Multiforme Cases Research Articles

Unlocking the Glioblastoma Enigma: Exploring PD-L1 (Programmed Death-Ligand 1) and IDH1 (Isocitrate Dehydrogenase-1) Expression and Their Immunotherapeutic Implications.

Objective In order to establish a connection between programmed death-ligand 1 (PD-L1) expression and glioma grades as well as the presence of IDH1 mutations, it is necessary to investigate the expression of PD-L1 and isocitrate dehydrogenase-1 (IDH1) in glioma patients andassess their potential as predictive markers for glioblastoma multiforme (GBM) immunotherapy. We analyzed the frequency of PD-L1 expression in glioma samples. Methodology In this two-year retrospective study, 45 glioma cases of varying grades (grades 2 to 4) were examined at a tertiary care hospital. Tumor samples that were formalin-fixed, paraffin-embedded (FFPE) were obtained from the pathology archives of the hospital. According to the WHO Classification of Central Nervous System Tumors, 5th edition, tumor grading and histopathological subtyping were carried out. PD-L1 antibody (clone 28-8) and IDH1 (R132H, clone QM002, Quartett Immunodiagnostika, 1:100 dilution) markers were used for immunohistochemistry (IHC). The sections underwent deparaffinization, rehydration, and antigen retrieval using Leica bond III staining platform. Based on the tumor proportion score (TPS), which is the proportion of viable tumor cells with membranous staining, PD-L1 expression was assessed. The literature's standardized cut-off values were used to determine positive expression. Staining intensity and tumor cell location were used to determine the status of IDH1 mutations. Age, sex, and tumor location were among the clinical and demographic information gathered about the patient. The association between PD-L1 expression, glioma grades, and IDH1 (R132H) mutation status was assessed statistically using SPSS software and a Chi-square test. The threshold for statistical significance was p < 0.05. For every IHC run, positive and negative controls were used as part of the quality control procedures. To reduce bias and guarantee consistency, two pathologists and post graduate residents independently reviewed the results. Results PD-L1 expression was found in 27 out of 36 (75%) grade 4 glioblastoma multiforme cases and six out of nine (66.7%) grade 2 gliomas. Overall, 33/45 (73.3%) of the gliomas had PD-L1 expression. However, PD-L1 expression and glioma grade did not correlate in a statistically significant way. IDH1 (R132H) expression and PD-L1 were found to be inversely correlated (p < 0.05). Conclusion The findings suggest that PD-L1 may be a promising therapeutic target, even in the absence of significant grade-specific trends bydemonstrating PD-L1 presence in the majority of glioma cases, highlighting its potential as a therapeutic target in GBM immunotherapy. The results provide insight into the immune landscape of gliomas and pave the way for future research into effective combination therapies for GBM, despite the lack of a significant correlation between glioma grade and PD-L1 expression.

Treatment of drug induced erythema multiforme Case report

Erythema Multiforme EM is an acute condition driven by the immune system, featuring the rapid emergence of distinct target like lesions on the skin and mucous membranes.

10027-CBMS-3 POSTOPERATIVE EPILEPTOGENICITY IN GLIOBLASTOMA ARE ACHIEVED AS THE RESULT OF INTERACTIVE FLUCTUATIONS OF GLUTAMATE AND STEM CELL MARKER

