Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare central nervous system neoplasm in which gliomatous tissue is diffusely identified in the subarachnoid space with no evidence of a primary intraparenchymal tumor. A 52-year-old man presented low back pain followed by sudden unconsciousness and had also cognitive dysfunction and meningeal sign. Examinations of cerebrospinal fluid (CSF) did not show malignant cells but increased protein and pleocytosis. Magnetic resonance (MR) imaging demonstrated diffuse leptomeningeal enhancement without any source of intraparenchymal lesion. Fluid-attenuated inversion recovery (FLAIR) also demonstrated individual diffuse high intensity area in the subarachnoid space. A biopsy disclosed wide spreading of anaplastic glial cells within the leptomeninges. He died 3 months later because of disease progression despite both radiotherapy and chemotherapy. Post-mortem examination identified PDLG and several neuropathological features of glioblastoma as well. Reviewing previous cases of PDLG instructs that this entity is rare, resembles meningitis in clinical pictures, usually occurs in a relatively younger population and has more progressive clinical course than the ordinary form of malignant gliomas.
A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M(0)) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.
Recent studies in our laboratory have shown that UCN-01 (7-hydroxystaurosporine), which is a derivative of the non-selective protein kinase inhibitor staurosporine that exhibits relative selectivity for protein kinase C (PKC), is a potent inhibitor of glioma growth in in vitro and in vivo models. This agent exhibits both cytotoxic and cytostatic effects, depending on the time period of drug exposure. In the present study, we examined whether UCN-01-induced cytotoxicity correlated with the induction of apoptosis, and characterized further the time course of this process as a prelude to application of UCN-01 in clinical trials. We first demonstrated that the cytotoxic effects of UCN-01 were associated with the induction of morphological features of apoptosis. Secondly, we identified electrophoretic features of apoptosis semiquantitatively at a series of time points using field inversion gel electrophoresis. These studies showed a peak in the induction of high-molecular-weight DNA fragmentation after 3-6 days of drug treatment. Thirdly, we measured the percentage of cells undergoing apoptosis at various time points using a terminal transferase-catalyzed in situ end-labeling technique, which confirmed a time- and concentration-dependent increase in apoptotic cell numbers. This correlated with a progressive decrease in the percentage of cells that were viable as assessed by trypan blue exclusion. Cell killing peaked within 2-4 days after beginning UCN-01 treatment, but continued at a lower level in the ensuing days. Taken together, these studies demonstrated that extended periods of exposure to UCN-01 are needed for optimal manifestation of cytotoxic effects against glioma cells, a factor that must be taken into consideration in the design of future clinical trials with this agent for malignant gliomas.
Solvent facilitated perfusion (SFP) has been proposed as a technique to increase the delivery of chemotherapeutic agents to tumors. SFP entails direct injection of the agent into the tumor in a water-miscible organic solvent, and because the solvent moves easily through both aqueous solutions and cellular membranes it drives the penetration of the solubilized anticancer agent throughout the tumor. To test this hypothesis, we compared the pharmacokinetics (PK) of 14C-labeled 1,3-bis-chlorethyl-1-nitrosourea (BCNU) in intra-cerebral 9L rat gliomas after intravenous (IV) infusion in 90% saline--10% ethanol or direct intratumoral (IT) injection of 14C-BCNU in 100% ethanol (DTI-015). Treatment with DTI-015 yielded a peak radioactive count (Cmax) for the 14C label that was 100-1000 fold higher in the tumor than in all other tissues in addition to a concentration in the tumor that was 100-fold higher than that achieved following IV infusion of 14C-BCNU. Pathologic and auto-radiographic analysis of tissue sections following IT injection of 14C-BCNU in ethanol into either tumor or normal rat brain revealed both an enhanced local volume of distribution and an increased concentration of BCNU delivered to tumor compared to non-tumor bearing brain. To investigate the mechanism behind the SFP of BCNU to the tumor both dynamic contrast and perfusion MRI were performed on 9L tumors before and after treatment and demonstrated a decrease in tumor perfusion following IT injection of DTI-015. Finally, initial PK of patient blood samples following administration of DTI-015 into relapsed high-grade glioma indicated a 20-fold decrease in systemic exposure to BCNU compared to IV infusion of BCNU providing further evidence for the enhanced therapeutic ratio observed for DTI-015.
Intratumoral (IT) administration of DTI-015 (BCNU in 100% ethanol) utilizes solvent facilitated perfusion for the treatment of tumors. RIF-1 tumors were treated by IT injection of either ethanol alone or 0.05-1.0 mg of DTI-015 or by i.v. injection of 0.5 mg of BCNU. Treatment with ethanol alone or i.v. injection of 0.5 mg of BCNU did not produce a significant growth delay. In contrast, IT administration of DTI-015 produced a significant growth delay at each of the treatment doses (p < 0.05 to p < 0.001). We have quantified the levels of N7-(2-hydroxyethyl) guanine (N7-HOEtG) in RIF-1 tumors 24h following either IT treatment with 0.5 mg DTI-015 or i.p. administration of 0.5 mg BCNU. Levels of N7-HOEtG (micromol/mol DNA) were < or = 0.08 for both untreated controls and following i.p. treatment with BCNU and 13.1 +/- 5.6 following IT administration of DTI-015. The levels of N7-HOEtG detected in RIF-1 tumors following IT administration of DTI-015 were 164-fold higher than the level(s) of N7-HOEtG in the i.p. BCNU treated tumor samples. These studies demonstrate that IT administration of DTI-015 produces high levels of DNA adducts in the tumor which correspond to a significant increase in tumor growth delay compared to the same dose of BCNU administered systemically.
Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.
Identification of cytotoxic T lymphocyte (CTL) epitopes from additional tumor antigens is essential for the development of specific immunotherapy of malignant tumors. Neuritin, a recently discovered antigen overexpressed in astrocytoma, is considered to be a promising target for biological therapy. In the present study, we predicted and identified HLA-A2-restricted CTL epitopes from neuritin by using the following four-step procedure: (1) computer-based epitope prediction from the amino acid sequence of neuritin; (2) peptide-binding assay to determine the affinity of the predicted peptide with HLA-A2.1 molecule; (3) stimulation of primary T cell response against the predicted peptides in vitro; and (4) testing of the induced CTLs toward target cells expressing neuritin and HLA-A2.1. The results demonstrated that effectors induced by peptides of neuritin containing residues 13-21, 121-129 and 4-12 could specifically-secrete interferon-γ and lyse target cells. Our results indicate that these peptides are new HLA-A2.1-restricted CTL epitopes, and may serve as valuable tools for astrocytoma immunotherapy.
Most tumor specific antigens characterized to date are restricted by HLA a*0201, which is the major HLA subtype in many ethnic groups. Cancer cells that express tumor antigens in association with the HLA a*0201 subtype have been shown to be responsive to various immunotherapies. We therefore sought to identify glioma cell lines that also express this HLA subtype and determine whether they had the molecular properties needed for tumor-peptide presentation. The HLA a*0201 allele was identified with PCR using sequence-specific primers followed by DNA sequencing. With this method, we screened 15 glioma cell lines to determine if they were of the HLA a*0201 genotype. Glioma cell lines that express the HLA a*0201 subtype were further studied for the expression of MHC class I and beta-2-microglobulin (beta2m) molecules by flow cytometry, and peptide presentation molecules TAP-1, TAP-2, and tapasin by RT-PCR. We identified six out of fifteen cell lines that were of the HLA a*0201 subtype. These cell lines are U87, T98, U373, U138, CRL2365 and UMN-4. All these six cell lines exhibited high levels of MHC class I and beta2m molecules. In addition, these cell lines all expressed molecules required for peptide presentation as shown by the presence of peptide presentation-related molecules TAP-1, TAP-2 and tapasin. The identification of glioma cell lines that express the HLA a*0201 subtype along with the necessary molecules for peptide-presentation will enable their use in developing new immunotherapeutic approaches for treating brain tumors. The method used to identify HLA a*0201 glioma cells is rapid and inexpensive, and suitable for screening tumor cells.
Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM).
To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM.
Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150-200 mg/m(2)/day on days 1-5 of each 28-day cycle. Thalidomide was given orally at 400 mg at bedtime (days 1-28) and increased to 1,200 mg as tolerated. Patients were evaluated with magnetic resonance imaging scans every 56 days. The study was designed to detect an increase of the historical 6PFS for GBM from 10 to 30%.
Forty-four patients were enrolled, 43 were evaluable for efficacy and safety. The study population included 15 women, 29 men; median age was 53 years (range 32-84); median Karnofsky performance status was 80% (range 60-100%). Thirty-six (82%) patients were chemotherapy-naïve. There were 57 reports of toxicity of grade 3 or greater. Non-fatal grade 3-4 granulocytopenia occurred in 15 patients (34%). The objective response rate was 7%. The estimated probability of being progression-free at 6 months with this therapy is 24% [95% confidence interval (C.I.) 12-38%]. The median time to progression is 15 weeks (95% C.I. 10-20 weeks). There was no observed correlation between serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS outcome.
This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.
The objective of this prospective, monocentric phase-II pilot study was to evaluate toxicity and efficacy of neoadjuvant temozolomide (TMZ) and 13-cis retinoic acid (13-cRA) treatment in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection. The primary endpoint of the study was median progression-free survival (PFS). Secondary endpoints were toxicity and PFS rates at 6, 12 and 24 months. Thirty-two adult patients were included in the study and treated with a median number of 10 TMZ and 13-cRA cycles (range 1-26). The majority of patients had favorable prognostic factors characterized by young age, complete resection, oligodendroglial histology, 1p/19q co-deletion, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation and isocitrate dehydrogenase 1 (IDH1) mutation. Grade 3/4 myelotoxicity occurred in 5/32 patients, and about 90% of patients suffered from grade 2/3 adverse events attributable to 13-cRA. The median PFS was 37.8 months (95% CI 22.2-53.4). The 6-, 12- and 24-month PFS rates were 84.4, 75 and 42.4%. The extent of tumor resection was the only prognostic factor associated with better PFS. TMZ and 13-cRA treatment did not improve PFS when retrospectively compared to the TMZ-treated group within the randomized NOA-04 phase-III trial. In conclusion, 13-cRA addition to TMZ in a neoadjuvant setting showed acceptable toxicity, but did not yield an advantage in PFS in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection.
The present study evaluated the feasibility and effectiveness of myeloablative high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed or progressed central nervous system germ cell tumors (CNS-GCTs). Eleven patients with non-germinomatous germ cell tumors and nine patients with germinomas were enrolled. Patients received between two and eight cycles of conventional chemotherapy prior to HDCT/autoSCT with or without radiotherapy. Overall, 16 patients proceeded to the first HDCT/autoSCT, and nine proceeded to the second HDCT/autoSCT. CTE (carboplatin-thiotepa-etoposide) and cyclophosphamide-melphalan (CM) regimens were used for the first and second HDCT, respectively. Toxicities during HDCT/autoSCT were acceptable, and there were no treatment-related deaths. Twelve patients experienced relapse or progression; however, four patients with germinomas remain alive after subsequent RT. Therefore, a total of 12 patients (four NGGCTs and eight germinomas) remain alive with a median follow-up of 47 months (range 22-90) after relapse or progression. The probability of 3-year overall survival was 59.1 ± 11.2 % (36.4 ± 14.5 % for NGGCTs vs. 88.9 ± 10.5 % for germinomas, P = 0.028). RT, particularly craniospinal RT, was associated with a better tumor response prior to HDCT/autoSCT and a better final outcome. In conclusion, HDCT/autoSCT was feasible, and survival rates were encouraging. Further study with a larger cohort of patients is needed to elucidate the role of HDCT/autoSCT in the treatment of relapsed or progressed CNS-GCTs.
The KIAA 0864 (KA) protein is a putative protein of a cDNA from 100 cDNA clones that was newly determined from a set of size-fractionated human brain cDNA libraries and their coding potentials of large proteins (180-200 kD) by using in vitro transcription assays. To elucidate the correlation between the KA protein and neuroepithelial tumors (NETs), the present study assessed the KA expression by the NETs using immunohistochemical and Western blot analyses with HFB-16 monoclonal antibody. Among the 55 NETs, a moderate-to-intense KA protein immunoreactivity was observed in 8 of 8 medulloblastomas, 1 of 1 central nervous system supratentorial primitive neuroectodermal tumor (CNS supratentorial PNET), 4 of 4 retinoblastomas, 1 of 1 neuroblastoma, 8 of 8 central neurocytomas, 4 of 4 oligodendrogliomas, 4 of 4 oligoastrocytomas, 1 of 1 extraventricular neurocytoma, and 1 of 1 gangliocytoma. No or a weak KA protein immunoreactivity was observed in 11 of 11 glioblastomas (GBs), 4 of 4 anaplastic astrocytomas, 4 of 4 astrocytomas, and 4 of 4 pilocytic astrocytomas. These results indicate that the antibody HFB-16 could be a useful marker for neuronal tumors and primitive neuroectodermal tumors that may originate from immature neural progenitor cells. In addition, it could be a useful tool for performing the differential diagnosis between GBs and CNS supratentorial PNET.
