153 results on '"Aa Brandes"'
Search Results
2. Adjuvant chemotherapy in adult medulloblastoma: is it an option for average-risk patients?
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Carmelo Lucio Sturiale, Maurizio Mascarin, Damiano Balestrini, Barbara Masotto, Enrico Franceschi, Rosalba Poggi, Lorenzo Volpin, Gianluca Marucci, Daniela Danieli, Alexandro Paccapelo, Aa Brandes, Marina Paola Gardiman, Marco Bartolotti, Raffaele Agati, and Claudio Ghimenton
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Adult ,Male ,Risk ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Cyclophosphamide ,medicine.medical_treatment ,Gastroenterology ,Neurosurgical Procedures ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Median follow-up ,Internal medicine ,medicine ,Humans ,Cerebellar Neoplasms ,Survival analysis ,Etoposide ,Retrospective Studies ,Medulloblastoma ,Chemotherapy ,business.industry ,Standard treatment ,Middle Aged ,medicine.disease ,Survival Analysis ,Surgery ,Radiation therapy ,Neurology ,Oncology ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,Radiotherapy, Adjuvant ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Follow-Up Studies ,medicine.drug - Abstract
The standard treatment in children with average-risk medulloblastoma (MB) is reduced-dose radiotherapy (RT) followed by chemotherapy. However, in adults, there is no agreement on the use of adjuvant chemotherapy. We performed a retrospective analysis of adult MB patients with average-risk disease, defined as no postsurgical residual (or ≤1.5 cm(2)) and no metastatic disease (M0). Main inclusion criteria were: age16 years, post-surgical treatment with craniospinal irradiation with or without adjuvant chemotherapy (cisplatin and etoposide ± cyclophosphamide). From 1988 to 2012 were accrued 43 average-risk MB patients treated with surgery and adjuvant RT. Fifteen (34.9 %) patients received also chemotherapy: 7 before RT, 5 after RT, and 3 before and after RT. Reasons to administer chemotherapy were presence of residual disease (even if ≤1.5 cm) and delay in RT. After a median follow up time of 10 years (range: 8-13), median survival was 18 years (95 % CI 9-28) in patients who receive RT alone, and was not reached in patients treated with RT plus chemotherapy. The survival rates at 5, 10 and 15 years were 100 %, 78.6 % (95 % CI 60.0-97.2 %) and 60.2 % (95 % CI 36.9-83.5 %), in patients treated with RT alone, and 100, 100 and 100 %, in patients treated with RT plus chemotherapy (p = 0.079). Our findings suggest a role for adjuvant chemotherapy in the treatment of average-risk MB adult patients. Further improvements might drive to add chemotherapy in average-risk setting with less favourable biological signatures (i.e., non-WNT group).
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- 2016
3. Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)
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Silvia Zanon, Enrico Franceschi, Marina Faedi, Aa Brandes, Marica Eoli, Elena Mazza, Michele Reni, and Giuseppe Lombardi
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Salvage therapy ,Neutropenia ,Toxicology ,Disease-Free Survival ,Meningioma ,03 medical and health sciences ,0302 clinical medicine ,Glioma ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Meningeal Neoplasms ,medicine ,Clinical endpoint ,Humans ,Hydroxyurea ,Pharmacology (medical) ,neoplasms ,Survival rate ,Aged ,Pharmacology ,business.industry ,Imatinib ,Middle Aged ,medicine.disease ,Surgery ,Survival Rate ,Radiation therapy ,Treatment Outcome ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Female ,Neoplasm Recurrence, Local ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Patients with recurrent or progressive WHO grade I–III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18–75 years, ECOG performance status 0–2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient’s refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75 %, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75 %, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.
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- 2015
4. 367MO Association between socioeconomic status and survival in glioblastoma: An Italian single-centre prospective, observational study
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C. Lamperini, Alicia Tosoni, M. Sisi, M. Di Battista, Aa Brandes, M. Mosca, Enrico Franceschi, Antonella Mura, Stefania Bartolini, Giacomo Nuvola, V. Di Nunno, S. Minichillo, and Lidia Gatto
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Single centre ,Oncology ,business.industry ,medicine ,Observational study ,Hematology ,medicine.disease ,Association (psychology) ,business ,Socioeconomic status ,Demography ,Glioblastoma - Published
- 2020
5. Gender and MGMT methylation in glioblastoma patients: interactions in the PERNO prospective study
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Giovanni Lanza, Maria Michiara, Claudia Biasini, Marina Faedi, A. Fioravanti, Aa Brandes, Enrico Maria Silini, Roberta Depenni, Luigino Tosatto, Michele Alessandro Cavallo, G. Pavesi, D. Bartolini, E. Giombelli, E. Zunarelli, Alicia Tosoni, Enrico Franceschi, F. Zanelli, and Benedetta Urbini
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Hematology ,Mgmt methylation ,medicine.disease ,business ,Prospective cohort study ,Glioblastoma ,NO - Published
- 2017
6. Dosimetric Analysis, Acute Toxicity and Long-Term Outcome of Craniospinal Irradiation Using Helical Tomotherapy in Children and Adults
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Giuseppe Cinalli, Eva Passone, Paola Chiovati, A. Drigo, M. Gigante, Elisa Coassin, Aa Brandes, Giovanni Franchin, G. Sartor, Barbara Masotto, Jerry Polesel, Maurizio Mascarin, and V. Kiren
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Cancer Research ,medicine.medical_specialty ,Radiation ,business.industry ,medicine.medical_treatment ,Acute toxicity ,Tomotherapy ,Craniospinal Irradiation ,Term (time) ,Oncology ,Medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,business - Published
- 2019
7. The role of clinical and molecular characteristics in low grade gliomas
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C Bortolotti, Andrea Talacchi, R. Degli Esposti, Antonella Mura, Michela Visani, Stefania Bartolini, Alexandro Paccapelo, Lorenzo Volpin, Giovenzio Genestreti, Alicia Tosoni, Enrico Franceschi, A. Fioravanti, Aa Brandes, Dario de Biase, Stefano Pizzolitto, Raffaele Agati, Giovanni Tallini, and S. Minichillo
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Hematology ,business - Published
- 2017
8. Histopathologic Modification in CNS Neuroectodermal Tumor: A Long Term Follow Up of a Clinical Case
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E, Franceschi, primary, M, Bartolotti, additional, AA, Brandes, additional, M, Antonelli, additional, F, Giangaspero, additional, G, Tallini, additional, D, Capper, additional, A, Pession, additional, M, Scarpelli, additional, S, Vecchioni, additional, D, Balestrini, additional, D, De Diase, additional, and MP, Foschini, additional
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- 2018
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9. The role of treatments in IDH mutant molecular astrocytomas
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Daniela Danieli, Maria Pia Foschini, S. Minichillo, Andrea Talacchi, Luigi Cirillo, Aa Brandes, M. Di Battista, Andrea Pession, C Bortolotti, Stefania Bartolini, Enrico Franceschi, Alicia Tosoni, Antonella Mura, Giovanni Tallini, Alexandro Paccapelo, and Giovenzio Genestreti
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03 medical and health sciences ,0302 clinical medicine ,Oncology ,business.industry ,030220 oncology & carcinogenesis ,Mutant ,Medicine ,Hematology ,business ,Molecular biology ,030217 neurology & neurosurgery - Published
