Jeffrey A. Winfield

Reversible pain and tactile deficits associated with a cerebral tumor compressing the posterior insula and parietal operculum

&NA; Extensive psychophysical tests were conducted on a patient with a well circumscribed tumor located just inferior and posterior to the retroinsular cortex of the right hemisphere. Statistically significant laterality differences were observed, with the left hand exhibiting:a higher mechanical pain threshold,a higher heat pain threshold,a greater cold pain tolerance, anda poorer ability to discriminate roughness. The patient was re‐examined 2.5 months after operative removal of the tumor and was found to have regained normal sensitivity in his left hand. Pre‐ and postoperative MRIs showed resolution of the tumors mass effect on the retroinsula and neighboring parietal operculum, which likely included the second somatosensory cortex. This dramatic change in sensory capacity signifies an essential role for the posterior insula and parietal operculum in normal pain and tactile perception.

Gossypol Treatment of Recurrent Adult Malignant Gliomas

Gossypol, a polyphenolic compound which depletes cellular energy by inhibition of several intracellular dehydrogenases, has been shown to have antiproliferative activity against human glial tumor cell lines in vitro and in nude mouse xenografts. Human trials of gossypol as a male contraceptive have demonstrated safety of long-term administration. We studied the activity of Gossypol 10 mg PO bid in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study.We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent.

In vitro and in vivo cytotoxicity of gossypol against central nervous system tumor cell lines

SummaryGossypol is a lipid soluble polyphenolic compound isolated from cotton seed oil which has been previously shown to have antiproliferative activityin vitro against a variety of human solid tumor cell lines. It has been extensively tested in clinical trials as a male contraceptive agent and found to be well tolerated. Its mechanism of action is thought to be inhibition of cellular energy metabolism. It inhibits glycolysis through inhibition of LDH isoenzyme type 5, and it inhibits mitochondrial oxidative phosphorylation and electron transport. We tested thein vitro antiproliferative effect of gossypol against four well characterized human glioma cell lines, HS 683, U373, U87 and U138, and one rat glioma cell line, C6, using the colorimetric Microculture Tetrazolium Assay (MTT). Cytotoxicity was found to be concentration and time dependent and increased with incubation times up to 8 days. The relative sensitivity of the glioma cell lines to gossypol at 48 hour incubation correlated with their respective LDH isoenzyme profiles, with the more sensitive cell lines expressing increased cathodal LDH isoenzymes (LDH 5). Thein vitro cytotoxicity of gossypol to these CNS tumor lines was compared to the other non central nervous system solid tumor cell lines which had been previously reported as being sensitive to gossypol, including SW-13 (adrenal), MCF-7 (breast), T47-D (breast), and HeLa (cervical). Additional lines tested included SK-MEL-3 (melanoma), Colo 201 (colon) and BRW, a line established in our laboratory from a patient with a Primitive Neuroectodermal tumor. C6, HS 683, and BRW had similar IC50s as the sensitive solid tumor cell lines. U373, U87 and U138 had significantly less sensitivity at 48 hours. There was greater cytotoxicity and no significant differences in the IC50s between any of cell lines at 8 day incubations. Additionally, we tested the cytotoxicity of gossypol against BRWin vivo, using the nude mouse xenograft model. Gossypol, given at a dose of 30 mg/kg per day five days a week for four weeks orally via gavage, was found to decrease the mean tumor weight of treated xenografts by more than 50% as compared to untreated xenografts. These findings suggest that gossypol has potential for further study as an agent for the treatment of primary CNS malignancies.

Resection and Permanent I-125 Brachytherapy Without Whole Brain Irradiation for Solitary Brain Metastasis from Non-small Cell Lung Carcinoma

We assessed a treatment plan of local therapy (resection and placement of permanent low dose-rate I-125 seeds) without whole brain irradiation in 15 patients with solitary brain metastasis (SBM) from primary non-small cell lung cancer between January, 1991 and May, 1996. Thirteen lesions were confirmed as solitary by MRI scan, and 2 patients had CT scan only.With median follow up of 14 months, 3 patients remain alive at 6, 33, and 62 months post-resection. Median survival is 14 months for all patients and 26 months for patients with SBM as the only site of disease. Five tumors failed in the brain: 2 solitary recurrences adjacent to the site of SBM, 2 multiple metastases outside the primary site, and 1 multiple recurrence including the primary site. No failures were seen with SBM <2.5 cm. Only 2 of 13 patients with SBM confirmed with MRI experienced relapses elsewhere in the brain. Recurrence rates both adjacent and outside the area of the initial brain lesion are similar to studies employing resection plus whole brain irradiation (WBI), and the patient is spared the acute and potential late toxicity of WBI. This approach may be considered for selected patients with solitary brain metastases (SBMs), although further experience with larger patient numbers is needed.

