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Yen-Ying Chen, Hsiang-Ling Ho, Shih-Chieh Lin, Tiffany Dai-Hwa Ho, Chih-Yi Hsu
Objectives: To evaluate the prognostic values of microRNAs (miRNAs) in glioblastoma, and to see if there is an association between miRNAs and MGMT promoter methylation status. Methods: We collected paraffin blocks from resection specimens from 114 glioblastoma patients who had received temozolomide treatment and radiotherapy. Real-time quantitative PCR was performed to determine the expression levels of five miRNAs. Results: Upregulation of miR 125b-5p, miR 181d-3p, miR 221-3p, miR-222-3p, and miR 224-5p was observed in 13...
March 10, 2018: American Journal of Clinical Pathology
Ornella Franzese, Fiorenzo Battaini, Grazia Graziani, Lucio Tentori, Maria Luisa Barbaccia, Angelo Aquino, Mario Roselli, Maria Pia Fuggetta, Enzo Bonmassar, Francesco Torino
In recent years, immune checkpoint inhibitors (ICpI) have provided the ground to bring tumor immunity back to life thanks to their capacity to afford a real clinical benefit in terms of patient's survival. Essential to ICpI success is the presence of tumor-associated neoantigens generated by non-synonymous mutations, since a direct relationship between mutation load of malignant cells and susceptibility to ICpI has been confidently established. However, it has been also suggested that high intratumor heterogeneity (ITH) associated with subclonal neoantigens could not elicit adequate immune responses...
March 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Frank A Giordano, Stefanie Brehmer, Bettina Mürle, Grit Welzel, Elena Sperk, Anke Keller, Yasser Abo-Madyan, Elisabeth Scherzinger, Sven Clausen, Frank Schneider, Carsten Herskind, Martin Glas, Marcel Seiz-Rosenhagen, Christoph Groden, Daniel Hänggi, Peter Schmiedek, Bahman Emami, Luis Souhami, Kevin Petrecca, Frederik Wenz
BACKGROUND: The median time to recurrence of glioblastoma (GB) following multimodal treatment is ∼7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may improve outcomes. OBJECTIVE: To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective. METHODS: INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials...
March 8, 2018: Neurosurgery
Lorena Gurrieri, Elisa De Carlo, Lorenzo Gerratana, Giovanna De Maglio, Marianna Macerelli, Federica Edith Pisa, Elena Masiero, Giuseppe Aprile, Alessandro Follador, Fabio Puglisi, Gianpiero Fasola, Simona Rizzato, Stefano Pizzolitto
AIM: MGMT promoter methylation has been associated with improved survival in glioblastoma multiforme treated with temozolomide. However, there is no consensus on specific cut-off levels of methylation. The aims of the study were to explore the prognostic impact of MGMT methylation status and to analyze the role of specific cut-off values. MATERIALS & METHODS: We analyzed 108 glioblastoma multiforme patients treated between 2008 and 2013 stratified according to three pyrosequencing-based quantitative methylation in: unmethylated (methylation <9%), intermediate (9-29%) and highly methylated (>29%)...
March 9, 2018: Future Oncology
Antonin Dréan, Shai Rosenberg, François-Xavier Lejeune, Larissa Goli, Aravindan Arun Nadaradjane, Jérémy Guehennec, Charlotte Schmitt, Maïté Verreault, Franck Bielle, Karima Mokhtari, Sanson Marc, Alexandre Carpentier, Delattre Jean-Yves, Ahmed Idbaih
ATP-binding cassette transporters (ABC transporters) regulate traffic of multiple compounds, including chemotherapeutic agents, through biological membranes. They are expressed by multiple cell types and have been implicated in the drug resistance of some cancer cells. Despite significant research in ABC transporters in the context of many diseases, little is known about their expression and clinical value in glioblastoma (GBM). We analyzed expression of 49 ABC transporters in both commercial and patient-derived GBM cell lines as well as from 51 human GBM tumor biopsies...