- 2017
10. IDH mutant and 1p19q codeleted low grade gliomas: to treat or not to treat?
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Andrea Pession, Stefano Pizzolitto, S. Minichillo, Enrico Franceschi, Dario de Biase, Antonella Mura, Alicia Tosoni, R. Degli Esposti, Stefania Bartolini, Daniela Danieli, Lorenzo Volpin, A. Fioravanti, Aa Brandes, Alexandro Paccapelo, Giovenzio Genestreti, and Raffaele Agati
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Oncology ,business.industry ,Mutant ,Cancer research ,Medicine ,Hematology ,business - Published
- 2017
11. Clinical risk or molecular risk: What matters in low grade gliomas? A study from the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)
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Gianluca Marucci, Antonella Mura, Dario de Biase, Lorenzo Volpin, Andrea Pession, Alicia Tosoni, L. Albini Riccioli, Enrico Franceschi, Michele Reni, C. Degli Esposti, Aa Brandes, Alexandro Paccapelo, Giovenzio Genestreti, Daniela Danieli, Stefania Bartolini, C Bortolotti, Giovanni Tallini, Claudio Ghimenton, Luigi Cirillo, and Rosalba Poggi
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,Hematology ,business ,Clinical risk factor - Published
- 2016
12. The role of clinical risk in Low Grade Glioma patients in the era of genomic medicine: a GICNO study
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Stefano Pizzolitto, Girolamo Crisi, A. Fioravanti, Aa Brandes, A. Gamboni, Giuseppe Pasini, Dario de Biase, Claudio Dazzi, M. Di Battista, Mino Zucchelli, Enrico Franceschi, Stefania Bartolini, E. Zunarelli, Roberta Depenni, Antonella Bacci, Rosalba Poggi, and Antonella Mura
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Oncology ,medicine.medical_specialty ,Pathology ,business.industry ,Internal medicine ,medicine ,Genomic medicine ,Low-Grade Glioma ,Hematology ,business ,Clinical risk factor - Published
- 2016
13. LB-05PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL
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M. J. B. Taphoorn, Felix Sahm, Michael Platten, Walter Taal, François Dubois, Carlos Bais, Aa. Brandes, Thierry Gorlia, Vassilis Golfinopoulos, M. J. van den Bent, D. Musmeci, Ahmed Idbaih, Wolfgang Wick, Paul Clement, Michel Fabbro, Julien Domont, Martin Bendszus, Roger Stupp, Michael Weller, and Mario Campone
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Oncology ,Cancer Research ,medicine.medical_specialty ,Temozolomide ,Bevacizumab ,Combination therapy ,business.industry ,Hazard ratio ,Lomustine ,medicine.disease ,Institut Gustave Roussy ,Internal medicine ,Concomitant ,medicine ,Neurology (clinical) ,business ,Progressive disease ,medicine.drug - Abstract
LB-05. PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND LOMUSTINE IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL W. Wick1, AA. Brandes2, T. Gorlia3, M. Bendszus1, F. Sahm1, W. Taal4, M. Taphoorn5, J. Domont6, A. Idbaih7, M. Campone8, P.M. Clement9, R. Stupp10, M. Fabbro11, F. Dubois12, C. Bais13, D. Musmeci3, M. Platten1, M. Weller10, V. Golfinopoulos3, and M. van den Bent4; University Medical Center & German Cancer Research Center, Heidelberg, Germany; Medical Oncology Department, AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italia; EORTC Headquarters, Brussels, Belgium; Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Medical Center Haaglanden, The Hague, The Netherlands The Netherlands; Institut Gustave Roussy, Villejuif, France; AP-HP, Hopital Universitaire La Pitie Salperiere and Sorbonne Universites, UPMC Univ Paris 06, Paris, France; Institut de Cancerologie de l’Ouest (ICO) Centre Rene Gauducheau, Saint-Herblain, France; U.Z. Leuven KU Leuven, Belgium; Zurich University Medical Center, Zurich, Switzerland; Institut regional du Cancer Montpellier, Montpellier, France; CHRU de Lille, Lille, France; Genentech Inc., South San Francisco, California, USA BACKGROUND: Phase II data from the BELOB trial indicated that the combination of bevacizumab and lomustine might produce an overall survival (OS) benefit compared with either monotherapy for patients with first progression of a glioblastoma. The primary objective of the phase III part of EORTC 26101 is to investigate whether the addition of bevacizumab to lomustine improves overall OS in patients with first progression of a glioblastoma compared to treatment with lomustine alone. METHODS: Patients with progressive disease after standard chemo-radiotherapy with temozolomide at least 3 months off the concomitant part were randomized 2:1 between lomustine 90 mg/m (cap. 160 mg) mg every six weeks plus 10 mg/kg bevacizumab every two weeks and lomustine single agent 110 mg/m (cap. 200 mg) every six weeks followed by best investigators choice at further progression. In the absence of hematological toxicity . grade 1 during the first cycle in the combination arms, the dose of lomustine could be escalated to 110 mg/m (cap 200 mg) in the second cycle. Neuroimaging according to a standard protocol was assessed locally and centrally. RESULTS: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (hazard ratio (HR) 0.95 (confidence interval (CI) 0.74, 1.21), p 1⁄4 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed progression-free survival (PFS) was longer with the addition of bevacizumab to lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the lomustine arm respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. CONCLUSIONS: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. The future challenge is to identify those patients deriving benefit from that treatment. Neuro-Oncology 17:v1–v1, 2015. doi:10.1093/neuonc/nov306 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.
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- 2015
14. Time to response (TTR) and early tumor shrinkage (ETS) in recurrent glioblastoma patients treated with bevacizumab: an exploratory analysis of the prospective randomized AVAREG (ML25739) phase II study
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Giacomo Cartenì, Aa Brandes, Giovanni Rosti, Matteo Clavarezza, Emanuela Proietti, Alessandra Fabi, Alicia Tosoni, Claudia Caserta, Enrico Franceschi, Raffaele Agati, Michele Reni, Alexandro Paccapelo, Evaristo Maiello, Vittorina Zagonel, and Gaetano Finocchiaro
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,Bevacizumab ,business.industry ,Recurrent glioblastoma ,Tumor shrinkage ,Phases of clinical research ,Hematology ,Exploratory analysis ,medicine.disease ,nervous system diseases ,Surgery ,Transthyretin ,Internal medicine ,medicine ,biology.protein ,business ,Glioblastoma ,medicine.drug - Abstract
2047 Background: The treatment of recurrent glioblastoma (GBM) remains an open issue, and the role of bevacizumab (BEV) has been widely debated since a few studies compared this agent with the stan...
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- 2015
15. Randomized Phase Ii Trial Avareg (Ml25739) with Bevacizumab (Bev) or Fotemustine (Ftm) in Recurrent Gbm: Final Results from the Randomized Phase Ii Trial
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Simona Doria, Aa Brandes, Raffaele Agati, Matteo Clavarezza, Michele Reni, Giacomo Cartenì, Marica Eoli, Gaetano Finocchiaro, V. Eusebi, Giuseppe Lombardi, Anna Galli, Alessandra Fabi, M. Monteforte, Enrico Franceschi, Giovanni Rosti, Evaristo Maiello, Claudia Caserta, and Vittorina Zagonel
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medicine.medical_specialty ,Bevacizumab ,business.industry ,Perforation (oil well) ,Phases of clinical research ,Hematology ,Neutropenia ,medicine.disease ,Gastroenterology ,Surgery ,Pulmonary embolism ,Oncology ,Internal medicine ,medicine ,Clinical endpoint ,Fotemustine ,business ,Survival rate ,medicine.drug - Abstract
Aim: The treatment of recurrent glioblastoma (GBM) remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. Methods: A multicenter, open label, randomized (2:1), non-comparative phase II study (EudraCT 2011-001363-46; AVAREG - ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks was conducted. Primary endpoint was overall survival at 6 months (OS6). Stratification factors were age ( 55 yrs) and resection for recurrent disease (yes vs no). Results: 91 patients (pts) with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 yrs (range: 28-78), ECOG PS was 0/1/2 in 42/35/14 pts. All pts received RT/TMZ accordingly with EORTC 26981-22981/NCIC CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At the time of recurrence, 21 pts (23.1%) underwent re-resection before the inclusion into the study (13/8 pts in BEV/FTM arms, respectively). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI: 48.4 - 74.5) and 73.3% (95%CI: 54.1 - 87.7), OS9 was 37.9% (95%CI: 25.5–51.6) and 46.7% (95%CI 28.3–65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI: 5.8 - 9.2) in the BEV arm and 8.7 months (95%CI: 6.3-15.4) in the FTM arm. In the BEV arm, OS6 and OS9 were 77.8% (95%CI: 57.7–91.4) and 59.3% (95%CI: 38.8 - 77.6) in pts ≤55 yrs, and were 48.4% (95%CI: 30.1 - 66.9) and 19.3% (95%CI: 7.4 - 37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts ≤55 yrs was 2.0 (95%CI: 1.0-4.1, p = 0.05). G 3-4- toxicity BEV FTM Neutropenia 1 (1.7%) 4 (12.5%) Thrombocytopenia 0 7 (21.9%) Intestinal perforation 2 (3.4%) 0 Cerebral ischaemia/haemorrage 2 (3.4%) 0 Pulmonary embolism 1 (1.7%) 0 Acute myocardial infarction 1 (1.7%) 0 Conclusions: BEV in recurrent GBM showed survival rates superimposable with FTM. Disclosure: V. Zagonel: Roche – Speaker; M. Reni: Genentech - Advisory board; G. Rosti: Roche - Speaker A. Galli: Roche – employee; S. Doria: Roche – employee; All other authors have declared no conflicts of interest.
- Published
- 2014
16. Epigenetic landscape reorganization and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma.
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Ghisai SA, van Hijfte L, Vallentgoed WR, Tesileanu CMS, de Heer I, Kros JM, Sanson M, Gorlia T, Wick W, Vogelbaum MA, Brandes AA, Franceschi E, Clement PM, Nowak AK, Golfinopoulos V, van den Bent MJ, French PJ, and Hoogstrate Y
- Abstract
Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is however difficult and, apart from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. Experimental Design: RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n=138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. We used the DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) that is based on classification scores derived from a CNS-tumor classifier. We found that the CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with i) an upregulation of cell cycling genes; ii) a downregulation of glial differentiation genes; iii) an upregulation of embryonic development genes (e.g. HOX, PAX and TBX) and iv) an upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes.
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- 2024
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17. Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial.
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Kessler T, Schrimpf D, Doerner L, Hai L, Kaulen LD, Ito J, van den Bent M, Taphoorn M, Brandes AA, Idbaih A, Dômont J, Clement PM, Campone M, Bendszus M, von Deimling A, Sahm F, Platten M, Wick W, and Wick A
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- Humans, DNA Methylation, Prognosis, Bevacizumab therapeutic use, Lomustine, DNA Modification Methylases genetics, O(6)-Methylguanine-DNA Methyltransferase genetics, DNA Repair Enzymes genetics, Biomarkers, High-Throughput Nucleotide Sequencing, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma pathology, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms pathology
- Abstract
Purpose: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma., Experimental Design: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival., Results: Of patients' samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment., Conclusions: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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18. Glioblastoma treatment slowly moves toward change: novel druggable targets and translational horizons in 2022.
