(CeeNu) articles in PubMed
- Current management of low-grade gliomas. [Journal Article]
- Curr Opin Neurol 2016 Sep 26CO
- CONCLUSIONS: Regarding molecular prognostic factors, IDH wild-type LGGs have the worst prognosis, independent of therapy, whereas patients with mutated IDH, codeleted 1p/19q LGGs fared best regarding progression-free survival (PFS). In high-risk LGGs, PFS is similar regardless of whether patients have been treated with radiation or TMZ. In the second trial, patients who were treated with combination radiation and chemotherapy showed significant longer overall survival.
- The Role of Molecular Diagnostics in the Management of Patients with Gliomas. [Review]
- Curr Treat Options Oncol 2016; 17(10):51CT
- The revised World Health Organization (WHO) classification of tumors of the central nervous system of 2016 combines biology-driven molecular marker diagnostics with classical histological cancer diag...
The revised World Health Organization (WHO) classification of tumors of the central nervous system of 2016 combines biology-driven molecular marker diagnostics with classical histological cancer diagnosis. Reclassification of gliomas by molecular similarity beyond histological boundaries improves outcome prediction and will increasingly guide treatment decisions. This change in paradigms implies more personalized and eventually more efficient therapeutic approaches, but the era of molecular targeted therapies for gliomas is yet at its onset. Promising results of molecularly targeted therapies in genetically less complex gliomas with circumscribed growth such as subependymal giant cell astrocytoma or pilocytic astrocytoma support further development of molecularly targeted therapies. In diffuse gliomas, several molecular markers that predict benefit from alkylating agent chemotherapy have been identified in recent years. For example, co-deletion of chromosome arms 1p and 19q predicts benefit from polychemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) in patients with anaplastic oligodendroglioma, and the presence of 1p/19q co-deletion was integrated as a defining feature of oligodendroglial tumors in the revised WHO classification. However, the tremendous increase in knowledge of molecular drivers of diffuse gliomas on genomic, epigenetic, and gene expression levels has not yet translated into effective molecular targeted therapies. Multiple reasons account for the failure of early clinical trials of molecularly targeted therapies in diffuse gliomas, including the lack of molecular entry controls as well as pharmacokinetic and pharmacodynamics issues, but the key challenge of specifically targeting the molecular backbone of diffuse gliomas is probably extensive clonal heterogeneity. A more profound understanding of clonal selection, alternative activation of oncogenic signaling pathways, and genomic instability is warranted to identify effective combination treatments and ultimately improve survival.
- Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma. [Journal Article]
- Oncotarget 2016 Jul 28O
- Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemot...
Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.
- Targeting homologous recombination by pharmacological inhibitors enhances the killing response of glioblastoma cells treated with alkylating drugs. [Journal Article]
- Mol Cancer Ther 2016 Jul 29MC
- Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First and second line therapeutics for glioblastomas are alkylating agents, including the...
Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First and second line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNUs) lomustine, nimustine, fotemustine and carmustine. These agents target the tumor DNA, forming O6-chloroethylguanine adducts and secondary DNA interstrand crosslinks (ICLs). These crosslinks are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacological inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggests that pharmacological inhibition of HR, e.g. by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs.
- Case of a miniature dachshund with a primitive neuroectodermal tumor confined to the forebrain region treated with a combination of surgery and chemotherapy. [Journal Article]
- J Vet Med Sci 2016 Jul 18JV
- A miniature dachshund aged 9 years and 7 months with a history of polyuria/polydipsia and depression was referred. General physical and neurological examinations revealed no obvious abnormalities. MR...
A miniature dachshund aged 9 years and 7 months with a history of polyuria/polydipsia and depression was referred. General physical and neurological examinations revealed no obvious abnormalities. MRI of the brain revealed a large space-occupying lesion in the left frontal lobe. This was surgically removed and pathologically diagnosed as a primitive neuroectodermal tumor (PNET). Although the clinical signs had been improved, follow-up MRI revealed recurrence of the tumor. Lomustine was administered, but 1 year after surgery, the dog exhibited cluster seizures and died. This is the first reported case of a dog with PNET confined to the forebrain region treated by surgical resection in combination with chemotherapy, as observed by repeated follow-up MRI.
- A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma. [Journal Article]
- J Neurooncol 2016; 129(3):487-94JN
- Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy...
Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m(2)). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5-6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.
- Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. [Journal Article]
- Neuro Oncol 2016 Jul 1NO
- CONCLUSIONS: There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology.
- Chemotherapy for Adults with Malignant Glioma: A Systematic Review and Network Meta-analysis. [Journal Article]
- Turk Neurosurg 2015 Aug 25TN
- CONCLUSIONS: The results of this analysis suggest that bevacizumab plus temozolomide combination therapy is not significantly more effective than temozolomide alone in improving survival of glioma patients. Moreover, bevacizumab was associated with higher hematologic toxicities. Based on the results, we suggest that bevacizumab should be used with caution in glioma patients. Additional randomized controlled trials are required to confirm this finding.
- A retrospective evaluation of lomustine (CeeNU) in 32 treatment naïve cats with intermediate to large cell gastrointestinal lymphoma (2006-2013). [Journal Article]
- Vet Comp Oncol 2016 Jun 9VC
- Multi-drug chemotherapy protocols for feline lymphoma have demonstrated variable efficacy and tolerability. In phase I trials, lomustine has demonstrated efficacy for cats with lymphoma though its us...
Multi-drug chemotherapy protocols for feline lymphoma have demonstrated variable efficacy and tolerability. In phase I trials, lomustine has demonstrated efficacy for cats with lymphoma though its use for treatment naïve feline intermediate/large cell gastrointestinal (GI) lymphoma remains unknown. This study evaluated the efficacy and tolerability of lomustine for the treatment of feline GI lymphoma. Thirty-two cats with histologically or cytologically confirmed intermediate/large cell GI lymphoma were evaluated retrospectively. Factors assessed included clinical signs, hematologic/biochemical parameters and use of l-asparaginase at induction. A response rate of 50% (16/32), with median duration of response of 302 days (range 64-1450 days), was found. Median progression-free interval was 132 days (range 31-1450 days), with overall median survival time of 108 days (range 4-1488 days). History of hyporexia, presence of anaemia and dose of lomustine were significantly associated with progression-free survival. Overall, lomustine is a well-tolerated and effective treatment for feline GI lymphoma.
New Search Next
- Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma. [Journal Article]
- PLoS One 2016; 11(5):e0156369Plos
- CONCLUSIONS: Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted.