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- Temozolomide salvage chemotherapy for recurrent anaplastic oligodendroglioma and oligo-astrocytoma. [Journal Article]
- J Korean Neurosurg Soc 2013 Dec; 54(6):489-95.
To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA).A multi-center retrospective trial enrolled seventy-two patients with histologically proven AO/AOA who underwent TMZ chemotherapy for their recurrent tumors from 2006 to 2010. TMZ was administered orally (150 to 200 mg/m(2)/day) for 5 days per 28 days until unacceptable toxicity occurred or tumor progression was observed.TMZ chemotherapy cycles administered was median 5.3 (range, 1-41). The objective response rate was 24% including 8 cases (11%) of complete response and another 23 patients (32%) were remained as stable disease. Severe side effects (≥grade 3) occurred only in 9 patients (13%). Progression-free survival (PFS) of all patients was a median 8.0 months (95% confidence interval, 6.0-10.0). The time to recurrence of a year or after was a favorable prognostic factor for PFS (p<0.05). Overall survival (OS) was apparently differed by the patient's histology, as AOA patients survived a median OS of 18.0 months while AO patients did not reach median OS at median follow-up of 11.5 months (range 2.7-65 months). Good performance status of Eastern Cooperative Oncology Group 0 and 1 showed prolonged OS (p<0.01).For recurrent AO/AOA after surgery followed by radiation therapy, TMZ could be recommended as a salvage therapy at the estimated efficacy equal to procarbazine, lomustine, and vincristine (PCV) chemotherapy at first relapse. For patients previously treated with PCV, TMZ is a favorable therapeutic option as 2nd line salvage chemotherapy with an acceptable toxicity rate.
- Expression and regulation of prostate apoptosis response-4 (par-4) in human glioma stem cells in drug-induced apoptosis. [Journal Article]
- PLoS One 2014; 9(2):e88505.
Gliomas are the most common and aggressive of brain tumors in adults. Cancer stem cells (CSC) contribute to chemoresistance in many solid tumors including gliomas. The function of prostate apoptosis response-4 (Par-4) as a pro-apoptotic protein is well documented in many cancers; however, its role in CSC remains obscure. In this study, we aimed to explore the role of Par-4 in drug-induced cytotoxicity using human glioma stem cell line - HNGC-2 and primary culture (G1) derived from high grade glioma. We show that among the panel of drugs- lomustine, carmustine, UCN-01, oxaliplatin, temozolomide and tamoxifen (TAM) screened, only TAM induced cell death and up-regulated Par-4 levels significantly. TAM-induced apoptosis was confirmed by PARP cleavage, Annexin V and propidium iodide staining and caspase-3 activity. Knock down of Par-4 by siRNA inhibited cell death by TAM, suggesting the role of Par-4 in induction of apoptosis. We also demonstrate that the mechanism involves break down of mitochondrial membrane potential, down regulation of Bcl-2 and reduced activation of Akt and ERK 42/44. Secretory Par-4 and GRP-78 were significantly expressed in HNGC-2 cells on exposure to TAM and specific antibodies to these molecules inhibited cell death suggesting that extrinsic Par-4 is important in TAM-induced apoptosis. Interestingly, TAM decreased the expression of neural stem cell markers - Nestin, Bmi1, Vimentin, Sox2, and Musashi in HNGC-2 cell line and G1 cells implicating its potential as a stemness inhibiting drug. Based on these data and our findings that enhanced levels of Par-4 sensitize the resistant glioma stem cells to drug-induced apoptosis, we propose that Par-4 may be explored for evaluating anti-tumor agents in CSC.
- Benefit From Procarbazine, Lomustine, and Vincristine in Oligodendroglial Tumors Is Associated With Mutation of IDH. [JOURNAL ARTICLE]
- J Clin Oncol 2014 Feb 10.
Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT.Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT.IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT.IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.
