Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Asymmetry of neuronal activity during extracellular microelectrode recording from left and right human temporal lobe neocortex during rhyming and line-matching.

Recordings of neuronal activity in humans have identified few correlates of the known hemispheric asymmetries of functional lateralization. Here, we examine single-unit activity recorded from both hemispheres during two delayed match-to-sample tasks that show strong hemispheric lateralization based on lesion effects; a line-matching (LM) task related to the right hemisphere, and a rhyming (RHY) task related to the left. Nineteen neuronal populations were recorded with extracellular microelectrodes from the left temporal neocortex of 11 awake patients, and 18 from the right in 9 patients during anterior temporal lobectomy for complex partial seizures under local anesthesia. All subjects were left hemisphere dominant for language. Twelve (32%) populations exhibited statistically significant changes in activity at p <.05. Although changes in firing frequency were recorded from both hemispheres during both tasks, the RHY task elicited changes in activity several hundred milliseconds earlier on the left side than on the right. The LM task, on the other hand, induced changes earlier on the right side than on the left. Both hemispheres contained units active during verbal responses regardless of which behavior elicited the response. Our results indicate that cerebral dominance is reflected in earlier neuronal activity in the anterior temporal lobe during tasks lateralized to that hemisphere.

Intraoperative hippocampal electrocorticography to predict the extent of hippocampal resection in temporal lobe epilepsy surgery.

OBJECT: Among the variety of surgical procedures that are performed for the treatment of medically refractory mesial temporal lobe epilepsy (TLE), no consensus exists as to how much of the hippocampus should be removed. Whether all patients require a maximal hippocampal resection has not yet been determined. METHODS: At the University of Washington, all TLE operations are performed in a tailored fashion, guided by electrocorticography (ECoG). The amount of hippocampal resection is determined intraoperatively by the extent of interictal epileptiform abnormalities on ECoG recorded from that structure, resulting in a hippocampal resection that is individualized for each patient. Using this approach, the authors prospectively observed 140 consecutive patients who underwent surgery for mesial TLE with pathological diagnoses of either mesial temporal sclerosis with neuronal loss (MTS group) or mild gliosis without neuronal loss (non-MTS group) to determine whether the extent of hippocampal resection correlates with outcome when a tailored approach is used. Additionally, the authors analyzed whether the presence of residual interictal epileptiform activity on ECoG following mesial temporal resection predicts poorer seizure control. With at least 18 months of clinical follow up, 67% of the 140 patients were seizure free or had only a single postoperative seizure. There was no correlation between the size of the hippocampal resection and seizure control in the group as a whole or when stratified by pathological subtype. Using an intraoperatively tailored strategy, individuals with a larger hippocampal resection (> 2.5 cm) were not more likely to have seizure-free outcomes than patients with smaller resections (p = 0.9). Additionally, both MTS and non-MTS patients, in whom postoperative ECoG detected residual epileptiform hippocampal (but not cortical or parahippocampal) interictal activity following surgical resection, had significantly worse seizure outcomes (p = 0.01 in the MTS group; p = 0.002 in the non-MTS group). CONCLUSIONS: Intraoperative hippocampal ECoG can predict how much hippocampus should be removed to maximize seizure-free outcome, allowing for sparing of possibly functionally important hippocampus.

The role of spatiotemporal edges in visibility and visual masking.

What parts of a visual stimulus produce the greatest neural signal? Previous studies have explored this question and found that the onset of a stimulus's edge is what excites early visual neurons most strongly. The role of inhibition at the edges of stimuli has remained less clear, however, and the importance of neural responses associated with the termination of stimuli has only recently been examined. Understanding all of these spatiotemporal parameters (the excitation and inhibition evoked by the stimulus's onset and termination, as well as its spatial edges) is crucial if we are to develop a general principle concerning the relationship between neural signals and the parts of the stimulus that generate them. Here, we use visual masking illusions to explore this issue, in combination with human psychophysics, awake behaving primate neurophysiology in the lateral geniculate nucleus of the thalamus, and optical recording in the primary visual cortex of anesthetized monkeys. The edges of the stimulus, rather than its interior, generate the strongest excitatory and inhibitory responses both perceptually and physiologically. These edges can be imaged directly by using optical recording techniques. Excitation and inhibition are moreover most powerful when the stimulus turns both on and off (what might be thought of as the stimulus's temporal edges). We thus conclude that there is a general principle that relates the generation of neural signals (excitatory and inhibitory) to the spatiotemporal edges of stimuli in the early visual system.

