical factors such as duration of caregiving, performance status, symptom burden and disease or demographic related factors were not predictive. Psychological distress affects a significant proportion of caregivers of patients living longer with HGG. The presence of caregiver strain and low patient functional well-being are the most important predictors of psychological distress among this cohort of caregivers.

HG-05 * DAAM2 PROMOTES TUMOR PROLIFERATION AND MIGRATION IN GLIOBLASTOMA

Glioblastoma multiforme (GBM) is one of the most common and aggressively malignant high-grade gliomas in humans. GBM tumors as are comprised of astrocytes and oligodendrocytes. Genes involved in the development of these glial cells have been linked to GBM tumorigenesis. Considering tumorigenesis is currently viewed as a convergence of genetic mutation and developmental context, we want to understand how the mechanisms which govern glial cell fate decisions contribute to GBM formation. The Wnt signaling pathway, for example, has well defined functions in neural progenitor self-renewal during development. This function is dysregulated in several cancers, yet surprisingly poorly defined in GBM. Given our finding that Daam2 plays a key role in Wnt signaling in the developing and CNS, we hypothesize that Daam2 is a key component of the Wnt signaling pathway which is dis-regulated in GBM. Indeed, we found that Daam2 is highly expressed in human GBM samples. Subsequent analysis of Daam2 function in GBM reveals that it promotes tumor proliferation and migration both in vitro and in vivo. The way we approached gain and loss of function in vivo study is to use In Utero Electroporation (IUE) technology to target astro-glial lineages with oncogenes. The attributes of this model are rapid and efficient generation of GBM after three weeks. Currently, I am working to precisely define Daam2 molecular mechanism in tumor. It shows that Daam2 potentiates canonical Wnt signaling in GBM tumor cell lines. Moreover, we surprisingly find that Daam2 not only functions through Wnt signaling pathway in GBM, but also interacts with PI3K. These studies represent the first characterization of Daam2/Wnt signaling/ PI3K function in GBM.

Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis.

Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.

ME-19 * ANALYSIS OF TREG RECRUITMENT AND FOXP3 EXPRESSION IN GLIOMAS REGARDING THE INTRAOPERATIVE FLUORESCENCE OF 5-ALA

Not only are regulatory T cells (Tregs) an essential component of the immune system in maintaining immunologic self-tolerance but they are also involved in the suppression of anti-tumor immune responses. The transcription factor forkhead box P3 (FOXP3) is widely used as a marker for the identification of Tregs being essential for the functionality. Oral 5 aminolevulinic acid (5-ALA) is used to assist surgical resection of high-grade gliomas, being known as an indicator of malignancy as it is able to pass the blood brain barrier in high-grade gliomas. Gaining more knowledge regarding the pathogenesis of gliomas, the tumor microenvironment came to the fore. In this study, patterns of Treg recruitment and FOXP3 expression in the microenvironment of gliomas were characterized, regarding the fluorescence of 5-ALA. Glioma tissue positive and negative for intraoperative fluorescence of 5-ALA was analyzed and compared. Tregs present in the tumor microenvironment were detected by double-immunohistochemistry for FOXP3 and the glioma marker, anti- glial fibrillary acidic protein (GFAP). FOXP3 mRNA expression was examined, using quantitative real-time-PCR. Tregs were found in the tumor microenvironment as well as within tumor cell islets, and FOXP3 mRNA expression in the tumors was significantly higher than in normal brain. Intriguingly, single FOXP3+ cells exhibited morphologic characteristics of glioma cells. 5-ALA positive tumor tissue showed a higher accumulation of Tregs than 5-ALA negative tissue. Gliomas recruit Tregs into their microenvironment, presumably in order to suppress immunosurveillance, thus avoiding destruction by the immune system. Endogenous FOXP3 expression in glioma cells might present a novel mechanism of immune escape. Our study showed differences between the amount of Treg and FOPX3 expression in 5-ALA positive and negative glioma tissue indicating that Tregs are more present in high-grade malignant gliomas. These findings suggest FOXP3 and Tregs as a possible therapeutic target in the therapy of gliomas.

