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Temozolomide

Web Resources: Temozolomide
Recent Research Publications

Web Resources: Temozolomide (6 links)


Recent Research Publications

Feng J, Yan PF, Zhao HY, et al.
Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway.
Biomed Res Int. 2016; 2016:1450843 [PubMed] Free Access to Full Article Related Publications
Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 μM)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.

Xu H, Jia F, Singh PK, et al.
Synergistic anti-glioma effect of a coloaded nano-drug delivery system.
Int J Nanomedicine. 2017; 12:29-40 [PubMed] Free Access to Full Article Related Publications
The anti-glioma effect of temozolomide (Tem) is sometimes undermined by the emerging resistance. Recently, resveratrol (Res), herbal medicine extracted from grape seeds, has been demonstrated for its potential use in chemosensitization. In the current study, both these drugs were loaded simultaneously into nanoparticles with methoxy poly(ethylene glycol)-poly epsilon caprolactone (mPEG-PCL) as drug carriers in order to achieve better antitumor efficiency. Tem/Res-coloaded mPEG-PCL nanoparticles were constructed, characterized, and tested for antitumor effect on glioma cells by using in vitro and xenograft model system. The nanoparticle constructs were satisfactory with drug loading content (Res =~12.4%; Tem =~9.3%) and encapsulation capacity of >85% for both the drugs. In addition, the coencapsulation led to better in vitro stability of the nanoparticles than Tem-loaded nanoparticles. An in vitro uptake study demonstrated a high uptake efficiency of the nanoparticles by glioma cells. The synergistic antitumor effect against glioma cells was observed in the combinational treatment of Res and Tem. Tem/Res-coloaded nanoparticles induced higher apoptosis in U87 glioma cells as compared to cells treated by the combination of free drugs. Tem/Res-coloaded particles caused more effective inhibition of phosphor-Akt, leading to upregulation of the downstream apoptotic proteins. In addition, the in vivo study showed the superior tumor delaying effect of coloaded nanoparticles than that of free drug combination. These results suggest that Tem/Res-coloaded nanoparticles could be a potential useful chemotherapeutic formulation for glioma therapy.

Miyata H, Ashizawa T, Iizuka A, et al.
Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide-resistant Glioblastoma Cell Line.
Cancer Genomics Proteomics. 2017; 14(1):83-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Temozolomide-resistant (TMZ-R) glioblastoma is very difficult to treat, and a novel approach to overcome resistance is needed.
MATERIALS AND METHODS: The efficacy of a combination treatment of STAT3 inhibitor, STX-0119, with rapamycin was investigated against our established TMZ-resistant U87 cell line.
RESULTS: The growth-inhibitory effect of the combination treatment was significant against the TMZ-R U87 cell line (IC50: 78 μM for STX-0119, 30.5 μM for rapamycin and 11.3 μM for combination of the two). Western blotting analysis demonstrated that the inhibitory effect of STX-0119 on S6 and 4E-BP1 activation through regulation of YKL-40 expression occurred in addition to the inhibitory effect of rapamycin against the mTOR pathway.
CONCLUSION: These results suggest that the STAT3 pathway is associated with the mTOR downstream pathway mediated by YKL-40 protein, and the combination therapy of the STAT3 inhibitor and rapamycin could be worth developing as a novel therapeutic approach against TMZ-resistant relapsed gliomas.

Polivka J, Polivka J, Holubec L, et al.
Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme.
Anticancer Res. 2017; 37(1):21-33 [PubMed] Related Publications
Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single anti-angiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.

Clark PA, Gaal JT, Strebe JK, et al.
The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells.
J Clin Neurosci. 2017; 36:120-124 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a ⩾10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC50=160μM; 22GSCs: IC50=44μM) compared to MGMT non-expressing (33GSCs: IC50=1.5μM; 114GSCs: IC50=5.2μM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74±2.9% and 38±3.2%, respectively; 22GSC: 61±11% and 38±2.6%, respectively; 33GSC: 56±9.5% and 60±7.1%, respectively; 114 GSC: 79±3.5% and 41±4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., ± MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications.

Crespo G, Jiménez-Fonseca P, Custodio A, et al.
Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience.
Future Oncol. 2017; 13(7):615-624 [PubMed] Related Publications
BACKGROUND & METHODS: Capecitabine and temozolomide chemotherapy was used in 65 patients with grade 1/2 neuroendocrine tumors (NETs). 46 patients (70.8%) had pancreatic NETs (pNETs).
RESULTS: Response rate was 47.7%, with two complete responses (3.1%), 29 partial responses (44.6%) and 27 patients (41.5%) achieved stable disease. Median progression-free survival was 16.1 months (95% CI: 10.7-21.6) and overall survival was 38.3 months (95% CI: 24.6-51.9). Differences in progression-free survival and overall survival between pNETs and non-pNETs were not found. Nine (13.8%) patients experienced grade 3/4 toxicities, mainly thrombocytopenia (10.8%) and neutropenia (7.7%).
CONCLUSION: This is the largest reported series of NETs treated with capecitabine and temozolomide in daily practice and shows that this combination is a promising treatment option for both grade 1/2 pNETs and non-pNETs.

