- Clinical effectiveness of bevacizumab in patients with recurrent brain tumours: A population-based evaluation. [Review]
- JOJ Oncol Pharm Pract 2016 Nov 30
- CONCLUSIONS: Bevacizumab therapy seems to be effective in delaying disease progression in patients with recurrent brain tumour, but with limited benefits on the overall survival, when used outside the clinical trial setting.
- Deferred radiotherapy and upfront procarbazine-ACNU-vincristine administration for 1p19q codeleted oligodendroglial tumors are associated with favorable outcome without compromising patient performance, regardless of WHO grade. [Journal Article]
- OTOnco Targets Ther 2016; 9:7123-7131
- Recently updated phase III trials revealed the favorable effect of add-on procarbazine-lomustine-vincristine chemotherapy (CT) to radiotherapy (RT) in treating anaplastic oligodendrogliomas with 1p19...
Recently updated phase III trials revealed the favorable effect of add-on procarbazine-lomustine-vincristine chemotherapy (CT) to radiotherapy (RT) in treating anaplastic oligodendrogliomas with 1p19q codeletion (codel). However, the underlying rationality of deferring RT and upfront CT administration for these tumors is yet to be elucidated. Here, we retrospectively analyzed the long-term outcome of our case series with oligodendroglial tumors treated with deferred RT and upfront procarbazine+nimustine+vincristine (PAV) in the introduction administration. We enrolled 36 patients with newly diagnosed oligodendroglial tumors (17, grade II and 19, grade III) treated during 1999-2012 and followed up for a median period of 69.0 months. Their clinical and genetic prognostic factors were analyzed, and progression-free survival, overall survival (OS), and deterioration-free survival (DFS) were evaluated. Regardless of the WHO grade, the 25 patients with 1p19q codel tumors never received RT initially, and of these 25, 23 received PAV treatment upfront. The 75% OS of patients with 1p19q codel tumor was 135.3 months (did not reach the median OS), indicating a favorable outcome. Multivariate analysis revealed that IDH mutation and 1p19q, not WHO grade, are independent prognostic factors; furthermore, IDH and 1p19q status stratified the cohort into 3 groups with significantly different OS. The DFS explained the prolonged survival without declining performance in patients with both grade II and III 1p19q codel tumors. Deferred RT and upfront PAV treatment for 1p19q codel oligodendrogliomas were associated with favorable outcomes without compromising performance status, regardless of WHO grade.
- High-dose methotrexate based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN-study). [Journal Article]
- LLeukemia 2016 Nov 15
- To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma (PCNSL), we conducted a multicentre single arm trial....
To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma (PCNSL), we conducted a multicentre single arm trial. One cycle consisted of rituximab (375 mg/m(2), day 1, 15, 29), high-dose methotrexate (3 g/m(2) days 2, 16, 30), procarbazine (60 mg/m(2) day 2-11), and lomustine (110 mg/m(2), day 2)-R-MPL protocol. Due to infectious complications we omitted lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary endpoint was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared to R-MPL (37.7%), but respective 2-year PFS (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and OS (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less⩾grade 3 toxicities compared to R-MPL (71.1% versus 87.0%). R-MP is more feasible while still associated with similar efficacy compared to R-MPL and warrants further improvement in future studies.Leukemia accepted article preview online, 15 November 2016. doi:10.1038/leu.2016.334.
- Structural-conformational aspects of tRNA complexation with chloroethyl nitrosourea derivatives: A molecular modeling and spectroscopic investigation. [Journal Article]
- JPJ Photochem Photobiol B 2016 Nov 06; 166:1-11
- Chloroethyl nitrosourea derivatives (CENUs) represent an important family of anticancer chemotherapeutic agents, which are used in the treatment of different types of cancer such as brain tumors, res...