March 8, 2018: Journal of Neuro-oncology
Carolina Belmar-Lopez, Carlos A Castaneda, Miluska Castillo, Pamela García-Corrochano, Enrique Orrego, Barbara Meléndez, Sandro Casavilca, Claudio Flores, Enrique Orrego
Purpose: O6 -methylguanine-DNA methyltransferase ( MGMT ) promoter methylation predicts the outcome and response to alkylating chemotherapy in glioblastoma. The aim of this study is to evaluate the prevalence of MGMT methylation in Peruvian glioblastoma cases. Patients and methods: We evaluated retrospectively 50 cases of resected glioblastoma during the period 2008-2013 at Instituto Nacional de Enfermedades Neoplasicas in Peru. Samples consisted of paraffin embedded and frozen tumour tissue...
2018: Ecancermedicalscience
Agm Mostofa, Surendra R Punganuru, Hanumantha Rao Madala, Kalkunte S Srivenugopal
Whether the antimutagenic DNA repair protein MGMT works solo in human cells and if it has other cellular functions is not known. Here, we show that human MGMT associates with PCNA and in turn, with the cell cycle inhibitor, p21cip1 in glioblastoma and other cancer cell lines. MGMT protein was shown to harbor a nearly perfect PCNA-Interacting Protein (PIP box) motif. Isogenic p53-null H1299 cells were engineered to express the p21 protein by two different procedures. Reciprocal immunoprecipitation/western blotting, Far-western blotting, and confocal microscopy confirmed the specific association of MGMT with PCNA and the ability of p21 to strongly disrupt the MGMT-PCNA complexes in tumor cells...
March 2, 2018: Neoplasia: An International Journal for Oncology Research
Chang Shu, Qiong Wang, Xiaoling Yan, Jinhuan Wang
The aim of our study is to build a framework for a better understanding of high-grade glioma (HGG) prognostic-related biomarkers. Whole-genome gene expression microarray was performed to identify differently expressed genes between HGGs and low-grade diffuse gliomas. Several machine learning algorithms were used to filter prognostic-related genes. One hundred ninety-three HGG patients after surgical resection were selected for survival analysis. Immunohistochemistry were performed on these tumor samples to analyze IDH1 mutation status and protein expression of WEE1...
March 3, 2018: Journal of Molecular Neuroscience: MN
Claudio Festuccia, Andrea Mancini, Alessandro Colapietro, Giovanni Luca Gravina, Flora Vitale, Francesco Marampon, Simona Delle Monache, Simona Pompili, Loredana Cristiano, Antonella Vetuschi, Vincenzo Tombolini, Yi Chen, Thomas Mehrling
BACKGROUND: The use of alkylating agents such as temozolomide in association with radiotherapy (RT) is the therapeutic standard of glioblastoma (GBM). This regimen modestly prolongs overall survival, also if, in light of the still dismal prognosis, further improvements are desperately needed, especially in the patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors, in which the benefit of standard treatment is less. Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor (AK-DACi) molecule that fuses the DNA damaging effect of bendamustine with the fully functional pan-histone deacetylase (HDAC) inhibitor, vorinostat, in a completely new chemical entity...
February 27, 2018: Journal of Hematology & Oncology
Micaela Freitas, Fábio Ferreira, Sónia Carvalho, Fernanda Silva, Paula Lopes, Luís Antunes, Sofia Salta, Francisca Diniz, Lúcio Lara Santos, José Flávio Videira, Rui Henrique, Carmen Jerónimo
BACKGROUND: Colorectal cancer (CRC) is one of the most incident cancers, associated with significant morbidity and mortality, and usually classified into three main molecular pathways: chromosomal instability, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Currently, available screening methods are either costly or of limited specificity, impairing global implementation. More cost-effective strategies, including DNA methylation-based tests, might prove advantageous...
