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T Siegal

Publications and source records attributed to T Siegal.

At least 37 records · Page 2Linked to original sources
PubMed1996

Control of vasogenic edema in a brain tumor model: comparison between dexamethasone and superoxide dismutase.

OBJECTIVE: The production of prostaglandin (PG) within brain tumors probably generates excessive amounts of oxygen free radicals that may disrupt microvessel permeability within the tumor and in the adjacent brain. We evaluated the effect of systemic therapy with recombinant human manganese-superoxide dismutase (r-hMnSOD) and with dexamethasone on the vascular permeability (VP) of a brain tumor and the adjacent brain. Treatment effect was also evaluated in control animals subjected to mild penetration injury. METHODS: Fischer rats were injected stereotactically with either 10(5) cells of malignant sarcoma or with vehicle into the right parietal hemisphere. Nine days later, the animals were treated with r-hMnSOD (50 mg/kg of body weight every 12 h [one intravenous, then two intraperitoneal injections]; serum levels, 1100-1800 micrograms/ml), dexamethasone (2 mg/kg every 12 h [one intravenous, then two intraperitoneal injections]), or vehicle and were killed after 30 hours for evaluation of VP and PG production. RESULTS: The VP was markedly increased within the tumor (P < 0.001), in the brain adjacent to it, and in the vehicle injection site. The VP of the normal brain was unaffected by r-hMnSOD or dexamethasone treatment, unlike the VP in the tumor, the adjacent brain, and the injection sites of control animals, where it was reduced by 50, 54, and 23%, respectively (P < 0.04), for r-hMnSOD and 50, 41, and 71%, respectively (P < 0.05), for dexamethasone. A one- to threefold increase in synthesis of thromboxane and PGE2 was measured within the tumor, the adjacent brain, and the injection sites of control animals (P < 0.0001). Treatment with r-hMnSOD had no effect on tumor PG production, but it reduced the synthesis in the brain tissue adjacent to the tumor and in traumatized control animals (P < 0.04). Immunohistochemical evaluation revealed vascular proliferation with abnormal basal membrane, atypical astrocytes, and large numbers of reactive macrophages present in the adjacent brain and at the injection sites of control animals but not within the tumor mass. CONCLUSION: Oxygen free radicals probably enhance vasogenic brain edema resulting from tumor and penetration injury. The edema can be attenuated by systemic r-hMnSOD therapy, which has been proven to be as effective as steroid treatment. An inflammatory response may account for oxygen free radical production in brain tissue adjacent to the tumor and at the injection site of vehicle solution, but other mechanisms probably generate oxygen free radicals within the tumor mass.

Animals↗
PubMed1996

Clinical significance of diffuse dural enhancement detected by magnetic resonance imaging.

This study was performed to determine the clinical significance of diffuse dural enhancement (DDE) detected by magnetic resonance (MR) imaging and to typify enhancing patterns related to inflammatory or metastatic causes. The authors retrospectively evaluated the clinical, imaging, and laboratory characteristics of 20 consecutive patients with DDE. Those with DDE and an underlying neoplastic disease (13 patients) were compared to 11 consecutive patients with cytological evidence of neoplastic leptomeningeal metastasis evaluated by MR imaging. The DDE was often associated with an underlying malignancy (13 (65%) of 20 patients) but it coexisted with leptomeningeal metastasis in only one patient. Skull metastases were evident in 10 (77%) of 13 patients and cranial nerve palsies in six (46%) of 13. Other causes of DDE were related to cerebrospinal fluid (CSF) leak or shunting (five (25%) of 20), with or without symptoms of intracranial hypotension, and to dural sinus thrombosis and pachymeningitis. Dural biopsies obtained in two patients with DDE showed a narrow rim of granulation-like tissue adherent to the dural surface facing the inner skull table. Magnetic resonance subtraction, diffusion, and perfusion studies revealed unique characteristics in patients with metastatic causes as compared to those with DDE secondary to CSF leak. None of the patients with proven leptomeningeal metastasis had DDE, but four of them presented with focal dural enhancement and two displayed apparent leptomeningeal enhancement. The findings indicate that DDE is not a radiographic hallmark of leptomeningeal metastasis in spite of the similarities in clinical manifestations (for example, headache and cranial polyneuropathy). Nonetheless, DDE is most frequently associated with metastatic malignancies and particularly with skull metastases and CSF leak. Special MR techniques can discern the underlying cause and elucidate the disparity in the pathophysiological mechanisms leading to DDE.