The frequency of both neurologic toxicity and therapeutic response due to intra-arterial (IA) chemotherapy is decreased by dose reduction. A method to individualize IA drug dosage is needed to provide each patient with the safest, most effective dose. Most trials of IA chemotherapy for malignant glioma have used body surface area (BSA) to calculate dosage; but brain size and arterial distribution do not correlate well with BSA. Fixed doses of cisplatin and BCNU were used in combination to perform 35 IA infusions in 20 malignant gliomas patients. Doses modified by the number of major intracranial vessels supplied by the infused artery were used in 34 infusions in 19 patients. Patients receiving 150 to 200 mg CP and 300 mg BCNU had an incidence of neurologic deficit of 5.6% if greater than or equal to 3 vessels were supplied by the infused artery compared to 42% for those with only 2 vessels. This crude dose modification maintained efficacy while reducing neurologic toxicity. Further refinement is possible using well established intra-arterial pharmacokinetic principles. Intra-arterial dosing based on volume flow at the site of infusion would yield a more reproducible exposure of the infused capillary bed to a drug than methods currently in use. More consistent drug exposure should reduce toxicity due to over dosing and treatment failure due to under dosing.
Malignant gliomas, especially glioblastoma multiforme, are composed of a considerable number of cells undergoing DNA synthesis and cells that contain various amounts of DNA. We have characterized cells dissociated from biopsy specimens of such tumors by sorting vital cell populations on the basis of DNA content and have determined the sensitivity of sorted cells to BCNU. Cultured human glioma cells from seven malignant gliomas were stained with Hoechst 33342 dye; the colony-forming efficiency (CFE) of stained tumor cells ranged from 2-50%. Stained cells were sorted on a fluorescence-activated cell sorter (FACS-III). The surviving fraction of each population was determined after exposure to graded doses (2.5-10 micrograms/ml X 2 h) of BCNU. Sorted populations of cells from 5 tumors had dose-response curves that were similar, although differences in cell kill of up to a half-log were commonly found between cells from different DNA peaks treated with the same BCNU dose. For two tumors, cells from the first peak (smallest DNA content) had distinct BCNU sensitivity compared to cells from the second and third peaks (largest DNA content); compared to other tumors in the series, cell kill differences were significant and greater than 1 log in magnitude for one anaplastic astrocytoma. This lack of uniformity in the response of cells within a tumor demonstrates the problem imposed by heterogeneity with regard to the interpretation of chemosensitivity testing of all cells within a single tumor.
Although TMZ replaced BCNU as the standard initial chemotherapy in the treatment of GBM, no studies have been reported comparing BCNU with TMZ. We therefore did a retrospective analysis comparing these agents as initial therapy in GBM.
Eighty-one patients with GBM in our institution received both radiation and chemotherapy as initial treatment after surgery or biopsy; 49 receiving BCNU and 32 TMZ. These were analyzed for overall survival (OS) and progression-free survival (PFS) versus the type of chemotherapy used. The influence of salvage therapy on the outcome was investigated also.
Median OS was superior in the TMZ versus the BCNU group (15.9 vs. 11.5 months) and the curves were judged to be significantly different by the log-rank test; P < 0.02. However, PFS was not significantly different between the two groups. Bevacizumab plus irinotecan (BI) was used as salvage therapy in one-third of the TMZ patients but in none of the BCNU patients. When patients receiving BI were omitted from the TMZ group the OS curve overlapped that of BCNU patients.
These data suggest that the superior OS of the TMZ-treated GBM patients was not due to better tumor control by TMZ but was possibly related to the newer salvage therapy that was available to them.
Human glioma-derived cell lines previously determined by a microtiter chemotherapy assay to be either 'sensitive' or 'resistant' to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were treated with BCNU (1-80 micrograms/ml) and observed using microcinematography, scanning electron microscopy, and transmission electron microscopy. Striking bleb formation and cell retraction were observed to occur in a dose-dependent relationship within minutes in the cells known to be BCNU-sensitive. At 15 micrograms/ml, 69% of cells showed blebs by 30 min, 87% by 90 min, and 100% by 4 hr. This activity was not seen in BCNU-resistant cells. These morphological changes occur at a time too early to be accounted for by the known BCNU mechanism of DNA alkylation and cross-link formation and suggest that cytoplasmic and/or membrane events may be significant initial events in the cytotoxic actions of BCNU.
This work aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. The objectives are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to harmonize the healthcare of patients affected by PCNST. Following a feasibility study, including an estimate of the gross incidence of PCNST (15.8/100,000 person-years) in France, all French neuropathology and neurosurgery departments decided to participate in the program. For each patient, the neurosurgeon and the neuropathologist complete a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault is authorized to compile the data files with personal identifiers. In 2.5 years, 10,093 cases of newly diagnosed PCNST have been recorded. Tumor resections were performed in 75.3%, while biopsies accounted for 24.7%. Histological diagnoses included glioma (49.6%), other neuroepithelial tumors (3.8%), meningioma (30.9%), neurinoma (8.7%), lymphoma (2.9%) and others (4.1%). Cryopreservation was reported for 2,261 PCNST specimens. Clinical and radiological aspects were also recorded. Preliminary results are encouraging and stimulating for the long-term goal of creating a National Registry and a National Network for patients affected by PCNST. To our knowledge, this is the first European databank dedicated to PCNST, with collection of clinical, radiological and histological data (including cryopreservation of the specimen). The creation of this registry and this database may have major clinical and fundamental implications.
Immunostaining patterns of glial fibrillary acidic protein (GFAP), S-100 protein (S-100p) and vimentin were studied using immunohistochemical techniques on 48 paraffin embedded glial tumors. GFAP was positive in all tumor cases except in two oligodendrogliomas. S-100p was found in most astroglial tumors and in half of the oligodendrogliomas. Vimentin was positive in many astrocytomas but in no oligodendrogliomas. Most astroglial tumors showed similar immunoreactivity for GFAP and S-100p. Fibrillary processes, however, showed stronger and more crisp staining with anti-GFAP than with anti-S-100p, whereas cell nuclei were labeled only for S-100p. Vimentin was localised mainly in juxtanuclear positions. In many astrocytomas with different degrees of malignancy co-expression of GFAP, S-100p and vimentin was found. The presence of GFAP and S-100p was not correlated with the degree of differentiation in astrocytomas. Vimentin was more positive in anaplastic astrocytomas but this finding was not statistically significant. It seems that GFAP is a superior marker to S-100p and vimentin in the identification of human gliomas.
