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PURPOSE Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with dismal prognosis. This tumor is characterized by extensive heterogeneity, thus is difficult to treat and every established or new treatment faces significant hazard of resistance. Temozolomide (TMZ), an oral alkylating agent, is the first-line treatment for GBM, but resistance to TMZ is a major problem. Herewith, we investigated the combined effect of TMZ, difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, and radiation in GBM cell lines. METHODS We used the U87G, U251MG and T98G GBM cell lines. A linac 6MV accelerator (Varian Medical Systems) was used for cell irradiation. Viability and proliferation of the cells were examined with trypan blue exclusion assay, crystal violet and xCELLigence system. Cell cycle and activation of caspase-8 were evaluated with flow cytometry. RESULTS The combination treatment resulted in a consistent higher suppression of proliferation in all cell lines treated and induced a significant higher cell cycle arrest in G2/M phase in U251MG and T98G cell lines. In U251MG cells caspase-8 was increased with each treatment alone, however the combination treatment had lower level of caspase-8 induction, suggesting a co-existence of another mechanism of cell death apart from apoptosis. In T98G cells the combination treatment increased the activation of caspase-8. CONCLUSION Combination treatment with DFMO, TMZ and radiation significantly reduced cell viability in all cell lines tested. Given that both TMZ and DFMO can be administered orally and are related to minimal toxicities, this combination treatment may be a novel treatment strategy for GBM that deserves further investigation.

1. Schuster FL, Ramirez-Avila L. Current world status of Balantidium coli. Clin Microbiol Rev 2008; 21:626-38. 2. Bandyopadhyay A, Majumder K, Goswami BK. Balantidium coli in urine sediment: Report of a rare case presenting with hematuria. J Parasit Dis 2013;37:283-5. 3. Costache C, Bursasiu S, Filipas C, Colosi I. A case of ciliate protozoa Colpoda spp (Ciliata: Colpodidae) detected in human urine. Iranian J Parasitol 2011;6:99-104. 4. Mitra AK, Haldar DP. First record of Chilodonella hexasticha (Kiernik, 1909) Kahl, 1931 (Ciliophora: Chilodonellidae) infesting a freshwater fish Nandus nandus (Hamilton) from Gangetic West Bengal, India. Anim Biol 2004;54:111-8. 5. Pomajbikova K, Obornik M, Horak A, Petrzelkova KJ, Grim JN, Levecke B. Novel insights into the diversity of Balantidium and Balantidium like cyst forming ciliates. PLoS Negl Trop Dis 2013;7:e2140.

Purpose Gliomas constitute the most frequent primary brain tumors. Glioblastoma, the most common and malignant glioma in adults, has dismal prognosis with any current therapy. On the other hand, low-grade gliomas, the second most common type of gliomas, are potentially curative with appropriate treatment. Methods We conducted a meta-analysis to assess the performance of PET tracers with the best available evidence, namely, fluorodeoxyglucose (FDG), C-11-methionine (MET), and F-18-fluoroethyltyrosine (FET), in differentiating low- from high-grade gliomas. Results Twenty-three studies with a total of 994 participants were included in this meta-analysis. The pooled sensitivities of both MET PET and FET PET were found to be significantly higher than of FDG PET (94%, 88%, and 63% respectively, P < 0.001). The pooled specificity of FDG PET was found to be significantly greater compared with both MET PET and FET PET (89%, 55%, and 57%, respectively; P = 0.002). Fluorodeoxyglucose PET was superior in terms of higher positive likelihood ratio values compared with both FET PET and MET PET. Conclusions This meta-analysis indicated that both MET and FET were superior to FDG in terms of sensitivity for identifying glioma grade.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. This highly aggressive tumor is difficult to treat and virtually all GBM patients succumb to the disease despite maximal surgical resection, radiotherapy and chemotherapy (1). Many chemotherapeutic agents have been tested against GBM; however the genetic heterogeneity and the diverse molecular pathology create difficulties to treat and virtually all tumors recur.