Aged↗
PubMed1995

Radiation-induced changes in the profile of spinal cord serotonin, prostaglandin synthesis, and vascular permeability.

PURPOSE: To investigate the profile of biochemical and physiological changes induced in the rat spinal cord by radiation, over a period of 8 months. METHODS AND MATERIALS: The thoraco-lumbar spinal cords of Fisher rats were irradiated to a dose of 15 Gy. The rats were then followed and killed at various times afterward. Serotonin (5-HT) and its major metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed as well as prostaglandin synthesis. Microvessel permeability was assessed by quantitative evaluation of Evans blue dye extravasation. RESULTS: None of the rats developed neurologic dysfunction, and histologic examination revealed only occasional gliosis in the ventral white matter at 240 days after irradiation. Serotonin levels were unchanged at 2, 14, and 56 days after radiation but increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated thoracic and cervical segments (p < 0.01) and age-matched controls (p < 0.03). The calculated utilization ratio of serotonin (5-HIAA/5-HT) remained unchanged. Immediately after radiation (at 3 and 24 h) an abrupt but brief increase in the synthesis of prostaglandin-E2 (PGE2), thromboxane (TXB2), and prostacyclin [6 keto-PGF1 alpha (6KPGF)] was noted, which returned to normal at 3 days. This was followed after 7 and 14 days by a significant fall off in synthesis of all three prostaglandins. Thereafter, at 28, 56, 120, and 240 days, escalated production of thromboxane followed, while prostacyclin synthesis remained markedly reduced (-88% of control level at 240 days). Up to 7 days after radiation the calculated TXB2/6KPGF ratio remained balanced, regardless of the observed abrupt early fluctuations in their rate of synthesis. Later, between 7 and 240 days after radiation, a significant imbalance was present which became more pronounced over time. In the first 24 h after radiation, a 104% increase in microvessel permeability was observed which returned to normal by 3 days. Normal permeability was maintained at 14 and 28 days, but at 120 and 240 days a persistent and significant increase of 98% and 73% respectively above control level was noted. CONCLUSIONS: Radiation induces severe impairment in microvessel function even in the histologically unaffected spinal cord, and alters the secretory phenotype of various cell systems in the central nervous system.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Spontaneous involution of an intra-axial brain stem lesion: a case report.

This report describes the spontaneous involution of an intrinsic brain stem lesion whose clinical and MRI characteristics strongly suggest a tumor etiology. Nonoperative experiences with central nervous system tumors have shown that they may sometimes exhibit prolonged periods of dormancy. There are several reports of 'disappearing' CT lesions which have all been inflammatory, infective, or immunological. No histologically proven tumor has been shown to spontaneously involute, nor have 'disappearing' lesions been described for MRI.

Brain Neoplasms↗
PubMed1995

Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy.