Optical images of visible and invisible percepts in the primary visual cortex of primates.

We optically imaged a visual masking illusion in primary visual cortex (area V-1) of rhesus monkeys to ask whether activity in the early visual system more closely reflects the physical stimulus or the generated percept. Visual illusions can be a powerful way to address this question because they have the benefit of dissociating the stimulus from perception. We used an illusion in which a flickering target (a bar oriented in visual space) is rendered invisible by two counter-phase flickering bars, called masks, which flank and abut the target. The target and masks, when shown separately, each generated correlated activity on the surface of the cortex. During the illusory condition, however, optical signals generated in the cortex by the target disappeared although the image of the masks persisted. The optical image thus was correlated with perception but not with the physical stimulus.

DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma.

PURPOSE: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT). PATIENTS AND METHODS: Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. RESULTS: Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. CONCLUSION: These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal.

Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O6-position of guanine. O6-benzylguanine (O6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial to define the presurgical dose required for depletion of tumor AGT activity in patients with malignant glioma. MATERIALS AND METHODS: Patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m2 given over 1 hour. Resected tumor was snap-frozen in liquid nitrogen and AGT activity analyzed by high-pressure liquid chromatography (HPLC). Up to 13 patients were treated at a specific dose of O6-BG, with a target end point of > or = 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein). RESULTS: Thirty patients with malignant gliomas were enrolled, with 11 of 11 patients treated at 100 mg/m2 O6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated. CONCLUSION: These results indicate that 100 mg/m2 of O6-BG can maintain tumor AGT levels less than 10 fmol/mg protein for at least 18 hours after treatment, a time interval in which bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully converted into interstrand cross-links. A 100-mg/m2 dose of O6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU.

Overview of functional imaging.

Provides an overview of the many different modalities of imaging techniques, including positron emission tomography, single-photon emission computed tomography, functional magnetic resonance imaging, optical imaging, and magnetic source imaging.

Intraoperative optical imaging of epileptiform and functional activity.

Although intraoperative optical imaging is still a research tool, optical imaging has the potential to establish itself as an intraoperative tool in the future, and may be able to be used for studies into language dominance, memory, and higher cognitive functions.

Neuropsychiatric complications after temporal lobe limbic system surgery.

Although control of seizure activity is the main goal of temporal lobectomies for complex partial epilepsy, the results of surgery must be viewed within the larger context of possible ramifications of limbic system disruption. The neuropsychiatric complications may be significant and influence the patient's perceived qualify of life, thus detracting from the benefits of seizure control. It is apparent from the previous studies that the modalities affected are influenced by the laterality of the resection, with left-sided lobectomies more often affecting verbal memory and learning, whereas right-sided resections may cause visual/spatial memory and cognitive declines. Preoperative neuropsychologic testing may help to predict these possible complications. General psychosocial function, memory, and cognition all seem to be less affected when complete seizure control is attained, with nearly 80% experiencing no significant change in neuropsychologic testing and the gain and losses being equal in magnitude. Also, younger patients and those with a shorter history of seizure activity may fare better after surgery because of a greater capacity for neuronal plasticity to subserve these functions. These findings support the contention that early diagnosis and surgical treatment may help to minimize potential neuropsychiatric complications in conjunction with improved postoperative seizure control.

Cerebral lateralization of neuronal activity during naming, reading and line-matching.