Future OncologyVol. 13, No. 2 EditorialFrom bench to operating theater: has the time come for a molecular scalpel?George Vartholomatos, George A Alexiou, Georgios D Lianos & Athanasios P KyritsisGeorge Vartholomatos Haematology Laboratory-Unit of Molecular Biology, University of Ioannina School of Medicine, 45110, Ioannina, Greece, George A Alexiou*Author for correspondence: E-mail Address: alexiougrg@yahoo.gr Neurosurgical Institute, University of Ioannina School of Medicine, 45110, Ioannina, Greece, Georgios D Lianos Neurosurgical Institute, University of Ioannina School of Medicine, 45110, Ioannina, Greece & Athanasios P Kyritsis Neurosurgical Institute, University of Ioannina School of Medicine, 45110, Ioannina, GreecePublished Online:4 Nov 2016https://doi.org/10.2217/fon-2016-0413AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: flow cytometryintraoperative cell cycle analysessurgical marginssurgical oncologyReferences1 Swinney C, Li A, Bhatti I, Veeravagu A. Optimization of tumor resection with intra-operative magnetic resonance imaging. J. Clin. Neurosci. doi:10.1016/j.jocn.2016.05.030 (2016) (Epub ahead of print).Crossref, Medline, Google Scholar2 Hauser SB, Kockro RA, Actor B, Sarnthein J, Bernays RL. Combining 5-aminolevulinic acid fluorescence and intraoperative magnetic resonance imaging in glioblastoma surgery: a histology-based evaluation. Neurosurgery 78(4), 475–483 (2016).Crossref, Medline, Google Scholar3 Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre Phase III trial. Lancet Oncol. 7(5), 392–401 (2006).Crossref, Medline, CAS, Google Scholar4 Widhalm G, Kiesel B, Woehrer A et al. 5-Aminolevulinic acid induced fluorescence is a powerful intraoperative marker for precise histopathological grading of gliomas with non-significant contrast-enhancement. PLoS ONE 8(10), e76988 (2013).Crossref, Medline, CAS, Google Scholar5 Jarmusch AK, Pirro V, Baird Z, Hattab EM, Cohen-Gadol AA, Cooks RG. Lipid and metabolite profiles of human brain tumors by desorption electrospray ionization-MS. Proc. Natl Acad. Sci. USA 113(6), 1486–1491 (2016).Crossref, Medline, CAS, Google Scholar6 Balog J, Sasi-Szabó L, Kinross J et al. Intraoperative tissue identification using rapid evaporative ionization mass spectrometry. Sci. Transl. Med. 5(194), 194ra93 (2013).Crossref, Medline, Google Scholar7 Ifa DR, Eberlin LS. Ambient ionization mass spectrometry for cancer diagnosis and surgical margin evaluation. Clin. Chem. 62(1), 111–123 (2016).Crossref, Medline, CAS, Google Scholar8 Vartholomatos G, Alexiou G, Batistatou A, Kyritsis AP. Intraoperative cell-cycle analysis to guide brain tumor removal. Proc. Natl Acad. Sci. USA 111(36), E3755 (2014).Crossref, Medline, CAS, Google Scholar9 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011).Crossref, Medline, CAS, Google Scholar10 Alexiou GA, Vartholomatos G, Goussia A et al. Fast cell cycle analysis for intraoperative characterization of brain tumor margins and malignancy. J. Clin. Neurosci. 22(1), 129–132 (2015).Crossref, Medline, Google Scholar11 Alexiou GA, Vartholomatos G, Stefanaki K et al. The role of fast cell cycle analysis in pediatric brain tumors. Pediatr. Neurosurg. 50(5), 257–263 (2015).Crossref, Medline, Google Scholar12 Giesen C, Wang HA, Schapiro D et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat. Methods 11(4), 417–422 (2014).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByIntraoperative Flow Cytometry in Pediatric Brain Tumors1 January 2022The Past, Present and Future of Flow Cytometry in Central Nervous System Malignancies26 January 2021 | Methods and Protocols, Vol. 4, No. 1The emerging role of intraoperative flow cytometry in intracranial tumor surgeryClinical Neurology and Neurosurgery, Vol. 192Intraoperative cell cycle analysis for tumor margins evaluation: The future is now?International Journal of Surgery, Vol. 53Effectiveness of flow cytometry for brain tumor excisionPhotodiagnosis and Photodynamic Therapy, Vol. 18 Vol. 13, No. 2 eToC Sign up Follow us on social media for the latest updates Metrics Downloaded 40 times History Published online 4 November 2016 Published in print January 2017 Information© Future Medicine LtdKeywordsflow cytometryintraoperative cell cycle analysessurgical marginssurgical oncologyFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Objectives: Flow cytometry provides a powerful tool to assess cells in G(0)/G(1), S and G(2)/M phase and ploidy. The purpose of the present study was to investigate the correlation between diffusion tensor (DTI) and dynamic susceptibility contrast (DSC) MRI metrics with cell cycle analysis findings in gliomas.Patients and methods: We studied thirty patients who were operated on for glioma. DTI and DSC MRI were performed within a week prior to surgical excision. Lesion/normal ratios were calculated for the ADC, FA and rCBV. In an excised tumour sample flow cytometric analysis was performed.Results: There were 24 glioblastomas, 2 anaplastic astrocytomas, 1 oligoastrocytoma and 3 diffuse astrocytomas. There were significant differences between low and high-grade gliomas for rCBV and ADC values. Low grade tumours had higher G(0)/G(1) phase fraction and lower S-phase, G(2)/M, S + G(2)/M and S + G(2)/M/G(0)/G(1) fractions There was a significant negative correlation between rCBV and Go/Gi phase fraction and a positive correlation with G(2)/M, S + G(2)/M and the S + G(2)/M/G(0)/G(1) fraction. Significant correlation was also observed between FA ratio and S + G(2)/M/G(0)/G(1). There was a negative significant correlation between ADC and S + G(2)/M and the S + G(2)/M/G(0)/G(1) fraction. There were 21 (70%) diploid and 9(30%) aneuploid tumours. No significant difference was found between diploid and aneuploid tumours with respect to rCBV, ADC and FA values.Conclusion: Dynamic susceptibility contrast MRI and diffusion tensor imaging metrics are correlated to tumour aggressiveness as assessed by cell cycle analysis. (C) 2015 Elsevier B.V. All rights reserved.