Anthracyclines entrapped in small-sized, sterically stabilized liposomes have the advantage of long circulation time, reduced systemic toxicity, increased uptake into systemic tumors, and gradual release of their payload. To date, there is no information on the behavior of these liposomes in brain tumors. The objective of this study was to compare the biodistribution and clinical efficacy of free doxorubicin (F-DOX) and stealth liposome-encapsulated DOX (SL-DOX) in a secondary brain tumor model. Nine days after tumor inoculation Fischer rats with a right parietal malignant sarcoma received an intravenous dose of 6 mg/kg of either F-DOX or SL-DOX for evaluation of drug biodistribution. For therapeutic trials a single dose of 8 mg/kg was given 6 or 11 days after tumor induction, or alternatively, weekly doses (5 mg/kg) were given on Days 6, 13, and 20. Liposome-encapsulated DOX was slowly cleared from plasma with a t1/2 of 35 hours. Free-DOX maximum tumor drug levels reached a mean value of 0.8 microgram/g and were identical in the adjacent brain and contralateral hemisphere. In contrast, SL-DOX tumor levels were 14-fold higher at their peak levels at 48 hours, declining to ninefold increased levels at 120 hours. A gradual increase in drug levels in the brain adjacent to tumor was noted between 72 and 120 hours (up to 4 micrograms/g). High-performance liquid chromatography analysis identified a small amount of aglycone metabolites within the tumor mass from 96 hours and beyond, after SL-DOX injection. Cerebrospinal fluid levels were barely detectable in tumor-bearing rats treated with F-DOX up to 120 hours after drug injection (< or = 0.05 microgram/ml), whereas the levels found after SL-DOX were 10- to 30-fold higher. An F-DOX single-dose treatment given 6 days after tumor inoculation increased the rats' life span (ILS) by 135% over controls (p < 0.05) but was not effective if given on Day 11. In contrast, SL-DOX treatment resulted in an ILS of 168% (p < 0.0003) with no difference when given after 6 or 11 days. Treatment with three weekly doses of SL-DOX produced an ILS of 189% compared to 126% by F-DOX (p < 0.0002). The authors conclude that the use of long-circulating liposomes as cytotoxic drug carriers in brain tumor results in enhanced drug exposure and improved therapeutic activity, with equal effectiveness against early small- and large-sized brain tumors.

Animals↗
PubMed1994

Pharmacodynamics of phenobarbital anesthesia and pentylenetetrazol-induced maximal seizures in a rat model of neoplastic spinal cord compression.

The purpose of this investigation was to determine whether paraplegia induced by neoplastic cord compression affects the pharmacodynamics of phenobarbital general anesthesia or of pentylenetetrazol (PTZ)-induced convulsions. Paraplegic rats harboring a thoracolumbar epidural tumor, or an identical hindlimb tumor mass, received an i.v. infusion of phenobarbital until the onset of anesthesia. At that point, the phenobarbital concentrations in the CSF and serum were measured. Similarly, PTZ was infused until the onset of maximal seizures. It was found that changes related to systemic tumor growth and newly developed paraplegia due to neoplastic spinal cord compression did not attenuate the pharmacodynamics of phenobarbital. However, sustained paraplegia of 4 days' duration reduced CNS sensitivity to the hypnotic action of the barbiturate as evidenced by the higher cerebrospinal fluid phenobarbital concentration required to induce anesthesia (170 +/- 31 vs 125 +/- 20 mg/L; P < 0.05). On the other hand, sustained paraplegia did not affect brain threshold concentration for PTZ-induced seizures.

Anesthesia↗
PubMed1994

Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy.

Thirty-one (23%) of 137 patients treated for leptomeningeal metastases (LM) achieved a sustained off-therapy response of at least 6 months' duration following treatment by a standard protocol. Of the 31 patients, equal distribution was found among various tumors: lymphoma, 13/44 (29%); breast carcinoma, 10/51 (20%); and other tumors, 8/42 (19%). Neuroimaging of the neuraxis disclosed subarachnoid deposits in 70%, with unexpected findings in 55%. At withdrawal of therapy, all 13 patients with lymphomas had achieved a complete response, and for those with the other tumors, 61% had a partial response. Off-therapy relapse was unrelated to the type of attained response and occurred in nine patients (29%) after a median time of 12 months. Five patients obtained a second prolonged response, mainly by systemic therapy. All eight patients who received only systemic therapy for their LM responded to treatment, four with a complete response. All others received both systemic and intra-CSF treatment and maintained a systemic response. Delayed complications occurred in 58%, with leukoencephalopathy equally affecting patients exposed and patients not exposed to cranial irradiation. The median survival of the whole group was 23 months. We conclude that in LM (lymphomas excluded), a partial response is compatible with a prolonged off-therapy response. Since LM may respond to systemic treatment, the role of intra-CSF therapy, with its associated complications, deserves a prospective reevaluation.

