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- Pattern of care of anaplastic oligodendroglioma and oligoastrocytoma in a Korean population: the Korean radiation oncology group study 13-12. [JOURNAL ARTICLE]
- J Neurooncol 2014 Nov 13.
This study investigated the treatment of anaplastic oligodendroglial tumors across nine Korean institutions. We reviewed the medical records from 381 patients with histologically confirmed anaplastic oligodendroglioma or anaplastic oligoastrocytoma (AOA) from 2000 to 2010. Clinical factors and treatment patterns were analyzed for each year. Post-operative therapy was performed in 354 patients (94.1 %), of which 133 received radiotherapy (RT) alone and 189 received both RT and chemotherapy. RT alone was the preferred treatment toward the end of the study period (29.4 % in 2000-2001 vs. 56.3 % in 2010, P = 0.005). The use of procarbazine, lomustine, and vincristine (PCV) decreased (57.6 % in 2000-2001 vs. 28.6 % in 2010, P = 0.001) and the use of temozolomide (TMZ) increased (0 % in 2000-2001 vs. 61.9 % in 2010, P < 0.001) over the study period. A combination of chemotherapy and RT was used more often than RT alone in young patients (P = 0.036) and patients with a good performance status (P = 0.023). The 1p/19q co-deletion status and O-6-methyguanine-DNA methyltransferase methylation were analyzed since 2004 but were not significant factors for determining whether to administer chemotherapy. Among the patients who received chemotherapy, TMZ was used more often in patients with AOA (P = 0.007) and PCV was used more often in patients with either multiple lesions (P = 0.027) or the 1p/19q co-deletion (P = 0.026). Our results demonstrate that the treatment pattern for oligodendroglial tumors changed significantly across the study period. In particular, TMZ has replaced PCV, and the use of molecular markers as well as RT alone has increased, but a unified protocol remains to be established.
- Multidisciplinary management of adult low grade gliomas. [Journal Article]
- Chirurgia (Bucur) 2014 Sep-Oct; 109(5):590-9.
Adult hemispheric low grade gliomas (LGG) cover a pathologic spectrum which has specific clinical, histological and molecular characteristics. The optimal management of these tumors is still a controversial topic in international literature.We evaluated scientific papers from the literature (Medline and Cochrane Library to date) and we compared the results found there with our experience, trying to create a pattern of treatment of our own.The advances in microsurgical and neuromonitoring techniques, as well as in neuroimaging, allow for a more aggressive resection of LGG with a significant improvement in overall survival and quality of life. The potential risks of the "wait and see" policy and the neurotoxicity of radiotherapy are challenged by the benefits of careful surgical resection and up-front chemotherapy. The present day treatment strategy, based on recent evidence, should include a maximal surgical resection when possible, with the full preservation of the patients ability, and delayed radiotherapy. The role of temozolomide in the management of LGG and the identification of the therapeutic modality with the best quality of life profile will be determined by ongoing trials. The further characterization of prognostic relevance of molecular markers and data from advanced imaging techniques needs an intensification of research and validation efforts.LGG: low grade gliomas, WHO: World Health Organization, OS: overall survival, PFS: progression-free survival, MRI: Magnetic resonance imaging, MRS: Magnetic resonance spectroscopy, MPFS: malignant progression-free survival, rCBV: Relative Cerebral Blood Volume, QOL: quality of life, FLAIR: Fluid attenuated inversion recovery, MGMT: O6-methylguanine DNA methyltransferase enzyme, DSC MR imaging: Dynamic Susceptibility Contrast Perfusion MR imaging, 1H-MRS: Proton Magnetic Resonance Spectroscopy, IDH1: isocitrate dehydrogenase 1 gene, SPECT: Single-photon emission computed tomography, PET: Positron emission tomography, DTI-FT: Diffuse Tensor Imaging-fiber tracking technique, DES: direct electrical stimulation, EEG: Electroencephalography, EcoG: Electrocorticography, MEP: motor evoked potentials, EMG: Electromyography, AED: anti-epileptic drugs, TMZ: Temozolomide, EORTC: European Organization for Research and Treatment of Cancer, NCCTG: North Central Cancer Treatment Group, RTOG: Radiation Therapy Oncology Group, ECOG: Eastern Cooperative Oncology Group, EOR: extent of resection, Gy: Gray (unit), GyE: gray equivalent, RT: radiation therapy, IMRT: image-guided intensity modulated radiotherapy, FSRT: fractionated stereotactic radiotherapy, SRS: proton therapy or stereotactic radiosurgery, LET: high-linear energy transfer beams, RBE: relative biological effectiveness, CTCAE: Common Terminology Criteria for Adverse Events, PCV: procarbazine, lomustine, and vincristine chemotherapy.