We read with great interest the recent article by Santagata et al. (1) on the value of intraoperative mass spectrometry during brain tumor surgery. The authors, using desorption electrospray ionization (DESI) MS, detected rapidly the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas. With DESI MS the authors identified isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity, providing diagnostic, prognostic, and predictive information. Furthermore, 2-HG levels correlated with tumor content, thereby indicating tumor margins (1).

IRAK1 gene polymorphism rs3027898 (located in the 3’-untranslated region) has been associated previously with atherothrombotic celebral infarction in Japanese patients. The present study addresses, for fi rst time, the role of IRAK1 polymorphism rs3027898 in Caucasian ischemic stroke (IS) patients. IRAK1 gene is located on chromosome X (Xq28) and according to a recent study, the genotype-based analysis of X-linked polymorphisms should be performed in females, which is the case of the present study. On the other hand, stroke tends to be more severe in women than in males. Therefore, if this polymorphism is confi rmed to be associated with disease severity, this could strengthen further the association with IS.

Background: Apolipopr/INS;otein E (ApoE) is a plasma protein exhibiting three common isoforms (E2, E3, E4). Its involvement in lipoprotein metabolism may have an impact on stroke occurrence. As results in literature are inconclusive further studies are needed to elucidate its role.

Alexiou, George A. MD, PhD1; Voulgaris, Spyridon MD, PhD1; Tsiouris, Spyridon MD2; Fotopoulos, Andreas D. MD, PhD2; Kyritsis, Athanasios P. MD, PhD3 Author Information

To the Editor: We read with great interest the recent article by Cornelius et al1 discussing the value of positron emission tomography (PET) imaging in intracranial meningiomas. The authors reviewed the role of the current PET tracers for meningiomas imaging. They suggested that PET holds promise for the preoperative grading of meningiomas and identifying aggressive tumor areas that should be resected, provides better tumor delineation, and allows the assessment of metabolic response to chemotherapy earlier than the volume response measured by magnetic resonance imaging. The authors also discussed some important PET limitations and concluded that this molecular imaging modality is promising for brain tumor management. In addition to PET, single-photon emission computed tomography (SPECT) is a molecular imaging modality that has been used in nuclear medicine. The most important advantages of SPECT over PET are its lower cost and wider availability. Furthermore, some PET tracers have a short half-life, necessitating an onsite cyclotron for synthesis. SPECT tracers are stable, are readily available, do not require a cyclotron, and have a relative long half-life. On the other hand, PET imaging has a higher sensitivity and provides images of better resolution compared with SPECT. Over the last years, we have investigated the brain tumor imaging properties of technetium-99m-tetrofosmin (99mTc-TF), a SPECT tracer routinely used for myocardial perfusion imaging. We demonstrated in vivo that, contrary to 99mTc-MIBI, an extensively studied SPECT tracer, 99mTc-TF uptake is not related to the multidrug-resistant phenotype of brain tumors. Thus, 99mTc-TF is superior for brain tumor imaging.2 Furthermore, compared with several PET tracers, 99mTc-TF does not cross the intact blood-brain barrier. Consequently, brain lesions are readily identifiable, even if there is faint tracer uptake. In our previous studies, we have shown that 99mTc- TF may accurately differentiate malignant from benign meningiomas. A lesion-to-normal uptake value of 9.6 was demonstrated as the optimal cutoff value thresholding the discrimination between the 2 groups, with 96% sensitivity and 100% specificity. In addition, the intensity of 99mTc-TF uptake correlated significant with meningioma aggressiveness as assessed by the Ki-67 index, the cell percentage on the S phase, and DNA ploidy.3,4 In conclusion, we believe that 99mTc-TF brain SPECT may offer a valuable alternative to PET imaging, especially in healthcare units without an onsite PET facility. Further well-designed comparative studies between 99mTc-TF and PET tracers are needed.

Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor in adults, exhibiting poor survival. The efficacy of chemotherapy is often limited by the development of multidrug resistance by the tumor cells. In the current study, we investigated the prognostic significance of the multidrug resistance protein 5 (MRP5) in patients with GBM.

The aim of this study was to compare between ambulatory patients with multiple sclerosis (MS) and control subjects, bone mineral density (BMD), and body composition, that is, percent of bone minerals (M%), fat (F%), and remaining substances (L%). Total body composition and BMD were measured by dual-energy X-ray absorptiometry in 68 patients with definite MS and Expanded Disability Status Scale (EDSS) score ≤ 6.5 (41 females and 27 males) and 114 control individuals (72 females and 42 males). The amount of F%, L%, M%, and BMD in the whole body, arms, and trunk was not statistically different between MS patients (males and females) and controls, except in the lower extremities of female patients where there was increased F% and reduced L% compared with controls. There were no correlations between F%, L%, M%, and BMD at any anatomic region with EDSS or the cumulative corticosteroid dose. The reduced L% in the lower extremities of female patients suggests a possible increased subsequent risk of osteoporosis in the legs. Brief steroid courses administered during disease exacerbations in ambulatory MS patients did not result in obvious adverse consequences.

The present study investigates the histological alterations and expression of matrix metalloproteinase 9 (MMP-9) in disc specimens of 43 patients who underwent surgery for lumbar disc herniation. The immunostaining for MMP-9 was evaluated semi-quantitatively. Histologic degeneration was scored between 0 and 12 depending on the degree of chondrocyte proliferation and presence of tears and clefts, granular changes and mucous degeneration. Herniation was graded as grade 1 (protrusion), grade 2 (extrusion) or grade 3 (sequestration) on MRI. Although there was no significant statistical difference between the histologic degeneration score and age, degenerative changes were more pronounced in higher grade of herniation (p<0.0001). MMP-9 expression was related to histologic degenerative score in all age groups (p=0.0065). MMP-9 was also related to herniation grade in patients younger than 30 years of age (p=0.0037). No significant association was found between MMP-9 expression and herniation grade in patients who were 30–60 years or over 60 years of age.

