Howard J. Landy

Drug resistance in brain tumors

SummaryResistance to chemotherapy in brain tumors is complex and may involve multiple mechanisms. For commonly used drugs, such as nitrosoureas and platinum compounds, major mechanisms may involve increaded DNA repair or removal of the drug-DNA adducts. For water soluble nitrosoureas and also for platinum compounds, other mechanisms, such as alteration in drug transport, may be important. Another major mechanism may involve glutathione and glutathione-S-transferase pathways. For vinca alkaloids and epipodophyllotoxins p-glycoprotein mediated MDR appears to be the major feature in drug resistance. In addition, alteration of tubulin and topoisomerase II have been described in resistance to vinca alkaloids and epipodophyllotoxins respectively. Recently, increased multidrug resistance associated protein gene expression has been found in glioma cells and brain tumor samples; its clinical significance requires further investigation.

Effects of vagal nerve stimulation on laryngeal function

Functional electrical stimulation is a developing methodology that shows significant potential in the management of peripheral neuromuscular deficits. Potential applications in the head and neck area, including control of bilateral vocal fold paralysis and spasmodic dysphonia, have recently been explored. Despite promising early results, very little is known about the mechanisms of action or the long-term effects of electrical stimulation on human laryngeal function. Recent development of implantable vagal nerve stimulators as a method to control intractable seizures in individuals who have not responded to medication provides a unique opportunity to study its effect on the normal human larynx. Laryngeal and vocal function testing was studied on five individuals who had undergone vagal nerve stimulator implants for intractable seizures. Consistent abduction/adduction of the left vocal fold was achieved at 20 and 40 Hz, respectively. Higher levels of electrical stimulation produced hemispasm of the larynx. Results were consistent with studies in the literature of recurrent laryngeal nerve stimulation in animal and human models. The vagus nerve provides relatively easy access for implantation of electrodes to provide electrical stimulation to the muscles of the larynx. Vagal nerve stimulation may prove efficacious in the treatment of movement disorders of the larynx; further study is needed.

Corpus Callosotomy for Seizures Associated with Band Heterotopia

Summary: Band heterotopia is a severe form of neuronal migration disorder associated with intractable epilepsy and neurologic impairment. Surgical treatment of seizures associated with this malformation has not been reported previously. We report a patient with band heterotopia and poorly controlled atonic seizures causing falls and injury. The patient was treated with anterior corpus callosotomy, with significant postoperative decrease in seizure frequency. Corpus callosotomy is a reasonable alternative to consider in management of patients with cortical heterotopia and intractable seizures.

Temporal lobectomy for seizures associated with unilateral schizencephaly

Schizencephaly is characterized by unilateral or bilateral cerebral clefts associated with neurologic deficits and epilepsy. Most commonly schizencephaly is attributed to abnormal neuronal migration, and these malformations are well visualized by current neuroimaging techniques. This report describes a patient with unilateral schizencephaly and poorly controlled complex partial seizures who was found to have a temporal lobe seizure focus; anterior temporal lobectomy produced nearly complete control of the seizures. Despite the extensive malformation, relatively restricted resection was of significant benefit. The principles of seizure focus localization and resection are applicable to the management of patients with schizencephaly.

The role of steroids in the management of metastatic carcinoma to the brain : a pilot prospective trial

This prospective study attempted to evaluate the indications for glucocorticoids which are commonly given to patients with brain metastases. Twelve patients with histologically confirmed malignancies and radiographically documented brain metastases were enrolled. Patients were scored for general performance status and neurologic function class. All subjects were given high-dose dexamethasone (HDD) for 48 hours and then randomized to receive either intermediate-dose dexamethasone (IDD) or no steroids with cranial radiotherapy. Of these 12 study patients, 3 achieved a complete response, 1 partial response, and 8 nonresponses to HDD. Seven patients had IDD, while five received no IDD. Although a small sample size prevented any statistical analysis, this study does suggest that the place for using glucocorticoids in treating patients with metastatic carcinoma to the brain remains uncertain and should be evaluated in a cooperative prospective trial.

The role of hyperfractionated re-irradiation in metastatic brain disease: A single institutional trial

Progression of brain metastases after brain irradiation has prompted several studies on retreatment of the brain. Increased durations of survival and improved quality of life have been reported. Fifteen patients with previously treated brain metastases were entered into this pilot study between May 1990 and January 1994. All patients had neurologic and/or radiologic evidence of progression of brain metastases. The lung was the primary site in 60% of cases. The remaining 40% had breast, ovarian, and skin primaries. The median interval between the first treatment and retreatment was 10 months. All patients received whole-brain irradiation with or without a boost for their initial treatment course. Doses ranged from 3,000 to 5,500 cGy for initial treatments (median, 3,000). Retreatment consisted of limited fields with a median side equivalent square of 8.8 cm. Patients were retreated with a median dose of 3,000 cGy (range, 600-3,000 cGy). A median cumulative dose of 6,000 cGy was achieved. Retreatment consisted of twice-daily fractions (150 cGy/fraction). Retreatment was tolerated without serious complications. Of the 15 patients treated, nine (60%) experienced improvement, and five (27%) had stabilization of neurologic function and/or radiographic parameters. Median survival was 3.2 months; two of the reirradiated patients survived > or = 9 months. In conclusion, reirradiation is a viable option in patients with recurrent metastatic lesions of the brain, and the use of a limited retreatment volume makes this a well-tolerated, low-morbidity treatment that leads to clinical benefits and, in some instances, enhanced survival. The influence of hyperfractionation on the outcome needs to be investigated further in large series.