Yount G, Soroceanu L, Wang HJ, et al.
Selective Toxicity of a Highly Potent Camptothecin Analogue: A Pilot Study with Glioblastoma Multiforme Cells.
Anticancer Res. 2016; 36(11):5845-5848 [PubMed] Related Publications
BACKGROUND/AIM: We developed a novel camptothecin analogue, CPT417, that yields reduced toxicity compared to other analogues used in chemotherapeutic regimens. In this pilot study, we assessed the activity of CPT417 against glioblastoma multiforme (GBM) cells and glioma stem cells.
MATERIALS AND METHODS: The human U251 GBM cell line and normal human astrocytes were cultured in parallel for clonogenic survival analysis following exposure to increasing concentrations of CPT417. Cell viability of a glioma stem cell line was assessed 5 days after exposure to a range of CPT417 concentrations.
RESULTS: CPT417 completely inhibited clonogenic survival of GBM cells at 10 nM, whereas this concentration only inhibited astrocytes by approximately 50%. Cell viability analysis of glioma stem cell cultures yielded a half-maximal response at 15 nM.
CONCLUSION: CPT417 acts selectively against GBM cells at concentrations that are at least an order of magnitude below reported values for related alkylating agents in clinical use.

Pasi F, Fassina L, Mognaschi ME, et al.
Pulsed Electromagnetic Field with Temozolomide Can Elicit an Epigenetic Pro-apoptotic Effect on Glioblastoma T98G Cells.
Anticancer Res. 2016; 36(11):5821-5826 [PubMed] Related Publications
Treatment with pulsed electromagnetic fields (PEMFs) is emerging as an interesting therapeutic option for patients with cancer. The literature has demonstrated that low-frequency/low-energy electromagnetic fields do not cause predictable effects on DNA; however, they can epigenetically act on gene expression. The aim of the present work was to study a possible epigenetic effect of a PEMF, mediated by miRNAs, on a human glioblastoma cell line (T98G). We tested a PEMF (maximum magnetic induction, 2 mT; frequency, 75 Hz) that has been demonstrated to induce autophagy in glioblastoma cells. In particular, we studied the effect of PEMF on the expression of genes involved in cancer progression and a promising synergistic effect with temozolomide, a frequently used drug to treat glioblastoma multiforme. We found that electromagnetic stimulation in combination with temozolomide can elicit an epigenetic pro-apoptotic effect in the chemo- and radioresistant T98G glioblastoma cell line.

Ohba S, Hirose Y
Current and Future Drug Treatments for Glioblastomas.
Curr Med Chem. 2016; 23(38):4309-4316 [PubMed] Related Publications
Glioblastomas are the most aggressive of all gliomas and have the worst prognosis, with 5-year survival rates of less than 10%. Temozolomide (TMZ) is a DNA-methylating agent. Now that TMZ is available, the standard treatment is maximal safe resection, followed by treatment with radiation and TMZ. TMZ has also been used for maintenance therapy. Recently, bevacizumab, which is a monoclonal antibody to vascular endothelial growth factor, has been used for the initial treatment of glioblastomas and for the treatment of recurrent glioblastomas. A 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafer can also be placed on the surface of the cavity after near-complete tumor resection. These are currently the three drugs that are most often used to treat glioblastomas. In the near future, other therapeutic options such as immunotherapy may be used to treat glioblastomas.

Beppu T, Terasaki K, Sasaki T, et al.
MRI and 11C-methyl-L-methionine PET Differentiate Bevacizumab True Responders After Initiating Therapy for Recurrent Glioblastoma.
Clin Nucl Med. 2016; 41(11):852-857 [PubMed] Related Publications
PURPOSE: Normalization of tumor vasculature after administering bevacizumab (BEV) makes assessment of therapeutic response using MRI difficult. The aim of this study was to clarify whether PET with C-methyl-L-methionine (MET-PET) would supplement MRI assessing of response after initiating BEV in glioblastoma.
METHODS: Twenty patients with recurrent glioblastoma were treated with biweekly BEV plus temozolomide. Both MRI and MET-PET were performed before treatment (baseline) and at 4 and 8 weeks after starting treatment. Results on MRI (response or nonresponse) were compared with those on MET-PET, with response defined as a tumor-to-normal brain ratio of SUV (SUVT/N) of less than 1.6. Progression-free survival (PFS) was compared between responders and nonresponders on MRI alone and MET-PET alone. Progression-free survival was also compared between patients showing response on both MRI and MET-PET and patients showing response on MRI but nonresponse on MET-PET at each time point.
RESULTS: PFS was significantly longer in responders than nonresponders on both MRI at 4 and 8 weeks and MET-PET at 8 weeks, whereas MET-PET at 4 weeks provided no information regarding outcomes. Combined assessment with MRI and MET-PET at 4 weeks was not provide predictive of PFS, whereas patients showing response on both modalities (true responders) at 8 weeks exhibited significantly longer PFS than did patients showing response on MRI but nonresponse on MET-PET (pseudoresponders).
CONCLUSIONS: Combined assessment with MRI and MET-PET at 8 weeks can differentiate true responders who are predicted to show more favorable prognosis from pseudoresponders.