Abstract BACKGROUND AND OBJECTIVE In our recent Glioblastoma multiforme (GBM) cases, postoperative epilepsy mostly occurred later than twenty-eight days after surgery. CD44, a stem cell marker, is known to relate with tumor cell invasiveness, however, little are known with epilepsy nor glutamate (Glu). We investigated the relationship between CD44 and the pathophysiology of this post operative late-phase epilepsy. MATERIALS AND METHODS A total of 10 GBM cases received surgery and postoperative treatment at our institute were divided into two groups; 4 cases of epilepsy onset, group E, and 6 cases without, group NE. In each group, the tumor was separated into core and periphery, from which Glu was measured (Amino Acid Analyzer L8900; Hitachi High-Tech Corporation) with expression of xCT, EAAT2 and CD44 examined (Western blot). The same objects were also examined on our three glioma stem-like cell (GSC) lines. In addition, we figured Factor X (F-X) as a key related factor, and evaluated the same objects on the GSCs under conditioned F-X (under submission). RESULTS Group E showed higher Glu than group NE both in the core and periphery. CD44 expression was significantly higher in group E in the periphery, and xCT was higher in group E both in the core and periphery. EAAT2 was lower in group E both in the core and periphery. Among the GSCs, GSC-2 had the highest CD44 expression while having the lowest xCT and extracellular Glu, and the highest EAAT2. In addition, CD44 knockdown in GSC-2 resulted in significant increase of xCT expression and extracellular Glu. Furthermore, changing the concentration of F-X low to high led to decreased expression of CD44 and increased xCT. CONCLUSION The postoperative epileptogenicity could be gained by the increase of Glu which results from the alterations of CD44, xCT and EAAT2. F-X could enhance the ability of Glu discharge.

A pediatric case of exudative erythema multiforme probably associated with asymptomatic COVID-19

COVID-19 is a pandemic involving severe acute respiratory syndrome-coronavirus SARS-CoV-2, which started in China at the end of 2019 and has spread globally. Among COVID-19 patients, 17.8% are under 20 years of age. Most children infected with SARS-CoV-2 are asymptomatic or only oligosymptomatic and can easily be overlooked. We followed an 11-year-old boy showing exudative erythema multiforme, which appeared during isolation at home following a positive polymerase chain reaction (PCR) test for COVID-19. Our case, although otherwise asymptomatic, showed typical clinical and histological manifestations of the erythema multiforme-like lesions associated with COVID-19. The presence of such an asymptomatic SARS-CoV-2 carrier who developed erythema multiforme-like skin lesions provides the possibility that some undefined infectious organisms, such as SARS-CoV-2, could be the origin of exudative erythema multiforme cases without any apparent cause.

The Impact of Extent of Ablation on Survival of Patients With Newly Diagnosed Glioblastoma Treated With Laser Interstitial Thermal Therapy: A Large Single-Institutional Cohort.

Upfront laser interstitial thermal therapy (LITT) can be used as part of the treatment paradigm in difficult-to-access newly diagnosed glioblastoma multiforme (ndGBM) cases. The extent of ablation, though, is not routinely quantified; thus, its specific effect on patients' oncological outcomes is unclear. To methodically measure the extent of ablation in the cohort of patients with ndGBM and its effect, and other treatment-related parameters, on patients' progression-free survival (PFS) and overall survival (OS). A retrospective study was conducted on 56 isocitrate dehydrogenase 1/2 wild-type patients with ndGBM treated with upfront LITT between 2011 and 2021. Patient data including demographics, oncological course, and LITT-associated parameters were analyzed. Patient median age was 62.3 years (31-84), and the median follow-up duration was 11.4 months. As expected, the subgroup of patients receiving full chemoradiation was found to have the most beneficial PFS and OS (n = 34). Further analysis showed that 10 of them underwent near-total ablation and had a significantly improved PFS (10.3 months) and OS (22.7 months). Notably, 84% excess ablation was detected which was not related to a higher rate of neurological deficits. Tumor volume was also found to influence PFS and OS, but it was not possible to further corroborate this finding because of low numbers. This study presents data analysis of the largest series of ndGBM treated with upfront LITT. Near-total ablation was shown to significantly benefit patients' PFS and OS. Importantly, it was shown to be safe, even in cases of excess ablation and therefore could be considered when using this modality to treat ndGBM.

