Phase I-II clinical trial design: a state-of-the-art paradigm for dose finding.

Background: Conventional phase I algorithms for finding a phase-2 recommended dose (P2RD) based on toxicity alone is problematic because the maximum tolerated dose (MTD) is not necessarily the optimal dose with the most desirable risk-benefit trade-off. Moreover, the increasingly common practice of treating an expansion cohort at a chosen MTD has undesirable consequences that may not be obvious. Patients and methods: We review the phase I-II paradigm and the EffTox design, which utilizes both efficacy and toxicity to choose optimal doses for successive patient cohorts and find the optimal P2RD. We conduct a computer simulation study to compare the performance of the EffTox design with the traditional 3 + 3 design and the continuous reassessment method. Results: By accounting for the risk-benefit trade-off, the EffTox phase I-II design overcomes the limitations of conventional toxicity-based phase I designs. Numerical simulations show that the EffTox design has higher probabilities of identifying the optimal dose and treats more patients at the optimal dose. Conclusions: Phase I-II designs, such as the EffTox design, provide a coherent and efficient approach to finding the optimal P2RD by explicitly accounting for risk-benefit trade-offs underlying medical decisions.

A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Free energy generalization of the Peierls potential in iron.

In body-centered-cubic (bcc) crystals, 1/2<111> screw dislocations exhibit high intrinsic lattice friction as a consequence of their nonplanar core structure, which results in a periodic energy landscape known as the Peierls potential U(P). The main features determining plastic flow, including its stress and temperature dependences, can be derived directly from this potential, hence its importance. In this Letter, we use thermodynamic integration to provide a full thermodynamic extension of U(P) for bcc Fe. We compute the Peierls free energy path as a function of stress and temperature and show that the critical stress vanishes at 700 K, supplying the qualitative elements that explain plastic behavior in the athermal limit.

Mood disturbance in glioma patients.

Patients diagnosed with primary brain tumors such as glioma experience psychological distress throughout the illness trajectory. Determining which patient characteristics are associated with more severe mood disturbance throughout the illness trajectory can help identify patients at risk and assist in developing targeted interventions based on these factors. Adult glioma patients were eligible for participation. Data collection tools included an investigator completed clinician assessment tool, patient completed demographic form and the Profile of mood states-short form. A multiple regression model was used to describe the relationship between the patient groups and clinical factors. The study enrolled 186 glioma patients of various tumor grades, who were categorized in three groups (newly diagnosed, on-treatment, follow-up) based on disease status at time of visit. Newly diagnosed patients experienced more total mood disturbance than all the other groups. Characteristics associated with more severe mood disturbance varied by patient group: newly diagnosed patients who were not on corticosteroids and were not married were more likely to have higher mood disturbance [R(2) = 0.27, F (2, 29) = 5.31, p < 0.02]. For those on treatment, the use of concomitant medications, having more than 1 recurrence and low income predicted higher mood disturbance [R(2) = 0.417, F (4, 67) = 11.98, p < 0.001]. For those not on active treatment, female sex, anti-depressant use and having a lower income was associated with higher mood disturbance [R(2) = 0.183, F (3, 55) = 4.11, p < 0.02]. Additionally, when compared to other cancer groups, glioma patients reported similar mood disturbance to those with breast cancer. Factors other than disease characteristics are associated with higher mood disturbance and vary according to current disease status. The use of concomitant medications, demographic factors, recurrence and income are associated with mood disturbance and interventions may need to be tailored to these underlying factors.

Development of BNBSL: A ß-ν spectra library for spectrometry applications.

While modern nuclear decay data can provide many details of a given nuclides ß-decay modes (branching ratios, decay heating etc.), knowledge of the emitted ß-energy spectrum is often not included. This limitation hampers the use of decay data in some analysis, such as ß-spectrometry of irradiated material, prediction of ß-decay Bremsstrahlung or antineutrino, ν̄, detection. To address this deficiency, and for increased ease of ß-spectrometry studies of complex samples, a library of ß, ν and Bremsstrahlung-spectra, called BNBSL (Beta-Neutrino-Bremsstrahlung spectra library), has been produced. It has been found that the content compares favourably with experimental data and methodologies for its application to complex nuclear inventories have been developed. BNBSL contains spectra for over 1500 nuclides, which is hoped will benefit applied nuclear, radiation and materials science studies.

Two phase II trials of temozolomide with interferon-alpha2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme.