Isakoff SJ, Puhalla S, Domchek SM, et al.
A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale.
Future Oncol. 2017; 13(4):307-320 [PubMed] Related Publications
Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

Lin L, Wang G, Ming J, et al.
Analysis of expression and prognostic significance of vimentin and the response to temozolomide in glioma patients.
Tumour Biol. 2016; 37(11):15333-15339 [PubMed] Related Publications
Gliomas are the most common primary intracranial malignant tumors in adults. Surgical resection followed by optional radiotherapy and chemotherapy is the current standard therapy for glioma patients. Vimentin, a protein of intermediate filament family, could maintain the cellular integrity and participate in several cell signal pathways to modulate the motility and invasion of cancer cells. The purpose of the present research was to identify the relationship between vimentin expression and clinical characteristics and detect the prognostic and predictive ability of vimentin in patients with glioma. To determine the expression of vimentin in glioma tissues, paraffin-embedded blocks from glioma patients by surgical resection were obtained and evaluated by immunohistochemistry. To further investigate the association of vimentin expression with survival, we employed mRNA expression of vimentin genes from the Chinese Glioma Genome Atlas (CGGA) and the GSE 16011 dataset. Kaplan-Meier analysis and Cox regression model were used to statistical analysis. We detected positive vimentin straining in 84 % of high-grade compared to 47 % in low-grade glioma patients. Additionally, vimentin mRNA expression was correlated with glioma grade in both CGGA and GSE16011 dataset. Patients with low vimentin expression have longer survival than high expression. In multivariate analysis, vimentin was an independent significant prognostic factor for high-grade glioma patients. We also identified that glioblastoma patients with low vimentin expression had a better response to temozolomide therapy. Vimentin expression has a significant association with tumor grade and overall survival of high-grade glioma patients. Low vimentin expression may benefit from temozolomide therapy.

Thomas JG, Rao G, Kew Y, Prabhu SS
Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma.
Neurosurg Focus. 2016; 41(4):E12 [PubMed] Related Publications
OBJECTIVE Glioblastoma (GBM) is the most common and deadly malignant primary brain tumor. Better surgical therapies are needed for newly diagnosed GBMs that are difficult to resect and for GBMs that recur despite standard therapies. The authors reviewed their institutional experience of using laser interstitial thermal therapy (LITT) for the treatment of newly diagnosed or recurrent GBMs. METHODS This study reports on the pre-LITT characteristics and post-LITT outcomes of 8 patients with newly diagnosed GBMs and 13 patients with recurrent GBM who underwent LITT. RESULTS Compared with the group with recurrent GBMs, the patients with newly diagnosed GBMs who underwent LITT tended to be older (60.8 vs 48.9 years), harbored larger tumors (22.4 vs 14.6 cm(3)), and a greater proportion had IDH wild-type GBMs. In the newly diagnosed GBM group, the median progression-free survival and the median survival after the procedure were 2 months and 8 months, respectively, and no patient demonstrated radiographic shrinkage of the tumor on follow-up imaging. In the 13 patients with recurrent GBM, 5 demonstrated a response to LITT, with radiographic shrinkage of the tumor following ablation. The median progression-free survival was 5 months, and the median survival was greater than 7 months. CONCLUSIONS In carefully selected patients with recurrent GBM, LITT may be an effective alternative to surgery as a salvage treatment. Its role in the treatment of newly diagnosed unresectable GBMs is not established yet and requires further study.