Diffusion tensor imaging changes in patients with glioma-associated seizures

IntroductionStructural white matter changes associated with certain epilepsy subtypes have been demonstrated using diffusion tensor imaging (DTI). This observational study aims to identify potential water diffusion abnormalities in glioma patients with associated seizures.MethodsTwo cohorts from two centers were analyzed independently: (A) Prospectively recruited patients diagnosed with glioma who received preoperative DTI to measure mean diffusivity (MD) and fractional anisotropy (FA) in regions-of-interest (ROIs) including the marginal tumor zone (TU), adjacent peritumoral white matter as well as distant ipsilateral and contralateral white matter and cortex. Data were compared between patients with and without seizures and tested for statistical significance. (B) A retrospective cohort using an alternative technical approach sampling ROIs in contrast enhancement, necrosis, non-enhancing tumor, marginal non-enhancing tumor zone, peritumoral tissue, edema and non-tumorous tissue.Results(A) The prospective study cohort consisted of 23 patients with 12 (52.2%) presenting with a history of seizures. There were no significant seizure-associated differences in MD or FA for non-tumor white matter or cortical areas. MD-TU was significantly lower in patients with seizures (p = 0.005). (B) In the retrospective cohort consisting of 46 patients with a seizure incidence of 50.0%, significantly decreased normalized values of MD were observed for non-enhancing tumor regions of non-glioblastoma multiforme (GBM) cases in patients with seizures (p = 0.022).ConclusionDTI analyses in glioma patients demonstrated seizure-associated diffusion restrictions in certain tumor-related areas. No other structural abnormalities in adjacent or distant white matter or cortical regions were detected.

English

Glioblastoma multiforme is a primary brain neoplasm, consisting of a genetically and phenotypically heterogeneous group of tumours.1 The term glioblastoma multiforme (GBM) was introduced by Cushing in the second half of the nineteenth century, while the first operation on a patient suffering from this type of tumour was conducted in Vienna in 19041. Ninety percent of glioblastoma multiforme cases develop de novo (primary glioblastoma) from normal glial cells by multistep tumorigenesis.1 The remaining 10% of gliomas are cases of secondary neoplasm, developing through progression from low-grade tumours (diffuse or anaplastic astrocytoma’s), which takes about 4–5 years.1 Secondary glioma is diagnosed mostly in persons with the mean age of 39 years, grows more slowly and has a better prognosis.1 Glioblastoma multiforme, which develops de novo, grows within 3 months. 1 Although the genetic basis, as well as the molecular pathways underlying development of primary and secondary gliomas are different these two types show no morphological differences.1 Alkaptonuria is an ultra-rare (1:250.000–1.000.000 incidence) autosomal recessive inborn error of catabolism of the aromatic amino acids’ phenylalanine and tyrosine due to a deficient activity of the enzyme homogentisate 1,2-dioxygenase. This leads to the accumulation of homogentisic acid (HGA, 2, 5- dihydroxyphenylacetic acid).2 HGA oxidizes to benzoquinone acetic acid (BQA), which in turn forms melanin-based polymers, deposited in the connective tissue of various organs, causing a pigmentation known as ochronosis, leading to dramatic tissue degeneration. 3 A severe form of arthropathy is the most common AKU clinical presentation.4

Optimizing Interstitial Photodynamic Therapy Planning With Reinforcement Learning-Based Diffuser Placement.

To develop new algorithms that generate high-quality plans by optimizing over the light source positions, along with their powers, to minimize the damage to organs-at-risk while eradicating the tumor. The optimization algorithms should also accurately model the physics of light propagation through the use of Monte-Carlo simulators. We use simulated-annealing as a baseline algorithm to place the sources. We propose different source perturbations that are likely to provide better outcomes and study their impact. To minimize the number of moves attempted (and effectively runtime) without degrading result quality, we use a reinforcement learning-based method to decide which perturbation strategy to perform in each iteration. We simulate our algorithm on virtual brain tumors modeling real glioblastoma multiforme cases, assuming a 5-ALA PpIX induced photosensitizer that is activated at[Formula: see text] wavelength. The algorithm generates plans that achieve an average of 46% less damage to organs-as-risk compared to the manual placement used in current clinical studies. Having a general and high-quality planning system makes iPDT more effective and applicable to a wider variety of oncological indications. This paves the way for more clinical trials.