BACKGROUND: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon alpha2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls. METHODS: Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150-200 mg m(-2) per day x 5 days every month) combined with either 4 million units per m(2) subcutaneously (SQ) three times weekly of IFN or 0.5 microg kg(-1) SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks. RESULTS: On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35-38% and 18-21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study. CONCLUSION: In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.

Antiepileptic drugs for preventing seizures in people with brain tumors.

BACKGROUND: Seizures can present at any time before or after diagnosis of a brain tumor. The risk of seizures varies by tumor type and its location in the brain. For a long time we believed that preventing seizures with antiepileptic drugs (seizure prophylaxis) was effective and necessary, but the supporting evidence was little and mixed. Such evidence was the basis for previous reviews to conclude that seizure prophylaxis was ineffective in people with brain tumors. OBJECTIVES: To estimate the effectiveness of seizure prophylaxis in people with brain tumors, and to estimate the adverse event rates in the identified clinical trials. SEARCH STRATEGY: A search strategy that included free-text and MeSH terms in LILACS, EMBASE, PubMed, CENTRAL, and The Cochrane Library (1966 to 2007). SELECTION CRITERIA: Controlled clinical trials with random allocation, blinded or unblinded, and placebo or observation in the control groups. DATA COLLECTION AND ANALYSIS: We screened the articles, extracted the data, and rated the validity of each trial to assess the risk of bias. Our primary outcome was the occurrence of a first seizure. The secondary outcome was adverse events. We pooled the aggregate data for each outcome into a random-effects model meta-analysis using the relative risk (RR). For adverse events, we also included the number needed to harm (NNH) using the absolute risk increase to compute the NNH. MAIN RESULTS: There was no difference between the treatment interventions and the control groups in preventing a first seizure in participants with brain tumors. The risk of an adverse event was higher for those on antiepileptic drugs than for participants not on antiepileptic drugs (NNH 3; RR 6.10, 95% CI 1.10 to 34.63; P = 0.046). AUTHORS' CONCLUSIONS: The evidence is neutral, neither for nor against seizure prophylaxis, in people with brain tumors. These conclusions apply only for the antiepileptic drugs phenytoin, phenobarbital, and divalproex sodium. The decision to start an antiepileptic drug for seizure prophylaxis is ultimately guided by assessment of individual risk factors and careful discussion with patients.

Methotrexate neurotoxicity: in vitro studies using cerebellar explants from rats.

The mechanism of methotrexate (MTX)-induced neurotoxicity was investigated using cerebellar explant cultures from fetal rats. After 3 weeks of growth, myelinated cultures were treated with MTX at 1 microM, lysolecithin at 1 mg/dl, or unaltered nutrient medium. Myelin sheaths devoid of axons were observed by histological and electron microscopic preparations after 2 weeks of MTX exposure. After 5 weeks, cultures were almost entirely devoid of myelin sheaths. Myelin basic protein in the media removed from the cultures showed an increase in concentration after 3 weeks of MTX exposure and was significantly greater than control after 5 weeks of exposure. 2',3'-Cyclic nucleotide 3'-phosphohydrolase activity, a measure of oligodendroglial function, was not significantly different in the MTX group compared to controls. Lysolecithin-treated cultures showed widespread destruction and an early increase in myelin basic protein release into the medium. These data indicate that, in the cerebellar explant cultures, MTX is primarily a neuronal toxin, and the demyelination is a consequence of axonal loss and is not related to a change in oligodendroglial cell function. These findings provide new insight into the pathogenesis of MTX-induced neurotoxicity.

Phase II study of paclitaxel in patients with recurrent malignant glioma.

PURPOSE: To assess the efficacy and toxicity of paclitaxel administered as a 3-hour infusion to patients with recurrent malignant glioma. PATIENTS AND METHODS: Adult patients with recurrent malignant glioma following radiation therapy, who had received no more than one prior chemotherapy regimen and who had a Karnofsky performance status (KPS) > or = 60, were treated with a 3-hour infusion of paclitaxel every 3 weeks. The initial dose was 210 mg/m2; dose escalation to 240 mg/m2 was allowed. Tumor response was assessed at 6-week intervals using radiographic and clinical criteria. Treatment was continued until documented tumor progression or a total of 12 paclitaxel infusions. RESULTS: Of 41 eligible patients, all were assessable for treatment toxicity and 40 (98%) were assessable for response. The response rate (disease stabilization or better) was 35%. Twenty-nine patients (71%) underwent dose escalation to 240 mg/m2 without the use of growth factors. Toxicities included alopecia (98%), nausea (22%), arthralgias (32%), CNS toxicity (24%), peripheral neuropathy (15%), cardiac toxicity (7%), and myelosuppression (10% grade 3 or 4 hematologic toxicity). No patient developed febrile neutropenia. There was one allergic reaction (2%). CONCLUSION: Paclitaxel is well tolerated at this dose schedule in patients with recurrent malignant glioma, and affords a modest response rate. Because minimal myelotoxicity was encountered in our patients, a dose-escalating phase I/II study of paclitaxel is planned to determine the maximal-tolerated dose (MTD).