Rennert RC, Carroll KT, Ali MA, et al.
Safety of stereotactic laser ablations performed as treatment for glioblastomas in a conventional magnetic resonance imaging suite.
Neurosurg Focus. 2016; 41(4):E7 [PubMed] Related Publications
OBJECTIVE Stereotactic laser ablation (SLA) is typically performed in the setting of intraoperative MRI or in a staged manner in which probe insertion is performed in the operating room and thermal ablation takes place in an MRI suite. METHODS The authors describe their experience, in which SLA for glioblastoma (GBM) treatment was performed entirely within a conventional MRI suite using the SmartFrame stereotactic device. RESULTS All 10 patients with GBM (2 with isocitrate dehydrogenase 1 mutation [mIDH1] and 8 with wild-type IDH1 [wtIDH1]) were followed for > 6 months. One of these patients underwent 2 independent SLAs approximately 12 months apart. Biopsies were performed prior to SLA for all patients. There were no perioperative morbidities, wound infections, or unplanned 30-day readmissions. The average time for a 3-trajectory SLA (n = 3) was 436 ± 102 minutes; for a 2-trajectory SLA (n = 4) was 321 ± 85 minutes; and for a single-trajectory SLA (n = 4) was 254 ± 28 minutes. No tumor recurrence occurred within the blue isotherm line ablation zone, although 2 patients experienced recurrence immediately adjacent to the blue isotherm ablation line. Overall survival for the patient cohort averaged 356 days, with the 2 patients who had mIDH1 GBMs exhibiting the longest survival (811 and 654 days). CONCLUSIONS Multitrajectory SLA for treatment of GBM can be safely performed using the SmartFrame stereotactic device in a conventional MRI suite.

Wu Y, Dong L, Bao S, et al.
FK228 augmented temozolomide sensitivity in human glioma cells by blocking PI3K/AKT/mTOR signal pathways.
Biomed Pharmacother. 2016; 84:462-469 [PubMed] Related Publications
Temozolomide is a novel cytotoxic agent currently used as first-line chemotherapy for glioblastoma multiforme (GBM). Romidepsin (FK228), a histone deacetylase inhibitor, is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, combination of the two drugs in glioma remains largely unknown. In the present study, we evaluated the combinatory effects of FK228 with TMZ in glioma, and its molecular mechanisms responsible for these effects. Glioma cell lines were treated with TMZ, FK228 or the combination of drugs. The resistance effect including cytotoxicity and apoptosis was determined in glioma cells, respectively. We further evaluated the effects of FK228 in the PI3K/Akt-signaling pathway in vitro. Mice engrafted with 5×10(6) LN382 cells were treated with TMZ, FK228 or the combination of two drugs, and tumor weights and volumes were measured, respectively. FK228 enhanced the cytotoxic effects of TMZ in glioma cells compared to vehicle-treated controls or each drug alone. The combination of FK228 and TMZ-induced apoptosis was demonstrated by increased expression of cleaved-Caspase 3, Bax, cleaved-PARP, and decreased Bcl-2 expression. Furthermore, the expression of key components of the PI3K/Akt-signaling pathway showed that combination of FK228 and TMZ block PI3K/Akt pathways in vitro. This block effect was also confirmed in vivo in mice models. Mice treated with both FK228 and TMZ drugs showed significantly reduced tumor weights and volumes, compared to each drug alone. Our results suggested that FK228 augmented temozolomide sensitivity in human glioma cells partially by blocking PI3K/AKT/mTOR signal pathways. It thus may provide a promising target for improving the therapeutic outcome of TMZ-resistant gliomas, although further studies will be needed.

Shahi MH, Farheen S, Mariyath MP, Castresana JS
Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance.
Tumour Biol. 2016; 37(11):15107-15114 [PubMed] Related Publications
Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments. GANT61 very efficiently inhibited cell colony growth in glioma cell lines, compared to temozolomide. Moreover, a synergic effect of GANT61 and temozolomide drastically decreased the LD50 of temozolomide in the cell colony experiments. Therefore, our results suggest that there is a potential nexus of Shh-Gli1-BMI1 cell signaling to regulate MRP1 and to promote chemoresistance in glioma. Henceforth, our study opens the possibility of facing new targets, Gli1 and BMI1, for the effective treatment of glioma suppression of chemoresistance with adjuvant therapy of GANT61 and temozolomide.

Lester A, Rapkins R, Nixdorf S, et al.
Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?
Clin Transl Oncol. 2017; 19(3):273-278 [PubMed] Related Publications
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.

Brunner TB
The rationale of combined radiotherapy and chemotherapy - Joint action of Castor and Pollux.
Best Pract Res Clin Gastroenterol. 2016; 30(4):515-28 [PubMed] Related Publications
This article aims to review the rationale behind the combination of radiotherapy and chemotherapy. Theoretical concepts describing the principles of the joint effects of chemoradiotherapy are reviewed. Preclinical and clinical evidence are collected and summarised demonstrating the co-operation between the two modalities which form the mainstay of the treatment of most solid tumours. Initially, the evolution of chemoradiotherapy was mostly empirically driven which is true for both, the early studies and the experimental investigations, rather than relying on scientific rationale. To date, the revised Steel's model proposes five mechanisms, spatial cooperation, cytotoxic enhancement, biological co-operation, temporary modulation and normal tissue protection to describe the interaction between radiotherapy and chemotherapy. Chemoradiotherapy has become the standard modality for most patients with locally advanced solid tumours due to better control of loco-regional disease and prolonged survival. Gradually, molecular prediction of efficacy is integrated such as MGMT status for combining temozolomide with radiotherapy in glioblastoma. As molecular targeted drugs are ready to be taken into triple combinations with chemoradiotherapy it is crucial to have a good understanding of the mechanisms of chemoradiotherapy for the rational development of future combinations.