Abstract 2317: Genetic risk scores from structural variation predict life-time individual cancer risk

Abstract Background. The current best predictor of lifetime risk for many forms of cancer is family history. Family history is transmitted through germ line DNA. Analysis of germ-line DNA should be able to predict lifetime risk at least as well family history. Genetic risk scores, used to predict lifetime risk from DNA, usually consist of linear combinations of SNPs. These scores ignore structural variations and epistatic effects (non-linear combinations). The objective of this study is to test whether germline DNA structural information along with machine learning algorithms, which can use non-linear combinations, can be used to predict whether a person will develop different types of cancer. Methods. We tested this objective using data compiled by The Cancer Genome Atlas (TCGA) project and the UK Biobank. The TCGA data consisted of information on DNA chromosome scale length variation extracted from the peripheral blood of 8,821 different patients, each of whom had one of 32 different types of cancer. The UK Biobank data consisted of about 1500 women diagnosed with breast cancer (cases) and about 5000 women who have no record of any type of cancer(controls). We characterized structural variation by a quantitative measure of chromosomal-scale length variation. Chromosomal-scale length variation is computed from array data. A person's DNA (chromosomes 1-22) can be characterized by a series of 22 numbers, each representing the log base 2 ratio of the chromosome's length compared to the average chromosome length. Using these 22 numbers for each person, we set up a machine learning classification problem to differentiate those people diagnosed with a particular form of cancer from those who have not been diagnosed with that cancer. We used the h2o libraries in R to test how well different machine-learning algorithm can classify with these datasets. Results. In two independent datasets, the Cancer Genome Atlas (TCGA) project and the UK Biobank, we could classify whether or not a patient had a certain cancer based solely on chromosomal scale length variation. We found that all 32 different types of cancer in the TCGA dataset tested could be predicted better than chance using structural variation data. Specifically, in the TCGA dataset we measured the area under the receiver operator curve, known as the AUC, for ovarian cancer in women (0.89), glioblastoma multiforme (0.86), breast cancer in women (0.75), and colon adenocarcinoma (0.79), with a 95% confidence interval width of less than 0.01 in each case. This method could predict 10% of glioblastoma multiforme cases with less than 1 in 10,000 false positives in the TCGA dataset. In the UK Biobank dataset, we could predict breast cancer in women with an AUC=0.83. Conclusion. Genetic risk scores based on structural variation can effectively predict whether a person will eventually develop may different types of cancer. Citation Format: Chris Toh, Charmeine Ko, James P. Brody. Genetic risk scores from structural variation predict life-time individual cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2317.

Shutter-Speed DCE-MRI Analyses of Human Glioblastoma Multiforme (GBM) Data.

The shutter-speed model dynamic contrast-enhanced (SSM-DCE) MRI pharmacokinetic analysis adds a metabolic dimension to DCE-MRI. This is of particular interest in cancers, since abnormal metabolic activity might happen. To develop a DCE-MRI SSM analysis framework for glioblastoma multiforme (GBM) cases considering the heterogeneous tissue found in GBM. Prospective. Ten GBM patients. 3T MRI with DCE-MRI. The corrected Akaike information criterion (AICc ) was used to automatically separate DCE-MRI data into proper SSM versions based on the contrast agent (CA) extravasation in each pixel. The supra-intensive parameters, including the vascular water efflux rate constant (kbo ), the cellular efflux rate constant (kio ), and the CA vascular efflux rate constant (kpe ), together with intravascular and extravascular-extracellular water mole fractions (pb and po , respectively) were determined. Further error analyses were also performed to eliminate unreliable estimations on kio and kbo . Student's t-test. For tumor pixels of all subjects, 88% show lower AICc with SSM than with the Tofts model. Compared to normal-appearing white matter (NAWM), tumor tissue showed significantly larger pb (0.045 vs. 0.011, P < 0.001) and higher kpe (3.0 × 10-2 s-1 vs. 6.1 × 10-4 s-1 , P < 0.001). In the contrast, significant kbo reduction was observed from NAWM to GBM tumor tissue (2.8 s-1 vs. 1.0 s-1 , P < 0.001). In addition, kbo is four orders and two orders of magnitude greater than kpe in the NAWM and GBM tumor, respectively. These results indicate that CA and water molecule have different transmembrane pathways. The mean tumor kio of all subjects was 0.57 s-1 . We demonstrate the feasibility of applying SSM models in GBM cases. Within the proposed SSM analysis framework, kio and kbo could be estimated, which might be useful biomarkers for GBM diagnosis and survival prediction in future. 4 TECHNICAL EFFICACY: Stage 1 J. Magn. Reson. Imaging 2020;52:850-863.