February 27, 2018: Journal of Translational Medicine
Anna Lee, Irini Youssef, Virginia W Osborn, Joseph Safdieh, Daniel J Becker, David Schreiber
Multiple studies have identified O6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation status to be an important prognostic factor in glioblastoma (GBM). We used the National Cancer Data Base (NCDB) to analyze completeness of coding for MGMT as well as to compare outcomes of GBM patients treated with adjuvant chemoradiation based on MGMT promoter methylation status (positive, negative, unknown). Patients diagnosed with GBM from 2010 to 2012 who received adjuvant chemoradiation were identified...
February 23, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Caroline Happold, Nina Stojcheva, Manuela Silginer, Tobias Weiss, Patrick Roth, Guido Reifenberger, Michael Weller
O6 -methylguanine DNA methyltransferase (MGMT) promoter methylation is a predictive biomarker for benefit from alkylating chemotherapy, specifically temozolomide (TMZ), in glioblastoma, the most common malignant intrinsic brain tumor. Glioma-initiating cells (GIC) with stem-like properties have been associated with resistance to therapy and progression. We assessed the levels of MGMT mRNA and MGMT protein by real-time PCR and immunoblot and evaluated the impact of MGMT on TMZ sensitivity in clonogenicity assays in GIC sphere cultures (S) or differentiated adherent monolayer cultures (M)...
February 26, 2018: Journal of Neurochemistry
Tamara Ius, Daniela Cesselli, Miriam Isola, Giovanni Toniato, Giada Pauletto, Giovanni Sciacca, Sara Fabbro, Enrico Pegolo, Simona Rizzato, Antonio Paolo Beltrami, Carla di Loreto, Miran Skrap
PURPOSE OF REVIEW: The purpose of this study was to retrospectively evaluate the use of carmustine wafers (CWs) in the management of high-grade gliomas (HGGs). The data from our monoinstitutional series was compared with studies reported in the literature. Special emphasis was placed on the evaluation of side effects and the analysis of extent of resection and molecular profile as risk factors. RECENT FINDINGS: The implantation of CWs into the resection cavity during HGG treatment to deliver localized chemotherapy, followed by the Stupp protocol, remains debated in a clinical setting, largely due to the lack of appropriate phase III studies...
February 23, 2018: Current Treatment Options in Neurology
Hakyoung Kim, Do Hoon Lim, Tae Gyu Kim, Jung-Il Lee, Do-Hyun Nam, Ho Jun Seol, Doo-Sik Kong, Jung Won Choi, Yeon-Lim Suh, Sung Tae Kim
AIM: Leptomeningeal enhancement (LME) on preoperative brain magnetic resonance imaging (MRI) does not always indicate leptomeningeal seeding (LMS). With Stupp's regimen, authors have treated glioblastoma patients with LME on preoperative brain MRI but here we tried to find the clinical impact of LME. METHODS: From 2005 to 2015, 290 patients with glioblastoma have been treated with Stupp's regimen at Samsung Medical Center. Among these, 33 patients showed LME on preoperative brain MRI...
February 23, 2018: Asia-Pacific Journal of Clinical Oncology
Johann-Martin Hempel, Jens Schittenhelm, Uwe Klose, Benjamin Bender, Georg Bier, Marco Skardelly, Ghazaleh Tabatabai, Salvador Castaneda Vega, Ulrike Ernemann, Cornelia Brendle
PURPOSE: To assess the diagnostic performance of dynamic susceptibility contrast perfusion magnetic resonance perfusion imaging (DSC-MRI) for in vivo human glioma molecular profiling. METHODS: In this study 100 patients with histopathologically confirmed glioma who provided written informed consent were retrospectively assessed between January 2016 and February 2017 in two prospective trials that were approved by the local institutional review board. Cerebral blood volume (CBV) measurements from DSC-MRI were assessed, and histogram parameters of relative CBV (rCBV) results were compared among World Health Organization (WHO) 2016 based histological findings and molecular characteristics...