- Extranodal Lymphoma with Peripheral Nervous System Involvement in a Dog. [JOURNAL ARTICLE]
- J Vet Med Sci 2014 Jan 13.
An 8-year-old neutered female Cavalier King Charles Spaniel was evaluated for progressing right forelimb lameness. Upon magnetic resonance imaging, the right-sided radius nerves and the caudal brachial plexus were swelled. The histological and molecular biological diagnosis of partial the C8 spinal nerve was T-cell lymphoma. Co-administration of lomustine and irradiation was started. However, this therapy was ineffective. At necropsy, neoplastic tissues were seen extending into the subarachnoid space of the spinal cord, the liver, pancreas and kidneys as gross findings. A large mass was also identified occupying the caudal thorax. Histologic findings included infiltration in these organs and mass by neoplastic lymphocytes. To date, involvement of peripheral nerves (neurolymphomatosis) is rarely reported in veterinary species.
- Effect of the Addition of Chemotherapy to Radiotherapy on Cognitive Function in Patients With Low-Grade Glioma: Secondary Analysis of RTOG 98-02. [Journal Article]
- J Clin Oncol 2014 Feb 20; 32(6):535-41.
The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival.A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini-Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5.Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms.The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.
- Adults with CNS primitive neuroectodermal tumors/pineoblastomas: results of multimodal treatment according to the pediatric HIT 2000 protocol. [Journal Article]
- J Neurooncol 2014 Feb; 116(3):567-75.
Central nervous system primitive neuroectodermal tumors (CNS-PNET) and pineoblastomas (PBL) are rare in adulthood. Knowledge on clinical outcome and the efficacy and toxicities of chemotherapy in addition to radiotherapy is limited. Patients older than 21 years at diagnosis were followed in the observational arm of the prospective pediatric multicenter trial HIT 2000. After surgery, craniospinal irradiation and maintenance or sandwich chemotherapy were recommended. Radiotherapy was normo- (35.2 Gy; tumor region, 55.0 Gy; metastasis, 49.6 Gy) or hyperfractionated (40.0 Gy; tumor bed, 68.0 Gy; metastasis, 50-60 Gy). Maintenance chemotherapy consisted of eight courses (vincristine, lomustine, cisplatin). Sandwich chemotherapy included two cycles of postoperative chemotherapy followed by radiotherapy, and four courses of maintenance chemotherapy. Seventeen patients (CNS-PNET, n = 7; PBL, n = 10), median age 30 years, were included. Eight patients had a postoperative residual tumor and four patients metastatic disease. The median follow-up of ten surviving patients was 41 months. The estimated rates for 3-year progression-free survival (PFS) and overall survival were 68 ± 12 and 66 ± 13 %, respectively. PBL compared to CNS-PNET tended towards a better PFS, although the difference was not clear (p = 0.101). Both chemotherapeutic (maintenance, n = 6; sandwich, n = 8) protocols did not differ in their PFS and were feasible with acceptable toxicities. Intensified regimens of combined chemo- and radiotherapy are generally feasible in adults with CNS-PNET/PBL. The impact of intensified chemotherapy on survival should be further assessed.
- Spectroscopic analysis of the interaction of lomustine with calf thymus DNA. [Journal Article]
- J Photochem Photobiol B 2014 Jan 5.:281-6.
Investigation of drug-DNA interaction is important for understanding the drug action at molecular level and for designing specific DNA targeted drug. Lomustine (CCNU=1-[2-chloroethyl]-3-cyclohexyl-1-nitroso-urea) is an alkylating antineoplastic nitrosourea derivative, used to treat different types of cancer. In the present study, conformational and structural effects of lomustine on DNA are investigated using different spectroscopic approaches. Different drug/DNA molar ratios are analyzed to determine the binding sites and binding mode of lomustine with DNA. Fourier transform infrared spectroscopic (FTIR) results suggest binding of lomustine with nitrogenous bases guanine and cytosine along with weak interaction to the sugar-phosphate backbone of DNA. Circular dichroism (CD) spectroscopic results show perturbation in the local conformation of DNA upon binding of lomustine with DNA helix. These local conformational changes may act as recognition site for alkylating enzymes that further causes alkylation of DNA. Spectroscopic results confirm the formation of an intermediate stage of DNA that occurs during the transition of B-conformation into A-conformation.