Tumor growth patterns in central nervous system tumors with astrocytic differentiation

Background and Aim: Glial tumors with astrocytic differentiation are the most common primary malignant brain tumors. Hans Joachim Scherer established histological criteria based on hematoxylin and eosin (H&E) staining, which form the basis of the World Health Organization (WHO) glial tumor grades. The aim of this study was to investigate the incidence of Scherer structures across different classes of WHO grade tumors with astrocytic differentiation and determine whether secondary structures can be used as a grade-defining tool. Materials and Methods: Tumor samples were obtained from 36 patients with central nervous system (CNS) tumors with astrocytic differentiation between February 2018 and March 2019. The study was approved by the Committee on Ethics for Scientific Research, Medical University—Varna “Prof. Dr. Paraskev Stoyanov,” Protocol no. 20 [1] on April 26, 2012. The presence or absence of primary Scherer structures (pseudopalisading necrosis, glomeruloid vascular proliferation) and secondary Scherer structures (subpial palisading, fascicular aggregation, satellitosis around neurons, and blood vessels) was analyzed in H&E stained samples. Results: The samples were divided into two groups: 28 glioblastoma multiforme (GBM) cases and 8 lower grade astrocytoma cases. All 28 GBM cases exhibited pseudopalisading necrosis. Glomeruloid vascular proliferation was present only in 89.3% of the GBM cases. The GBM group also showed 67.9% subpial palisading, 78.5% fascicular aggregation of tumor cells, 96.4% perineuronal, and 100% perivascular satellitosis. The lower grade astrocytoma group had 0% pseudopalisading necrosis and glomeruloid vascular proliferation. Among all cases of lower grade gliomas, 50.0% showed subpial palisading, 87.5% fascicular aggregation, 100% perineuronal, and 100% perivascular satellitosis. Conclusions: Secondary Scherer structures can be considered as natural phenomena in glial tumors but cannot be used as features for grading.

Formin-like 1 (FMNL1) Is Associated with Glioblastoma Multiforme Mesenchymal Subtype and Independently Predicts Poor Prognosis.

Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in these processes. However, the role of formin-like 1 (FMNL1) in cancer remains unclear. We studied FMNL1 expression in glioblastoma samples using immunohistochemistry. We sought to analyze the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from The Cancer Genome Atlas and analyzed using gene set enrichment analysis (GSEA). FMNL1 was an independent predictor of poor prognosis in a cohort of 217 glioblastoma multiforme cases (p < 0.001). FMNL1 expression was significantly higher in the mesenchymal subtype. FMNL1 upregulation and downregulation were associated with mesenchymal and proneural markers in the GSEA, respectively. These data highlight the important role of FMNL1 in the neural-to-mesenchymal transition. Conversely, FMNL1 downregulation suppressed glioblastoma multiforme cell migration and invasion via DIAPH1 and GOLGA2, respectively. FMNL1 downregulation also suppressed actin fiber assembly, induced morphological changes, and diminished filamentous actin. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression.

Optimizing interstitial photodynamic therapy with custom cylindrical diffusers.

Interstitial photodynamic therapy (iPDT) has shown promise recently as a minimally invasive cancer treatment, partially due to the development of non-toxic photosensitizers in the absence of activation light. However, a major challenge in iPDT is the pre-treatment planning process that specifies the number of diffusers needed, along with their positions and allocated powers, to confine the light distribution to the target volume as much as possible. In this work, a new power allocation algorithm for cylindrical light diffusers including those that can produce customized longitudinal (tailored) emission profiles is introduced. The proposed formulation is convex to guarantee the minimum over-dose possible on the surrounding organs-at-risk. The impact of varying the diffuser lengths and penetration angles on the quality of the plan is evaluated. The results of this study are demonstrated for different photosensitizers activated at different wavelengths and simulated on virtual tumors modeling virtual glioblastoma multiforme cases. Results show that manufacturable cylindrical diffusers with tailored emission profiles can significantly outperform those with conventional flat profiles with an average damage reduction on white matter of 15% to 55% and on gray matter of 23% to 58%.