Changes in human right or left temporal cortical neuronal activity during language and visuospatial tasks were investigated during craniotomy under local anesthesia for medically intractable epilepsy in patients known to be left dominant for language based on preoperative intracarotid amobarbital perfusion testing. Extracellular recordings were obtained from 57 neuronal populations (26 from the left hemisphere) in the superior and middle temporal gyri of 34 patients. Frequency of activity was compared during over and silent object naming, word reading and line-matching. Although all recordings were from the cortex not essential for language, statistically significant changes in activity during these tasks were identified in 49% of the populations. Most populations showed significant changes to only one of the tasks, indicating discrete neural networks for reading and naming. Nearby neuronal populations recorded by the same microelectrode usually had different behavioral correlates. There were no significant differences in the proportion of neurons changing activity with language or spatial measures between right (non-dominant) or left (dominant) temporal lobes. Left superior and middle temporal gyrus populations, however, demonstrated significant early reductions in activity during overt or silent naming, while right middle temporal gyrus recordings showed significant early increased activity only during overt naming. Although reading measures elicited more activity from the non-dominant temporal lobe, early reductions in activity were recorded exclusively from the dominant side. Visuospatial tasks evoked changes in neuronal frequency predominantly in the middle temporal gyrus, and during one of these tasks, significant later increases in activity were present bilaterally. Our results indicate that the functional lateralization of cognitive behaviors may depend less on the anatomic location of the associated neuronal activity than on the neurophysiologic characteristics of that activity.

Enhanced optical imaging of human gliomas and tumor margins.

One of the potential variables affecting the overall survival and quality of life of patients with intracranial gliomas is the extent of tumor resection that results in the smallest volume of residual disease. A technique involving enhanced optical imaging of human gliomas has the potential to localize tumors, identify tumor remaining at the resection margins, and determine the grade of the tumor. In a preliminary study involving nine patients undergoing surgery for the removal of intrinsic brain tumors, enhanced optical imaging was performed using indocyanine green as an intravenous contrast-enhancement agent. Optical images were obtained before and after injection of the indocyanine green. The studies in the nine patients showed differences in the dynamic optical signals among normal brain, low-grade astrocytomas, and malignant astrocytomas. Optical imaging of the resection margins in malignant tumors showed differences between adjacent normal tissue and remaining tumor tissue. Enhanced optical imaging of human gliomas using a contrast-enhancing dye, indocyanine green, provides a potential means to differentiate between normal brain and tumor tissue at the cortical surface and the depths of the resection margins. Having the ability to obtain real-time information and feedback in the operating room may allow neurosurgeons to maximize the extent of tumor resection while sparing normal brain and increasing the diagnostic accuracy of intraoperative biopsies. Enhanced optical imaging potentially could facilitate the accuracy and safety of surgery when tumors are removed at sites even outside the central nervous system.

Causes, prevention, and treatment of post-traumatic epilepsy.

Post-traumatic seizures often occur after severe head injury. Acutely, these seizures complicate management of the head-injured patient by increasing intracranial pressure and causing postictal decreases in level of consciousness. In the long term, epilepsy can have a negative effect on the patient's functioning and integration into society. The more severe the head injury, the more likely that post-traumatic seizures will occur. The risk of late seizures exceeds 30% for patients with penetrating head injury, intracerebral hematoma, subdural hematoma, depressed skull fracture, or seizure within the first week after injury. Late post-traumatic seizures are treated the same as any epileptic seizures of the same type. Phenytoin and carbamazepine are effective in preventing seizures in the first week after head injury, but are not effective in preventing late seizures. Both additional antiepileptic drugs and neuroprotective agents that may lessen the damage that leads to seizures are being investigated to determine if they are effective in preventing the occurrence of post-traumatic epilepsy.

The future of pediatric epilepsy surgery. Signposts and science.

Many of the advances in pediatric epilepsy surgery should reflect scientific, technical, and conceptual issues identical to those seen with adult epilepsy surgery. However, there are certainly some unique issues involving the developing brain, and these aspects require significant input from the discipline of developmental neurobiology and the study of cortical plasticity. These developmental disciplines may prove as critical as more traditional areas of electrophysiology thought to be key to the advancement of epilepsy surgery. Pediatric epilepsy surgery may turn out to be the major beneficiary of the basic scientific advancements in these burgeoning fields.