Chloroethyl nitrosourea derivatives (CENUs) represent an important family of anticancer chemotherapeutic agents, which are used in the treatment of different types of cancer such as brain tumors, resistant or relapsed Hodgkin's disease, small cell lung cancer and malignant melanoma. This work focuses towards understanding the interaction of chloroethyl nitrosourea derivatives; lomustine, nimustine and semustine with tRNA using spectroscopic approach in order to elucidate their auxiliary anticancer action mechanism inside the cell. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), Fourier transform infrared difference spectroscopy, circular dichroism spectroscopy and UV-visible spectroscopy were employed to investigate the binding parameters of tRNA-CENUs complexation. Results of present study demonstrate that all CENUs, studied here, interact with tRNA through guanine nitrogenous base residues and possibly further crosslink cytosine residues in paired region of tRNA. Moreover, spectral data collected for nimustine-tRNA and semustine-tRNA complex formation indicates towards the groove-directed-alkylation as their anti-malignant action, which involves the participation of uracil moiety located in major groove of tRNA. Besides this, tRNA-CENUs adduct formation did not alter the native conformation of biopolymer and tRNA remains in A-form after its interaction with all three nitrosourea derivatives studied. The binding constants (Ka) estimated for tRNA complexation with lomustine, nimustine and semustine are 2.55×10(2)M(-1), 4.923×10(2)M(-1) and 4.223×10(2)M(-1) respectively, which specify weak type of CENU's binding with tRNA. Moreover, molecular modeling simulations were also performed to predict preferential binding orientation of CENUs with tRNA that corroborates well with spectral outcomes. The findings, presented here, recognize tRNA binding properties of CENUs that can further help in rational designing of more specific and efficient RNA targeted chemotherapeutic agents.
- Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs. [Journal Article]
- MCMol Cancer Ther 2016; 15(11):2665-2678
- 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 th...
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 (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O(6)-chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links 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 pharmacologic 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 suggest that pharmacologic inhibition of HR, for example by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs. Mol Cancer Ther; 15(11); 2665-78. ©2016 AACR.
- Current management of low-grade gliomas. [Journal Article]
- COCurr Opin Neurol 2016; 29(6):782-788
- 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.
- Inhibition of histone deacetylases sensitizes glioblastoma cells to lomustine. [Journal Article]
- COCell Oncol (Dordr) 2016 Oct 20
- CONCLUSIONS: From our data we conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM.
- SPINAL MAST CELL TUMORS IN DOGS: IMAGING FEATURES AND CLINICAL OUTCOME OF FOUR CASES. [Journal Article]
- VRVet Radiol Ultrasound 2016 Oct 9
- Published information regarding canine vertebral column mast cell tumors (MCTs) is limited. The objectives of this study were to report clinical and advanced imaging findings for a group of dogs with...
Published information regarding canine vertebral column mast cell tumors (MCTs) is limited. The objectives of this study were to report clinical and advanced imaging findings for a group of dogs with confirmed spinal MCT. Inclusion criteria for this retrospective case series were dogs with spinal magnetic resonance imaging (MRI) or computed tomography (CT) scans and a histological diagnosis of spinal MCT. Clinical, imaging, treatment, and outcome data were recorded. Four dogs met inclusion criteria. One dog had primary spinal MCT and three dogs had metastatic spinal MCT. All four dogs presented for paraspinal hyperesthesia and subacute progressive or acute myelopathy. All CT and MRI lesions were extradural. Two cases exhibited distinct masses in the epidural space. In one case, an epidural tumor invaded from the paravertebral musculature. One case exhibited polyostotic lesions indistinguishable from multiple myeloma by MRI. One dog with a primary epidural low-grade MCT remains clinically normal 4 years postoperatively, following adjunctive lomustine. An epidural high-grade MCT, metastatic from a cutaneous tumor, recurred within 2 months of surgery despite adjunctive vinblastine. Two high-grade cases with concurrent visceral involvement were euthanized immediately after imaging. In dogs, MCT should be considered as a differential diagnosis for a progressive painful myelopathy and CT or MRI evidence of an extradural spinal lesion (epidural, paravertebral, or polyostotic). While more often associated with cutaneous or disseminated disease, MCT may also occur as a primary tumor of the epidural space in dogs.
- The Role of Molecular Diagnostics in the Management of Patients with Gliomas. [Review]
- CTCurr Treat Options Oncol 2016; 17(10):51
- 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.
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- Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma. [Journal Article]
- OOncotarget 2016 Jul 28
- 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.