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Gatto L, Franceschi E, Tosoni A, Di Nunno V, Bartolini S, and Brandes AA
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- Adult, Humans, Immunotherapy methods, Combined Modality Therapy, Glioblastoma drug therapy, Glioblastoma pathology, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Oncolytic Virotherapy methods
- Abstract
Introduction: Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM treatment options have been the same for the past 30 years and have only modestly extended survival, despite aggressive multimodal treatments. The progressively better knowledge of GBM biology and a comprehensive analysis of its genomic profile have elucidated GBM heterogeneity, contributing to a more effective molecular classification and to the development of innovative targeted therapeutic approaches., Areas Covered: This article reports all the noteworthy innovations for immunotherapy and targeted therapy, providing insights into the current advances in trial designs, including combination therapies with immuno-oncology agents and target combinations., Expert Opinion: GBM molecular heterogeneity and brain anatomical characteristics critically restrain drug effectiveness. Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific 'off-the-shelf' CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance: hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies.
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- 2023
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19. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial.
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Omuro A, Brandes AA, Carpentier AF, Idbaih A, Reardon DA, Cloughesy T, Sumrall A, Baehring J, van den Bent M, Bähr O, Lombardi G, Mulholland P, Tabatabai G, Lassen U, Sepulveda JM, Khasraw M, Vauleon E, Muragaki Y, Di Giacomo AM, Butowski N, Roth P, Qian X, Fu AZ, Liu Y, Potter V, Chalamandaris AG, Tatsuoka K, Lim M, and Weller M
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- Humans, Temozolomide therapeutic use, Nivolumab therapeutic use, Disease-Free Survival, Progression-Free Survival, Antineoplastic Agents, Alkylating therapeutic use, DNA Modification Methylases genetics, Tumor Suppressor Proteins genetics, DNA Repair Enzymes genetics, Glioblastoma drug therapy, Glioblastoma genetics, Brain Neoplasms drug therapy, Brain Neoplasms genetics
- Abstract
Background: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter., Methods: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS., Results: A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively., Conclusions: The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2023
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20. How to treat histone 3 altered gliomas: molecular landscape and therapeutic developments.
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Di Nunno V, Franceschi E, Gatto L, Tosoni A, Bartolini S, and Brandes AA
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- Humans, Histones genetics, Histones therapeutic use, Retrospective Studies, Prospective Studies, Mutation, Brain Neoplasms therapy, Brain Neoplasms drug therapy, Glioma therapy, Glioma drug therapy
- Abstract
Introduction: Diffuse midline gliomas (DMG) and diffuse hemispheric glioma (DHG) are both rare tumors characterized and recognized for specific alterations of histone 3 including H3K27 (DMG) and H3G34 (DHG). Despite these tumors arising from alterations of the same gene their clinical, radiological, and molecular behaviors strongly diverge, requiring a personalized therapeutic approach., Areas Covered: We performed a review on Medline/PudMed aiming to search papers relative to prospective trials, retrospective studies, case series, and case reports of interest in order to investigate current knowledge toward the main clinical and molecular characteristics, radiology, and diagnosis, loco-regional and systemic treatments of these tumors. Moreover, we also evaluated the novel treatments under investigation., Expert Opinion: Thanks to an increased knowledge of the genomic landscape of these rare tumors, there are novels promising therapeutic targets for these malignancies. However, the majority of available trials allowed enrollment only in DMG, while few studies are focused on or allow the inclusion of DHG patients.
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- 2023
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21. Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101.
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Le Rhun E, Oppong FB, van den Bent M, Wick W, Brandes AA, Taphoorn MJ, Platten M, Idbaih A, Clement PM, Preusser M, Golfinopoulos V, Gorlia T, and Weller M
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- Humans, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bevacizumab adverse effects, Feasibility Studies, Lomustine adverse effects, Neoplasm Recurrence, Local pathology, Retrospective Studies, Brain Neoplasms therapy, Glioblastoma therapy, Thrombocytopenia chemically induced, Thrombocytopenia drug therapy
- Abstract
Background: Thrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine in recurrent glioblastoma., Methods: We performed a retrospective analysis of the associations of thrombocytopenia with treatment delivery and outcome in EORTC 26101, a randomised trial designed to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma., Results: A total of 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients (57%) of group 1 and 187 patients (66%) of group 2 experiencing at least one episode of thrombocytopenia, 36 patients (16%) in group 1 and 93 (33%) in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. On adjusted analysis accounting for major prognostic factors, dose modification induced by thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumours in groups 1 and 2. This effect was noted for overall survival, too, but only for group 2 patients., Conclusion: Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine chemotherapy in recurrent glioblastoma. Mitigating thrombocytopenia to enhance lomustine exposure might improve outcome in patients with MGMT promoter-methylated tumours., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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22. Beyond Imaging and Genetic Signature in Glioblastoma: Radiogenomic Holistic Approach in Neuro-Oncology.
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Gatto L, Franceschi E, Tosoni A, Di Nunno V, Tonon C, Lodi R, Agati R, Bartolini S, and Brandes AA
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Glioblastoma (GBM) is a malignant brain tumor exhibiting rapid and infiltrative growth, with less than 10% of patients surviving over 5 years, despite aggressive and multimodal treatments. The poor prognosis and the lack of effective pharmacological treatments are imputable to a remarkable histological and molecular heterogeneity of GBM, which has led, to date, to the failure of precision oncology and targeted therapies. Identification of molecular biomarkers is a paradigm for comprehensive and tailored treatments; nevertheless, biopsy sampling has proved to be invasive and limited. Radiogenomics is an emerging translational field of research aiming to study the correlation between radiographic signature and underlying gene expression. Although a research field still under development, not yet incorporated into routine clinical practice, it promises to be a useful non-invasive tool for future personalized/adaptive neuro-oncology. This review provides an up-to-date summary of the recent advancements in the use of magnetic resonance imaging (MRI) radiogenomics for the assessment of molecular markers of interest in GBM regarding prognosis and response to treatments, for monitoring recurrence, also providing insights into the potential efficacy of such an approach for survival prognostication. Despite a high sensitivity and specificity in almost all studies, accuracy, reproducibility and clinical value of radiomic features are the Achilles heel of this newborn tool. Looking into the future, investigators' efforts should be directed towards standardization and a disciplined approach to data collection, algorithms, and statistical analysis.
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- 2022
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23. Factors associated with health-related quality of life (HRQoL) deterioration in glioma patients during the progression-free survival period.
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Coomans MB, Dirven L, Aaronson N, Baumert BG, van den Bent M, Bottomley A, Brandes AA, Chinot O, Coens C, Gorlia T, Herrlinger U, Keime-Guibert F, Malmström A, Martinelli F, Stupp R, Talacchi A, Weller M, Wick W, Reijneveld JC, and Taphoorn MJB
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- Humans, Quality of Life, Progression-Free Survival, Brain Neoplasms therapy, Glioma
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Background: Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period., Methods: We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period., Results: Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9-29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8-5.4 months, and median time-to-deterioration between 8.2-11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period., Conclusions: HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients' functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2022
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24. Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors.