CN-06 * IS HYPOPITUITARISM CLINICALLY RELEVANT IN GLIOMA PATIENTS? - A CROSS-SELECTIONAL TRIAL IN PATIENTS WITH HIGH-GRADE GLIOMAS

BACKGROUND: The outcome of patients with malignant high-grade glioma (HGG) has improved significantly during the last decade. In most patients the radiation field includes parts of the hypothalamus and/or the pituitary gland, which may cause a complex pattern of neuroendocrine dysfunction. The objective to this cross-sectional study was to evaluate the prevalence of secondary and tertiary hypothyroidism in patients following standard therapy of HGG. METHODS: Serum concentrations of pituitary and peripheral thyroid and sexual hormones were measured in 258 subjects (122 female, 136 male) with HGG. All patients had been treated with standard radio-chemotherapy (radiation up to 60 Gy, followed by adjuvant chemotherapy with temozolomide) up to ten years before testing. RESULTS: TSH was reduced in 22% and increased in 18% of all cases (n = 258). Circulating fT4 and fT3 levels were lowered in 5% and 20%, but increased in 10% and 3%, respectively. With regards to the sexual hormones, we observed an interesting hormonal profile in men (n = 123). Pituitary hormones LH, FSH and prolactin were increased in 64%, 62% and 47% of all men. However, circulating testosterone levels were decreased in 40% of men ≤ 50 years and 16% of men > 50 years. In contrast, LH and FSH concentrations were below the lower reference limit in 75% of women > 50 years, but only in 6% of women ≤ 50 years. Serum progesterone and estrogen levels were lowered in 39% and 36% of women ≤ 50 years and in 43% and 0% of women > 50 years. Of note, 78% of women ≤ 50 years and 78% of women > 50 years featured increased circulating testosterone levels. CONCLUSIONS: Standard treatment for HGG results in multiple changes of the pituitary-endocrine axis. Expecially the finding on increased testosterone concentrations in women is striking and warrants further investigation.

Abstract 1402: Regulation of Id2 In the proliferation of glioma-initiating neural progenitor cells

Abstract There are more than 14,000 new cases of malignant high grade glioma diagnosed each year in the US, and although surgical resection, radiation, and cytotoxic therapies are available, these current treatment methods are not curative. Inhibitor of DNA Binding 2 (Id2), a helix-loop-helix (HLH) protein, functions as a dominant negative inhibitor of basic helix-loop-helix (bHLH) transcription factors and is highly expressed in glioma. Recent data from our laboratory defines a critical role for Id2 in the pathogenesis of a subset of glioma known as proneural glioma. Id2 protein function has been characterized in neural progenitor cells (NPCs) where it acts to suppress differentiation and enhance cell cycle progression. These are two key characteristics that are shared with glioma-derived stem cells. We have identified three phosphorylation sites on Id2 in proliferating NPCs using mass spectrometry, and prepared altered Id2 molecules that cannot be phosphorylated at each of these sites. Id2-/- NPCs expressing WT and phosphorylation-site-ablated Id2 have been prepared to examine the role of Id2 phosphorylation in mediating its interactions with binding partners and in modulating the rate of proteasome-dependent degradation. We found an increased level of Id2 in NPCs expressing a mutant form of Id2 that cannot by phosphorylated when compared with NPCs expressing WT Id2. Moreover, the level of WT Id2 protein decreases when NPCs exit the cell cycle; however, unphosphorylated Id2 resists this degradation and exhibits a longer half-life. Stable isotope labeling by amino acids in cell culture (SILAC) experiments revealed that unphosphorylated Id2 molecules bind significantly less than WT Id2 to several anaphase promoting complex (APC) subunits. These findings suggested a possible mechanism for phosphorylation-dependent proteasome-mediated degradation of Id2 in NPCs. Understanding the effect of Id2 phosphorylation in modulating steady state levels of this important protein will inform future studies designed to identify pathways of interest in the transformation of NPCs and the malignant progression of NPC-initiated glioma. This work was supported in part by the Theodora B. Betz Foundation. Citation Format: Jaclyn Sullivan, Matthew Havrda, Brenton Paolella, Arminja Kettenbach, Scott Gerber, Mark A. Israel. Regulation of Id2 In the proliferation of glioma-initiating neural progenitor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1402. doi:10.1158/1538-7445.AM2014-1402

Knockdown of Rho-associated protein kinase 1 suppresses proliferation and invasion of glioma cells.