Shah BK, Bista A, Sharma S
Survival Trends in Elderly Patients with Glioblastoma in the United States: a Population-based Study.
Anticancer Res. 2016; 36(9):4883-6 [PubMed] Related Publications
BACKGROUND/AIM: Concomitant and adjuvant temozolomide along with radiotherapy following surgery (the Stupp regimen) is the preferred therapy for young patients with glioblastoma as well as for elderly (>70 years) ones with favorable risk factors. This study investigated the survival trend since the introduction of the use of the Stupp regimen in elderly patients in a population-based setting.
MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results 18 database was used to identify patients aged ≥70 years with glioblastoma as the first primary cancer diagnosed from 1999 to 2010. Chi-square test, Kaplan-Meier analysis with log-rank test and Cox proportional hazard method were used for analysis.
RESULT: A total of 5,575 patients were included in the survival analysis. Survival in Stupp era (year of diagnosis ≥2005) was significantly better compared to the pre-Stupp era with p<0.001 by log-rank test, with 1-, 2- and 3-year overall survival of 18.8% vs. 12.9%, 6.5% vs. 2.1% and 3.1% vs. 0.9% respectively, and hazard ratio for death in 3 years in the Stupp era was 0.87 (95% confidence interval=0.82-0.92; p<0.001) when compared with the pre-Stupp era. Factors such as younger age (<85 years), female sex, married status, Caucasian race and total resection favored better survival compared to their counterparts.
CONCLUSION: This study shows that the survival of elderly patients with glioblastoma has improved since the introduction of the Stupp regimen. However, there are significant differences in survival rates among various cohorts.

Kim SK, Kim TM, Lee ST, et al.
The survival significance of a measurable enhancing lesion after completing standard treatment for newly diagnosed glioblastoma.
J Clin Neurosci. 2016; 34:145-150 [PubMed] Related Publications
The goal of this study was to analyze the survival outcome according to the treatment response after completing standard treatment protocol for newly diagnosed glioblastoma (GBM) and to suggest a patient who should be considered for further treatment. After approving by our Institutional Review Board, 57 patients (38 male, 19 female; median age, 52years; age range, 16-81years) with newly diagnosed GBM who completed standard treatment protocol were examined retrospectively. According to the treatment response using the RANO criteria, there were 20 patients with complete response (CR), five patients with partial response (PR), 13 patients with stable disease (SD) and 19 patients with progressive disease (PD) after the completion of standard treatment. Patients (PR+SD+PD) with a measurable enhancing lesion were categorized the MEL group (n=37). We analyzed the difference of survival outcome between CR group and MEL group. The median progression-free survival (PFS) in the CR group was significantly better than that of the MEL group (18.0months vs. 3.0months, p=0.004). The median overall survival (OS) was also significantly longer in the CR group (25.0months vs. 15.0months, p=0.005). However, there was no significant difference in the survival outcome of the CR group compared with that of the subset of MEL group patients who showed PR or SD. Poor survival outcome was found only in MEL group patients who exhibited progression. Patients with a measurable enhancing lesion showing progression after completion of standard treatment protocol are appropriate candidates for further treatment.

Zhang J, Yang JH, Quan J, et al.
Identification of MGMT promoter methylation sites correlating with gene expression and IDH1 mutation in gliomas.
Tumour Biol. 2016; 37(10):13571-13579 [PubMed] Related Publications
O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation was reported to be an independent prognostic and predictive factor in glioma patients who received temozolomide treatment. However, the predictive value of MGMT methylation was recently questioned by several large clinical studies. The purpose of this study is to identify MGMT gene promoter CpG sites or region whose methylation were closely correlated with its gene expression to elucidate this contradictory clinical observations. The methylation status for all CpG dinucleotides in MGMT promoter and first exon region were determined in 42 Chinese glioma patients, which were then correlated with MGMT gene expression, IDH1 mutation, and tumor grade. In whole 87 CpG dinucleotides analyzed, three distinct CpG regions covering 28 CpG dinucleotides were significantly correlated with MGMT gene expression; 10 CpG dinucleotides were significantly correlated with glioma classification (p < 0.05). Isocitrate dehydrogenase 1 (IDH1) mutation and MGMT gene hypermethylation significantly co-existed, but not for MGMT gene expression. The validation cohort of gliomas treated with standard of care and comparison of the CpGs we identified with the current CpGs used in clinical setting will be very important for gliomas individual medicine in the future.