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Lassman AB, Hoang-Xuan K, Polley MC, Brandes AA, Cairncross JG, Kros JM, Ashby LS, Taphoorn MJB, Souhami L, Dinjens WNM, Laack NN, Kouwenhoven MCM, Fink KL, French PJ, Macdonald DR, Lacombe D, Won M, Gorlia T, Mehta MP, and van den Bent MJ
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials, Phase III as Topic, Humans, Lomustine therapeutic use, Neoplasm Recurrence, Local drug therapy, Procarbazine therapeutic use, Vincristine therapeutic use, Brain Neoplasms drug therapy, Oligodendroglioma drug therapy
- Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV., Competing Interests: Andrew B. LassmanConsulting or Advisory Role: Karyopharm Therapeutics, Sapience Therapeutics, Bayer, Orbus Therapeutics, BioClinica, Novocure, Elsevier, Vivacitas Oncology, ChimerixResearch Funding: AbbVie (Inst), Novartis (Inst), Genentech/Roche (Inst), Aeterna Zentaris (Inst), Kadmon (Inst), BeiGene (Inst), VBI Vaccines (Inst), Pfizer (Inst), Millennium (Inst), Karyopharm Therapeutics (Inst), Bayer (Inst), QED Therapeutics (Inst), Orbus Therapeutics (Inst), BMS (Inst), Chimerix (Inst), NextSource (Inst), DelMar Pharmaceuticals (Inst), Corden (Inst), Kazia Therapeutics (Inst), Servier (Inst), Semus (Inst), Novocure (Inst)Travel, Accommodations, Expenses: Karyopharm Therapeutics, QED Therapeutics, Novartis, Pfizer, VBI Vaccines, Chimerix, Orbus Therapeutics, Novocure Khê Hoang-XuanHonoraria: BTG J. Gregory CairncrossOther Relationship: IQVIA Lynn S. AshbyHonoraria: Arbor Pharmaceuticals Luis SouhamiHonoraria: Varian Medical SystemsConsulting or Advisory Role: AbbVieResearch Funding: Sanofi (Inst)Travel, Accommodations, Expenses: Varian Medical Systems Winand N.M. DinjensConsulting or Advisory Role: Bristol Myers Squibb, Roche, Bayer, AstraZeneca, Novartis, LillySpeakers' Bureau: medtlks Nadia N. LaackResearch Funding: Bristol Myers Squib (Inst) Karen L. FinkResearch Funding: Northwest Biotherapeutics (Inst), Novocure (Inst), Orbus Therapeutics (Inst), Denovo Biopharma (Inst), Translational Genomics Research Institute (Inst), CNS Pharmaceuticals (Inst), Agios (Inst), Incyte (Inst) Pim J. FrenchEmployment: Bristol Myers Squibb (I), Janssen-Cilag (I)Stock and Other Ownership Interests: Bristol Myers Squibb (I)Honoraria: AurikamedConsulting or Advisory Role: Clarionhealthcare David R. MacdonaldResearch Funding: Celgene (Inst), SERVIER (Inst). Minesh MehtaLeadership: OncoceuticsStock and Other Ownership Interests: ChimerixConsulting or Advisory Role: Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics, XoftPatents, Royalties, Other Intellectual Property: WARF patent 14/934,27, Topical Vasoconstritor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and RadiotherapyUncompensated Relationships: Xcision Medical SystemsUncompensated Relationships: ViewRay Martin J. van den BentEmployment: AstraZeneca (I)Consulting or Advisory Role: Boehringer Ingelheim, Bayer, carthera, Genenta Science, Nerviano Medical Sciences, Boston Pharmaceuticals, chimerix, AstraZenecaResearch Funding: AbbVie (Inst)No other potential conflicts of interest were reported.
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- 2022
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25. Expertise is crucial to prolong survival in average risk medulloblastoma: long-term results of a retrospective study.
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Franceschi E, Minichillo S, Tosoni A, Mascarin M, Mura A, Di Battista M, Di Nunno V, Gatto L, Lodi R, Bartolini S, and Brandes AA
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- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chemotherapy, Adjuvant, Disease-Free Survival, Humans, Retrospective Studies, Cerebellar Neoplasms radiotherapy, Medulloblastoma pathology, Medulloblastoma therapy
- Abstract
Purpose: Medulloblastoma is a rare tumor in adults and the use of adjuvant chemotherapy in average risk patients is debated., Methods: Patients included in our study were ⩾16 years of age, had histologically confirmed medulloblastoma, and underwent adjuvant radiotherapy with or without chemotherapy. Average risk was defined according to the Chang classification., Results: We included 48 average-risk patients. Median follow-up was 151.5 months (95% confidence interval, 124.5-178.5). Both progression-free survival (PFS) and overall survival (OS) were significantly influenced by adjuvant chemotherapy (PFS: hazard ratio [HR], 0.334, p = 0.05; OS: HR, 0.187, p = 0.017) and by receiving the treatment in a referral center (PFS: HR, 0.250, p = 0.008; OS: HR, 0.295, p = 0.038)., Conclusions: Treating patients with average-risk medulloblastoma in a referral center improves both PFS and OS, does adding adjuvant chemotherapy.
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- 2022
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26. Tumor-Associated Microenvironment of Adult Gliomas: A Review.
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Di Nunno V, Franceschi E, Tosoni A, Gatto L, Bartolini S, and Brandes AA
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The glioma-associated tumor microenvironment involves a multitude of different cells ranging from immune cells to endothelial, glial, and neuronal cells surrounding the primary tumor. The interactions between these cells and glioblastoma (GBM) have been deeply investigated while very little data are available on patients with lower-grade gliomas. In these tumors, it has been demonstrated that the composition of the microenvironment differs according to the isocitrate dehydrogenase status (mutated/wild type), the presence/absence of codeletion, and the expression of specific alterations including H3K27 and/or other gene mutations. In addition, mechanisms by which the tumor microenvironment sustains the growth and proliferation of glioma cells are still partially unknown. Nonetheless, a better knowledge of the tumor-associated microenvironment can be a key issue in the optic of novel therapeutic drug development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Nunno, Franceschi, Tosoni, Gatto, Bartolini and Brandes.)
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- 2022
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27. Hypermutation as a potential predictive biomarker of immunotherapy efficacy in high-grade gliomas: a broken dream?
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Gatto L, Franceschi E, Tosoni A, Nunno VD, Bartolini S, and Brandes AA
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- Biomarkers, Tumor genetics, Colorectal Neoplasms, Humans, Immunotherapy, Neoplastic Syndromes, Hereditary, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms therapy, Glioma genetics, Glioma therapy
- Abstract
A high tumor mutational burden and mismatch repair deficiency are observed in 'hypermutated' high-grade gliomas (HGGs); however, the molecular characterization of this distinct subtype and whether it predicts the response to immune checkpoint inhibitors (ICIs) are largely unknown. Pembrolizumab is a valid therapeutic option for the treatment of hypermutated cancers of diverse origin, but only a few clinical trials have explored the activity of ICIs in hypermutated HGGs. HGGs appear to differ from other cancers, likely due to the prevalence of subclonal versus clonal neoantigens, which are unable to elicit an immune response with ICIs. The main aim of this review is to summarize the current knowledge on hypermutation in HGGs, focusing on the broken promises of tumor mutational burden and mismatch repair deficiency as potential biomarkers of response to ICIs.
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- 2022
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28. Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial.
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Tesileanu CMS, Sanson M, Wick W, Brandes AA, Clement PM, Erridge SC, Vogelbaum MA, Nowak AK, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Rogers L, Taal W, Rudà R, Weller M, McBain C, van Linde ME, Aldape K, Jenkins RB, Kros JM, Wesseling P, von Deimling A, Hoogstrate Y, de Heer I, Atmodimedjo PN, Dubbink HJ, Brouwer RWW, van IJcken WFJ, Cheung KJ, Golfinopoulos V, Baumert BG, Gorlia T, French PJ, and van den Bent MJ
- Subjects
- Antineoplastic Agents, Alkylating, DNA Methylation, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Dacarbazine, Humans, Isocitrate Dehydrogenase genetics, Prospective Studies, Temozolomide therapeutic use, Astrocytoma drug therapy, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms radiotherapy, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma radiotherapy
- Abstract
Purpose: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase-wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]., Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis., Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82-1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival., Conclusions: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population., (©2022 American Association for Cancer Research.)
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- 2022
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29. Molecular Characterization of Pancreatic Ductal Adenocarcinoma Using a Next-Generation Sequencing Custom-Designed Multigene Panel.
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Malvi D, Vasuri F, Maloberti T, Sanza V, De Leo A, Fornelli A, Masetti M, Benini C, Lombardi R, Offi MF, Di Marco M, Ravaioli M, Fiorino S, Franceschi E, Brandes AA, Jovine E, D'Errico A, Tallini G, and de Biase D
- Abstract
Despite the efforts made in the management of PDAC, the 5-year relative survival rate of pancreatic ductal adenocarcinoma (PDAC) still remains very low (10%). To date, precision oncology is far from being ready to be applied in cases of PDAC, although studies exploring the molecular and genetic alterations have been conducted, and the genomic landscape of PDAC has been characterized. This study aimed to apply a next-generation sequencing (NGS) laboratory-developed multigene panel to PDAC samples to find molecular alterations that could be associated with histopathological features and clinical outcomes. A total of 68 PDACs were characterized by using a laboratory-developed multigene NGS panel. KRAS and TP53 mutations were the more frequent alterations in 75.0% and 44.6% of cases, respectively. In the majority (58.7%) of specimens, more than one mutation was detected, mainly in KRAS and TP53 genes. KRAS mutation was significantly associated with a shorter time in tumor recurrence compared with KRAS wild-type tumors. Intriguingly, KRAS wild-type cases had a better short-term prognosis despite the lymph node status. In conclusion, our work highlights that the combination of KRAS mutation with the age of the patient and the lymph node status may help in predicting the outcome in PDAC patients.
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- 2022
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30. Pharmacotherapeutic Treatment of Glioblastoma: Where Are We to Date?