Local delivery of biologic agents, such as gene and viruses, has been tested preclinically with encouraging success, and in some instances clinical trials have also been performed. In addition, the positive pressure infusion of various therapeutic agents is undergoing human testing and approval has already been granted for routine clinical use of biodegradable implants that diffuse a chemotherapeutic agent into peritumoral regions. Safety in glioma patients has been shown, but anticancer efficacy needs additional refinements in the technologies employed. In this review, we will describe these modalities and provide a perspective on needed improvements that should render them more successful.
Adult brainstem gliomas (BSG) are uncommon and poorly understood with respect to prognostic factors. We retrospectively evaluated the clinical, radiographic, histologic, and treatment features from 101 adults with presumed or biopsy proven BSG to determine prognostic factors.
We reviewed the records of patients diagnosed from 1987-2005. We used Cox proportional hazard models to determine prognostic factors.
These 50 male and 51 female patients ranged in age from 18 to 79 years at diagnosis (median 36 years) with follow-ups from 1 to 261 months (median 47 months). The overall survival for all patients at 5 and 10 years was 58% and 41%, respectively, with a median survival of 85 months (range 1-228). Out of 24 candidate prognosis factors, we selected seven covariates for proportional hazards model by Lasso procedure: age of diagnosis, ethnicity, need for corticosteroids, tumor grade, dysphagia, tumor location, and karnofsky performance status (KPS). Univariate analysis showed that these seven factors are significantly associated with survival. Multivariate analysis showed that four covariates significantly increased hazard for survival: ethnicity, tumor location, age of diagnosis, and tumor grade.
In this study, we identified four prognostic factors that were significantly associated with survival in adults with BSGs. Overall, these patients have a better prognosis than children with BSGs reported in the literature. These results call for larger prospective studies to fully assess the importance of these factors in the clinical setting and to help stratify patients in future clinical studies.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a reciprocal translocation between chromosomes 9 and 22. Imatinib mesylate is a potent and selective inhibitory of the BCR/ABL tyrosine kinase. Imatinib is a first choice of treatment of chronic phase CML. It has also shown activity in patients with CML in accelerated or blastic phases. However, the penetration of the drug and its active metabolites into the central nervous system (CNS) is poor. Therefore, the CNS is sanctuary site for malignant cells in patients treated with imatinib. Herein, we report a patient with CML in accelerated phase that developed central nervous system disease while on imatinib mesylate therapy.
Glioblastoma multiforme continues to be a devastating disease despite modest improvements in survival achieved at present, and there is an urgent need for innovative treatment concepts. Five-aminolevulinic acid (ALA) is a drug which induces protoporphyrin IX accumulation in malignant gliomas and has been explored for fluorescence-guided resections of these tumors. ALA is also under investigation as a photosensitizer. We report a case of a patient with prior left frontal glioblastoma multiforme treated by surgery, radiation and chemotherapy, who developed a remote lesion in the left insula, which was refractory to secondary treatments. In a compassionate use setting she was treated by oral application of ALA (20 mg/kg bodyweight), and stereotactic phototherapy achieved by positioning four laser diffusors using 3-dimensional irradiation planning, and a 633 nm diode laser. The lesion disappeared 24 h after therapy. Circumferential contrast enhancement was observed at 72 h, which disappeared in the course of subsequent months. Edema resolved completely. The patient is still free of recurrence 56 months after treatment, demonstrating an impressive and long-lasting response to this novel mode of therapy.
Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.
Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.
The pupose of this study is to assess the long-term outcome and toxicity of fractionated stereotactic radiation therapy (FSRT) and stereotactic radiosurgery (SRS) for 100 vestibular schwannomas treated at a single institution. From 1993 to 2007, 104 patients underwent were treated with radiation therapy for vestibular schwannoma. Forty-eight patients received SRS, with a median prescription dose of 12.5 Gy for SRS (range 9.7-16 Gy). For FSRT, two different fraction schedules were employed: a conventional schedule (ConFSRT) of 1.8 Gy per fraction (Gy/F) for 25 or 28 fractions to a total dose of 45 or 50.4 Gy (n = 19); and a once weekly hypofractionated course (HypoFSRT) consisting of 4 Gy/F for 5 fractions to a total dose of 20 Gy (n = 37). Patients treated with FSRT had better baseline hearing, facial, and trigeminal nerve function, and were more likely to have a diagnosis of NF2. The 5-year progression free rate (PFR) was 97.0 after SRS, 90.5% after HypoFSRT, and 100.0% after ConFSRT (p = NS). Univariate analysis demonstrated that NF2 and larger tumor size (greater than the median) correlated with poorer local control, but prior surgical resection did not. Serviceable hearing was preserved in 60.0% of SRS patients, 63.2% of HypoFSRT patients, and 44.4% of ConFSRT patients (p = 0.6). Similarly, there were no significant differences in 5-year rates of trigeminal toxicity facial nerve toxicity, vestibular dysfunction, or tinnitus.
Equivalent 5-year PFR and toxicity rates are shown for patients with vestibular schwanoma selected for SRS, HypoFSRT, and ConFSRT after multidisciplinary evaluation. Factors correlating with tumor progression included NF2 and larger tumor size.
Seventeen untreated primary adult glioblastomas were analyzed using immunocytochemistry for the expression of EGF-R, c-neu/erbB2, TGF-alpha, and phosphotyrosine. Patients were divided by median survival into long-term or short-term survivors (LTS, N = 10, median > 4 years; versus STS, N = 7, median 61 weeks). There were no significant differences between the two groups in terms of age, extent of resection, post-operative Karnofsky status, or treatment. Diagnostic sections from each tumor were stained with antibodies to EGF-R, c-neu/erbB2, TGF-alpha and phosphotyrosine. Double-labelling for TGF-alpha and EGF-R was also performed. All 10/10 LTS were considered to be EGF-R negative/scant, while 4/7 STS were EGF-R positive. EGF-R negativity significantly correlated with long-term survival. The differences in c-neu/erbB2 expression did not reach significance. However, 4/7 STS were positive for both proteins and 76% of the 17 cases were either double negative or positive for EGF-R and c-neu/erbB2. TGF-alpha and phosphotyrosine were frequently expressed, but neither were prognostic. Recurrent tumors were studied in 7 STS. EGF-R expression was increased in 4/7 of these cases and c-neu/erbB2 was increased in all 7 cases, compared to the pretreatment baselines. Increased expression of these proteins in glioblastomas may be associated with aggressive clinical behavior and treatment resistance.