Rho-associated protein kinase 1 (ROCK1), a serine/threonine protein kinase, affects cell invasion and migration by changing the status of the cytoskeleton. In recent years, ROCK1 was found to be overexpressed in a variety of tumors. However, the information of ROCK1 in glioma still remains elusive. In our study, the expression of ROCK1 in glioma tissues was examined by real-time PCR and the relationship between ROCK1 expression and clinical characteristics of patients with glioma was also analyzed. With the inhibition of ROCK1 expression by RNAi, the effects of ROCK1 on biological behaviors of glioma cells including cell viability, cell cycle, and cell invasion were probed in the U251 cell line by methyl thiazolyl tetrazolium (MTT) assay, flow cytometer analysis, and Transwell invasion experiment. In addition, the effects of ROCK1 on the regulation of Ki67, cyclin D1, matrix metalloproteinases 9 (MMP9), and E-cadherin were also investigated. The results indicated that ROCK1 messenger RNA (mRNA) was increased significantly compared to that in the adjacent normal tissue (P < 0.05) and the expression level of ROCK1 mRNA in high-grade malignant glioma tissue was significantly higher than that in low-grade malignant glioma tissue (P < 0.05). MTT assay and flow cytometer analysis revealed that the cell viability and cell proliferation in the ROCK1 small interfering RNA (siRNA) transfection group were markedly lower than those in the blank or negative control group (P < 0.05), and no obvious differences were found between the blank group and negative control group. The Transwell invasion experiments showed that the invasive ability of U251 cells in the ROCK1 siRNA transfection group was obviously lower than that in the blank or negative control group (P < 0.05), and there were no visible differences between the blank group and negative control group. Western blot demonstrated that the protein levels of Ki67, cyclin D1, and MMP9 in the ROCK1 siRNA transfection group were distinctly lower than those in the blank or negative control group (P < 0.05) and that the protein level of E-cadherin displayed an opposite variation (P < 0.05). In summary, the expressions of ROCK1 in glioma tissue were visibly upregulated and the increase of ROCK1 had a positive correlation with the malignant grade of glioma. The results implied that the proliferation and metastasis of the glioma cell could be inhibited by suppressing the expression of ROCK1, and our findings would provide a new target for intervention and treatment of glioma.

Característica clínica e topográfica do glioma maligno em adolescente – Influência do tratamento intranasal com álcool perílico

Resumo Objetivo: Analisar a influência da topografia da lesão tumoral na resposta ao tratamento intranasal com álcool perílico (POH) em jovens com glioma maligno recidivo. Método: Tendo como padrão a faixa etária de 0 a 19 anos, foram incluídos pacientes do sexo masculino (#153; #31) e feminino (#178) com glioma maligno em estágio terminal, recebendo terapia de suporte paliativa e administração intranasal diária de 440 mg de POH. Resultados: Cefaleia intensa, tontura, vômito, crise convulsiva, alteração de comportamento, fraqueza muscular, alteração visual e hemiplegia à direita foram os sintomas prevalentes antes da confirmação diagnóstica de glioma. Análise de imagem mostrou lesão tumoral nas regiões troncocerebral (#153), talamomesencefálica esquerda (#178) e frontotemporal e insular direita (#31). Paciente #178 não respondeu ao tratamento, evoluindo a óbito em três semanas, e paciente #31 permaneceu em tratamento com POH por aproximadamente 54 semanas. Apesar de nova recidiva, paciente #153 apresenta doença estável, sem qualquer evidência clínica de recorrência para mais de 200 semanas em tratamento exclusivo com álcool perílico por via intranasal. Conclusão: Pacientes adolescentes com glioma maligno recidivo apresentaram heterogeneidade de sintomas compatível com a região anatômica comprometida, indicando que a topografia da lesão tumoral foi um fator prognóstico de sobrevida, influenciando inclusive na resposta ao tratamento intranasal com o álcool perílico.