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Gatto L, Di Nunno V, Franceschi E, Tosoni A, Bartolini S, and Brandes AA
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- Humans, Immunotherapy methods, Neoplasm Recurrence, Local drug therapy, Brain Neoplasms, Glioblastoma drug therapy, Receptors, Chimeric Antigen therapeutic use
- Abstract
The clinical management of glioblastoma (GBM) is still bereft of treatments able to significantly improve the poor prognosis of the disease. Despite the extreme clinical need for novel therapeutic drugs, only a small percentage of patients with GBM benefit from inclusion in a clinical trial. Moreover, often clinical studies do not lead to final interpretable conclusions. From the mistakes and negative results obtained in the last years, we are now able to plan a novel generation of clinical studies for patients with GBM, allowing the testing of multiple anticancer agents at the same time. This assumes critical importance, considering that, thanks to improved knowledge of altered molecular mechanisms related to the disease, we are now able to propose several potential effective compounds in patients with both newly diagnosed and recurrent GBM. Among the novel compounds assessed, the initially great enthusiasm toward trials employing immune checkpoint inhibitors (ICIs) was disappointing due to the negative results that emerged in three randomized phase III trials. However, novel biological insights into the disease suggest that immunotherapy can be a convincing and effective treatment in GBM even if ICIs failed to prolong the survival of these patients. In this regard, the most promising approach consists of engineered immune cells such as chimeric antigen receptor (CAR) T, CAR M, and CAR NK alone or in combination with other treatments. In this review, we discuss several issues related to systemic treatments in GBM patients. First, we assess critical issues toward the planning of clinical trials and the strategies employed to overcome these obstacles. We then move on to the most relevant interventional studies carried out on patients with previously untreated (newly diagnosed) GBM and those with recurrent and pretreated disease. Finally, we investigate novel immunotherapeutic approaches with special emphasis on preclinical and clinical data related to the administration of engineered immune cells in GBM., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2022
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31. Corticosteroids use and neurocognitive functioning in patients with recurrent glioblastoma: Evidence from European Organization for Research and Treatment of Cancer (EORTC) trial 26101.
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Caramanna I, de Kort JM, Brandes AA, Taal W, Platten M, Idbaih A, Frenel JS, Wick W, Preetha CJ, Bendszus M, Vollmuth P, Reijneveld JC, and Klein M
- Abstract
Background: In patients with recurrent glioblastoma, corticosteroids are frequently used to mitigate intracranial pressure and to improve patient neurological functioning. To date, in these patients, no systematic studies have been performed to assess neurocognitive functioning (NCF) in relation to corticosteroid treatment., Methods: Using baseline data (ie, prior to randomization) of European Organization for Research and Treatment of Cancer (EORTC) trial 26101, we performed regression analysis to assess the predictive value of corticosteroid intake on performance of the EORTC brain tumor clinical trial NCF test battery. The battery is comprised of the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association Test (COWA), and Trail Making Test (A and B)., Results: Out of 321 patients, 148 (46.1%) were not using corticosteroids, and 173 were using dexamethasone (34.3%), methylprednisolone (9.7%), or other corticosteroids (9.9%). Patients on corticosteroids had worse performance on all neurocognitive tests. Regression analyses demonstrated a negative association between corticosteroids use and the HVLT-R free recall score ( R
2 change = 0.034, F change (1, 272) = 13.392, P < .001) and HVLT-R Delayed Recall score ( R2 change = 0.028, F change (1, 270) = 10.623, P = .002). No statistically significant association was found for HVLT-R Delayed recognition, COWA, TMT part A and TMT part B ( P > .05)., Conclusions: Glioblastoma patients prescribed with corticosteroids show poorer memory functions, expressive language, visual-motor scanning speed, and executive functioning than patients not using corticosteroids. Furthermore, we found a negative association between corticosteroid intake and memory functions. The possibility of deleterious effects of corticosteroids on NCF should be considered during clinical decision making., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)- Published
- 2022
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32. Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance.
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Di Nunno V, Franceschi E, Tosoni A, Gatto L, Bartolini S, and Brandes AA
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Glioblastoma is an aggressive tumor and is associated with a dismal prognosis. The availability of few active treatments as well as the inexorable recurrence after surgery are important hallmarks of the disease. The biological behavior of glioblastoma tumor cells reveals a very complex pattern of genomic alterations and is partially responsible for the clinical aggressiveness of this tumor. It has been observed that glioblastoma cells can recruit, manipulate and use other cells including neurons, glial cells, immune cells, and endothelial/stromal cells. The final result of this process is a very tangled net of interactions promoting glioblastoma growth and progression. Nonetheless, recent data are suggesting that the microenvironment can also be a niche in which glioblastoma cells can differentiate into glial cells losing their tumoral phenotype. Here we summarize the known interactions between micro-environment and glioblastoma cells highlighting possible therapeutic implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Nunno, Franceschi, Tosoni, Gatto, Bartolini and Brandes.)
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- 2022
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33. Corrigendum to: Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG 08.02) randomized clinical trial.
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Song AJ, Ding K, Alnahhas I, Laperriere NJ, Perry J, Mason WP, Winch C, O'Callaghan CJ, Menten JJ, Brandes AA, Phillips C, Fay MF, Nishikawa R, Osoba D, Cairncross JG, Roa W, Wick W, and Shi W
- Abstract
[This corrects the article DOI: 10.1093/noajnl/vdab153.]., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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- 2022
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34. Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?
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Gatto L, Franceschi E, Tosoni A, Di Nunno V, Bartolini S, and Brandes AA
- Abstract
Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer "orphan" entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.
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- 2022
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35. Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVAglio ancillary study.
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Jiguet-Jiglaire C, Boissonneau S, Denicolai E, Hein V, Lasseur R, Garcia J, Romain S, Appay R, Graillon T, Mason W, Carpentier AF, Brandes AA, Ouafik L', Wick W, Baaziz A, Gigan JP, Argüello RJ, Figarella-Branger D, Chinot O, and Tabouret E
- Subjects
- Adult, Aged, Angiogenesis Inhibitors pharmacology, Bevacizumab pharmacology, Brain Neoplasms metabolism, Brain Neoplasms pathology, Female, Glioblastoma metabolism, Glioblastoma pathology, Humans, Male, Matrix Metalloproteinase 2 blood, Middle Aged, Treatment Outcome, Young Adult, Angiogenesis Inhibitors therapeutic use, Bevacizumab therapeutic use, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Matrix Metalloproteinase 9 blood, Neutrophils metabolism
- Abstract
We previously identified matrix metalloproteinase 2 (MMP2) and MMP9 plasma levels as candidate biomarkers of bevacizumab activity in patients with recurrent glioblastoma. The aim of this study was to assess the predictive value of MMP2 and MMP9 in a randomized phase III trial in patients with newly diagnosed glioblastoma and to explore their tumor source. In this post hoc analysis of the AVAglio trial (AVAGlio/NCT00943826), plasma samples from 577 patients (bevacizumab, n = 283; placebo, n = 294) were analyzed for plasma MMP9 and MMP2 levels by enzyme-linked immunosorbent assay. A prospective local cohort of 38 patients with newly diagnosed glioblastoma was developed for analysis of tumor characteristics by magnetic resonance imaging and measurement of plasma and tumor levels of MMP9 and MMP2. In this AVAglio study, MMP9, but not MMP2, was correlated with bevacizumab efficacy. Patients with low MMP9 derived a significant 5.2-month overall survival (OS) benefit with bevacizumab (HR 0.51, 95% CI 0.34-0.76, p = 0.0009; median 13.6 vs. 18.8 months). In multivariate analysis, a significant interaction was seen between treatment and MMP9 (p = 0.03) for OS. In the local cohort, we showed that preoperative MMP9 plasma levels decreased after tumor resection and were correlated with tumor levels of MMP9 mRNA (p = 0.03). However, plasma MMP9 was not correlated with tumor size, invasive pattern, or angiogenesis. Using immunohistochemistry, we showed that MMP9 was expressed by inflammatory cells but not by tumor cells. After cell sorting, we showed that MMP9 was expressed by CD45+ immune cells. Finally, using flow cytometry, we showed that MMP9 was expressed by tumor-infiltrating neutrophils. In conclusion, circulating MMP9 is predictive of bevacizumab efficacy and is released by tumor-infiltrating neutrophils., (© 2021. The Author(s).)
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- 2022
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36. Immune-checkpoint inhibitors in pituitary malignancies.
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Di Nunno V, Franceschi E, Tosoni A, Gatto L, Maggio I, Lodi R, Bartolini S, and Brandes AA
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- Adrenocorticotropic Hormone biosynthesis, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols, Growth Hormone biosynthesis, Humans, Immune Checkpoint Inhibitors administration & dosage, Immune Checkpoint Inhibitors adverse effects, Ipilimumab therapeutic use, Neoplasm Metastasis, Nivolumab therapeutic use, Tumor Microenvironment drug effects, Immune Checkpoint Inhibitors therapeutic use, Pituitary Neoplasms drug therapy, Pituitary Neoplasms pathology
- Abstract
To date, there are no standardized systemic treatment options for patients with metastatic pituitary carcinoma progressed to chemo and radiation therapy. Immune-checkpoint inhibitors (ICIs) have been successfully assessed in other solid malignancies and could be a concrete hope for these patients. We performed a critical review of the literature aimed to evaluate studies assessing ICIs in pituitary malignancies. We also conducted research about published translational data assessing immune-contexture in these malignancies. Some preliminary reports reported a successful administration of pembrolizumab or the combination between nivolumab and ipilimumab in patients with metastatic ACTH-secreting pituitary carcinomas. Translational data suggest that adenomas secreting growth hormone and ACTH have a suppressed immune-microenvironment, which could be more likely to benefit from ICIs. Immune-checkpoint inhibitors can be an effective treatment in patients with pituitary carcinoma and maybe also recurrent adenoma. Tumors secreting growth hormone and ACTH are more likely to benefit from ICIs due to a different immune-microenvironment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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37. Clinical and Molecular Features of Patients with Gliomas Harboring IDH1 Non-canonical Mutations: A Systematic Review and Meta-Analysis.
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Di Nunno V, Franceschi E, Tosoni A, Gatto L, Maggio I, Lodi R, Angelini D, Bartolini S, and Brandes AA
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- Humans, Isocitrate Dehydrogenase genetics, Mutation, Brain Neoplasms genetics, Glioma diagnosis, Glioma genetics
- Abstract
Introduction: The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH-mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear., Methods: We performed a systematic review and meta-analysis to assess the clinical role of IDH non-canonical mutations., Results: Overall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 glioma including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4-10.7%) in patients with IDH-mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference 31%, 95% CI 23-38%) and presented a significantly prolonged survival (pooled HR 0.47, 95% CI 0.28-0.81) as compared to those with IDH1 R132H mutation., Conclusion: Non-canonical IDH1 mutations occur in 7.9% of IDH-mutated gliomas and identify a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for improved stratification and selection of patients., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)
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- 2022
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38. Deep-learning-based synthesis of post-contrast T1-weighted MRI for tumour response assessment in neuro-oncology: a multicentre, retrospective cohort study.
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Jayachandran Preetha C, Meredig H, Brugnara G, Mahmutoglu MA, Foltyn M, Isensee F, Kessler T, Pflüger I, Schell M, Neuberger U, Petersen J, Wick A, Heiland S, Debus J, Platten M, Idbaih A, Brandes AA, Winkler F, van den Bent MJ, Nabors B, Stupp R, Maier-Hein KH, Gorlia T, Tonn JC, Weller M, Wick W, Bendszus M, and Vollmuth P
- Subjects
- Algorithms, Brain Neoplasms diagnostic imaging, Brain Neoplasms pathology, Diffusion Magnetic Resonance Imaging, Disease Progression, Feasibility Studies, Germany, Glioblastoma diagnosis, Glioblastoma diagnostic imaging, Humans, Middle Aged, Neoplasms, Prognosis, Radiology methods, Retrospective Studies, Tumor Burden, Brain pathology, Brain Neoplasms diagnosis, Contrast Media administration & dosage, Deep Learning, Gadolinium administration & dosage, Magnetic Resonance Imaging methods, Neural Networks, Computer
- Abstract
Background: Gadolinium-based contrast agents (GBCAs) are widely used to enhance tissue contrast during MRI scans and play a crucial role in the management of patients with cancer. However, studies have shown gadolinium deposition in the brain after repeated GBCA administration with yet unknown clinical significance. We aimed to assess the feasibility and diagnostic value of synthetic post-contrast T1-weighted MRI generated from pre-contrast MRI sequences through deep convolutional neural networks (dCNN) for tumour response assessment in neuro-oncology., Methods: In this multicentre, retrospective cohort study, we used MRI examinations to train and validate a dCNN for synthesising post-contrast T1-weighted sequences from pre-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences. We used MRI scans with availability of these sequences from 775 patients with glioblastoma treated at Heidelberg University Hospital, Heidelberg, Germany (775 MRI examinations); 260 patients who participated in the phase 2 CORE trial (1083 MRI examinations, 59 institutions); and 505 patients who participated in the phase 3 CENTRIC trial (3147 MRI examinations, 149 institutions). Separate training runs to rank the importance of individual sequences and (for a subset) diffusion-weighted imaging were conducted. Independent testing was performed on MRI data from the phase 2 and phase 3 EORTC-26101 trial (521 patients, 1924 MRI examinations, 32 institutions). The similarity between synthetic and true contrast enhancement on post-contrast T1-weighted MRI was quantified using the structural similarity index measure (SSIM). Automated tumour segmentation and volumetric tumour response assessment based on synthetic versus true post-contrast T1-weighted sequences was performed in the EORTC-26101 trial and agreement was assessed with Kaplan-Meier plots., Findings: The median SSIM score for predicting contrast enhancement on synthetic post-contrast T1-weighted sequences in the EORTC-26101 test set was 0·818 (95% CI 0·817-0·820). Segmentation of the contrast-enhancing tumour from synthetic post-contrast T1-weighted sequences yielded a median tumour volume of 6·31 cm
3 (5·60 to 7·14), thereby underestimating the true tumour volume by a median of -0·48 cm3 (-0·37 to -0·76) with the concordance correlation coefficient suggesting a strong linear association between tumour volumes derived from synthetic versus true post-contrast T1-weighted sequences (0·782, 0·751-0·807, p<0·0001). Volumetric tumour response assessment in the EORTC-26101 trial showed a median time to progression of 4·2 months (95% CI 4·1-5·2) with synthetic post-contrast T1-weighted and 4·3 months (4·1-5·5) with true post-contrast T1-weighted sequences (p=0·33). The strength of the association between the time to progression as a surrogate endpoint for predicting the patients' overall survival in the EORTC-26101 cohort was similar when derived from synthetic post-contrast T1-weighted sequences (hazard ratio of 1·749, 95% CI 1·282-2·387, p=0·0004) and model C-index (0·667, 0·622-0·708) versus true post-contrast T1-weighted MRI (1·799, 95% CI 1·314-2·464, p=0·0003) and model C-index (0·673, 95% CI 0·626-0·711)., Interpretation: Generating synthetic post-contrast T1-weighted MRI from pre-contrast MRI using dCNN is feasible and quantification of the contrast-enhancing tumour burden from synthetic post-contrast T1-weighted MRI allows assessment of the patient's response to treatment with no significant difference by comparison with true post-contrast T1-weighted sequences with administration of GBCAs. This finding could guide the application of dCNN in radiology to potentially reduce the necessity of GBCA administration., Funding: Deutsche Forschungsgemeinschaft., Competing Interests: Declaration of interests SH reports grants from the German Research Council and Dietmar-Hopp Foundation, outside of the submitted work. JD reports grants from ViewRay, the Clinical Research Institute, Accuray, RaySearch Laboratories, Vision RT, Merck, Astellas Pharma, AstraZeneca, Siemens Healthcare, Solution Akademie, Egomed, Quintiles, Pharmaceutical Research Association, Boehringer Ingelheim, PTW-Freiburg, and Nanobiotix, outside of the submitted work. MP reports non-financial support from Pfizer, and grants and personal fees from Bayer, outside of the submitted work. MP also has a licensed patent for IDH1 vaccines, a patent H3 vaccine pending, and a patent AHR inhibitor with royalties paid to Bayer. AI reports grants and travel funding from Carthera; research grants from Transgene, Sanofi, Air Liquide, and Nutritheragene; travel funding from Leo Pharma; and is on the advisory board for Novocure and Leo Pharma, outside the submitted work. MjvdB reports personal fees from Roche, Cellgene, Bristol Myers Squibb, Agios, Merck Sharpe & Dohme, and Boehringer Ingelheim; and grants and personal fees from AbbVie, outside of the submitted work. BN is on the scientific advisory board for Karyopharm and BTG Pharmaceuticals and is on the data safety and monitoring board for the University of Pennsylvania (Philadelphia, PA, USA), outside of the submitted work. J-CT reports personal fees from BrainLab and carThera, outside of the submitted work. WW reports grants from Apogenix, Boehringer Ingelheim, and Pfizer; grants and personal fees from Merck Sharp and Dohme and Roche; and personal fees from Bristol Myers Squibb and Celldex, outside of the submitted work. MB reports personal fees from Boehringer Ingelheim, Merck, Bayer, Teva, B Braun, Springer, and Vascular Dynamics; grants and personal fees from Novartis, Codman, and Guerbet; and grants from Siemens, Hopp Foundation, the German Research Council, the EU, Stryker, and Medtronic, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2021
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39. Engineered CAR-T and novel CAR-based therapies to fight the immune evasion of glioblastoma: gutta cavat lapidem.
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Gatto L, Franceschi E, Di Nunno V, Maggio I, Lodi R, and Brandes AA
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- Humans, Neoplasm Recurrence, Local, Tumor Microenvironment, Glioblastoma immunology, Glioblastoma therapy, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, Tumor Escape
- Abstract
Introduction: The field of cancer immunotherapy has achieved great advancements through the application of genetically engineered T cells with chimeric antigen receptors (CAR), that have shown exciting success in eradicating hematologic malignancies and have proved to be safe with promising early signs of antitumoral activity in the treatment of glioblastoma (GBM)., Areas Covered: We discuss the use of CAR T cells in GBM, focusing on limitations and obstacles to advancement, mostly related to toxicities, hostile tumor microenvironment, limited CAR T cells infiltration and persistence, target antigen loss/heterogeneity and inadequate trafficking. Furthermore, we introduce the refined strategies aimed at strengthening CAR T activity and offer insights in to novel immunotherapeutic approaches, such as the potential use of CAR NK or CAR M to optimize anti-tumor effects for GBM management., Expert Opinion: With the progressive wide use of CAR T cell therapy, significant challenges in treating solid tumors, including central nervous system (CNS) tumors, are emerging, highlighting early disease relapse and cancer cell resistance issues, owing to hostile immunosuppressive microenvironment and tumor antigen heterogeneity. In addition to CAR T cells, there is great interest in utilizing other types of CAR-based therapies, such as CAR natural killer (CAR NK) or CAR macrophages (CAR M) cells for CNS tumors.