Concerns regarding long-term toxicities have led to the avoidance of post-operative radiation (PORT) in young children with intracranial ependymoma. We investigated the association between post-operative radiation therapy and overall survival (OS) in children younger than 3 years and compared their survival to other age groups. The study sample from the SEER database included 804 patients with intracranial ependymoma, grades 2-3, and diagnosed between 1988 and 2005. OS was estimated using the Kaplan-Meier method, and hazard ratios (HR) and 95% confidence limits (CL) were calculated based on multivariable Cox proportional hazards models. A total of 804 patients were selected and PORT was administered to 35% of patients younger than 3 years. With a median follow-up of 3 years (range 0.1-18 years), the 3 year OS was 61% for children younger than 3 years, 83% for those ages 3-20 years, and 69% for patients older than 20 years (P < 0.001). In multivariable analysis, OS was significantly improved for patients receiving PORT (HR 0.8, 95% CL 0.6-0.9), and gross total resection (HR 0.6, 95% CL 0.5-0.8). Among children younger than 3 years, the 3 year OS was significantly greater among those who received PORT compared to those who did not (81% vs. 56%, respectively, P = 0.005). The majority of children younger than 3 years with intracranial ependymoma did not receive PORT. Children younger than 3 years who did not receive PORT had a relatively poor outcome, while those who received radiation therapy had a survival similar to older patients.
The relative importance or utility of the carbon dioxide laser within the total context of multimodality therapy and in comparison to conventional surgical techniques is unknown. Over a 36 month period, 421 operations for tumors of the brain and spinal cord were performed in our clinic. Of these, 111 (26%) were carried out with the aid of the laser. After excluding stereotactic and transsphenoidal operations, a comparison was made between 105 laser and 216 non-laser craniotomies. With the exception of pituitary tumors, the most frequent diagnoses in both the laser and non-laser cases were the same: malignant astrocytoma (48.6 vs 33.9%), meningioma (11.4 vs 14.2%) and low grade astrocytoma (8.6 vs 8.7%). The number of reoperations in the laser group (60.1%) was higher than in the non-laser group (32.7%; p less than 0.000001) and the mean operating time (299 minutes vs 237 minutes; p less than 0.00001) was longer, but there was no significant mean difference in mortality, CNS morbidity, mean blood loss (638 ml vs 671 ml) or mean length of stay (23 vs 25 days). For the subgroup of 134 cases of malignant astrocytoma, 82% of laser procedures were reoperations versus 50% for non-laser cases (p less than 0.0002) and the mean operating time was slightly longer (p less than 0.02). The length of stay for laser cases tended to be less (21 vs 27 days; p less than 0.04), but there was again no difference in blood loss (457 ml vs 522 ml), CNS morbidity (7.8 vs 4.8%) or mortality.(ABSTRACT TRUNCATED AT 250 WORDS)
Recently, many studies have found that the miR-106b ~25 cluster plays an oncogenic role in tumor progression. However, the precise role of each microRNAs (miRNAs) in the cluster is not yet clear. In the present study, we examined the expression of miR-106b in glioma samples and a tissue microarray by real-time PCR and in situ hybridization (ISH), respectively, finding that miR-106b is overexpressed in the majority of gliomas. Meanwhile, the expression of miR-106b was positively correlated with tumor grade (p < 0.05). The transfection of a miR-106b anti-sense oligonucleotide (ASON) into three human glioma cell lines (U251, LN229 and TJ905) suppressed the proliferation of these cells. Moreover, the growth of xenograft tumors in nude mice treated with miR-106b ASON was significantly impaired. A bioinformatics analysis predicted that RBL2 may be the target of miR-106b, and dual-luciferase reporter assays identified RBL2, but not RB1 or RBL1, as a target of miR-106b. These results suggest that miR-106b facilitates glioma cell growth by promoting cell cycle progression through the negative regulation of RBL2.
MicroRNAs (miRNAs), small non-protein-coding RNA molecules, modulate target gene expression by binding to 3'untranslated regions (UTR) of target mRNA. These molecules are aberrantly expressed in many human cancers, and can function either as tumor suppressors or oncogenes. In the current study, we show that miR-107 is down-regulated in glioma tissues and cell lines, and its overexpression leads to inhibition of the migratory and invasive ability of glioma cells via direct targeting of Notch2, which is known to transactivate Tenascin-C and Cox-2. Experiments with Notch2 siRNA further suggest that miR-107 may exerts its anti-invasive activity through Notch2 signaling pathways. Our findings collectively indicate that miR-107 is involved in glioma cell migration and invasion, and support its utility as a potential target for glioma treatment.
MicroRNAs and cancer stem cells have emerged as critical players in glioblastoma, one of the deadliest human cancers. In this study, we investigated the expression and function of microRNA-10b in glioblastoma cells and stem cells. An analysis of The Cancer Genome Atlas data revealed a correlation between high miR-10b levels and poor prognosis in glioblastoma patients. We measured the levels of miR-10b and found that it is upregulated in human glioblastoma tissues, glioblastoma cell and stem cell lines as compared to normal human tissues or astrocytes. Inhibition of miR-10b with a specific antagomir inhibited the proliferation of glioblastoma established and stem cell lines. Inhibition of miR-10b strongly reduced cell invasion and migration in glioblastoma cell and stem cell lines while overexpression of miR-10b induced cell migration and invasion. We also investigated several predicted targets of miR-10b but could not verify any of them experimentally. Additionally, miR-10b inhibition significantly decreased the in vivo growth of stem cell-derived orthotopic GBM xenografts. Altogether, our findings confirm the oncogenic effects of miR-10b in GBM cells and show for the first time a role of this microRNA in GBM stem cells. Targeting miR-10b might therefore inhibit glioblastoma stem cells, which are thought to be at the origin of glioblastoma and to contribute its recurrence and resistance to therapy.