Adolescent↗
PubMed1993

Serotonergic manipulations in experimental neoplastic spinal cord compression.

The effects of differing strategies of serotonergic manipulation on vascular permeability, prostaglandin E2 (PGE2) synthesis, and the clinical course are evaluated in an experimental model of neoplastic spinal cord compression in rats. Serotonergic manipulations include in vivo inhibition of serotonin (5-HT) synthesis by p-chlorophenylalanine (p-CPA) and in vivo blockage of serotonin type 2 (5-HT2) receptors either by the selective antagonist ketanserin or by cyproheptadine. In paralyzed rats, the ratio of 5-hydroxyindole-3-acetic acid (5-HIAA) to 5-HT is significantly elevated in the compressed segments, suggesting that 5-HT utilization is increased. Treatment with p-CPA attenuates spinal 5-HT levels by 62.8% +/- 5.1% (mean +/- standard deviation) and reduces the elevated 5-HIAA:5-HT ratio to the normal value. The increased synthesis of PGE2 observed in the compressed cord is unaffected by p-CPA or ketanserin treatment but is markedly attenuated by cyproheptadine. Ketanserin reduces the 10-fold increase in spinal cord permeability observed in paralyzed rats in a clearly dose-related manner. If given at the first sign of neurological dysfunction, ketanserin delays the onset of paraplegia with the 1-mg/kg dose being clearly superior. Cyproheptadine and p-CPA also reduce the increased permeability and protract the course to paraplegia. A comparison of the effect of dexamethasone, indomethacin, cyproheptadine, p-CPA, and ketanserin reveals that they protract the disease course by 48%, 57%, 60%, 64%, and 78%, respectively. These data suggest that 5-HT2 receptors mediate some of the deleterious vascular consequences observed in the compressed spinal cord by a mechanism not coupled with PGE2 synthesis. A potential benefit of serotonergic manipulations for the acute treatment of neoplastic spinal cord compression is suggested.

Animals↗
PubMed1992

Spinal subarachnoid hemorrhage associated with leptomeningeal metastases.

Retrospective evaluation of 120 patients treated for leptomeningeal metastases at the Hadassah Hebrew University Hospital disclosed 3 patients with spontaneous spinal subarachnoid hemorrhage (SAH) occurring in the absence of bleeding tendency. These patients are described in detail. A search of the English literature revealed only 2 additional cases. The primary neoplasm originated in the central nervous system in 4 of these 5 patients; a resection of an intraparenchymal posterior fossa tumor antedated the development of subarachnoid seeding in 3 of the 5 patients; SAH occurred in face of a negative CSF cytology and in the presence of macroscopic subarachnoid deposits that were diagnosed with the aid of neuroimaging techniques. It is suggested that spontaneous spinal SAH in a patient with a history of primary or secondary brain tumor and with no bleeding tendency indicates probable presence of macroscopic leptomeningeal deposits.

Adolescent↗
PubMed1992

Numb chin syndrome in cancer patients: etiology, response to treatment, and prognostic significance.

We retrospectively evaluated 42 consecutive cancer patients with numb chin syndrome (NCS). Breast cancer comprised 64% of the primary tumors, and lymphoproliferative neoplasms comprised 14%. A standard workup (including imaging of the brain, base of skull, and mandible, and CSF analysis) led to the diagnosis of a metastatic etiology in 89% of the patients. Fifty percent of the patients had mandibular metastases, 14% base-of-skull bone lesions, and 22% leptomeningeal seeding. NCS was a late manifestation of malignancy, associated with disease progression in 67% of the patients or heralding a relapse, which was often confined to the leptomeninges, in 31%. Although various therapeutic strategies led to resolution of NCS, median survival after its diagnosis was 5 months when due to bone metastases and 12 months if associated with leptomeningeal seeding.

Adult↗
PubMed1991

Muscle cramps in the cancer patient: causes and treatment.

Muscle cramps may occur in healthy individuals without any apparent cause; these are regarded as benign cramps. Cramps may also develop as a symptom of a systemic disease, such as uremia. Cramps probably originate in the distal portion of the motor nerve. It is unclear whether the nerve terminals are hyperexcitable or prone to repetitive activity in the various related conditions. In the cancer patient, muscle cramps may not be a benign complaint because they often represent an unsuspected underlying pathologic condition associated either with the neoplastic process or the undesirable side effects of therapy. Initial evaluation with a detailed neurologic examination, a complete biochemical profile with magnesium levels and muscle enzymes, and electrodiagnostic examination will lead to the diagnosis in the majority of these patients. Recognized etiologies of cramps may be related to neurologic abnormalities or to nonneurologic causes. Treatment decisions should be oriented according to the following classification: (1) reversible causes; (2) potentially reversible causes and (3) irreversible causes. Whereas the remedy in the first category is to attack the underlying process, if possible, pharmacologic suppression of cramps is the primary approach in the others. Membrane-stabilizing agents, such as quinine, phenytoin or carbamazepine, may be selected according to either nocturnal or daytime predominant occurrence of cramps.

Clinical Protocols↗
PubMed1991

Participation of serotonergic mechanisms in the pathophysiology of experimental neoplastic spinal cord compression.

We evaluated the role of serotonin (5-HT) in neoplastic cord compression in paraplegic rats harboring a thoracolumbar epidural tumor. We measured serotonin and its major metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), in the C-1 to C-7, T-1 to T-6, T-7 to T-12, and T-13 to L-3 spinal segments of tumor-free and tumor-bearing rats. In normal controls, a consistent rostral-to-caudal gradient for 5-HT and 5-HIAA was evident, but the 5-HIAA/5-HT ratio remained constant. In paralyzed rats, 5-HT levels were unchanged, but the 5-HIAA/5-HT ratio was elevated, especially in the compressed segments. Treatment with either dexamethasone or indomethacin delayed onset of paraplegia but had no effect on 5-HT metabolism. Blocking 5-HT receptors by cyproheptadine, evaluated 30 hours after onset of paralysis and treatment, resulted in a reduction in the high water content, vascular permeability, and prostaglandin E2 synthesis in the compressed cord. Early administration of cyproheptadine effectively delayed the onset of paraplegia. These data indicate that receptor-activated serotonergic mechanisms participate in the disruption of the blood-spinal cord barrier and that these effects can be manipulated pharmacologically.

Animals↗
PubMed1990

Cisplatin-induced peripheral neuropathy. Frequent off-therapy deterioration, demyelinating syndromes, and muscle cramps.

Forty-five patients with cisplatin-induced peripheral neuropathy (PN) were evaluated retrospectively after treatment with cumulative doses of cisplatin ranging from 201 to 1952 mg/m2. The patients were followed for up to 23 months (median, 4.5 months), and 32 of them were evaluated more than once. Severity of symptoms was related to higher cumulative doses of cisplatin but with marked individual variability. Off-therapy deterioration of the PN continued in 14 patients (31%) for 2.5 to 5.5 months after withdrawal of cisplatin, and only four patients showed some improvement during the follow-up period. Symptomatic deterioration often was heralded by new onset of muscle cramps (with normal Ca2+/Mg2+ levels) and/or by manifestations of probable spinal dorsal column and/or nerve root demyelinating syndromes presenting as either Lhermitte's sign and/or as an electric-shock sensation along the upper extremities when outstretched in 90 degrees shoulder abduction. Cramps and demyelinating syndromes were each noted in 31% of the patients. Muscle cramps tended to resolve several months after withdrawal of therapy, and demyelinating syndromes were always transient (1.5 to 6.0 months) and did not progress despite ongoing therapy in five patients. Our study indicates that, after withdrawal of therapy, patients with cisplatin-induced PN may continue to deteriorate for several months. Manifestations of muscle cramps and demyelinating syndromes signify a worsening course of the PN but should not automatically indicate interruption of therapy.

Adult↗
PubMed1990

Gliomas following low-dose irradiation to the head report of three cases.

Three patients developed cerebral gliomas decades after exposure to low-dose x-ray irradiation in childhood for the treatment of tinea capitis. One of the patients had a glioblastoma multiforme concomitant with multiple intracranial meningiomas, a condition highly correlated with previous irradiation. The other tumors were malignant cerebellar astrocytoma and a diffuse cerebral astrocytoma. We review the evidence suggesting that low-dose irradiation is involved in the pathogenesis of gliomas.

Adult↗
PubMed1990

Experimental neoplastic spinal cord compression: effect of ketamine and MK-801 on edema and prostaglandins.

Excitotoxin-induced neural tissue damage is mediated through specific receptors. We studied the in vivo effect of two selective N-methyl-D-aspartate receptor antagonists on the compressed spinal cord segments of rats harboring a thoracolumbar epidural tumor. The effect of a single intramuscular treatment with either MK-801 (3 mg/kg) or ketamine (110 mg/kg) given at the onset of paraplegia was evaluated 30 hours later. In saline-treated control animals, significant increases in water content, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were evident. Treatment with either agent resulted in a normal water content in the compressed segments but had no effect on prostaglandin synthesis. Evaluation of the effect of treatment on the course of the disease required dose reduction by 45% for ketamine and by 30% for MK-801, to avoid the excessive sedative effect. Treatment was started at the first appearance of neurological dysfunction (Grade 1) and continued to paraplegia (Grade 5). The mean time interval between Grades 1 and 5 was 2.1 +/- 0.3 days in saline-treated control animals, and it was not significantly altered by either ketamine or MK-801. Our study indicates that in the end stage of epidural compression, when ischemia is present, excitotoxins probably participate in the evolution of a cytotoxic edema. It is suggested that treatment initiated at the onset of paraplegia may still reduce the cytotoxic edema, but its potential clinical value requires further investigations.

Analysis of Variance↗
PubMed1990

Experimental neoplastic spinal cord compression: effect of anti-inflammatory agents and glutamate receptor antagonists on vascular permeability.

It has been demonstrated in paraplegic rats harboring an epidural neoplasm that an antiedema effect can be achieved by in vivo treatment with either steroidal or nonsteroidal anti-inflammatory agents or by glutamate receptor antagonists. The effect of these treatments on vascular permeability of the normal and compressed spinal cord was quantitated by the Evans blue dye technique. Tumor-free and tumor-bearing rats were assigned randomly for treatment as follows: 0.5 ml of saline or three doses at 12-hour intervals of either dexamethasone (5 mg/kg), methylprednisolone (30 mg/kg), indomethacin (5 mg/kg every 24 hours), or a single dose of either ketamine (110 mg/kg) or MK-801 (3 mg/kg). Treatment was given at the onset of paraplegia, and the animals were killed after 30 hours. In tumor-bearing rats in the early symptomatic stage, extravasation of Evans blue dye was 4.8 times greater than that of the normal cord (P less than 0.001) and at the onset of paraplegia it was 9.9 times greater (P less than 0.0006). Glucocorticoids and indomethacin reduced dye extravasation in paraplegic animals (P less than 0.01 and P less than 0.003, respectively), but the decreased permeability induced by ketamine and MK-801 did not reach the level of significance. In tumor-free control animals permeability was not changed by administration of either glucocorticoids or indomethacin but was significantly reduced by ketamine or MK-801 (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