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- 2021
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40. BET inhibitors: the promise of a new generation of immunotherapy in glioblastoma.
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Nunno VD, Franceschi E, Gatto L, and Brandes AA
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- 2021
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41. Is There a Role for Surgical Resection of Multifocal Glioblastoma? A Retrospective Analysis of 100 Patients.
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Friso F, Rucci P, Rosetti V, Carretta A, Bortolotti C, Ramponi V, Martinoni M, Palandri G, Zoli M, Badaloni F, Franceschi E, Asioli S, Fabbri VP, Rustici A, Foschini MP, Brandes AA, Mazzatenta D, Sturiale C, and Conti A
- Subjects
- Humans, Karnofsky Performance Status, Neurosurgical Procedures methods, Retrospective Studies, Brain Neoplasms diagnostic imaging, Brain Neoplasms drug therapy, Brain Neoplasms surgery, Glioblastoma diagnostic imaging, Glioblastoma surgery
- Abstract
Background: Glioblastoma with multiple localizations (mGBMs) can be defined as multifocal, where enhancing lesions present a connection visible on magnetic resonance imaging fluid-attenuated inversion recovery imaging, or multicentric, in the absence of a clear dissemination pathway., Objective: To evaluate the role of the extent of resection (EOR) in the treatment of mGBMs and its correlation with overall survival (OS) and progression free survival (PFS)., Methods: One hundred patients with mGBMs were treated at our Institution between 2009 and 2019. Clinical, radiological, and follow-up data were collected. EOR of the contrast-enhancing part of lesions was classified as gross total resection (GTR, absence of tumor remnant), subtotal resection (STR, residual tumor < 30% of the initial mass), partial resection (PR, residual tumor > 30% of the initial mass), and needle or open biopsy (residual tumor > 75% of the initial mass)., Results: Approximately 15% of patients underwent GTR, 14% STR, 32% PR, and 39% biopsy. Median OS was 17 mo for GTR, 11 mo for STR, 7 mo for PR, and 5 mo for biopsy. Greater EOR was associated with a significantly longer OS than biopsy. GTR and STR were associated with a longer PFS in Kaplan-Meier survival analyses. After adjusting for age, Karnofsky performance status (KPS), number of lesions, and adjunctive therapy in multivariable Cox regression analyses, GTR, STR, and PR were still associated with OS, but only GTR remained associated with PFS., Conclusion: Our study suggests that EOR may positively influence survival of patients with mGBM. Surgical resection can be a reasonable option when performance and access to adjuvant treatment can be preserved., (© Congress of Neurological Surgeons 2021.)
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- 2021
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42. Radiomics, mirnomics, and radiomirRNomics in glioblastoma: defining tumor biology from shadow to light.
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Maggio I, Franceschi E, Gatto L, Tosoni A, Di Nunno V, Tonon C, and Brandes AA
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- Biology, Biomarkers, Tumor genetics, Humans, Magnetic Resonance Imaging methods, Brain Neoplasms diagnostic imaging, Brain Neoplasms genetics, Glioblastoma diagnostic imaging, Glioblastoma genetics, MicroRNAs genetics
- Abstract
Introduction: Glioblastoma is a highly aggressive brain tumor with an extremely poor prognosis. Genetic characterization of this tumor has identified alterations with prognostic and therapeutic impact, and many efforts are being made to improve molecular knowledge on glioblastoma. Invasive procedures, such as tumor biopsy or radical resection, are needed to characterize the tumor., Areas Covered: The role of microRNA in cancer is an expanding field of research as many microRNAs have been shown to correlate with patient prognosis and treatment response. Novel methodologies like radiomics, radiogenomics, and radiomiRNomics are under evaluation to improve the amount of prognostic and predictive biomarkers available., Expert Opinion: The role of radiomics, radiogenomics, and radiomiRNomic for the characterization of glioblastoma will further improve in the coming years.
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- 2021
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43. Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial.
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Song AJ, Ding K, Alnahhas I, Laperriere NJ, Perry J, Mason WP, Winch C, O'Callaghan CJ, Menten JJ, Brandes AA, Phillips C, Fay MF, Nishikawa R, Osoba D, Cairncross JG, Roa W, Wick W, and Shi W
- Abstract
Background: Lymphopenia may lead to worse outcomes for glioblastoma patients. This study is a secondary analysis of the CCTG CE.6 trial evaluating the impact of chemotherapy and radiation on lymphopenia, and effects of lymphopenia on overall survival (OS)., Methods: CCTG CE.6 randomized elderly glioblastoma patients (≥ 65 years) to short-course radiation alone (RT) or short-course radiation with temozolomide (RT + TMZ). Lymphopenia (mild-moderate: grade 1-2; severe: grade 3-4) was defined per CTCAE v3.0, and measured at baseline, 1 week and 4 weeks post-RT. Preselected key factors for analysis included age, sex, ECOG, resection extent, MGMT methylation, Mini-Mental State Examination, and steroid use. Multinomial logistic regression and multivariable Cox regression models were used to identify lymphopenia-associated factors and association with survival., Results: Five hundred and sixty-two patients were analyzed (281 RT vs 281 RT+TMZ). At baseline, both arms had similar rates of mild-moderate (21.4% vs 21.4%) and severe (3.2% vs 2.9%) lymphopenia. However, at 4 weeks post-RT, RT+TMZ was more likely to develop lymphopenia (mild-moderate: 27.9% vs 18.2%; severe: 9.3% vs 1.8%; p<0.001). Developing any lymphopenia post-RT was associated with baseline lymphopenia ( P < .001). Baseline lymphopenia (hazard ratio [HR] 1.3) was associated with worse OS (HR: 1.30, 95% confidence interval [CI] 1.05-1.62; P = .02), regardless of MGMT status., Conclusions: Development of post-RT lymphopenia is associated with addition of TMZ and baseline lymphopenia and not with RT alone in patients treated with short-course radiation. However, regardless of MGMT status, only baseline lymphopenia is associated with worse OS, which may be considered as a prognostic biomarker for elderly glioblastoma patients., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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- 2021
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44. Discovering the Molecular Landscape of Meningioma: The Struggle to Find New Therapeutic Targets.
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Maggio I, Franceschi E, Di Nunno V, Gatto L, Tosoni A, Angelini D, Bartolini S, Lodi R, and Brandes AA
- Abstract
Meningiomas are the most common primary CNS tumors. They are usually benign but can present aggressive behavior in about 20% of cases. The genetic landscape of meningioma is characterized by the presence (in about 60% of cases) or absence of NF2 mutation. Low-grade meningiomas can also present other genetic alterations, particularly affecting SMO, TRAF7, KLF4 AKT1 and PI3KCA. In higher grade meningiomas, mutations of TERT promoter and deletion of CDKN2A/B seem to have a prognostic value. Furthermore, other genetic alterations have been identified, such as BAP1, DMD and PBRM1. Different subgroups of DNA methylation appear to be correlated with prognosis. In this review, we explored the genetic landscape of meningiomas and the possible therapeutic implications.
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- 2021
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45. Liquid Biopsy in Glioblastoma Management: From Current Research to Future Perspectives.
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Gatto L, Franceschi E, Di Nunno V, Tosoni A, Lodi R, and Brandes AA
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- Biomarkers, Tumor genetics, Humans, Liquid Biopsy, Prognosis, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Brain Neoplasms therapy, Glioblastoma diagnosis, Glioblastoma genetics, Glioblastoma therapy, MicroRNAs
- Abstract
Glioblastoma (GBM) is the most common primary tumor of the central nervous system. Arising from neuroepithelial glial cells, GBM is characterized by invasive behavior, extensive angiogenesis, and genetic heterogeneity that contributes to poor prognosis and treatment failure. Currently, there are several molecular biomarkers available to aid in diagnosis, prognosis, and predicting treatment outcomes; however, all require the biopsy of tumor tissue. Nevertheless, a tissue sample from a single location has its own limitations, including the risk related to the procedure and the difficulty of obtaining longitudinal samples to monitor treatment response and to fully capture the intratumoral heterogeneity of GBM. To date, there are no biomarkers in blood or cerebrospinal fluid for detection, follow-up, or prognostication of GBM. Liquid biopsy offers an attractive and minimally invasive solution to support different stages of GBM management, assess the molecular biology of the tumor, identify early recurrence and longitudinal genomic evolution, predict both prognosis and potential resistance to chemotherapy or radiotherapy, and allow patient selection for targeted therapies. The aim of this review is to describe the current knowledge regarding the application of liquid biopsy in glioblastoma, highlighting both benefits and obstacles to translation into clinical care. IMPLICATIONS FOR PRACTICE: To translate liquid biopsy into clinical practice, further prospective studies are required with larger cohorts to increase specificity and sensitivity. With the ever-growing interest in RNA nanotechnology, microRNAs may have a therapeutic role in brain tumors., (© 2021 AlphaMed Press.)
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- 2021
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46. Correction: Visani et al. miR-196B-5P and miR-200B-3P Are Differentially Expressed in Medulloblastomas of Adults and Children. Diagnostics 2020, 10 , 265.