Oligodendroglial tumors frequently have deletions ofchromosomal loci on 1p and 19q. Loss of heterozygosity (LOH) of chromosome 10 may be a negative prognostic factor. We reviewed 23 patients with oligodendroglial tumors, to evaluate the frequency of 1p and 10q LOH and correlate with clinical outcome. Three loci (D1S402, D1S1172, MCT118) on 1p and 2 loci (D10S520 and D10S521) on 10q were analyzed for LOH using PCR techniques. Sixteen oligodendrogliomas (6 low grade and 10 anaplastic) and 7 oligoastrocytomas (1 low grade and 6 anaplastic) were studied. Overall 14/22 (64%) showed 1p LOH and 7/23 (30%) showed 10q LOH. Of 7 patients with some response to chemotherapy, all showed 1p LOH and none had 10q LOH. Of 5 patients with stable or progressive disease, 1 had 1p LOH and 2 showed 10q LOH. The presence of 1p LOH was significantly associated with response to chemotherapy (p = 0.02). Median progression free survival (PFS) was 31 months for 1p intact patients and 118 months for the 1p LOH group (p = 0.014). Median PFS for 10q LOH patients was 31 and 118 months for patients with intact chromosome 10 (p = 0.016).1p LOH is a predictor of response to chemotherapy and a good prognostic factor. 10q LOH is less common in oligodendroglial tumors but predicts for worse outcome. Molecular genotyping of oligodendroglial tumors is recommended as part of the standard diagnostic workup.
Chromosome 10q allelic loss commonly occurs in glioblastoma. Disruption of PTEN, one of three known 10q tumor suppressor genes, affects the immune system by increasing tumor expression of immunosuppressive protein B7-H1 and by increasing tumor release of Th2-inducing cytokines. While the former might impair antitumor cellular immunity, a consideration for immunotherapy, the latter could cause 10q-maintaining tumor patients to experience comparatively higher rates of bacterial infections, a source of morbidity and mortality in glioblastoma patients.
We retrospectively reviewed 58 glioblastoma patients whose tumors were designated "normal-10q" (n = 16) or "LOH-10q" (n = 42) using loss of heterozygosity (LOH) assays of microsatellite markers in constitutional/tumor DNA pairs. Records were reviewed for symptomatic, microbiologically or radiographically confirmed infections in the first 2 years after diagnosis.
Infection occurred more frequently in "normal-10q" than "LOH-10q" patients (56% vs. 14% of patients experiencing infection; P = 0.001). "Normal-10q" patients more commonly developed all four infection types studied (urinary tract = 38% vs. 13%, craniotomy wound = 19% vs. 0%, pneumonia = 19% vs. 5%, sepsis = 6% vs. 3%). "Normal-10q" and "LOH-10q" patients had similar survival, ages, chemotherapy treatment rates, and frequency of patients on dexamethasone 1 month after radiation therapy (P = 0.4-0.98), making these factors unlikely to explain the observed difference in infection rates.
While tumor mutations may inhibit antitumor immunity, the effects of these mutations on systemic immunity remain undetermined. We found higher infection rates after glioblastoma diagnosis in patients whose tumors maintained chromosome 10q than in patients whose tumors had allelic 10q loss. Differing effects of this genetic alteration on antitumor and systemic immunity may warrant further investigation, potentially providing insight into mechanisms of antitumor immunity and host defenses against local and systemic infections.
We thoroughly examined loss of heterozygosity (LOH) around three candidate tumor suppressor genes on chromosome 10q to determine whether LOH of each tumor suppressor gene is associated with the previously defined clinical prognostic indices. We also examined whether LOH can help predict prognostic variables in astrocytomas. We selected samples from 40 astrocytomas (grades 2-4), performed Ki-67 immunostaining, and counted positive cells. Using DNA from aliquots of tumor blocks and leukocytes, we investigated LOH around the PTEN, NEURL, and DMBTI genes (10q23.3-26.1) with the silver staining procedure. We then statistically evaluated the relationship among histological features, regional LOH on chromosome 10q, and survival. The mean survival period for patients with LOH around PTEN was 7.2 months after surgery, while that for patients without LOH around PTEN was 21.4 months. Thus, LOH around PTEN was closely associated with a reduced overall survival (p = 0.0020) but LOH at NEURL or DMBTI was not (p > 0.05). The combined features of an increase in histological grading and Ki-67-positive cells and the presence of LOH around PTEN significantly correlated with poor prognosis. These factors may be useful predictors of survival, and LOH analysis of tumor suppressor genes on chromosome 10q can contribute greatly to the treatment of patients with astrocytoma.
Loss of heterozygosity (LOH) of chromosome 22q has been investigated in 160 gliomas. LOH at one or more microsatellite increased with increasing grade of the tumor (P < 0.01). LOH22q was more frequent in astrocytic tumors (37%) compared to mixed or oligodendroglial tumors (21%) (P = 0.02). LOH22q was correlated to 10q loss but not to 1p or 9p loss. Taken together, these data suggest that LOH22q is an alteration associated with malignant progression of gliomas.
There are conflicting reports regarding gliosarcomas. The goal of this study is to examine clinical, radiological, surgical and therapeutic aspects of 11 patients with gliosarcoma. Between 1993 and 2001, 11 patients with cerebral gliosarcoma were treated at our Institute. Ten patients underwent surgery and one patient had stereotactic biopsy. Four patients received whole brain radiotherapy with (60)Co, five underwent radiotherapy with LINAC extended 2 cm beyond the edema margins. One patient refused any additional treatment after surgery and one patient was not treated postoperatively for poor clinical conditions (KPS 40). Chemotherapy (temozolomide) was administered to four patients. Four patients had a prevalence of sarcomatous component that corresponded to surgical and radiological aspects similar to meningioma while six patients showed a prevalence of gliomatous component and radiological and surgical aspects similar to those of glioblastomas. Surgical resection was total in six and subtotal in four patients. Patients with prevalent sarcomatous component showed median survival time more prolonged than patients with prevalent gliomatous component (71 +/- 6 weeks vs. 63 +/- 6; P=0.0417). Moreover, the survival rate differed in relation to the therapy: patients treated with multimodality therapy (surgery, radiotherapy and chemotherapy) had a longer survival time than patients treated in single or bimodality. Despite prognosis of gliosarcomas remains poor, a multidisciplinary approach (surgery, radiotherapy and chemotherapy) seems to be associated with slight more prolonged survival times.