A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acute toxicity, and response was assessed via serial magnetic resonance imaging. Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival.

Highlights of This Issue

Recurrent malignant gliomas carry a poor prognosis, and targeted therapy is an area of active investigation. A noninvasive biomarker that accurately assesses the treatment response with prognostic value is critically needed. Schwarzenberg and colleagues examine the amino-acid-analogue L-3,4-dihydroxy-6-18F-fluorophenyl-alanine (18F-FDOPA) PET imaging in patients with recurrent high-grade malignant gliomas on antiangiogenic treatment with bevacizumab. This biomarker predicted treatment response successfully as early as 1 to 2 weeks after starting therapy and provided prognostic information. The results of the study can guide the selection of treatment for these patients by identifying responders from nonresponders at an early time after starting therapy.The identification of mutated tumor antigens, which have been found in many cases to represent the predominant targets of tumor-reactive T cells, remains a challenging and time-consuming process. In an attempt to streamline this process, Lu and colleagues developed a novel genetic strategy that involved the screening of tandem minigene libraries encoding nonsynonymous mutations identified by whole-exome sequencing. Use of this approach, which resulted in the identification of mutated antigens recognized by the two populations of melanoma-reactive T cells that were initially evaluated, may facilitate the development of new adoptive cell therapies that target mutated antigens.One of the immunotherapy approaches for cancer is the blocking of immunoinhibitory pair PD-1 and PD-L1 on the surface of lymphocytes and tumor cells. In a large panel of melanoma cell lines, Atefi and colleagues investigated the effect of targeted therapy drugs on expression of PD-L1 and provided indications that different mechanisms of resistance to the BRAF inhibitor vemurafenib may have differential effects on expression of PD-L1. Moreover, they provided evidences for combinatorial effects of targeted and immune therapy by indicating the paradoxical effect of vemurafenib on restoring activity of the MAPK pathway and cytokine production in PD-L1 exposed lymphocytes.The development of new drugs and the evolution of mutations that lead to treatment resistance both require longitudinal response assessment. Accurate assessment can decrease exposure to the toxicities of futile treatments and speed access to beneficial alternatives. Zhao and colleagues characterized variability in measuring tumor change on CT in patients with metastatic colorectal carcinoma. They found that computer-aided analysis produced total system variability of 11% for longest diameters, 19% for bidimensional measurements, and 22% for whole tumor volumes. Any changes exceeding these values are likely to be biologically meaningful and can serve as indications to refine patient management.

CURRENT APPROACHES TO CHEMORADIOTHERAPY FOR MALIGNANT GLIOMAS

High-grade malignant gliomas (WHO grade G III–IV) account for more than 50% of all primary brain tumors. Despite aggressive treatment, survival rates are still very low with a median reported survival of no more than 1.5 years.Radiation therapy is an integral part of the combined treatment, but often does not influence lethally on resistant tumor cells. Thereby, in recent decades there has been an active search for novel approaches to the treatment of malignant gliomas (chemotherapeutic drugs, biological modifiers, local hyperthermia). Experimental data showed that the effect of high temperatures has both a direct damaging effect on tumor cells and a sensitizing effect. Significant advantages are achieved when the complex treatment of different malignant tumorsincludes local hyperthermia. However data on the treatment of patients with primary and recurrent gliomas G III–IV using local hyperthermia are scarce.The literature review is given in the article provides an overview of the existing treatment methods for brain tumors.

Clinical presentation and patterns of care for short-term survivors of malignant glioma.