Sequences of taxol and cisplatin: a phase I and pharmacologic study.

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.

Comparison of survival of amiodarone-treated patients with coronary artery disease and malignant ventricular arrhythmias with that of a control group with coronary artery disease.

Although amiodarone is effective in the treatment of ventricular arrhythmias, it is associated with serious toxic effects. In addition, the prognosis of patients with malignant ventricular arrhythmias and coronary artery disease treated with amiodarone remains poor. The survival of 54 consecutive patients with angiographically documented coronary artery disease and symptomatic ventricular tachycardia or ventricular fibrillation treated with amiodarone was compared with that of 5,125 medically treated patients with coronary artery disease. The amiodarone group was older, with worse left ventricular function and more peripheral and cerebrovascular disease. The 1 year survival probability was 0.73 for the amiodarone group and 0.94 for the control coronary artery disease group. At 2 years of follow-up, the survival probabilities were 0.60 and 0.90 for the amiodarone and the control group, respectively. When the survival curves were adjusted for group differences in baseline prognostic characteristics (integrated as a previously published hazard score), there was no difference in the prognosis of the two groups. These findings suggest that treatment with amiodarone of malignant ventricular arrhythmias associated with coronary artery disease maintains patients on an underlying survival curve determined by the degree of myocardial dysfunction, clinical characteristics and coronary anatomy, and that amiodarone does not have a deleterious effect on survival.

Characterization of retrograde conduction by direct endocardial recording from an accessory atrioventricular pathway.

Accessory pathway electrograms are rarely recorded in patients with Wolff-Parkinson-White syndrome. In one patient, during electrophysiologic study, simultaneous local ventricular (V) accessory pathway (AP) and atrial (A) deflections were recorded during bipolar catheter endocardial mapping over the pathway. Analysis of changes in electrographic intervals during performance of the ventricular extrastimulus technique allowed characterization of the retrograde conduction properties of the pathway. As coupling intervals were decreased, an initial increase was seen in the AP2A2 interval with subsequent ventriculoatrial block between the accessory pathway and atrium. When coupling intervals were further decreased, the V2AP2 interval lengthened with ultimate block between the ventricle and accessory pathway. These findings support the concept of impedance mismatch as the cause of conduction block in accessory pathways with the distal junction of the accessory pathway being the most vulnerable.

Early diagnosis of spinal epidural metastases using out-patient computed tomographic myelography.

Twenty patients with known malignancies, back pain, abnormal roentgenograms of the spine, and normal neurological examinations were evaluated by outpatient computed tomographic (CT) myelography to determine the presence and extent of epidural tumor. Spinal CT following the intrathecal administration of low doses of water soluble contrast agents provided high quality diagnostic information. Three patients experienced adverse effects from this procedure which were mild and easily managed in the outpatient setting. Epidural tumor was identified in 15 of 20 (75%) patients. Patients were followed for 9-27 months following myelography. The 14 patients with epidural tumor treated with local radiation experienced pain relief and only one of these patients developed signs or symptoms of recurrent epidural tumor in the treated site. This study documents the high incidence of epidural tumor in selected patients without neurological deficits and the excellent palliative results of non-emergent, carefully planned radiation therapy. It also demonstrates that high resolution CT myelography can be performed safely in an outpatient setting in patients at high risk for epidural tumor. Outpatient myelography facilitates the early diagnosis of epidural tumor and provides needed information on the extent of the tumor for radiation treatment planning while conserving health care resources. For these reasons, outpatient CT myelography should be considered in selected patients with cancer who are at high risk for epidural metastases.

Incidence and nature of neurologic problems in patients with solid tumors.