- Bevacizumab alone at 5 mg/kg in an every-3-week schedule for patients with recurrent glioblastomas: a single center experience. [Journal Article]
- Tumori 2013 Sep-Oct; 99(5):601-3.
The use of bevacizumab is increasingly reported in neuro-oncology. The most common schedule is 10 mg/kg every 2 weeks. We retrospectively investigated the efficacy of a 3-week schedule of 5 mg/kg bevacizumab in patients with recurrent glioblastomas. Fourteen patients (median age, 46 years) were included in the study. The median number of bevacizumab cycles was 4 (range, 2-8). Five patients (36%) had a partial response, 7 (50%) had stable disease, and 2 (14%) had progressive disease. No grade III-IV toxicities were observed. The median progression-free and overall survival were 3.6 months and 6.4 months, respectively. Every-3-week low-dose single-agent bevacizumab showed substantial activity and a safe profile in patients with recurrent glioblastoma.
- Use of lomustine (CCNU) in a case of cutaneous equine lymphoma. [Journal Article]
- Can Vet J 2013 Dec; 54(12):1137-41.
A 12-year-old gelding was diagnosed with recurrent lymphoma in multiple cutaneous sites. A highly invasive preputial mass caused urethral obstruction. The horse was treated with surgery and chemotherapy consisting of lomustine (CCNU) and prednisolone. The treatment was well-tolerated and effective. This is the first reported use of lomustine (CCNU) in a horse for the treatment of equine lymphoma.
- Evaluation of outcome and prognostic factors in patients of glioblastoma multiforme: A single institution experience. [Journal Article]
- J Neurosci Rural Pract 2013 Aug; 4(Suppl 1):S46-55.
We present retrospective analysis of patients of glioblastoma multiforme (GBM) and discuss clinical characteristics, various treatment protocols, survival outcomes, and prognostic factors influencing survival.From January 2002 to June 2009, 439 patients of GBM were registered in our department. The median age of patients was 50 years, 66.1% were males, and 75% underwent complete or near-total excision. We evaluated those 360 patients who received radiotherapy (RT). Radiotherapy schedule was selected depending upon pre-RT Karnofsky Performance Status (KPS). Patients with KPS < 70 (Group I, n = 48) were planned for RT dose of 30-35 Gy in 10-15 fractions, and patients with KPS ≥ 70 (Group II, n = 312) were planned for 60 Gy in 30 fractions. In group I, six patients and in group II, 89 patients received some form of chemotherapy (lomustine or temozolomide).Statistical analysis was done using Statistical Package for Social Sciences, version 12.0. Overall survival (OS) was calculated using Kaplan-Meier method, and prognostic factors were determined by log rank test. The Cox proportional hazards model was used for multivariate analysis.The median follow-up was 7.53 months. The median and 2-year survival rates were 6.33 months and 2.24% for group I and 7.97 months and 8.21% for group II patients, respectively (P = 0.001). In multivariate analysis, site of tumor (central vs. others; P = 0.006), location of tumor (parietal lobe vs. others; P = 0.003), RT dose (<60 Gy vs. 60 Gy; P = 0.0001), and use of some form of chemotherapy (P = 0.0001) were independent prognostic factors for survival.In patients with GBM, OS and prognosis remains dismal. Whenever possible, we should use concurrent and/or adjuvant chemotherapy to maximize the benefits of post-operative radiotherapy. Patients with poor performance status may be considered for hypofractionated RT schedules, which have similar median survival rates as conventional RT.