- Molecular modeling and spectroscopic studies of semustine binding with DNA and its comparison with lomustine-DNA adduct formation. [JOURNAL ARTICLE]
- J Biomol Struct Dyn 2014 Oct 28.:1-16.
Chloroethyl nitrosoureas constitute an important family of cancer chemotherapeutic agents, used in the treatment of various types of cancer. They exert antitumor activity by inducing DNA interstrand cross-links. Semustine, a chloroethyl nitrosourea, is a 4-methyl derivative of lomustine. There exist some interesting reports dealing with DNA-binding properties of chloroethyl nitrosoureas; however, underlying mechanism of cytotoxicity caused by semustine has not been precisely and completely delineated. The present work focuses on understanding semustine-DNA interaction to comprehend its anti-proliferative action at molecular level using various spectroscopic techniques. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy is used to determine the binding site of semustine on DNA. Conformational transition in DNA after semustine complexation is investigated using circular dichroism (CD) spectroscopy. Stability of semustine-DNA complexes is determined using absorption spectroscopy. Results of the present study demonstrate that semustine performs major-groove-directed DNA alkylation at guanine residues in an incubation-time-drug-concentration-dependent manner. CD spectral outcomes suggest partial transition of DNA from native B-conformation to C-form. Calculated binding constants (Ka) for semustine and lomustine interactions with DNA are 1.53 × 10(3) M(-1) and 8.12 × 10(3) M(-1), respectively. Moreover, molecular modeling simulation is performed to predict preferential binding orientation of semustine with DNA that corroborates well with spectral outcomes. Results based on comparative study of DNA-binding properties of semustine and lomustine, presented here, may establish a correlation between molecular structure and cytotoxicity of chloroethyl nitrosoureas that may be instrumental in the designing and synthesis of new nitrosourea therapeutics possessing better efficacy and fewer side effects.
- Treatment of large low-grade oligodendroglial tumors with upfront procarbazine, lomustine, and vincristine chemotherapy with long follow-up: a retrospective cohort study with growth kinetics. [JOURNAL ARTICLE]
- J Neurooncol 2014 Oct 26.
We treated patients with newly diagnosed and large low-grade oligodendroglial tumors with upfront procarbazine, CCNU and vincristine (PCV) in order to delay radiotherapy. Patients were treated with PCV for a maximum of 6 cycles. The response to treatment was defined according to the RANO criteria; in addition change over time of mean tumor diameters (growth kinetics) was calculated. Thirty-two patients were treated between 1998 and 2006, 18 of which were diagnosed with 1p/19q co-deleted tumors. Median follow-up duration was 8 years (range 0.5-13 years). The median overall survival (mOS) was 120 months and the median progression-free survival (mPFS) was 46 months. Growth kinetics showed an ongoing decrease of the mean tumor diameter after completion of chemotherapy, during a median time of 35 months, but an increase of the mean tumor diameter did not herald progression as detected by RANO criteria. 1p/19q co-deletion was associated with a significant increase in OS (mOS 83 months versus not reached for codeleted tumors; p = 0.003)) and PFS (mPFS 35 months versus 67 months for codeleted tumors; p = 0.024). Patients with combined 1p/19q loss had a 10 year PFS of 34 % and the radiotherapy in these patients was postponed for a median period of more than 6 years. This long-term follow-up study indicates that upfront PCV chemotherapy is associated with long PFS and OS and delays radiotherapy for a considerable period of time in patients with low-grade oligodendroglial tumors, in particular with combined 1p/19q loss.
- Joint modeling of longitudinal health-related quality of life data and survival. [JOURNAL ARTICLE]
- Qual Life Res 2014 Oct 14.