Multiple myeloma is a B-lymphocyteneoplastic disorder. The incidence of its neurologic complications has been reported as high as 10 to 40% of the patients and may include peripheral neuropathy, spinal cord compression, stroke, cranial or spinal nerve involvement. Cognitive disorders occur due to intracranial lesion, renal in sufficiency, hypercalcemiaor serious anaemia. To describe the case of a 69-year-old man with no past medical history presented with gradually progressive dementia in a period of 15 months. By the time of the admission to our clinic had developed total disorientation and psychiatric symptoms, such as optical and acoustic hallucinations, impulsive behaviour and irritability. The neurological examination revealed asymmetric Parkinsonism signs (tremor, bradykinesia, rigidity and gait disorder). The laboratory tests showed only mild anaemia and the brain CT scan was negative. The patient was finally diagnosed with multiple myeloma IgA-lambda type, Durie-Salmon classification stage IIIA, and International Staging System stage III. Thereafter, he went onchemotherapy (cycles of VMP- Bortezomib 2.6 mg, Melphalan 10 mg, Prednisone 100 mg) and courses of radiation therapy for the spine osteolytic lesions. The patient responded well to the therapy, aslambda light chain decreased (measured by immunofixation of serum and urine) and a dramatic recovery of memory and other cognitive functions were evident within 3 weeks after the first cycle of the cytotoxic chemotherapy. To our knowledge, dementias a first symptom of Multiple Myeloma has never been reported. In addition, the differential diagnosis of dementias should always exclude secondary causes, since the aetiologic treatment could reverse the decline of the mental status of the patient.

Background: Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system originated by a complex interplay of environmental and genetic factors. The association of MS with the human leukocyte antigen (HLA) class II alleles was investigated in MS patients in northwest Greece, in the geographical region of Epirus.Objective: Our aim was to estimate the prevalence of the HLA-DRB1*1501, HLA-DQB1*0602 and HLA-DQA1*0102 alleles, consisting the most common susceptibility haplotype in North European and North American Caucasians. Methods: We studied 126 MS patients and 93 age and sex matched healthy controls. HLA typing was performed by a polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP) method.Results: We found that HLA-DRB1*1501, HLA-DQB1*0602 and HLA-DQA1*0102 alleles were significantly more frequent among patients (34% versus 11%, p = 0.00015; 69% versus 51%, p = 0.01; 76% versus 55%, p = 0.002, respectively). HLA-DRB1*1501, HLA-DQB1*0602, HLA-DQA1*0102 haplotype was significantly more common among patients (p = 0.00067). HLA-DRB1*1501 and HLA-DQB1*0602 alleles were more frequently detected in patients with initial symptoms from the brainstem or the cerebellum (p = 0.024). No significant correlation was observed among these alleles with sex, disease clinical course, or age at onsetConclusion: This is the first study to investigate genetic susceptibility to MS in Greece. Our results are in line with previous reports in North European and North American patients. (c) 2011 Elsevier B.V All rights reserved.

The authors regret that in the above published paper the author names were represented incorrectly. They are now represented correctly above. Comment on “Opportunistic cytomegalovirus infection in a patient receiving temozolomide for treatment of malignant glioma”Journal of Clinical NeuroscienceVol. 17Issue 3PreviewDear Professor Kaye, Full-Text PDF

The assessment of glioma proliferation rate is important to predict tumor behavior, response to therapy and prognosis. Various methods, largely involving immunohistological markers in tissue samples, have been proposed to this aim; however, they all require tissue removal through a biopsy or during a surgical procedure. Consequently, non-invasive imaging modalities that could reliably assess the proliferative potential of intracranial space-occupying lesions in vivo would be of obvious significance. In the present study we review the contribution of MRI, positron emission tomography and single-photon emission CT for the assessment of the proliferative potential of gliomas.