Pirtoli L, Belmonte G, Toscano M, et al.
Cyclin D1 Co-localizes with Beclin-1 in Glioblastoma Recurrences: A Clue to a Therapy-induced, Autophagy-mediated Degradative Mechanism?
Anticancer Res. 2016; 36(8):4057-62 [PubMed] Related Publications
BACKGROUND: Glioblastoma (GB) recurrences are rarely removed, therefore, tissue modifications induced by radiotherapy, and temozolomide chemotherapy are scarcely known. Nuclear cyclin D1 is associated with GB progression and resistance to therapy. We previously found that the expression of autophagic protein beclin-1 is a major determinant of prognosis in GB.
PATIENTS AND METHODS: In 31 patients with primary GB and their recurrences, we investigated the protein expression of cyclin D1 and beclin-1, before and after radiotherapy-temozolomide therapy by immunohistochemistry.
RESULTS: Most (20/31) primary GBs were negative for nuclear cyclin D1, and highly expressed beclin-1. In their recurrences, cytoplasmic cyclin D1 positivity was observable, which co-localized with beclin-1. Eleven primary GBs instead exhibited low beclin-1 expression and were positive for nuclear cyclin D1; three of their recurrences exhibited an increase of beclin-1, which co-localized with cyclin D1 in the cytoplasm.
CONCLUSION: Our results suggest therapy-induced degradation of cyclin D1 via autophagy.

Kesavan M, Turner JH
Myelotoxicity of Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: A Decade of Experience.
Cancer Biother Radiopharm. 2016; 31(6):189-98 [PubMed] Related Publications
AIM: This review of the literature, and the authors' own decade of experience with lutetium-177-octreotate-capecitabine±temozolomide peptide receptor radionuclide therapy (PRRT)-chemotherapy of GEPNETs, analyses the risk of both short- and long-term hematotoxicity.
BACKGROUND: Myelodysplastic syndrome (MDS) and acute leukemia (AL) have been associated with PRRT in heavily pretreated patients with a history of exposure to alkylating agents. Commenced 15 years ago, PRRT is now becoming established as first- and second-line therapy for gastroentero pancreatic neuroendocrine tumors (GEPNETs), and early treatment minimizes myelotoxicity, which is the most significant potential adverse event following PRRT.
RESULTS: Sixteen key articles involving primary research were identified. A total of 2225 patients were treated (2104 treated with PRRT monotherapy and 121 with PRRT combined with chemotherapy). The average age of patients in these studies ranged from 53 to 64 years with median duration of follow-up ranging from 6 to 62 months. Short-term myelotoxicity was observed in 221 patients (10%), occurring in 213 of 2104 patients treated with PRRT monotherapy and 8 of 121 patients treated with PRRT combined with chemotherapy. Acute toxicity manifested as modest self-limited grade 3/4 toxicity (CTCAE or WHO), most often affecting platelets during the first cycle of treatment. Toxicity manifesting early was easily managed with dose modification or therapy cessation and was ameliorated by appropriate patient selection. MDS/AL was a rare stochastic event occurring in 32 (1.4%) patients. Where bone marrow biopsy was performed, cases of MDS displayed cytogenetic abnormalities, consistent with secondary MDS. Factors associated with myelotoxicity included age >70 years, impaired renal function, baseline cytopenias, prior number of therapies, prior chemotherapy (alkylating agents), and prior radiotherapy.
CONCLUSION: Early therapy with PRRT-containing regimens improves outcomes, minimizes myelotoxicity, and renders the risk of MDS and AL negligible.

Uto M, Mizowaki T, Ogura K, et al.
Feasibility evaluation of hypofractionated radiotherapy with concurrent temozolomide in elderly patients with glioblastoma.
Int J Clin Oncol. 2016; 21(6):1023-1029 [PubMed] Related Publications
BACKGROUND: Although hypofractionated radiotherapy (HFRT) is preferred to conventionally fractionated radiotherapy when treating elderly patients with glioblastoma, the benefits and tolerability of HFRT with concurrent temozolomide (TMZ) remain unknown for such patients. We assessed the feasibility and outcomes of elderly patients with glioblastoma treated with HFRT and concurrent TMZ.
METHODS: We retrospectively reviewed the medical records of 11 patients aged ≥70 years who were treated with HFRT and concurrent TMZ. All patients had newly diagnosed and histologically confirmed glioblastoma and were treated at our institution between October 2011 and April 2015. The median age was 74 years (range, 70-85 years). Total resection/subtotal resection/biopsy were performed in 2/5/4 patients, respectively. The planning target volume included the T1-enhancing tumor and the resection cavity plus 2-cm margins, and all surrounding edema. The median prescription dose was 35 Gy (range, 35-42.5 Gy), delivered in 10 fractions. Seven patients received TMZ at 150 mg/m(2) for 5 days and 4 received TMZ at 75 mg/m(2) during HFRT. Overall survival (OS) was defined as the time from surgery to death or the last follow-up.
RESULTS: The median follow-up period was 13.2 months. The median OS and progression-free survival (PFS) times were 13.2 and 7.0 months, respectively. One patient experienced grade 4 neutropenia, lymphocytopenia, and thrombocytopenia. No grade 3 or higher nonhematological adverse event was noted.
CONCLUSION: Our analysis demonstrated the feasibility of HFRT with concurrent TMZ used to treat elderly patients with glioblastoma. Further prospective clinical trials are needed to define therapies that balance efficacy with tolerability.