Discriminating tumor infiltrative and vasogenic brain edema in malignant gliomas is important although challenging in clinical settings. This study challenged this issue by performing voxel-wise analysis of (18)F-fluorodeoxy glucose (FDG) and (11)C-methionine positron emission tomography (PET) in peritumoral brain edemas. The authors studied ten malignant glioma and nine meningioma patients with peritumoral brain edema. A voxel-wise analysis of FDG and (11)C-methionine PET was performed in order to quantify the correlation between uptake of these tracers in normal brain tissue and peritumoral brain edema. Decoupling score of the uptake of two tracers was calculated as the z-score from the estimated correlation between uptake of the two tracers in normal brain tissue. The decoupling score was also converted into images for visual inspection. Average decoupling score in the peritumoral brain edema was calculated and compared between those obtained from malignant gliomas and meningiomas. FDG and (11)C-methionine uptake showed a reproducible linear correlation in normal brain tissue. This correlation was preserved in peritumoral edema of meningioma, but not in that of malignant gliomas. In malignant gliomas, higher (11)C-methionine uptake compared to that estimated by the FDG uptake in normal brain tissue was observed, thus suggesting that decoupling was caused by tumor infiltration. Visual inspection of the decoupling score enabled discrimination of tumor infiltrative and vasogenic edema. The average decoupling scores of the peritumoral brain edema in malignant gliomas were significantly higher than those in meningiomas (2.9 vs. 0.7, P = 0.0003). As a conclusion, FDG/(11)C-methionine uptake decoupling score can be used for the discrimination of tumor infiltrative and vasogenic brain edema. The proposed method also suggests the possibility of accurately detecting tumor infiltration into brain tissues in gliomas, providing significant information for treatment planning and follow-up.
Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent. Previous studies indicated that antitumor activity of CPT-11 was mediated through interaction of the drug with its target enzyme, DNA topoisomerase I (topo I).
To elucidate the mechanisms of CPT-11 resistance, we have characterized glioma cell lines (T98G/CPT-11, C6/CPT-11) selected from the wild types (T98G. C6) for acquired resistance to CPT-11. T98G/CPT-11 and C6/CPT-11 cells demonstrated 5.4- and 7.3-fold increases, respectively, in resistance to CPT-11.
Total glutathione S-transferase (GST) and GST-p activities were similar in CPT-11-sensitive and -resistant cells. No difference in intracellular accumulation of CPT-11 was observed between CPT-11-resistant and parental cells, indicating that an alteration in the uptake was not responsible for resistance. In addition, CPT-11-resistant cell lines showed no change in the total activity of Topo I, indicating an alteration in total Topo I activity was not responsible for resistance.
In contrast, significantly increased intracellular glutathione (GSH) levels were found in T98G/CPT-11 and C6/CPT-11 cells (4.3- and 2.1-fold). Furthermore, Topo I samples from T98G/CPT-11 and C6/CPT-11 cells were at least 4- and 2-fold more resistant to the inhibitory effect of the CPT-11 on the relaxation activity of Topo I than were Topo I samples from their respective parent lines. The resistance of the enzyme itself to the effects of CPT-11 may be responsible for the resistance to CPT-11. Thus, at least two distinct mechanisms have been selected for the CPT-11-resistant cells.
Chordoid meningioma is an uncommon variant of meningioma, which histologically bears a great resemblance to chordoma and often follows an aggressive clinical course. We examine clinicopathologic features of 11 cases of this rare tumor to further elucidate its behavior. Thirteen specimens of chordoid meningioma belonging to 11 patients were obtained at a single institution from 1995 to 2009. Correlations of histologic parameters, immunohistochemical study, and clinical features were assessed. This series included six men and five women with a mean age of 60.8 years at first surgery. Aside from one patient (case 5) who died of disease immediately after the first operation, the mean postoperative follow-up period for the other 10 patients was 41.4 months. Two patients each had a local tumor recurrence. The mean time to recurrence was 10.4 years. No systemic manifestations of Castleman syndrome, such as iron-refractory hypochromic/microcytic anemia and dysgammaglobulinemia, were found. Six tumors (46%) were classified as benign (grade I) and seven tumors (54%) atypical (grade II), if based solely on histologic grading irrespective of chordoid or clear cell components in our cases. Lymphoplasmacytic infiltrate was moderate in one tumor (7%), mild in eight tumors (62%), and absent in four tumors (31%). The inflammatory cells were predominantly T cells (CD3+), with only scarce B cells (CD20+). There was a wide range of MIB-1 labeling indices (0.3-25.8%, mean 7.5%), which increased following tumor recurrence. Our study demonstrates that chordoid meningiomas are not always associated with Castleman's Syndrome, and that this histologic category can be seen in the elderly as opposed to only in younger age groups.
CPT-11 is a potent inhibitor of topoisomerase I and has shown antitumor activity in brain xenografts and in clinical trials in recurrent/progressive malignant glioma. VM-26 and VP-16 are topoisomerase II inhibitors and have also shown activity in phase II trials. We performed a phase II trial of intravenous CPT-11 (125 mg/m2) followed 24 h later by VM-26 (125 mg/m2). VP-16 (125 mg/m2) was later substituted for VM-26 due to drug shortage. For patients on anticonvulsants, the starting dose for all drugs was 150 mg/m2. Drugs were given weekly for 3 weeks followed by 1-week rest. Twenty-five patients were entered into the study. Three patients (12%) had improvement in CAT/MRI brain scans (95% confidence interval 3-31%). Fatigue and myelosuppression, mainly leukopenia, were the main toxicities. This combination of the topoisomerase I inhibitor CPT-11 followed by the topoisomerase II inhibitor, VM-26 or VP-16, has shown modest antitumor activity comparable to that reported for each drug singly. Myelosuppression is the main toxicity when topoisomerase I and II inhibitors are combined together.
A prospective Phase II study of irinotecan (CPT-11) in adult patients with recurrent surgery and radiotherapy-refractory WHO Grade I meningioma.
Sixteen patients (5 men; 11 women) ages 48-70 years (median 62.5), with recurrent meningioma were treated. All patients had previously been treated with surgery (complete in 4; partial in 9; biopsy in 3) and involved-field radiotherapy (median dose 54 Gy; 12 following first surgery and 4 following second surgery). Additionally, eight patients underwent re-operation (complete in 2; partial in 6) and eight patients were treated with salvage stereotactic radiosurgery. No patient was treated with prior chemotherapy. CPT-11 was administered intravenously every 3 weeks (350 mg/m2/day in patients on non-enzyme inducing anticonvulsants [NEIAED]; 600 mg/m2/day in patients on enzyme-inducing anticonvulsants [EIAED]) for 9 weeks (operationally defined as a single cycle). Neurological and neuroradiographic evaluation were performed every 10 weeks.
All patients were evaluable. A median of two cycles of CPT-11 (range 1-4) was administered. CPT-11 related-toxicity (> or = grade 3) included diarrhea (6 occurrences, 19% all cycles administered), granulocytopenia (6, 19%), leukopenia (5, 16%), thrombocytopenia (3, 10%) and anemia (3, 10%). Four patients required transfusion (3 RBC and 1 platelet). One patient developed neutropenic fever without bacteriologic confirmation. No treatment-related deaths occurred. No patient demonstrated a neuroradiographic complete or partial response (PR), 13 patients (81%) demonstrated stable disease but disease progressed after 2 cycles of CPT-11, and 3 patients (19%) had progressive disease (PD) following a single cycle of CPT-11. Time to tumor progression ranged from 2.5 to 5.0 months (median 5.0 months). Survival ranged from 4 to months (median 7.5 months).
