Tumors of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
DNA methylation patterns are increasingly recognized for their importance in gliomagenesis. Methylation of the promoter region of an enzyme called O [6]-methylguanine-DNA methyltransferase (MGMT) is of particular importance in high-grade gliomas. Alkylating chemotherapy agents such as temozolomide exert their cytotoxic effect by adding alkyl groups to DNA molecules. Alkylation at the O6 position of guanine is thought to be particularly cytotoxic. MGMT is a DNA repair enzyme that removes alkyl groups from this position. Methylation of the promoter region of the MGMT gene decreases expression of the DNA repair enzyme, leaving cells more susceptible to damage from alkylating chemotherapy. Patients whose tumors possess a silenced MGMT gene (from promoter methylation) have a better response to alkylating agent chemotherapy and improved survival compared with those with activation of the MGMT gene.
Combined radiotherapy and chemotherapy
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
In brain high-grade glioblastoma, Cochrane Reviews recently published a report on all the randomised controlled trials performed on the use of temozolomide and radiotherapy (26). In summary, in primary glioblastoma, temozolomide significantly increased overall survival (OS) (hazard ratio 0.60, p-value 0.0003) and progression-free survival (hazard ratio 0.63, p-value 0.02) without modification of the quality of life; the benefit was mainly observed when temozolomide was given both concomitantly and in an adjuvant setting. The risks of haematological complications, fatigue and infections were increased with temozolomide. The benefit of temozolomide was particularly striking in patients expressing silencing of the MGMT (O6-methyl-guanine-DNA methyltransferase) DNA repair gene by promoter methylation (27). In recurrent glioblastoma, the use of concomitant temozolomide and radiotherapy also significantly increased the progression-free survival in a subgroup of patients with grade IV glioblastoma (p-value 0.008) without increase in toxicity.
Advances in the Treatment of Brain Metastases
Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo in Lung Cancer, 2016
Sensitivity to temozolomide may depend on the tumor histology. In a phase II study by Siena et al. released in abstract form, patients with breast cancer, non–small-cell lung cancer and melanoma were treated with a dose-intense, alternating weekly regimen of temozolomide (95). Response rates were 19%, 24%, and 40%, respectively. In a single arm trial by Dardoufas, 20 patients (55% lung cancer) with newly diagnosed brain metastases received chemoradiotherapy with temozolomide (96). Patients with lung cancer had a superior response rate (86%) compared to the group as a whole (55%). In patients with grade IV gliomas, methylation of the promoter region of the O6-methylguanine DNA methyl-transferase (MGMT) gene has been shown to increase survival (97). Patients with squamous-cell carcinoma and adenocarcinoma have been found to have a 36% and 42% incidence of MGMT promoter methylation, respectively (98). The role of the MGMT in patients with brain metastases with various histologies is unknown.
The role of myeloid-derived suppressor cells in lung cancer and targeted immunotherapies
Published in Expert Review of Anticancer Therapy, 2022
Fateme Sheida, Sepideh Razi, Mahsa Keshavarz-Fathi, Nima Rezaei
Temozolomide is the most common chemotherapy drug used in the treatment of patients with glioblastoma. It can cause lymphopenia, which could have various effects on the response rate of immunotherapies. A research was conducted to compare the immune-modulatory effects of metronomic dose (25 mg/kg × 10 days) of temozolomide with its standard dose (50 mg/kg × 5 days) in the murine glioma models. They demonstrated that the modulation of temozolomide dose affects the peripheral and intratumoral immune microenvironments, including T-cell response to anti-PD-1 therapy [178]. The primary results of an ongoing phase II clinical trial, assessing nivolumab and temozolomide in treating recurrent or refractory SCLC patients (NCT03728361), revealed that there was an early decrease in the number of MDSCs and an increase in T-cell proliferation and function in a patient with refractory SCLC [179].
Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study
Published in Acta Oncologica, 2019
Magdalena Neuhauser, Thomas Roetzer, Stefan Oberndorfer, Melitta Kitzwoegerer, Franz Payer, Julia J. Unterluggauer, Johannes Haybaeck, Günther Stockhammer, Sarah Iglseder, Patrizia Moser, Claudius Thomé, Martin Stultschnig, Franz Wuertz, Tanisa Brandner-Kokalj, Serge Weis, Dave Bandke, Josef Pichler, Markus Hutterer, Karl J. Krenosz, Alexandra Boehm, Beate Mayrbaeurl, Andrea Hager-Seifert, Hannes Kaufmann, Martina Dumser, Angelika Reiner-Concin, Selma Hoenigschnabl, Waltraud Kleindienst, Markus Hoffermann, Karin Dieckmann, Barbara Kiesel, Georg Widhalm, Christine Marosi, Ulrich Jaeger, Andreas Hainfellner, Monika Hackl, Johannes A. Hainfellner, Matthias Preusser, Adelheid Woehrer
The systematic documentation of real-life patterns across second and third lines of treatment constitutes a major strength of our approach. So far, the probably largest and most detailed analysis of salvage therapy has come from the French LOC network [30]. Therein, the authors found poor overall survival for refractory/relapsed patients with many patients not receiving active salvage therapy upon relapse, and the relatively longest survival for those treated with induction CT and ASCT [30]. While we similarly found receipt of active salvage therapy the major bottleneck, our cohort differs from the French one in several aspects. First, we found a significantly higher proportion of refractory/relapsed patients (81.0 vs. 45.5%), which is, however, in line with previous studies with similarly extended follow-up times [31,32]. Second, in the Austrian cohort consolidation consisted mostly of whole-brain RT while the use of ASCT was much less prevalent, which is most likely due to a previous diagnostic period, that is, before 2010. Thus, it will be of special interest to prospectively follow the changing use of ASCT in light of newer trial results that advocate its safety and efficiency [3,33,34]. The same will be true for newer treatment approaches including PD-1 blockade [35]. Of interest, temozolomide, which is the drug of choice for many primary brain tumors such as glioma and which is being increasingly recognized also for the treatment of PCNSL [36], was rarely used in our patient population.
Expression and clinicopathological significance of Nck1 in human astrocytoma progression
Published in International Journal of Neuroscience, 2019
Ravindra Pramod Deshpande, Manas Panigrahi, Chandra Sekhar Y.B.V.K, Phanithi Prakash Babu
Forty-three surgically resected tissue samples (control brain: 07, GII: 08, GIII: 11, GIV: 17) were collected from Department of Neurosurgery, Krishna Institute of Medical Sciences, Secunderabad, India. Tissue samples were snap frozen with liquid nitrogen and stored at –80° C for further experiments. Grades of surgically removed tissue were confirmed by neuropathologists based on WHO classification criteria as cell and nuclear polymorphism, increased cellularity, etc. Proliferation index was determined by MIB-1 staining pattern. Location of tumor was confirmed by radiologic images. Age/sex of patients’ and follow-up details were retrieved from hospital registry. Temporal lobe epilepsy samples were used as control. In the low-grade astrocytoma cases, the tumor was generally surgically resected and not subjected to rigorous chemo and radiotherapy. Generally, patients were observed for the tumor recurrence. Young patients were generally not subjected to radiotherapy. For high-grade patients, surgical resection was most commonly practiced followed by the radio and chemotherapy. Temozolomide was the most common chemotherapeutic drug used. Gross total or subtotal resection was mostly followed. Generally, tumor located at frontal lobe was removed by the gross total resection. A part of sample collected was used for RNA isolation and western blotting and a part was used to prepare sections for immunohistochemistry (IHC) studies. Informed consent was obtained from all patients participating in present studies and institutional ethical guidelines were followed. All subjects participating were anonymized.