Yamasaki H, Miyamoto M, Yamamoto Y, et al.
Synovial sarcoma cell lines showed reduced DNA repair activity and sensitivity to a PARP inhibitor.
Genes Cells. 2016; 21(8):852-60 [PubMed] Related Publications
Synovial sarcoma is a soft-tissue sarcoma and a rare type of cancer. Unfortunately, effective chemotherapies for synovial sarcomas have not been established. In this report, we show that synovial sarcoma cell lines have reduced repair activity for DNA damage induced by ionizing radiation (IR) and a topoisomerase II inhibitor (etoposide). We also observed reduced recruitment of RAD51 homologue (S. cerevisiae; RAD51) at sites of double-strand breaks (DSBs) in synovial sarcoma cell lines that had been exposed to IR. These findings showed that synovial sarcoma cell lines are defective in homologous recombination (HR) repair. Furthermore, we found that a poly-(ADP-ribose) polymerase (PARP) inhibitor (AZD2281; olaparib) effectively reduced the growth of synovial sarcoma cell lines in the presence of an alkylating agent (temozolomide). Our findings offer evidence that treatment combining a PARP inhibitor and an alkylating agent could have therapeutic benefits in the treatment of synovial sarcoma.

Ignarro RS, Facchini G, Vieira AS, et al.
Sulfasalazine intensifies temozolomide cytotoxicity in human glioblastoma cells.
Mol Cell Biochem. 2016; 418(1-2):167-78 [PubMed] Related Publications
Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. This tumor type synthesizes the antioxidant glutathione through system X c (-) , which is inhibited by sulfasalazine (SAS). We exposed A172 and T98G human glioblastoma cells to a presumably clinically relevant concentration of TMZ (25 µM) and/or 0.5 mM SAS for 1, 3, or 5 days and assessed cell viability. For both cell lines, TMZ alone did not alter viability at any time point, while the coadministration of TMZ and SAS significantly reduced cell viability after 5 days. The drug combination exerted a synergistic effect on A172 cells after 3 and 5 days. Therefore, this particular lineage was subjected to complementary analyses on the genetic (transcriptome) and functional (glutathione and proliferating cell nuclear antigen (PCNA) protein) levels. Cellular pathways containing differentially expressed genes related to the cell cycle were modified by TMZ alone. On the other hand, SAS regulated pathways associated with glutathione metabolism and synthesis, irrespective of TMZ. Moreover, SAS, but not TMZ, depleted the total glutathione level. Compared with the vehicle-treated cells, the level of PCNA protein was lower in cells treated with TMZ alone or in combination with SAS. In conclusion, our data showed that the association of TMZ and SAS is cytotoxic to T98G and A172 cells, thus providing useful insights for improving TMZ clinical efficacy through testing this novel drug combination. Moreover, the present study not only reports original information on differential gene expression in glioblastoma cells exposed to TMZ and/or SAS but also describes an antiproliferative effect of TMZ, which has not yet been observed in A172 cells.

Antoni D, Jastaniah Z, Haoming QC, et al.
Patterns of relapse in patients with high grade glioma receiving combined treatments including stereotactic re-irradiation for a first relapse.
Cancer Radiother. 2016; 20(4):282-91 [PubMed] Related Publications
PURPOSE: Bevacizumab and stereotactic treatment are efficient combined or alone in relapse glioma. However, patterns of relapse after this kind of salvage treatment have never been studied. The purpose of this unicentric retrospective analysis was to assess and understand the patterns of relapse of high grade glioma treated with stereotactic radiation, with or without bevacizumab.
PATIENTS AND METHODS: Twenty patients with high grade glioma relapse received a stereotactic radiation; among them two patients received temozolomide and eight patients received bevacizumab; among the latter, four received also irinotecan. We matched the stereotactic radiation treatment planning scan with the images of the first treatment and of the second relapse in order to determine the patterns of failure and associate dosimetric profile.
RESULTS: For the total population, median follow-up from the first diagnosis and relapse were 46.1 and 17.6 months, respectively. Among the 13 patients who relapsed, ten did not receive chemotherapy and three received it (P<0.05), two received temozolomide and one bevacizumab. Patients who received bevacizumab had no "out-of-field" recurrences. Among the 32 irradiated relapses, 15 were "in-field" recurrences; among them two were treated with bevacizumab and 13 were not (P<0.05). For the 32 lesions, a favourable prognostic factor of control was the association of a high-dose of irradiation and the use of bevacizumab.
CONCLUSION: For patients with relapsed high grade glioma, local control was higher with combined bevacizumab and high-dose stereotactic radiation.

