Glioblastoma Multiforme Relapse Research Articles

Temozolomide induces the expression of the glioma Big Potassium (gBK) ion channel, while inhibiting fascin-1 expression: possible targets for glioma therapy

ABSTRACTObjective: Temozolomide (TMZ) improves Glioblastoma Multiforme (GBM) patient survival. The invasive behavior of the glioma cells is the cause of GBM relapse. The glioma BK ion channel (gBK) may provide glioma cells with a mechanism to invade surrounding tissue. gBK contains epitopes that cytolytic T lymphocytes (CTLs) can recognize and kill glioma cells. Fascin-1 is an actin crosslinking molecule that supports microvilli; these membrane protrusions provide a physical defense against CTLs. TMZ was investigated to determine its effect on gBK and fascin-1 expression.Research design and methods: Human glioma cells cultured in TMZ were analyzed for their altered mRNA and gBK protein levels by using quantitative real time PCR, immunostaining and cellular functional assays.Results: TMZ slowed glioma cell growth and inhibited their transmigratory properties due to loss of fascin-1. TMZ induced increased gBK and HLA expression and allowed these TMZ-treated cells to become better targets for gBK-specific CTLs.Conclusions: Besides its traditional chemotherapeutic effect, TMZ can have four other targeted pathways: 1) slowed glioma cell growth; 2) inhibited glioma cell transmigration; 3) increased HLA-A2 and gBK tumor antigen production; 4) increased CTL-mediated cytolysis of the TMZ treated glioma cells due to the loss of their defensive membrane protrusions supported by fascin-1.

AT-05 * PHASE II STUDY OF IFOSFAMIDE, CARBOPLATIN, AND ETOPOSIDE INPATIENTS WITH A FIRST RECURRENCE OF GLIOBLASTOMA MULTIFORME

Object The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life. Methods This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m2 on Days 1, 2, and 3), carboplatin (110 mg/m2 on Day 1), etoposide (100 mg/m2 on Days 1, 2, and 3), every 6 weeks. Results Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22–50%). The median duration of PFS was 17 weeks (95% CI 10–24 weeks). T...

435P - Use of Bevacizumab in Anticoagulated Recurrent Glioblastoma Multiforme Patients: an Australian Experience

ABSTRACT Aim: The prognosis for relapsed glioblastoma multiforme (GBM) remains poor despite advances in combined modality treatment plans in recent years. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) has been shown to improve progression free survival (PFS) in first line setting with no impact on overall survival and mixed results in relation to quality of life and cognition. As there is no standardized protocol in recurrent GBM setting, many clinicians have tried Bevacizumab in the recurrent setting with some hopeful results based on the principle that GBMs are highly vascularized tumors. Use of bevacizumab in this setting is often pursued with caution because of concerns in safety for both thrombosis and bleeding events, especially in a patient population that already has a high incidence of venous thromboembolism (VTE) and are often in full anticoagulation with low molecular weight heparin (LMWH). We aim to investigate the effectiveness and safety in using bevacizumab in anticoagulated recurrent GBM patients. Methods: In this retrospective analyasis, we searched through our own database from 1998-2014 and identfied all patients who has received bevacizumab in the recurrent setting (outside clinical trials). We then looked through medical records and databases in search of survival data, toxicity effects, dexamethasone doses. Results: There were 36 patients (often heavily pretreated) on anticoagulation prior to bevacizumab commencement (including 35 for VTE and 1 for atrial fibrillation). Out of these 36 patients, we identified 2 cases with further VTE events and 2 cases with epistaxis and 1 patient was recorded to have bowel perforation. We also recorded a median survival time on Bevacizumab of 5.37 months and a median overall survival time of 16.7 months with a significant reduction in steroid burden. Conclusions: In summary, Bevacizumab can be safely added to recurrent GBM patients that are already anticoagulated for venous thromboembolism with tolerable toxicity profiles and reasonable survival outcomes. Disclosure: All authors have declared no conflicts of interest.

Efficacy of erlotinib in patients with relapsed gliobastoma multiforme who expressed EGFRVIII and PTEN determined by immunohistochemistry

Epidermal growth factor receptor gene (EGFR) alteration is a common feature in most of glioblastoma multiforme (GBM). Robust response of anti-EGFR treatments has been mostly associated with the EGFR deletion mutant variant III (EGFRvIII) and expression of PTEN. We have performed a prospective trial in order to confirm the efficacy of erlotinib treatment in patients with relapsed GBM who expressed EGFRvIII and PTEN. All patients included in the trial were required to be PTEN (+++), EGFR (+++) and EGFRvIII (+++) positives by immunohistochemistry. This new phase II trial enrolled 40 patients and was design to be stopped in case of fewer than two responses in the first 13 patients. Patient eligibility included histopathology criteria, radiological progression, more than 18 years old, Karnofsky performed status, KPS > 50, and adequate bone marrow and organ function. There was no limit to the number of prior treatments for relapses. No enzyme-inducing antiepileptic drugs were allowed. The primary endpoints were response and progression-free survival at 6 months (PFS6). Thirteen patients (6 men, 7 women) with recurrent GBM received erlotinib 150 mg/day. Median age was 53 years, median KPS was 80, and median prior treatments for relapses were 2. There was one partial response and three stable diseases (one at 18 months). PFS at 6 months was 20 %. Dose reduction for toxicity was not needed in any patient. Dermatitis was the main treatment-related toxicity, grade 1 in 8 patients and grade 2 in 5 patients. No grade 3 toxicity was observed. Median survival was 7 months (95 % IC 1.41–4.7). As conclusion, monotherapy with erlotinib in GBM relapses patients with high protein expression for PTEN (+++), EGFR (+++), and EGFRvlII (+++) showed low toxicity but minimal efficacy and the trial stopped.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-013-1316-y) contains supplementary material, which is available to authorized users.

Case Report: Pregnancy in a patient with recurrent glioblastoma.

We report the case of a woman with relapsed glioblastoma multiforme (GBM) who recently gave birth. She announced her pregnancy shortly after the sixth cycle of a dense regimen of temozolomide, prescribed for treating the first recurrence of glioblastoma. Three years ago, in April 2008, she had undergone gross total resection of a glioblastoma multiforme in the postcentral region of the right hemisphere and had subsequently received treatment according to the actual standard therapy consisting of radiotherapy up to 60 Gy with concomitant and adjuvant temozolomide. The complete amount of temozolomide given before this pregnancy was 20.9 mg/m (2). Nevertheless, she delivered a 1890 g child by caesarean section in the 32/6 week of pregnancy. The child showed no anomalies and is developing normally under close surveillance by paediatricians.

Erratum to: Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme

Erratum to: Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme

Complete Remission and Long Term Survival in Recurrent Malignant Glioblastoma Treated with Fotemustine Monotherapy: A Case Report

Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. Conventional therapies are considered palliative and long-term progression-free survival remains low for most GBM patients even after surgical excision, concomitant radiotherapy and/or chemotherapy with nitrosoureas or Temozolomide. We report the case of a 47-year-old man who presented worsening headache over a month, accompanied by episodes of morning vomiting and hyposthenia of the left hemisoma. Cerebral tomographic scan revealed an expansive process on the right frontal site. Following surgical resection, the patient was diagnosed with diffusely infiltrating GBM. After surgery, the patient underwent radiotherapy and chemotherapy with Temozolomide for 6 months. Eleven months later, the patient underwent a second-look surgery with excision of a new right superior frontal nodule. This time the patient refused both radio and chemotherapy and underwent follow-up only. After 12 months he underwent a new craniotomy for the excision of a third GBM relapse. Following resection, the patient agreed to be treated for 6 months with fotemustine (FTM) 100 mg/m2 intravenously every 4 weeks as chemotherapy. After 3 months of treatment the patient underwent a full physical examination and diagnostic monitoring of the tumor using Magnetic Resonance Imaging (MRI) of the brain and whole body Computerised Tomography (CT). During FTM treatment, the most frequent, but reversible toxic effect was hematological grade 2 anemia and thrombocytopenia but no other grade >2 toxicity was recorded, so there was no reduction or delay in treatment. Presently, after 8 years of follow-up, the patient is in excellent health and has no evidence of intracranial disease recurrence. In light of this case, post-surgical FTM treatment seems to represent an interesting well-tolerated treatment possibility in patients with recurrent malignant GBM of the brain, given that there are very few reports of such a remission in the literature.

Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme

Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain. Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of verubulin administered in combination with carboplatin in patients with relapsed glioblastoma multiforme (GBM). Three pre-selected doses of verubulin were tested: 2.1, 2.7, and 3.3 mg/m(2) in a standard "3+3" design. Verubulin was given every second week of a 6-week cycle in the 2.1 mg/m(2) cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts. Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m(2) cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater verubulin- or carboplatin-related adverse event, including hypesthesia, cerebral ischemia, anemia, and thrombocytopenia. The mean plasma half life of verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m(2) with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no cerebral hemorrhage was observed.

Initial Experience Involving Treatment and Retreatment With Carmustine Wafers in Combination With Oral Temozolomide: Long-term Survival in a Child With Relapsed Glioblastoma Multiforme

Glioblastomas occur infrequently in children, and the prognosis is better than for glioblastomas seen in adults. Aggressive treatment is justified in pediatric patients. We present the case of a 6-year-old child with malignant posterior temporal glioma treated with surgery, radiotherapy, local chemotherapy with carmustine wafers, and oral therapy with temozolomide, both at initial diagnosis and at relapse 18 months later. After 6 years, the patient seems healthy with no focal neurologic signs, and imaging studies show no evidence of disease. Multimodal therapy was found to have a very positive outcome for a child with malignant glioma.

Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme

Relapsed glioblastoma multiforme (GBM) responds poorly to standard therapies. Vascular endothelial growth factor (VEGF) is implicated in the development of GBM and the anti-VEGF monoclonal antibody bevacizumab has shown early clinical promise against malignant glioma. We treated six patients with recurrent GBM using bevacizumab combined with carboplatin and etoposide chemotherapy (ACE regimen). Toxicity was that expected for carboplatin and etoposide alone, except for an ischemic stroke in one patient. We observed partial responses in five patients and one responding patient developed extensive tumour necrosis after 2 cycles of treatment. Median progression-free and overall survival was 19 and 29.9 weeks, respectively. Four responding patients developed recurrence, which was characterized by markedly less peri-tumoral edema, mass effect and necrosis compared with tumours at baseline. Two patients developed local extracranial extension. In conclusion, ACE was active in recurrent GBM and was mostly well tolerated.

A clinical study investigating MPC-6827 with carboplatin in the treatment of patients with relapsed glioblastoma multiforme.

2095 Background: MPC-6827 (Azixa; 4-arylaminoquinazoline) is a microtubule destabilizing agent that achieves high brain concentrations. MPC-6827 disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of MPC-6827 administered in combination with carboplatin. Methods: Three preselected doses of MPC-6827 were tested: 2.1, 2.7, and 3.3 mg/m2 in a standard “3 + 3” design. MPC-6827 was given as a 2-hr IV infusion every 2 of a 6 wk cycle in the 2.1 mg/m2 cohort or 3 wks of 4 in subsequent cohorts. Carboplatin was administered IV at AUC 4 every 2 wks for the cohort receiving 2.1 mg/m2 of MPC-6827 (n = 8) or on Day 1 of each 4 wk cycle for the 2.7 mg/m2 (n = 3) and 3.3 mg/m2 dose levels (n = 8). Patients were observed for acute DLTs during the first cycle. PK evaluations were performed. Results: As of December 7, 2009, 19 patients (median age, 51, range, 21-75; median number of prior therapies, 2, range 1-4) in first or second relapse were enrolled in the study. Fourteen patients (74%) had one lesion. Sixteen patients (95%) had a Karnofsky performance score greater than 70. All patients had previously received the Stupp regimen. Three patients (15.7%) experienced a grade 3 or greater MPC-6827 or carboplatin-related adverse event, including pyrexia (5.3%), transient ischemic attack (TIA) (5.3%), and thrombocytopenia (5.3%). The TIA occurred at the 3.3 mg/m2 dose level and was the only MPC-6827-related SAE and DLT at this dose level. The grade 4 thrombocytopenia occurred in a patient receiving carboplatin on the every 2 wk schedule. The median plasma half life of MPC-6827 was 3.22 hrs (range 2.04-9.03). Two subjects achieved a partial response in this study (duration 7.5 mos and at least 4.3 mos) by Macdonald criteria. Another 6 patients achieved stable disease (duration range 1–7 mos). The median progression-free survival time was 1.8 mos (95% CI: [1.3, 7.1]). Data collection is ongoing. Conclusions: The combination of MPC-6827 at 3.3 mg/m2 with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no incidence of cerebral hemorrhage has been reported. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Pharmaceuticals Myriad Pharmaceuticals Myriad Pharmaceuticals

Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme.

e12512 Background: The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good quality life. Methods: This trial was an open-label, single-center phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1,000 mg/m2 on Days 1, 2, and 3), carboplatin (110 mg/m2 on Day 1), etoposide (100 mg/m2 on Days 1, 2, and 3), every 6 weeks. Results: Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22%–50%). The median duration of PFS was 17 weeks (95% CI 10–24 weeks). The response rate was 25% (95% CI 9%–34%). Adverse events were generally mild and consisted mainly of alopecia. Conclusions: This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM. No significant financial relationships to disclose.

Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme

The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life. This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m(2) on Days 1, 2, and 3), carboplatin (110 mg/m(2) on Day 1), etoposide (100 mg/m(2) on Days 1, 2, and 3), every 6 weeks. Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22-50%). The median duration of PFS was 17 weeks (95% CI 10-24 weeks). The response rate was 25% (95% CI 9-34%). Adverse events were generally mild and consisted mainly of alopecia. This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM.

Second-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: a single institution experience

To evaluate efficacy and safety of fotemustine chemotherapy in temozolomide (TMZ) pretreated adults with recurrent glioblastoma multiforme (GBM). Primary endpoint was progression-free survival at 6 months. Twenty-seven patients (median age: 56 years; median Karnofsky performance status at progression: 80) with relapsed glioblastoma multiforme underwent fotemustine as second-line chemotherapy after failure of homogeneous postoperative treatment consisting of conformal radiotherapy (60 Gy in 30 fractions) with concomitant TMZ (75 mg/m2 per day), followed by six courses of TMZ (150-200 mg/m2 for 5 days every 28 days). Patients were assigned to Radiation Therapy Oncology Group recursive partitioning analysis classes for gliomas. After MRI-proven tumor relapse or progression, all patients underwent chemotherapy with fotemustine, given intravenously 100 mg/m2 every week for 3 consecutive weeks (induction phase) and then every 3 weeks (maintenance phase). Adequate liver, renal, and bone marrow functions were required. Toxicity grading was based on the National Cancer Institute's Common Toxicity Criteria (version 2.0). Response to treatment was assessed on MacDonald criteria. According to an intention-to-treat-analysis, data on all enrolled patients were included in statistical analysis. Eight partial responses (29.6%) and five cases of stable disease (18.5%) were observed. Median time to progression was 5.7 months. Progression-free survival at 6 months was 48.15%. Median survival from the beginning of fotemustine chemotherapy was 9.1 months. Median survival from diagnosis of glioblastoma was 21.2 months. Toxicity was manageable and mainly hematological (grade 3 thrombocytopenia: three cases; grade 4 leukopenia: one case). Fotemustine has shown therapeutic efficacy as single-drug second-line chemotherapy in treatment of TMZ pretreated patients.

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. Fifty-six patients with relapsed GBM (WHO grade IV) were treated with at least three vaccinations. Children and adults were treated similarly in three consecutive cohorts, with progressively shorter vaccination intervals per cohort. Feasibility and toxicity were assessed as well as effect of age, extent of resection, Karnofsky Performance Score, and treatment cohort on the progression-free (PFS) and overall survival (OS) using univariable and multivariable analysis. Since the prevaccine reoperation, the median PFS and OS of the total group was 3 and 9.6 months, respectively, with a 2-year OS of 14.8%. Total resection was a predictor for better PFS both in univariable analysis and after correction for the other covariates. For OS, younger age and total resection were predictors of a better outcome in univariable analysis but not in multivariable analysis. A trend to improved PFS was observed in favor of the faster DC vaccination schedule with tumor lysate boosting. Vaccine-related edema in one patient with gross residual disease before vaccination was the only serious adverse event. Adjuvant DC-based immunotherapy for patients with relapsed GBM is safe and can induce long-term survival. A trend to PFS improvement was shown in the faster vaccination schedule. The importance of age and a minimal residual disease status at the start of the vaccination is underscored.

CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme

Glioblastoma multiforme (GBM) is an incurable malignancy with inherent tendency to recur. In this study, we have comparatively analyzed the epigenetic profile of 32 paired tumor samples of relapsed GBM and their corresponding primary neoplasms with special attention to genes involved in the mitochondria-independent apoptotic pathway. The CpG island promoter hypermethylation status was assessed by methylation-specific polymerase chain reaction and selected samples were double checked by bisulfite genomic sequencing. Thirteen genes were analyzed for DNA methylation: the pro-apoptotic CASP8, CASP3, CASP9, DcR1, DR4, DR5 and TMS1; the cell adherence CDH1 and CDH13; the candidate tumor suppressor RASSF1A and BLU; the cell cycle regulator CHFR and the DNA repair MGMT. The CpG island promoter hypermethylation profile of relapsed GBM in comparison with their corresponding primary tumors was identical in 37.5% of the cases, whereas in 62.5% of patients, differences in the DNA methylation patterns of the 13 genes were observed. The most prominent distinction was the presence of previously undetected CASP8 hypermethylation in the GBM relapses (P = 0.031). This finding was also linked to the observation that an unmethylated CASP8 CpG island together with methylated BLU promoter in the primary GBM was associated with prolonged time to tumor progression (P = 0.0035). Our data strongly suggest that hypermethylation of the pro-apoptotic CASP8 is a differential feature of GBM relapses. These remarkable findings may foster the development of therapeutic approaches using DNA demethylating drugs and activators of the extrinsic apoptotic pathway to improve the dismal prognosis of GBM.

Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression

Cyclooxygenases (COX, prostaglandin endoperoxide synthases, PGG/H synthases) are potent mediators of edema, impeding blood flow and immunomodulation in the pathologically altered brain. Two COX iso-enzymes have been associated with brain disease, the constitutively expressed COX-1 and the cytokine-inducible COX-2. We have used single and double labeling immunohistochemistry to analyse COX-1 and COX-2 expression in twenty-six primary WHO grade II oligodendrogliomas, sixteen primary WHO grade III anaplastic oligodendrogliomas, twenty-seven matched recurrences and ten neuropathologically unaltered brains. COX-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of COX-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in primary anaplastic oligodendrogliomas ( P<0.0001) and in anaplastic oligodendroglioma relapses ( P=0.011). Patients with low COX-1 labeling scores in the primary tumors had significantly longer time to progression and overall survival ( P=0.0285) than those with high COX-1 labeling scores. COX-2 immunoreactivity was predominantly observed in disseminated neurons and astrocytes. In glioblastoma multiforme relapses, accumulation of COX-2 expressing astrocytes was observed surrounding areas of focal necrosis. The number of COX-2 expressing astrocytes was significantly ( P=0.0471) lower in primary oligodendrogliomas than in high grade oligodendroglioma relapses. These data provide convincing evidence for the differential accumulation of cyclooxygenase isoforms during oligodendroglioma progression in vivo.

Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression

Heme oxygenase (HO-1, HSP32) catalyzes the oxidation of heme to biliverdin and carbon monoxide, a putative neurotransmitter. In the brain, HO-1 expression has been associated with neuroprotection during oxidative stress and hypoxia. However, consecutive downstream mediation is involved in neoangiogenesis and consequent neoplastic outgrowth. We have analyzed HO-1 expression in 69 oligodendroglioma tissue samples, in rat intracranially transplanted C6 gliomas, and neuropathologically unaltered control brains by immunohistochemistry. Double labeling experiments confirmed the nature of HO-1 expressing cells. Reverse transcription–polymerase chain reaction was used to demonstrate HO-1 gene expression. HO-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of HO-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in their matched relapses ( P<0.0001) and lower in primary anaplastic oligodendrogliomas than in their relapses ( P=0.0006). Prominent accumulation of HO-1 expressing macrophages/microglial cells was observed in perinecrotic areas of both experimental rat and human glioblastoma relapses. HO-1 expressing neurons, macrophages/microglial cells and astrocytes were scattered in areas of infiltrative tumor growth. Surprisingly, HO-1 mRNA was detected in only one glioblastoma multiforme relapse. We conclude from these data that HO-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression in areas of focal necrosis. However, overall biological function of this phenomenon remains to be determined.