Single-stimulus dual-drug sensitive nanoplatform for enhanced photoactivated therapy

In the frame of accelerator-based BNCT, the 9Be(d,n)10B reaction was investigated as a possible source of epithermal neutrons. In order to determine the configuration in terms of bombarding energy, target thickness and Beam Shaping Assembly (BSA) design that results in the best possible beam quality, a systematic optimization study was carried out. From this study, the optimal configuration resulted in tumor doses ≥40 Gy-Eq, with a maximum value of 51 Gy-Eq at a depth of about 2.7 cm, in a 60 min treatment.The optimal configuration was considered for the treatment planning assessment of a real Glioblastoma Multiforme case. From this, the resulted dose performances were comparable to those obtained with an optimized 7Li(p,n)-based neutron source, under identical conditions and subjected to the same clinical protocol.

Abstract 5208: Neovascularization in brain metastasis is through both angiogenesis and vasculogenesis

Abstract Metastatic brain tumors are the most common brain tumor in adults with an incidence 10 times greater than primary brain tumors. A variety of malignancies eventually spread to the brain, with a majority arising from cancers of the lung, breast, kidney, and skin. Experimental studies using breast and melanoma cell lines have recently shown that growth of metastatic brain tumors may occur by utilizing pre-existing blood vessel, or by co-opting rather than inducing new vessel formation. Whether the same mechanisms of vascular utilization and expansion play a role in human metastatic brain tumors is unknown and is the focus of the present study. We examined the immuno-phenotype of blood vessels in primary and metastatic human brain tumors to determine the presence of new blood vessels formation. Glioblastoma multiforme (n = 12) and secondary tumors from melanoma (n = 10), breast (n = 10), kidney (n = 5), and lung (n = 13) all showed extensive immunoreactivity for endothelial marker CD31. We also found a significant number of endothelial cells expressing Ki-67, most notably among breast carcinoma, glioblastoma multiforme and melanoma cases, indicating microvessel proliferation and angiogenesis. Interestingly, both primary and secondary metastatic tumors also showed vascular endothelial cells concomitantly expressing stem cell markers, such as Oct4, suggesting that some of these microvessels are derived through vasculogenesis. These findings show that both proliferation of endothelial cells and de novo endothelial differentiation may underlie metastatic tumor growth to different degrees depending on their site of primary origin. Currently, our laboratory is determining the exact contribution of angiogenesis and vasculogenesis in brain metastasis. Our findings show that neo-vessels are evident in brain metastasis. Elucidating the source of these vessels may uncover new treatment targets for patients with brain metastasis. Citation Format: Stephanie Mok, Lee-Cyn Ang, Christopher J. Howlett, Zia A. Khan. Neovascularization in brain metastasis is through both angiogenesis and vasculogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5208. doi:10.1158/1538-7445.AM2015-5208

An Australian single institution experience in treating primary glioblastoma multiforme from 2010-2012.

e13043 Background: Over half of all glioblastoma multiforme (GBM) cases are diagnosed in patients older than 65 years. Several series demonstrate a median overall survival of 4-5 months in this age...

A pooled multisite analysis of the effects of atopic medical conditions in glioma risk in different ethnic groups

PurposeThe incidences of atopic conditions (allergies, asthma, or eczema) and glioma vary by ethnicity. Atopic conditions are inversely associated with gliomas. We conducted a pooled multisite study investigating the associations of atopic conditions with glioma in different race/ethnicity groups. MethodsUsing glioma cases and healthy controls, unconditional logistic regression was conducted to assess the associations of atopic conditions with glioma separately in white, black, Asian, and Hispanic subpopulations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. ResultsGlioblastoma multiforme cases were less likely than controls to report a history of atopic conditions in whites (OR = 0.46, [95% CI, 0.38–0.54]) and Asians (OR = 0.27, [95% CI, 0.10–0.73]). The same trend was seen when looking at glioma cases of all histologies. An inverse association was not seen in blacks for glioblastoma multiforme or all histologies combined. ConclusionsThe inverse association between glioma and atopic conditions may vary by ethnicity due to a difference in the biology of atopic conditions in different ethnicities but may be due to chance because of the limitations of small nonwhite sample sizes.

Relevance of IGFBP2 proteolysis in glioma and contribution of the extracellular protease ADAMTS1.

Expression of IGFBP2 (Insulin-like Growth Factor Binding Protein 2) has been positively correlated with glioma progression. Although the proteolysis of IGFBP2 has been widely recognized, with consequences as a major modulator of IGFII signaling, the relevance of this post-translational modification has not been well studied in tumors. Using an in vivo proteomic approach by Isotope-Coded Protein Label (ICPL), we identified IGFBP2 as a target of the extracellular protease ADAMTS1 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs 1). Notably, the proteolytic pattern of IGFBP2 was also detected in human glioma culture cells and, more importantly, in all glioma samples evaluated. In addition, high expression of ADAMTS1 correlates with higher levels of cleaved IGFBP2 in glioblastoma multiforme cases. Using gene expression public databases, we confirmed that IGFBP2 is a poor prognosis marker for gliomas, and we also observed an important contribution of ADAMTS1.Finally, we showed the impact of ADAMTS1 on IGFII-mediated IGF1R phosphorylation and cellular migration. Our results support a functional interaction between IGFBP2 and ADAMTS1 and suggest the need to evaluate post-translational modifications of IGFBP2 in glioma, in order to approach new therapies.

Glioblastoma multiforme - an overview.

Glioblastoma multiforme is a central nervous system tumor of grade IV histological malignancy according to the WHO classification. Over 90% of diagnosed glioblastomas multiforme cases are primary gliomas, arising from normal glial cells through multistep oncogenesis. The remaining 10% are secondary gliomas originating from tumors of lower grade. These tumors expand distinctly more slowly. Although genetic alterations and deregulations of molecular pathways leading to both primary and secondary glioblastomas formation differ, morphologically they do not reveal any significant differences. Glioblastoma is a neoplasm that occurs spontaneously, although familial gliomas have also been noted. Caucasians, especially those living in industrial areas, have a higher incidence of glioblastoma. Cases of glioblastoma in infants and children are also reported. The participation of sex hormones and viruses in its oncogenesis was also suggested. Progression of glioblastoma multiforme is associated with deregulation of checkpoint G1/S of a cell cycle and occurrence of multiple genetic abnormalities of tumor cells. Metastases of glioblastoma multiforme are rarely described. Treatment of glioblastoma multiforme includes tumor resection, as well as radiotherapy and chemotherapy. Drugs inhibiting integrin signaling pathways and immunotherapy are also employed. Treatment modalities and prognosis depend on the tumor localization, degree of its malignancy, genetic profile, proliferation activity, patient's age and the Karnofsky performance scale score. Although the biology of glioblastoma multiforme has recently been widely investigated, the studies summarizing the knowledge of its development and treatment are still not sufficient in terms of comprehensive brain tumor analysis.

9Be(d,n)10B-based neutron sources for BNCT

In the frame of accelerator-based BNCT, the 9Be(d,n)10B reaction was investigated as a possible source of epithermal neutrons. In order to determine the configuration in terms of bombarding energy, target thickness and Beam Shaping Assembly (BSA) design that results in the best possible beam quality, a systematic optimization study was carried out. From this study, the optimal configuration resulted in tumor doses ≥40Gy-Eq, with a maximum value of 51Gy-Eq at a depth of about 2.7cm, in a 60min treatment.The optimal configuration was considered for the treatment planning assessment of a real Glioblastoma Multiforme case. From this, the resulted dose performances were comparable to those obtained with an optimized 7Li(p,n)-based neutron source, under identical conditions and subjected to the same clinical protocol.