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Visani M, Marucci G, de Biase D, Giangaspero F, Buttarelli FR, Brandes AA, Franceschi E, Acquaviva G, Ciarrocchi A, Rhoden KJ, Tallini G, and Pession A
- Abstract
The authors wish to make the following corrections to this paper [...].
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- 2021
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47. Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma.
- Author
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Tesileanu CMS, van den Bent MJ, Sanson M, Wick W, Brandes AA, Clement PM, Erridge SC, Vogelbaum MA, Nowak AK, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Rogers L, Taal W, Rudà R, Weller M, McBain C, van Linde ME, Sabedot TS, Hoogstrate Y, von Deimling A, de Heer I, van IJcken WFJ, Brouwer RWW, Aldape K, Jenkins RB, Dubbink HJ, Kros JM, Wesseling P, Cheung KJ, Golfinopoulos V, Baumert BG, Gorlia T, Noushmehr H, and French PJ
- Subjects
- Adult, Chromosomes, Human, Pair 1, DNA Copy Number Variations, DNA Methylation, Homozygote, Humans, Isocitrate Dehydrogenase genetics, Mutation, Prognosis, Prospective Studies, Sequence Deletion, Brain Neoplasms genetics, Brain Neoplasms therapy, Glioma genetics, Glioma therapy
- Abstract
Background: Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients., Methods: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization., Results: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication., Conclusion: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2021
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48. Next-Generation Sequencing Panel for 1p/19q Codeletion and IDH1-IDH2 Mutational Analysis Uncovers Mistaken Overdiagnoses of 1p/19q Codeletion by FISH.
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de Biase D, Acquaviva G, Visani M, Marucci G, De Leo A, Maloberti T, Sanza V, Di Oto E, Franceschi E, Mura A, Ragazzi M, Serra S, Froio E, Bisagni A, Brandes AA, Pession A, and Tallini G
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Brain Neoplasms pathology, Cohort Studies, Cost-Benefit Analysis, DNA Mutational Analysis economics, DNA Mutational Analysis methods, Female, Glioma pathology, High-Throughput Nucleotide Sequencing economics, Humans, In Situ Hybridization, Fluorescence economics, Male, Middle Aged, Molecular Diagnostic Techniques economics, Molecular Diagnostic Techniques methods, Polymorphism, Single Nucleotide, Reproducibility of Results, Young Adult, Brain Neoplasms genetics, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 19 genetics, Gene Deletion, Glioma genetics, High-Throughput Nucleotide Sequencing methods, In Situ Hybridization, Fluorescence methods, Isocitrate Dehydrogenase genetics, Overdiagnosis, Translocation, Genetic genetics
- Abstract
The 1p/19q codeletion is the result of a translocation between chromosome 1 (Chr1p) and chromosome 19 (Chr19q) with the loss of derivative (1;19)(p10;q10) chromosome. The 1p/19q codeletion has predictive and prognostic significance, and it is essential for the classification of gliomas. In routine practice, the fluorescence in situ hybridization (FISH) diagnosis of 1p/19q codeletion is sometimes unexpected. This study aimed to develop a next-generation sequencing panel for the concurrent definition of the 1p/19q codeletion and IDH1/IDH2 mutation status to resolve these equivocal cases. A total of 65 glioma samples were investigated using a 1p/19q-single-nucleotide polymorphism (SNP)-IDH panel. The panel consists of 192 amplicons, including SNPs mapping to Chr1 and Chr19 and amplicons for IDH1/IDH2 analysis. The 1p/19q SNP-IDH panel consistently identified IDH1/IDH2 mutations. In 49 of 60 cases (81.7%), it provided the same 1p/19q results obtained by FISH. In the remaining 11 cases, the 1p/19q SNP-IDH panel uncovered partial chromosome imbalances as a result of interstitial amplification or deletion of the regions where the FISH probes map, leading to a mistaken overdiagnosis of 1p/19q codeletion by FISH. The 1p/19q SNP-IDH next-generation sequencing panel allows reliable analysis of the 1p/19q codeletion and IDH1/IDH2 mutation at the same time. The panel not only allows resolution of difficult cases but also represents a cost-effective alternative to standard molecular diagnostics procedures., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2021
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49. Is Molecular Tailored-Therapy Changing the Paradigm for CNS Metastases in Breast Cancer?
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Di Nunno V, Franceschi E, Tosoni A, Mura A, Minichillo S, Di Battista M, Gatto L, Maggio I, Lodi R, Bartolini S, and Brandes AA
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- Female, Humans, Oxazoles, Pyridines, Quinazolines, Receptor, ErbB-2, Breast Neoplasms drug therapy
- Abstract
Breast cancer (BC) is the second most common tumour spreading to the central nervous system (CNS). The prognosis of patients with CNS metastases depends on several parameters including the molecular assessment of the disease. Although loco-regional treatment remains the best approach, systemic therapies are acquiring a role leading to remarkable long-lasting responses. The efficacy of these compounds diverges between tumours with different molecular assessments. Promising agents under investigation are drugs targeting the HER2 pathways such as tucatinib, neratinib, pyrotinib, trastuzumab deruxtecan. In addition, there are several promising agents under investigation for patients with triple-negative brain metastases (third-generation taxane, etirinotecan, sacituzumab, immune-checkpoint inhibitors) and hormone receptor-positive brain metastases (CDK 4/5, phosphoinositide-3-kinase-mammalian target of rapamycin [PI3K/mTOR] inhibitors). Also, the systemic treatment of leptomeningeal metastases, which represents a very negative prognostic site of metastases, is likely to change as several compounds are under investigation, some with interesting preliminary results. Here we performed a comprehensive review focusing on the current management of CNS metastases according to molecular subtypes, site of metastases (leptomeningeal vs brain), and systemic treatments under investigation., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2021
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50. Patient-reported outcomes in a phase II randomised study of regorafenib compared with lomustine in patients with relapsed glioblastoma (the REGOMA trial).
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Lombardi G, Del Bianco P, Brandes AA, Eoli M, Rudà R, Ibrahim T, Lolli I, Rizzato S, Daniele B, Pace A, Pasqualetti F, Caccesse M, Bergo E, Magni G, De Salvo GL, and Zagonel V
- Subjects
- Aged, Female, Glioblastoma pathology, Humans, Lomustine pharmacology, Male, Middle Aged, Patient Reported Outcome Measures, Phenylurea Compounds pharmacology, Prospective Studies, Pyridines pharmacology, Recurrence, Surveys and Questionnaires, Glioblastoma drug therapy, Lomustine therapeutic use, Phenylurea Compounds therapeutic use, Pyridines therapeutic use
- Abstract
Background: The REGOMA trial showed that regorafenib significantly improved overall survival in patients with recurrent glioblastoma compared with lomustine. Patients treated with regorafenib experienced a higher occurrence of grade 3-4 drug-related adverse events than those receiving the standard treatment. Because this safety profile was expected, it was considered of great importance to assess the patient point of view regarding the disease and treatment impact on different aspects of life and patient well-being. We here report the final results of the health-related quality of life (HRQoL) assessment, a secondary end-point of the study. This trial is registered with ClinicalTrials.gov, NCT02926222., Methods: Patient-reported outcomes were assessed, within a prospective, randomised, multicentre, open-label phase II trial, by the European Organisation for Research and Treatment of Cancer core questionnaire and brain module at baseline and every 8-weekly neuroradiological assessment till disease progression. Mixed-effect linear models were fitted for each of the HRQoL domain to examine the change over progression-free time within and between arms. Furthermore, differences were also classified as clinically meaningful changes. To correct for multiple comparisons and avoid type I errors, the level of significance was set at P = 0.01 (2-sided)., Results: Of 119 enrolled patients, 56/59 (95%) patients and 58/60 (97%) patients treated with regorafenib and lomustime completed questionnaires at baseline, respectively. No significant differences were observed in any generic or cancer-specific domain during treatment in both arms, or between the two arms, except for the appetite loss and diarrhoea scales which were significantly worse in patients treated with regorafenib. The rate of patients with a clinically meaningful worsening for appetite loss, diarrhoea and for any other domain was not statistically different between the two arms., Conclusions: Regorafenib did not negatively affect HRQoL in patients with recurrent glioblastoma. These data combined with the survival benefit shown in the REGOMA trial support the use of regorafenib as a treatment option for these patients., Competing Interests: Conflict of interest statement GL has declared a consulting or advisory role for funding from Bayer, AbbVie, Orbus Therapeutics and BrainFarm; travel funding from Roche and Bayer; RR has declared research funding from Mundipharma, Novocure, UCB; BD has declared personal fees from EISAI, ELI LILLY, ASTRA ZENECA, MSD, ROCHE, AMGEN, personal grants and non-financial support from IPSEN, SANOFI and BAYER; VZ has declared consulting or advisory role funding from Bristol-Myers Squibb and Merck, Speakers Bureau funding from Bayer, Roche, Bristol-Myers Squibb, Astellas Pharma, Servier, AstraZeneca and Lilly, travel and accommodation funding from Bayer, Roche and Servier. All remaining authors have declared no conflict of interest to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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