The primary objective was to estimate the 6-month progression-free survival (PFS) after study entry. As no patient demonstrated PFS at 6-months, the study was stopped prematurely as specified by study design. Using CPT-11 in this moderately toxic dose schedule failed to demonstrate efficacy in this cohort of adult patients with recurrent surgery and radiotherapy-refractory meningioma.
Irinotecan (CPT-11) is a topoisomerase I inhibitor with antitumor activity on a wide variety of neoplasms in several preclinical studies, but it showed poor efficacy in patients with nervous system tumors. We have carried out an experimental study in order to evaluate the effect of CPT-11 on the growth of a subcutaneously implanted malignant neuroectodermal tumor, after administration by different routes. The results showed that CPT-11 administration by intraperitoneal injections (at dose 10 mg/kg, 5 days per week, for 2 weeks, followed by 7-days rest period--one course--to a total of two courses) had no significant antitumor effect. Nevertheless, continuous infusion by intraperitoneal osmotic minipump over 28 days (at an infusion rate of 4.4 microg/h) showed a significant delay in tumor growth in 4 weeks of the implantation. The best antitumor effects were observed after CPT-11 intratumoral administration (at dose of 5 mg/kg, 5 days per week, for 2 weeks, followed by 7-days rest period, to a total of three courses) reaching tumor regression in the treated animals. These results suggest the utility of CPT-11, by means of intralesional administration, on malignant tumors of the nervous system.
Medulloblastomas are primitive neuroectodermal tumors (PNETs) of the cerebellum with poorly understood pathogenesis. Previous molecular studies suggested a role for loci on chromosome 11 in the development of medulloblastomas-PNETs. In order to identify the frequency of loss and eventually the extent of allelic loss on chromosome 11, we have examined 23 pediatric medulloblastomas for loss of heterozygosity (LOH) with 16 polymorphic microsatellites. Our data reveal that LOH on 11p or 11q occurs rarely (13%) suggesting the unlikely involvement of chromosome 11 in most cases of medulloblastomas. The same frequency of LOH in medulloblastomas was detected using 8 microsatellites on 22q. Alterations of microsatellite length were found in only 4/594 PCR analyses using 28 markers located on chromosomes 2, 9, 11, 18, and 22, demonstrating that genomic instability is uncommon in medulloblastomas.
Recent studies suggest both normal and cancerous cells secrete vesicles into the extracellular space. These extracellular vesicles (EVs) contain materials that mirror the genetic and proteomic content of the secreting cell. The identification of cancer-specific material in EVs isolated from the biofluids (e.g., serum, cerebrospinal fluid, urine) of cancer patients suggests EVs as an attractive platform for biomarker development. It is important to recognize that the EVs derived from clinical samples are likely highly heterogeneous in make-up and arose from diverse sets of biologic processes. This article aims to review the biologic processes that give rise to various types of EVs, including exosomes, microvesicles, retrovirus like particles, and apoptotic bodies. Clinical pertinence of these EVs to neuro-oncology will also be discussed.
A prospective Phase II study of CPT-11 in adult patients with recurrent supratentorial glioblastoma multiforme (GBM).
Forty patients (25 men, 15 women) ages 32-71 years (median 59), with recurrent GBM were treated. All patients had previously been treated with surgery and involved field radiotherapy (median dose 60 Gy; range 59-60). Additionally, all patients were treated with adjuvant chemotherapy (BCNU in 20, PCV in 18, Procarbazine in 2). Twenty-five patients (62%) were on anticonvulsants (phenytoin in 15, carbamazepine in 10) and 26 patients (65%) were on dexamethasone. Recurrent disease was defined by neuroradiographic disease progression (>25% increase in tumor dimensions) using gadolinium-enhanced MR imaging. The starting dose of CPT-11 was 400 mg/m2 followed in three weeks by 500 mg/m2, operationally defined as one cycle. At week 6, all patients were evaluated with MRI and neurological examination.
All patients were evaluable. Two doses (one cycle) of CPT-11 were administered to all patients. CPT-11-related toxicity included: diarrhea (16 patients, 40%); thrombocytopenia (9 patients, 23%); and neutropenia (6 patients, 15%). No patient required transfusion nor was treatment for neutropenic fever required. No treatment-related deaths were observed. All patients demonstrated progressive disease following one cycle of CPT-11.
The lack of response to CPT-11 in this patient group with recurrent GBM suggests either CPT-11 has minimal activity or CPT-11 doses/schedule utilized in this study were sub-optimal. The latter is supported by the modest toxicity seen in this study and the previously documented enhanced clearance of CPT-11 in patients on anticonvulsants and dexamethasone.
This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.
Ependymoblastoma is a rare malignant brain tumor of early childhood. Data on clinical behavior and optimal treatment strategies are scarce. We report on 11 consecutively treated children with centrally confirmed diagnosis of CNS ependymoblastoma, registered between February 1994 and October 2006 to the prospective GPOH-HIT multicenter brain tumor trials, and treated by multimodal regimens. Median age at diagnosis was 3.5 years (range, 1.8-5.6 years), and the median follow-up of survivors was 5.9 years (range, 2.2-12.7 years). Initial stage was M0 in 9, and M0/1 (no cerebrospinal fluid examination done) in 2 patients. Gross-total tumor resection was achieved in 7 patients, incomplete resection in 4 patients. Further primary therapy included chemotherapy in all patients, craniospinal radiotherapy in 5 patients and high-dose chemotherapy in 2 patients. Tumor response to chemotherapy was observed in 1 of 4 evaluable patients. Tumor progression occurred in 7 patients after a median time of 5.0 months (range, 2.5-19.2 months). Five-year progression-free survival was 36.4% (±14.5%), 5-year overall survival 30.3% (±15.9%). Of 4 survivors, 3 had gross-total tumor resection, and all were treated by either craniospinal radiotherapy and/or high-dose chemotherapy with autologous blood stem cell rescue. Prognosis of children with ependymoblastoma is poor, but sustained remissions have been achieved after multimodal treatment. Considerable diagnostic discrepancies between local and central pathologists underscore the importance of central review. Further studies are needed to improve survival of children with this rare malignant central nervous system tumor.