Early MRI findings in high grade glioma

Magnetic resonance imaging (MRI) is more sensitive than computerized tomography in the detection of many intracerebral lesions; however, the significance of some MRI findings may be unclear. Over four years, nine patients, aged 40–79 years, have been encountered whose initial MRI scans were negative or had minimal abnormalities and soon thereafter had high grade glioma. Initial MRI was performed in eight patients for new-onset seizures and one patient for a focal deficit. MRI was negative in four of the patients and mildly abnormal in five of the patients (small areas of increased T2 and/or minimal enhancement). The initial diagnoses usually included inconclusive differentials of stroke and infection with neoplasm less frequently considered. Radiographic progression leading to the diagnosis of high grade glioma became evident on repeat MRI in 1–8 months with six patients showing progression within three months. All patients underwent surgery and had histologic diagnosis of glioma. Although MRI is quite sensitive, four of the initial scans were negative with reasonable quality studies. Conversely, in five of the initial scans, the tumors were detected when so small that the radiographic findings were not typically diagnostic. Glioma must be considered as a possible cause of initial seizures or new neurologic deficits in adults with normal or minimally abnormal MRI. In this group, seizures were the overwhelming hallmark of presentation. In such a clinical situation, close follow-up with short interval repeat MRI should be performed.

Spinal metastases of malignant intracranial meningioma

BACKGROUND Spinal metastasis of intracranial meningiomas has rarely been reported. Three out of ten previously reported cases of malignant meningioma metastasizing to the spine had undergone surgical debulking with no neurological improvement. The authors retrospectively reviewed the treatment course of three patients with malignant meningioma metastasizing to the spine who underwent early magnetic resonance imaging (MRI) and radiotherapy without surgical debulking. CASE DESCRIPTION Three patients with intracranial malignant meningiomas underwent multiple resections of intracranial lesions, and developed spinal intradural metastases an average of 64 months (range, 27-102 months) from their initial presentation. All three patients had at least two operations for recurrent intracranial tumors. All had localized back pain with motor weakness, and MRI scans demonstrated spinal involvement. No surgical exploration was performed for the spinal lesions; rather, all patients received steroids and radiotherapy for the spinal lesions. All three patients improved neurologically after the steroid and radiation treatments, and went on to survive from 3 to 18 months. CONCLUSION Early MRI should be performed in patients with spinal symptoms and signs after the treatment of intracranial meningiomas. Radiotherapy is an effective palliative treatment for spinal metastases.

Outcomes and Management Strategies after Nondiagnostic Stereotactic Biopsies of Brain Lesions

Background/Aims: A significant minority of stereotactic biopsies (SBs) of brain lesions is nondiagnostic, yet there are no optimal strategies for preventing nondiagnostic SB (NDSB) and for managing patients after NDSB. We performed this study in order to identify risk factors for NDSB, to determine how diagnoses are eventually reached in these patients, and to ascertain whether NDSB affects clinical outcomes. Methods: Retrospective chart review of patients at our institution who underwent SB of brain lesions. Results: Twenty-four out of 100 SBs were nondiagnostic. NDSB was less likely in contrast-enhancing brain lesions in immunocompetent patients, with larger lesions and in the setting of diagnostic findings on intraoperative frozen section analysis. Of 16 patients with adequate postoperative follow-up, a diagnosis was eventually reached in 11, via further review of the pathology, retrieval of additional tissue specimens or additional noninvasive testing. Survival times for patients with NDSB and eventual tumor diagnoses were within expected ranges for patients with similar tumors. Three of the 5 patients who never received a final diagnosis enjoyed prolonged survival without progressive symptoms. Conclusions: Surgeons should consider taking additional specimens in the case of nondiagnostic intraoperative frozen section during SB. If a tumor is suspected and final pathology is nondiagnostic, outside review of the slides may be helpful, and sampling further tissue should be considered. For diseases other than tumors, the diagnosis will generally be made without a repeat biopsy. The delays in diagnosis resulting from NDSB do not appear to affect survival, at least in patients eventually found to have brain tumors.

Computer controlled stereotaxic radiotherapy system

A computer-controlled stereotaxic radiotherapy system based on a low-frequency magnetic field technology integrated with a single fixation point stereotaxic guide has been designed and instituted. The magnetic field, generated in space by a special field source located in the accelerator gantry, is digitized in real time by a field sensor that is six degree-of-freedom measurement device. As this sensor is an integral part of the patient stereotaxic halo, the patient position (x, y, z) and orientation (azimuth, elevation, roll) within the accelerator frame of reference are always known. Six parameters--three coordinates and three Euler space angles--are continuously transmitted to a computer where they are analyzed and compared with the stereotaxic parameters of the target point. Hence, the system facilitates rapid and accurate patient set-up for stereotaxic treatment as well as monitoring of patient during the subsequent irradiation session. The stereotaxic system has been developed to promote the integration of diagnostic and therapeutic procedures, with the specific aim of integrating CT and/or MR aided tumor localization and long term (4- to 7-week) fractionated radiotherapy of small intracranial and ocular lesions.