Data-Driven Predictive Models of Diffuse Low-Grade Gliomas Under Chemotherapy
Mériem Ben AbdallahMarie BlonskiSophie Wantz-MézièresYann GaudeauLuc TaillandierJean-Marie MoureauxAmélie DarlixNicolas Menjot de ChampfleurHugues Duffau
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Abstract:
Diffuse low-grade gliomas (DLGG) are brain tumors of young adults. They affect the quality of life of the inflicted patients and, if untreated, they evolve into higher grade tumors where the patient's life is at risk. Therapeutic management of DLGGs includes chemotherapy, and tumor diameter is particularly important for the follow-up of DLGG evolution. In fact, the main clinical basis for deciding whether to continue chemotherapy is tumor diameter growth rate. In order to reliably assist the doctors in selecting the most appropriate time to stop treatment, we propose a novel clinical decision support system. Based on two mathematical models, one linear and one exponential, we are able to predict the evolution of tumor diameter under Temozolomide chemotherapy as a first treatment and thus offer a prognosis on when to end it. We present the results of an implementation of these models on a database of 42 patients from Nancy and Montpellier University Hospitals. In this database, 38 patients followed the linear model and four patients followed the exponential model. From a training data set of a minimal size of five, we are able to predict the next tumor diameter with high accuracy. Thanks to the corresponding prediction interval, it is possible to check if the new observation corresponds to the predicted diameter. If the observed diameter is within the prediction interval, the clinician is notified that the trend is within a normal range. Otherwise, the practitioner is alerted of a significant change in tumor diameter.Keywords:
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ÖZETGİRİŞ ve AMAÇ: Grade IV gliom olan glioblastoma multiforme (GBM), yetişkinlerde en sık görülen primer beyin tümörüdür.Biyopsi veya rezeksiyonu takiben, radyoterapi (RT) eş zamanlı ve adjuvan temozolomid (TMZ) kullanımı (6 kür), yeni teşhis edilmiş GBM vakaları için standart tedavi haline gelmiştir.Orijinal tedavi rejimi 6 kür TEMODAL kullanımını içermesine rağmen, bazı merkezler daha iyi sonuç elde etme umuduyla progrese olmayan hastalarda 12 veya daha fazla kür tedavi uygulamaktadır.Butedavi yaklaşımı tartışmalıdır.Çalışmamızın temel amacı, hastalıksız sağkalım (DFS) ve genel sağ kalım (OS) açısından standart kombine tedavi yaklaşımı ile tedavi edilen hastalarda TEMODAL tedavisinin uzatılmasının (6 aydan 12 aya kadar
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Despite of improvements in the biological and molecular characterization of glioblastoma multiforme and studies of factors associated with tumor growth and progression, this type of malignant astroglial brain tumor is still difficult to treat. The present article reviews established and emerging prognostic and predictive factors and their potential influence on future therapeutic efforts. Recent developments in standard treatment options (surgery, radiotherapy and chemotherapy) are summarized. The integration of the oral cytotoxic agent temozolomide into current treatment protocols of postoperative combination therapy with radiation and drugs is discussed, especially in the context of the recently published randomized trial of the EORTC/NCIC, which showed that radiotherapy plus concomitant and adjuvant temozolomide significantly improved progression-free and overall survival over radiotherapy alone. The study also provided hypotheses about the subgroups, which are most likely to benefit from this reasonably well tolerated regimen. In a subset of patients, investigation of MGMT promoter methylation in tumor tissue was performed. Survival was shorter in patients with unmethylated promoter in both study groups. Patients with methylated promoter treated with radiotherapy had a median survival of 15 months, those treated with radiation plus temozolomide of 22 months (p=0.007). In the unmethylated group, the difference in median survival was only 1 month (p=0.06). Especially for these patients, alternative treatments need to be developed. The optimum schedule of temozolomide administration and the influence of combinations with additional antineoplastic agents remains to be studied. Early results of clinical trials addressing these issues are presented. Keywords: Brain tumors, glioma, treatment, radiotherapy, chemotherapy, temozolomide
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Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007-treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-β1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients.
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"The role of temozolomide in newly-diagnosed glioblastoma multiforme." British Journal of Neurosurgery, 22(3), p. 456
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