In cancer research, outcome measures may co-vary. Treatment and treatment related impairment of health-related quality of life (HRQoL) may affect survival. When these effects are analyzed separately, bias may arise. Therefore, we investigated the combined effect of treatment and longitudinally measured HRQoL on survival.Patients with anaplastic oligodendrogliomas (n = 288) who were randomized (EORTC 26951) to radiotherapy (RT) alone or RT plus procarbazine, lomustine, and vincristine (PCV) chemotherapy were analyzed. HRQoL [appetite loss (AP)] was assessed with the EORTC QLQ-C30. We compared survival results from different analysis strategies: Cox model with treatment only [model 1 (M1)] or with treatment and time-dependent AP score [model 2 (M2)] and the joint model combining longitudinal AP score and survival [model 3 (M3)].The estimated hazard ratio (HR) for RT plus PCV was 0.76 (95 % CI 0.58-1.00) for M1, 0.72 (0.55-0.96) for M2, and 0.69 (0.52-0.92) for M3. This corresponds to a lower risk of death of 24 % in M1, 28 % in M2, and 31 % in M3, for patients treated with RT plus PCV chemotherapy. AP resulted in an increased risk of death, with estimated HR of 1.06 (1.01-1.12) for M2 and 1.13 (1.03-1.23) for M3: Every 10-point increase of AP resulted in a 13 % increased risk of death in M3 as compared to 6 % in M2.Part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients' HRQoL. In our study, up to 7 % of the theoretical treatment efficacy was lost when AP was not adjusted through joint modeling.
- [Management of gliomas.] [JOURNAL ARTICLE]
- Cancer Radiother 2014 Sep 4.
Gliomas are the most frequent primary brain tumors. Their care is difficult because of the proximity of organs at risk. The treatment of glioblastoma includes surgery followed by chemoradiation with the protocol of Stupp et al. The addition of bevacizumab allows an increase in progression-free survival by 4 months but it does not improve overall survival. This treatment is reserved for clinical trials. Intensity modulation radiotherapy may be useful to reduce the neurocognitive late effects in different types of gliomas. In elderly patients an accelerated radiotherapy 40Gy in 15 fractions allows a similar survival to standard radiotherapy. O(6)-methylguanine-DNA methyltransferase (MGMT) status may help to choose between chemotherapy and radiotherapy. There is no standard for the treatment of recurrent gliomas. Re-irradiation in stereotactic conditions allows a median survival of 8 to 12.4 months. Anaplastic gliomas with 1p19q mutation have a greater sensibility to chemotherapy by procarbazine, lomustine and vincristine. Chemoradiotherapy in these patients has become the standard treatment. Many studies are underway testing targeted therapies, their place in the therapeutic management and new radiotherapy techniques.
- The Effect of Common Antineoplastic Agents on Induction of Apoptosis in Canine Lymphoma and Leukemia Cell Lines. [JOURNAL ARTICLE]
- In Vivo 2014 09-10; 28(5):843-850.
Background/Aim: Lymphoma, the most common hematopoietic cancer in dogs is sensitive to chemotherapy which is the dominant treatment method. The aim of the present study was to evaluate the concentration-dependent cytotoxicity and ability to induce apoptosis of the anti-neoplastic agents cyclophosphamide (CYC), chlorambucil (CBL), cytosine arabinoside (ARA), dexamethasone (DEX), doxorubicin (DOX), etoposide (ETO), lomustine (LOM), prednisone (PRED) and vincristine (VINK) against GL-1, CL-1, CLBL-1 and Jurkat cell lines. Materials and Methods: To determine cell viability and level of apoptosis, three different tests were performed: Thiazolyl Blue Tetrazolium Bromide (MTT), annexin V/propidium iodide (An/PI) staining and flow cytometric DNA fragmentation. Results: All tested substances exhibited concentration-dependent inhibitory effects on the proliferation of the examined cell lines with a different level of apoptosis induction. VINK and DOX strongly decreased the viability of canine cell lines, whereas CYC induced the highest level of apoptosis. Conclusion: Canine lymphoma (CL-1, CLBL-1) and leukemia (GL-1) cell lines are a useful tool for developing new and more effective treatment regimes for canine neoplasia.
- Translesion polymerase eta is upregulated by cancer therapeutics and confers anticancer drug resistance. [JOURNAL ARTICLE]
- Cancer Res 2014 Aug 14.