Matsumura N, Nakajima N, Yamazaki T, et al.
Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low-grade astrocytoma.
Neuropathology. 2017; 37(1):58-63 [PubMed] Related Publications
Epithelioid glioblastoma (E-GBM) is a rare variant of glioblastoma (GBM), characterized by epithelioid cells with eosinophilic round cytoplasm devoid of stellate cytoplasmic processes. A number of studies have demonstrated that more than half of E-GBMs harbor a valine to glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E). However, there are no previous reports on E-GBM with telomerase reverse transcriptase (TERT) promoter mutation in addition to BRAF V600E mutation. Here, we report an E-GBM case in an 18-year-old man with BRAF V600E and TERT promoter mutations. The tumor composed of 80% E-GBM and 20% diffuse astrocytoma-like components, and BRAF V600E and TERT promoter mutations were detected in both. E-GBM generally arises as a primary lesion; however, a few previous cases have been demonstrated to accompany low-grade areas. Demonstration of concurrent BRAF V600E and TERT promoter mutations in low- and high-grade lesions strongly suggested their identical origin, and acquisition of each mutation may be an early event, possibly playing a pivotal role in the genesis and subsequent progression to E-GBM.

Horiguchi H, Nakata S, Nobusawa S, et al.
Adult-onset atypical teratoid/rhabdoid tumor featuring long spindle cells with nuclear palisading and perivascular pseudorosettes.
Neuropathology. 2017; 37(1):52-57 [PubMed] Related Publications
Atypical teratoid/rhabdoid tumors (AT/RTs) are rare malignant neoplasms of the CNS that preferentially affect young children. We herein report an adult case of AT/RT surviving for more than 5 years with the residual tumor. The patient, a 24-year-old man at onset, presented with a contrast-enhancing mass lesion in the left occipital lobe, and underwent partial tumor resection. Histologically, the tumor was predominantly composed of long spindle cells exhibiting nuclear palisading and perivascular pseudorosettes, which appeared to mimic mesenchymal, ependymal and Schwann cell tumors. A small number of isolated rhabdoid cells did not initially attract attention, and a tentative pathological diagnosis of a malignant mesenchymal tumor was made. In a later examination focusing on the small areas of rhabdoid cells, the extensive loss of the nuclear expression of INI1 was detected in all areas. Diffuse staining with vimentin and focal immunoreactivity for epithelial membrane antigen and alpha smooth muscle actin were observed not only in AT/RT foci, but also in spindle cell areas. Thus, polyphenotypic immunoreactivity was evident. Fluorescence in situ hybridization revealed a homozygous deletion of chromosome 22q covering the INI1 locus. Histopathological differences between infant and adult AT/RTs currently remain unclear. In the case of a malignant adult brain tumor showing a hardly classifiable morphology and immunophenotypic diversity, an analysis of the INI1 status may contribute to an accurate diagnosis.

Shevtsov M, Multhoff G
Recent Developments of Magnetic Nanoparticles for Theranostics of Brain Tumor.
Curr Drug Metab. 2016; 17(8):737-744 [PubMed] Related Publications
BACKGROUND: Glioblastoma multiforme, one of the most aggressive brain tumors, has a very poor clinical outcome. Despite the introduction of the alkylating reagent temozolomide (TMZ) to surgery and radiotherapy, the survival of patients could only be modestly increased up to less than 15 months. Therefore, innovative treatment strategies are urgently needed to improve survival of glioma patients.
OBJECTIVE: Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a lot of attention due to their widespread diagnostic and therapeutic applications in neuro-oncology. In this review article we discuss the possible application of the SPIONs for the diagnostic and theraputic approaches in brain cancer. Additionally we report on recent pre-clinical and clinical developments on the generation of heat in the tumors through the application of SPIONs subjected to an alternating magnetic field (AMF).
METHODS: A comprehensive review of the literature on the current status of using targeted SPIONs in brain tumor detection and therapy and also the potential hurdles to overcome was performed.
RESULTS: Functionalized nanoparticles carrying tumor-specific agents, such as antibodies or proteins might further improve their tumor targeting capacity. Furthermore, multifunctional, theranostic SPIONs can be used for simultaneous in vivo tumor imaging and targeted drug deliery. Application of the ultrasound and external magnetic field technologies significantly improves accumulation of nanoparticles in brain tumors. Hyperthermic treatment using AMF has a therapeutic potential in management of brain tumors.
CONCLUSION: Superparamagnetic nanoparticle-based imaging, drug delivery and hyperthermic treatment can potentially be a powerful tool for precise diagnosis and treatment of brain tumors.

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