The Hydroxyurea-induced Loss of Double-Minute Chromosomes Containing Amplified Epidermal Growth Factor Receptor Genes Reduces the Tumorigenicity and Growth of Human Glioblastoma Multiforme

OBJECTIVE We investigated whether the hydroxyurea-induced loss of double-minute chromosomes containing amplified epidermal growth factor receptor (EGFR) genes would lead to a loss of tumorigenicity of a glioblastoma multiforme cell line. METHODS Glioblastoma multiforme cells were treated in vitro with 0 (HU0) or 100 micromol/L (HU100) hydroxyurea and then injected into the flanks of nude mice. Survival and tumor volumes were evaluated. Pulsed-field gel electrophoresis, Southern blot hybridization, and slot-blot analysis were used to determine EGFR amplification levels. Flow cytometry and immunofluorescent staining were used for cell-cycle analysis and EGFR protein expression. RESULTS Prior to injection, HU100 cells lost 95% of their amplified EGFR genes and developed into tumors 6 weeks after injection versus 3 weeks for HU0 cells. Mice with HU100 tumors had a median survival of 62 days versus 43 days for control mice with HU0 tumors. Pulse-field gel electrophoresis analysis showed that HU100 tumors had reamplified the EGFR gene as double-minute chromosomes of the same size as those originally present before hydroxyurea treatment. When HU100 cells were cultured in the absence of hydroxyurea, the EGFR gene also reamplified. HU100 cells grew at less than half the rate of untreated HU0 control cells in culture and showed a decreased number of cells entering the cell cycle. Immunofluorescent staining of HU150 (150 micromol/L) cells showed decreased EGFR protein expression. CONCLUSION The EGFR gene is important for tumorigenicity in mice and growth in culture. Hydroxyurea induces the loss of double-minute chromosome-amplified EGFR genes against a selection gradient and significantly delays the onset of tumors. These results support the potential use of low-dose hydroxyurea for the treatment of human glioblastoma multiforme.

Stereotactic linear radiosurgery for cavernous angiomas.

Optimal management of symptomatic cavernous angiomas (CA) located in the thalamus and the brainstem is problematic. Clinical and radiological (MRI) follow-up series suggest that having hemorrhaged once, recurrent hemorrhage with progressive neurologic dysfunction may commonly occur. We have therefore chosen to treat these lesions when first symptomatic with stereotactic linear radiosurgery (SLR). We now report, after a median follow-up of 27 months, 12 patients with CAs (9 women, 3 men, mean age 40 years) treated in this fashion. Ten patients presented with hemorrhage (3 had more than one hemorrhage): two patients had new onset seizures. All patients had enhanced MRI/MRAs characteristic of CA. There were five brainstem and five thalamic CAs, and one each in the temporal lobe and insula. Cerebral angiograms were done in 8 patients for comparison with their respective MRAs. Only one CA was visualized in the late venous phase on cerebral angiogram and identical vascular features were appreciated on the MRA. The diameter of the CAs ranged from 1.0 to 3.0 cm with a mean of 1.6 cm. Dosimetry planning was based on MRI/CT features and the mean dose at the isocenter was 2.167 cGy (range = 2,000-2,500 cGy) delivered with a mean collimation diameter of 1.46 cm (range = 1.0-2.0 cm). All 12 patients continued to improve neurologically after SLR and had MRI-documented changes in their lesions: in general, the lesions became smaller and signal characteristics converted to methemaglobin. However, 1 patient had an early post-SLR hemorrhage, documented by MRI, at 4.5 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Fourth Ventricular Entrapment Caused by Rostrocaudal Herniation following Shunt Malfunction

The subacute development of isolated fourth ventricle (IFV) is a recognized complication following shunting of the lateral ventricles for congenital and acquired hydrocephalus. We present an unusual case of acute IFV in a clinical setting which has not previously been described. Subsequent to rostrocaudal herniation caused by an obstructed frontally placed ventricular catheter, IFV developed in our patient 24 h following shunt revision, necessitating placement of an additional fourth ventricle shunt system. No signs of intraventricular hemorrhage or cerebrospinal fluid (CSF) infection were detected at the time of shunt revision and there was no documentation of similar events in the perinatal history. Dependent upon the actual underlying etiology of this childs hydrocephalus, we hypothesize that two mechanisms may have accounted for this unusual and precipitous development of IFV. Following rostrocaudal herniation and caudal shift of the brainstem, progressive edema in the pons developed. If communicating hydrocephalus was the primary etiology, then midbrain edema occluded the aqueduct of Sylvius, preventing retrograde flow of CSF to the shunt. A distinctly different mechanism for acute IFV must be invoked if aqueductal stenosis was the preexisting cause for congenital hydrocephalus. Following herniation, brainstem displacement and edema resulted in obliteration of the lateral pontine and ambient cisterns, preventing the normal rostral migration of CSF around and over the mesencephalon. Cerebellar tonsillar herniation with impaction of the tonsils into the foramen magnum may have also contributed to obstruction of fourth ventricular outflow in both settings. This unusual case of acute onset IFV is presented in detail. The underlying etiologies and clinical settings in which IFV may develop is reviewed as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Salmonella Osteomyelitis with Epidural Abscess

Neurologic complications of sickle cell anemia are most commonly ischemic strokes secondary to sludging in cerebral arterioles. We, therefore, report a case of progressive paraparesis in a child with

An Unusual Syndrome of Pediatric Brainstem Trauma

We report 2 cases of children who developed a delayed hemiparesis following minor closed head injury with no alteration in consciousness and normal CT studies. MRI showed focal lesions in the ventral pons contralateral to the hemiparesis. Both patients recovered to near normal neurologic function within several days of injury. We postulate a mechanism of injury based on focal contusion of perforating brainstem arteries resulting in the delayed onset of vasospasm.