DNA repair processes are a key determinant of the sensitivity of cancer cells to DNA damaging chemotherapeutics, which may induce certain repair genes as a mechanism to promote resistance. Here we report the results of a screen for repair genes induced in cancer cells treated with DNA crosslinking agents, which identified the translesion polymerase eta (PolH) as a p53-regulated target acting as one defense against interstrand crosslink (ICL)-inducing agents. PolH was induced by fotemustine, mafosfamide and lomustine in breast cancer, glioma and melanoma cells in vitro and in vivo, with similar inductions observed in normal cells such as lymphocytes and diploid fibroblasts. PolH contributions to the protection against ICL-inducing agents were evaluated by its siRNA-mediated attenuation in cells, which elevated sensitivity to these drugs in all tumor cell models. Conversely, PolH overexpression protected cancer cells against these drugs. PolH attenuation reduced repair of ICL lesions as measured by host cell reactivation assays and enhanced persistence of γH2AX foci. Moreover, we observed a strong accumulation of PolH in the nucleus of drug-treated cells along with direct binding to damaged DNA. Taken together, our findings implicated PolH in ICL repair as a mechanism of cancer drug resistance and normal tissue protection.
- Evaluation of O6-methylguanine-DNA methyltransferase enzyme expression effect on survival of patients with Grade 4 brain astrocytoma. [Journal Article]
- J Res Med Sci 2014 May; 19(5):426-32.
High-grade astrocytoma (Grade 4) or glioblastoma multiforme (GBM) are deadly brain tumors. New therapies attempt to increase lifetime and quality of life in patients with malignant astrocytoma. O6-methylguanine-DNA methyltransferase (MGMT) enzyme expression may be effective in prognosis and response to treatment of these patients. The aim of this study was assessment of MGMT enzyme expression in patients with astrocytoma Grade 4.In this study, 48 patients with GBM that were treated with surgery, chemotherapy and radiotherapy were investigated and followed-up for 47 months for the survival rate. Pathology blocks of patients were examined for MGMT enzyme expression using immunohistochemistry method.The patients were 34 males and 14 females. The ages ranged from 24 to 77 years, with a mean age of 53.52 ± 13.39 years. There was no significant difference between two groups (positive and negative MGMT enzyme expression) in overall survival (median [range] 11.5 [4-30] vs. 13 [5-22], P = 0.9). The results of our study showed that patients although who were undergone near total surgery had higher overall survival than the group of patients who had biopsy only however, it was not significant. Patients who were treated with temozolomide (TMZ) (Temodal, Merck Canada) had significant overall median survival (14.5) more than the patients who were treated with Procarbazine (Roche, Swiss)-Lomustine (Lilly, USA)-Vincristine (Lilly, USA) regimen (8.75) (P < 0.05).O6-methylguanine-DNA methyltransferase enzyme expression had no effect on survival of patients with Grade 4 brain astrocytoma TMZ may increase survival rate.
- Emerging biomarkers in anaplastic oligodendroglioma: implications for clinical investigation and patient management. [Journal Article]
- CNS Oncol 2013 Jul; 2(4):351-8.
SUMMARY Oligodendrogliomas are heterogeneous tumors with a variable response to treatment. This clinical variability underlines the urgent need for markers that can reliably aid diagnosis and guide clinical decision-making. Long-term follow-up data from the EORTC 26951 and RTOG 9402 clinical trials in newly diagnosed anaplastic oligodendroglioma have established chromosome 1p19q codeletion as a predictive marker of response to procarbazine, lomustine and vincristine chemotherapy in anaplastic oligodendrogliomas. In addition, MGMT promoter hypermethylation has been strongly associated with glioma CpG island hypermethylation phenotype (G-CIMP(+)) status, this has been suggested as an epiphenomenon of genome-wide methylation, conferring a more favorable prognosis. Molecular profiling of these tumors has identified several other markers with potential clinical significance: mutations of IDH, CIC, FUBP1 and CDKN2A require further validation before they can be implemented as clinical decision-making tools. Additionally, recent data on the clinical significance of intrinsic glioma subtyping appears promising. Indeed, existing evidence suggests that comprehensive analyses such as intrinsic glioma subtyping or G-CIMP status are superior to single molecular markers. Clearly, with evolving treatment strategies and in the era of individualized therapy, broader omics-based molecular evaluations are required to improve outcome prediction and to identify patients who will benefit from specific treatment strategies.