Outcome after repeat lumbar microdiscectomy.

One of the standard treatments for herniation of lumbosacral disc material has become the microdiscectomy. Although multiple studies have assessed the outcome of microdiscectomy, only a few studies have evaluated the outcome of those patients who have undergone a second microdiscectomy at the same location as the original one. The purpose of this study was to review 55 patients who, over a 4-year period, underwent a second microdiscectomy at the same location as their original operation and to evaluate those factors associated with improved outcomes. The results showed the overall outcome to include 86% with complete or partial relief of all pain symptoms; 88% with complete or partial relief of sciatica; 85% with complete or partial relief of back pain; 100% returning to work in an average of 7 weeks; and 89% were glad they had the second operation. Those factors without predictive value included age, sex, weight, height, level of operation, side of operation, surgeon at the first or second operation (e.g. consultant or junior staff), length of the first operation ( < or = 60 min or > 60 min) and duration of symptoms before the first operation. The key features centred on preoperative job status, the interval between recurrence of symptoms and the second operation, and the duration of the second operation ( < or = 90 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced optical imaging of rat gliomas and tumor margins.

Current intraoperative methods used to maximize the extent of tumor removal are limited to intraoperative biopsies, ultrasound, and stereotactic volumetric resections. A new technique involving the optical imaging of an intravenously injected dye has the potential to localize tumors and their margins with a high degree of accuracy. In a rat glioma model, enhanced optical imaging was performed and indocyanine green was used as the contrast-enhancing agent. In all 22 animals, the peak optical change in the tumor was greater than in the ipsilateral brain around the tumor and the contralateral normal hemisphere. The clearance of the dye was significantly delayed to a greater extent in the tumor than in the brain around the tumor and the normal brain. After attempts were made at complete microscopic resection, enhanced optical imaging of the tumor margins and the histological samples demonstrated a specificity of 93% and a sensitivity of 89.5%. Enhanced optical imaging was capable of outlining the tumor even when the imaging was done through the cranium. The optical imaging of rat gliomas with a contrast-enhancing dye is able to differentiate between normal brain and tumor tissue both at the cortical surface and at the tumor margins. The application of these studies in an intraoperative clinical setting may allow for the more accurate determination of tumor margins and may increase the extent of tumor removal.

Rapid infusion system for neurosurgical treatment of massive intraoperative hemorrhage.

Using an illustrative case of severe closed head injury that resulted in a posterior fossa epidural hematoma (EDH) and supratentorial epidural/subdural hematomas (SDH), the massive blood losses associated with operative repair of the torn sigmoid sinus and the significant fluid losses associated with refractory diabetes insipidus were treated by the intraoperative use of the Rapid Infusion System (RIS, Haemonetics). The RIS can rapidly infuse warm blood, crystalloid, or colloid at rates up to 1.5 L/min, thereby limiting the commonly associated hypotension, hypothermia, and coagulopathies. During the suboccipital craniectomy for evacuation of the EDH and repair of the sigmoid sinus, the patient required 18 units of blood replacement secondary to a large tear in the sigmoid sinus. During a separate craniotomy for evacuation of the SDH, the patient also developed diabetes insipidus, which increased the operative fluid replacement to 39 L. Despite these massive blood and fluid losses, the RIS limited the hypotension to less than 2 min and prevented hypothermia and the frequently associated coagulopathies. When used in a neurosurgical setting associated with massive blood and/or fluid losses, the RIS accomplishes three important objectives: (1) rapid infusion of intravenous fluids for maintaining perfusion pressure, (2) rapid warming of fluids despite high intravenous infusion rates of cold crystalloids, thereby preventing intraoperative hypothermia, and (3) continuous monitoring of infusion rates and totals.

Cortical localization of temporal lobe language sites in patients with gliomas.