The medical records of all patients admitted to the solid tumor service of the Johns Hopkins Oncology Center over a three-month period were reviewed to determine the incidence and nature of major neurologic problems on the inpatient service of a university-based comprehensive cancer center. Seventy-four of 162 patients (46 percent) admitted during this time had tumor invading or compressing the nervous system, pain, seizures, or alteration in mental status. The most common problems were pain (34 patients) and altered mental status (25 patients). The evaluation or treatment of a neurologic problem constituted the second most common reason for admission to this inpatient oncology unit. Neurologic problems will soon be the most common reason for hospital admissions in patients with disseminated cancer as a result of changes in patterns of health care delivery and improvements in systemic therapy and supportive care.

Decreased phenytoin levels in patients receiving chemotherapy.

PURPOSE AND METHODS: Seizures and unexpectedly low phenytoin levels prompted a retrospective review of phenytoin doses and serum levels in patients with primary brain tumors following the administration of cisplatin and carmustine (BCNU) chemotherapy. RESULTS: All patients who received three or more cycles of this chemotherapeutic regimen required an increase in their maintenance phenytoin dose to maintain therapeutic phenytoin levels. The average increase in the daily phenytoin dose was 41% (range, 20% to 100%). In addition, 17 of 26 (65%) assessable chemotherapy cycles were accompanied by a greater than 20% decrease in phenytoin levels or an increase in phenytoin requirements. Significant changes in phenytoin levels occurred as early as two days after administration of chemotherapy and were seen exclusively in treatment cycles that contained cisplatin. Five additional cases were found in the literature in which serum phenytoin concentrations decreased after the administration of antineoplastic agents. CONCLUSIONS: These observations are important to physicians treating patients who are receiving phenytoin. Serious consequences can be avoided by expecting changes in phenytoin dosage requirements after the administration of chemotherapy, monitoring serum levels frequently, and making appropriate adjustments in phenytoin dosages. Prospective evaluations are needed to confirm these observations, to define the chemotherapeutic agents that predispose patients to these alterations in phenytoin's pharmacology, and to determine if drugs other than phenytoin are affected by the administration of chemotherapy.

Cryosurgical versus catheter ablation of the atrioventricular junction.

Results of catheter ablation of the atrioventricular (AV) junction in 41 patients were compared with results of cryosurgical ablation in 42 patients. Mean follow-up was 29 months among patients who underwent catheter ablation and 53 months among those who underwent cryosurgical ablation. In both groups complete heart block was produced in most patients (88% in the catheter ablation group, 86% in the cryosurgery group), and similar proportions of patients continued to receive antiarrhythmic drugs (27% in the catheter ablation group, 36% in the cryosurgery group). However, the short-term morbidity rate was significantly lower among patients who underwent catheter ablation (12% vs 42%) (p = 0.004). Long-term mortality and morbidity rates were not significantly different; most deaths were related to underlying cardiopulmonary disease and morbidity to problems with permanent pacemakers. Both catheter ablation and cryosurgical ablation of the AV junction are effective in creating complete AV block and controlling supraventricular tachycardia in medically refractory patients. Because catheter ablation is associated with lower short-term morbidity and avoids the need for a major surgical procedure, it is preferable to cryosurgical ablation of the AV junction when permanent abolition of AV conduction is necessary.

Value of the 12-lead electrocardiogram in discriminating atrioventricular nodal reciprocating tachycardia from circus movement atrioventricular tachycardia utilizing a retrograde accessory pathway.

The value of the 12-lead electrocardiogram for distinguishing atrioventricular (AV) nodal reciprocating tachycardia from circus movement AV tachycardia utilizing a retrograde accessory pathway was studied in 100 patients with narrow QRS complex tachycardia. Intracardiac electrograms showed AV nodal reciprocating tachycardia in 40 patients and circus movement AV tachycardia in 60. The 12-lead electrocardiograms recorded during tachycardia were randomly sorted and reviewed by 4 experienced cardiac electrophysiologists who were blinded to the diagnosis associated with each tracing, the relative proportion of each arrhythmia and the hypotheses to be tested. Each reviewer was asked to indicate the location of the P wave relative to the QRS complex, electrical axis of the P wave in the frontal and horizontal planes and presence or absence of QRS alternation, and to interpret the most likely mechanism. The performance of published electrocardiographic criteria to differentiate AV nodal reciprocating tachycardia from circus movement AV tachycardia was evaluated. The overall accuracy of the reviewers' interpretations was 75%, similar to the accuracy of the predefined criteria when applied by these observers (71% correct, difference not significant). Interobserver agreement of reviewer interpretations was 76% and the intraobserver agreement was 78%. Features associated with circus movement AV tachycardia by univariable analysis were P waves after the QRS complex, faster tachycardia rates and QRS alternation. Multivariable analysis showed that only the location of the P wave relative to the QRS complex was independently associated with the mechanism of tachycardia (p = 0.002). QRS alternation was found by multivariate analysis to be associated with the rate but not the mechanism of the tachycardia.