February 21, 2018: Clinical Neuroradiology
Csaba Tóth, Farkas Sükösd, Erzsébet Valicsek, Esther Herpel, Peter Schirmacher, László Tiszlavicz
Caudal type homeobox 2 (CDX2) has been well-established as a diagnostic marker for colorectal cancer (CRC); however, less is known about its regulation, particularly its potential interactions with the DNA repair proteins, adenomatous polyposis coli (APC) and β-catenin, in a non-transcriptional manner. In the present study, the protein expression of CDX2 was analyzed, depending on the expression of the DNA repair proteins, mismatch repair (MMR), O6-methylguanine DNA methyltransferase (MGMT) and excision repair cross-complementing 1 (ERCC1), and its importance in Wnt signaling was also determined...
March 2018: Oncology Letters
Yu Han, Lin-Feng Yan, Xi-Bin Wang, Ying-Zhi Sun, Xin Zhang, Zhi-Cheng Liu, Hai-Yan Nan, Yu-Chuan Hu, Yang Yang, Jin Zhang, Ying Yu, Qian Sun, Qiang Tian, Bo Hu, Gang Xiao, Wen Wang, Guang-Bin Cui
BACKGROUND: The methylation status of oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with treatment response in glioblastoma(GBM). Using pre-operative MRI techniques to predict MGMT promoter methylation status remains inconclusive. In this study, we investigated the value of features from structural and advanced imagings in predicting the methylation of MGMT promoter in primary glioblastoma patients. METHODS: Ninety-two pathologically confirmed primary glioblastoma patients underwent preoperative structural MR imagings and the efficacy of structural image features were qualitatively analyzed using Fisher's exact test...
February 21, 2018: BMC Cancer
Deborah T Blumenthal, Minhee Won, Minesh P Mehta, Mark R Gilbert, Paul D Brown, Felix Bokstein, David G Brachman, Maria Werner-Wasik, Grant K Hunter, Egils Valeinis, Kirsten Hopkins, Luis Souhami, Steven P Howard, Frank S Lieberman, Dennis C Shrieve, Merideth M Wendland, Cliff G Robinson, Peixin Zhang, Benjamin W Corn
Background: We previously reported the unexpected finding of significantly improved survival for newly-diagnosed glioblastoma patients when radiation therapy (RT) was initiated later (>4 weeks post-op) compared to earlier (≤2 weeks post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/RTOG trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly-diagnosed glioblastoma patients from two studies, treated with RT and concurrent TMZ followed by adjuvant TMZ...
February 15, 2018: Neuro-oncology
Stephanie E Combs, Kerstin A Kessel, Josefine Hesse, Christoph Straube, Claus Zimmer, Friederike Schmidt-Graf, Jürgen Schlegel, Jens Gempt, Bernhard Meyer
BACKGROUND: Generally, re-irradiation (Re-RT) is offered to patients with glioma recurrences with macroscopic lesions. Results are discussed controversially, and some centers postulate limited benefit of Re-RT. Re-RT is generally offered to tumors up to 4 cm in diameter. Re-resection is also discussed controversially; however, recent studies have shown significant benefit. OBJECTIVE: To combine proactive re-resection and early Re-RT in patients with recurrent glioma...
February 16, 2018: Neurosurgery
Niina Sandholm, Per-Henrik Groop
Diabetic kidney disease and other long-term complications are common in diabetes, and comprise the main cause of co-morbidity and premature mortality in individuals with diabetes. While familial clustering and heritability have been reported for all diabetic complications, the genetic background and the molecular mechanisms remain poorly understood. In recent years, genome-wide association studies have identified a few susceptibility loci for the renal complications as well as for diabetic retinopathy, diabetic cardiovascular disease and mortality...
February 13, 2018: Current Opinion in Genetics & Development
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