In a series of 40 patients undergoing an awake craniotomy for the removal of a glioma of the dominant hemisphere temporal lobe, cortical stimulation mapping was used to localize essential language sites. These sites were localized to distinct temporal lobe sectors and compared with 83 patients without tumors who had undergone language mapping for the treatment of intractable epilepsy. In patients with and without temporal lobe gliomas, the superior temporal gyrus contained significantly more language sites than the middle temporal gyrus. Both patient populations also had language sites anterior to the central sulcus in the superior temporal gyrus (12-16%). The patients without tumors had significantly more language sites in the superior temporal gyrus, compared with the superior temporal gyrus of patients with temporal lobe tumors. Multiple variables were studied for their effect on preoperative and postoperative language deficits and included age, sex, number of language sites, histology, size of the tumor, and the distance of tumor resection margins from the nearest language site. The distance of the resection margin from the nearest language site was the most important variable in determining the improvement in preoperative language deficits, the duration of postoperative language deficits, and whether the postoperative language deficits were permanent. If the distance of the resection margin from the nearest language site was > 1 cm, significantly fewer permanent language deficits occurred. Cortical stimulation mapping for the identification of essential language sites in patients with gliomas of the dominant hemisphere temporal lobe will maximize the extent of tumor resection and minimize permanent language deficits.

Neuronal activity in human lateral temporal cortex during serial retrieval from short-term memory.

Neuronal activity was recorded extracellularly from 20 populations in the lateral cortex of the left anterior temporal lobe of 11 patients undergoing awake craniotomy for epilepsy, during an input-distraction-retrieval measure of recent verbal memory that also included two later successive retrievals of the same information after additional distracting tasks. Changes in activity were determined for each 1 sec epoch in three major comparisons: (1) the same visual cues used for naming an input to recent memory, naming without a memory component, and a spatial matching task; (2) memory input (MI), distraction (S), and initial cued retrieval (R1) from memory, where object naming was the input to memory and naming of other objects the distractors; (3) initial retrieval (R1) and the two subsequent serial retrievals of the same information (R2, R3). Control comparisons were also made with serial naming and viewing of blank slides, and repeated naming of the same objects. In comparison 1, 13 of the 20 populations showed consistently increased activity during memory input ("memory units"); two others showed changes during language measures. In comparison 2, a significant proportion of all 20 populations, and the 13 memory units considered alone showed increased activity in initial epochs of MI and R1, confirming earlier findings of increased lateral temporal neuronal activity at memory entry and initial retrieval. In comparison 3, a significant proportion of the memory units showed increased activity in early epochs of R1 and decreased activity in late epochs of R3. This decrease in populations with increased activity at R1 was also evident when R1 was compared to R2 or R2 to R3.(ABSTRACT TRUNCATED AT 250 WORDS)

Thoracic disc disease: experience with the transpedicular approach in twenty consecutive patients.

TWENTY CONSECUTIVE PATIENTS were treated for symptomatic thoracic disc herniation with the transpedicular approach. Most patients had severe, incapacitating local or radicular pain. Myelopathy was uncommon as magnetic resonance imaging allowed an early diagnosis. Computed tomography, after myelography, provided further information necessary for surgical planning. Three patients had disc disease at two levels. Nine central and 14 lateral disc herniations were found. Disc calcification or an associated osteophyte was identified in six instances. Although the size of the disc herniation correlated with the amount of cord compression, no radiological features were found to be correlated with neurological function. The transpedicular approach was used in all patients. New curettes, specifically designed for the procedure, allowed the removal of all discs, including central and calcified fragments. A modified arthroscope was used to confirm neural decompression in some instances. One year after surgery, all 20 patients were significantly improved and 8 patients were asymptomatic. Apart from the duration of the symptoms, no other factors were found to affect outcome. The findings suggest that the prognosis of thoracic disc herniation is excellent if the disease is recognized early. The transpedicular approach, using curettes specifically designed for the procedure, can be an effective and safe method of surgical decompression in carefully selected patients.