Palliative care provision for patients with high-grade malignant glioma is often under-utilised. Difficulties in prognostication and inter-patient variability in survival may limit timely referral. This study sought to (1) describe the clinical presentation of short-term survivors of malignant glioma (survival time <120 days); (2) map their hospital utilisation, including palliative and supportive care service use, and place of death; (3) identify factors which may be important to serve as a prompt for palliative care referral. A retrospective cohort study of incident malignant glioma cases between 2003-2009 surviving <120 days in Victoria, Australia was undertaken (n = 482). Cases were stratified according to the patient's survival status (dead vs. alive) at the end of the diagnosis admission, and at 120 days from diagnosis. Palliative care was received by 78 % of patients who died during the diagnosis admission. Only 12 % of patients who survived the admission and then deteriorated rapidly dying in the following 120 days were referred to palliative care in their hospital admission, suggesting an important clinical subgroup that may miss out on being linked into palliative care services. The strongest predictor of death during the diagnosis admission was the presence of cognitive or behavioural symptoms, which may be an important prompt for early palliative care referral.

Prognostic utility of gene therapy with herpes simplex virus thymidine kinase for patients with high-grade malignant gliomas: a systematic review and meta analysis.

The aim of this study was to assess the effectiveness of adding viral vector-mediated gene therapy with herpes simplex virus thymidine kinase (HSV-tk) to standard treatment, in comparison with standard treatment alone to treat patients with high-grade gliomas (HGGs). A literature search of the databases PubMed, Embase, the Cochrane Library, Web of Science, and Chinese biomedicine was performed to identify eligible studies. Three randomized controlled trials (involving a total of 532 patients) were included in this systematic review. A meta-analysis of included studies demonstrated a significant increase in median survival time (MST) in patients who were treated with HSV-tk gene therapy (mean deviation 0.59, 95% CI: 0.41-0.76, p < 0.0001). The results of pooled analysis for different patient groups show that overall survival (OS) for all HGG patients was improved by adding gene therapy [hazard ratio (HR) = 0.91, 95% CI: 0.74-1.13, p = 0.42], while a different result was seen for glioblastoma multiforme (GBM) patients (HR = 1.06, 95% CI: 0.80-1.41, p = 0.70). Furthermore, the combined results for tumor progression implied that standard therapy was superior to gene therapy [odds ratio (OR) = 1.31, p = 0.09]; yet differences in HR and OR between experimental groups and control groups had no statistical significance (p > 0.05). Based on the best available evidence, it appears that adding gene therapy with HSV-tk has some effect in treating HGG patients, especially with respect to MST. However, neither the pooled analysis of OS, nor the combined analysis of tumor progress indicates any significant advantage to adding gene therapy compared with standard treatment alone. More prospective studies are needed to draw solid conclusions about whether gene therapy has significant prognostic advantage.

Endovascular superselective treatment of brain tumors: a new endovascular era? A quick review

BackgroundIntra-arterial therapy for malignant brain tumors, especially high-grade gliomas, has been administered since the 1950s and 1960s when the structure of the blood–brain barrier was first described. However, only with...

The role of direct DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) in high grade malignant glioma

Background High-grade [WHO, 2007grade III-IV] gliomas are undifferentiated or anaplastic, are highly infiltrating and termed as malignant. The overall prognosis and survival rate is very low. Only few highly sensitive and specific biomarkers for Glioma have been identified, but are yet to be put for routine use due to challenges in their clinical validation for early disease detection, diagnosis and monitoring to improve long-term survival of patients. The inefficacy of currently available chemotherapeutic and radio-therapeutic agents largely depends on a number of resistance mechanisms among which DNA repair plays an important role. Hence bio-molecules involved in DNA repair mechanisms will be promising biomarkers. Current status in the validation of DNA repair genes include, studying the promoter methylation of the only direct DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). MGMT is epigenetically inactivated via hypermethylation of the 5′-CpG islands located in promoter region. It is associated with prediction of successful alkylating agent therapy with temozolomide in combination with radiotherapy and also longer overall survival in patients. The silenced MGMT gene possibly enhances radiation effects by inducing radiation-mediated double stranded DNA (dsDNA) breaks and suppression of dsDNA repair pathways after radiation exposure.