Frequency, diagnosis and clinical characteristics of patients with multiple accessory atrioventricular pathways.

Multiple accessory atrioventricular (AV) pathways were documented in 52 of 388 patients (13%) who underwent detailed electrophysiologic evaluation. Multiple AV pathways were identified during intraoperative mapping or electrophysiologic study by different patterns of ventricular preexcitation during atrial fibrillation, flutter or atrial pacing with different delta-wave morphologic and ventricular activation patterns; different sites of atrial activation during right ventricular pacing or orthodromic reciprocating tachycardia; or preexcited reciprocating tachycardia using a second pathway as the retrograde limb of the tachycardia. A logistic model was used to determine which clinical, electrocardiographic and electrophysiologic variables were associated with multiple AV pathways. Right free-wall and posteroseptal accessory AV pathways were more common in patients with multiple AV pathways and were frequently associated. Multivariate logistic regression identified Ebstein's anomaly, and a history of preexcited reciprocating tachycardia as significant variables (p less than 0.0001). Pathway location was not subjected to statistical analysis because of confounding variables.

Computer-assisted intraoperative mapping of the entire ventricular epicardium in the Wolff-Parkinson-White syndrome.

Intraoperative mapping with a hand-held, roving electrode requires a sustained rhythm lasting 5 to 10 minutes. To overcome this limitation, a computerized mapping system that records from 60 epicardial electrodes simultaneously was used to study 16 patients with Wolff-Parkinson-White syndrome. A sock containing 6 rows of electrodes arranged concentrically from base to apex was place over the ventricles. The total time from placing the sock to analyzing the most basal row of electrode recordings was 5 minutes. A 39 X 44-mm plaque containing 56 electrodes was than placed across the atrioventricular (AV) groove for detailed simultaneous mapping of the ventricle and atrium in the preexcited region identified from the most basal row of sock electrodes. During plaque placement and recording, the remaining sock recordings were analyzed and a complete isochronal epicardial map was drawn. The plaque recordings were then analyzed. This technique rapidly detects early activation at the AV groove as do other computer systems using only a band of electrodes around the AV groove. Also, complete epicardial mapping supplied important additional information. One patient with a posterior paraseptal accessory pathway had ventricular epicardial breakthrough below the strip recorded by the AV band. When more than 1 early activation site was present along the AV groove, complete maps allowed multiple pathways to be differentiated from normal activation fronts ascending from the bundle branches. Complete epicardial maps allowed the study of rapidly changing or short-lived electrical events including isolated premature impulses, initiation and termination of reciprocating tachycardia by pacing, entrainment and changing degrees of fusion created by pacing during reciprocating tachycardia, and ventricular responses during atrial fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Glial differentiation: a review with implications for new directions in neuro-oncology.

Major advances in cell culture techniques, immunology, and molecular biology during the last 10 years have led to significant progress in understanding the process of normal glial differentiation. This article summarizes our current understanding of the cellular and molecular basis of glial differentiation based on data obtained in cell culture and reviews current hypotheses regarding the transcriptional control of the gene switching that controls differentiation. Understanding normal glial differentiation has potentially far-reaching implications for developing new forms of treatment for patients with glial neoplasms. If oncogenesis truly involves a blockage or a short circuiting of the differentiation process in adult glial progenitor cells, or if it results from dedifferentiation of previously mature cells, then a clear understanding of differentiation may provide a key to understanding and potentially curtailing malignancy. Differentiation agents represent a relatively new class of drugs that effect cellular gene transcription at the nuclear level, probably through alterations in chromatin configuration and/or differential gene induction. These exciting new agents may provide a means of preventing the dedifferentiation of low-grade gliomas or inducing malignant glioma cells to differentiate with minimal toxicity. In the future, genetic therapy has the potential of more specifically rectifying the defect in genetic control that led to oncogenesis in any given tumor.