Melvin K. Spigelman

Intracarotid dehydrocholate infusion: a new method for prolonged reversible blood-brain barrier disruption.

An animal model for prolonged reversible blood-brain barrier (BBB) disruption has been developed. The external carotid arteries of Osborn-Mendel rats were catheterized in a retrograde manner. Varying concentrations of sodium dehydrocholate were infused into the internal carotid artery by this technique. BBB disruption was evaluated qualitatively by the appearance in the infused hemisphere of the systemically administered dyes Evans blue and sodium fluorescein and quantitatively by the ratio of counts of the technetium-labeled chelate of diethylenetriaminepentaacetic acid (99mTc-DTPA) in the infused to the noninfused hemisphere. The ability of sodium dehydrocholate to disrupt the BBB was documented with all three markers. As the concentration of the infused dehydrocholate was increased, both the incidence and the degree of BBB disruption increased. Reversibility of BBB disruption was evaluated by the administration of sodium fluorescein and 99mTc-DTPA at varying times after BBB disruption. Depending on the concentration of the infused sodium dehydrocholate, altered BBB permeability can be maintained for over 3 days. This new model of prolonged reversible BBB disruption deserves further investigation both for basic studies of the BBB and for therapeutic studies of drug delivery into the central nervous system.

Phase I study of L-alanosine (NSC 15353)

L‐alanosine (NSC I5353) is a newly developed antitumor antibiotic which acts as an inhibitor of purine intermediary metabolism. Experimental antitumor activity was demonstrated in a variety of murine neoplasms. A phase I trial was undertaken on a daily × 5 (d × 5) schedule in 22 evaluable patients. Dose limiting toxicity was an oral mucositis characterized by beefy red oral, lingual and pharyngeal erythema. The maximum tolerated dose is 320 mg/m2/d × 5 every three weeks. The recommended dose for phase II evaluation is 160 mg/m2/d × 5 every three weeks.

Physiological and electrophysiological consequences of etoposide-induced blood-brain barrier disruption.

The present study investigates the effects of etoposide-induced blood-brain barrier (BBB) disruption on systemic blood pressure (SBP), intracranial pressure (ICP), and electroencephalographic (EEG) activity. A total of 29 rats were divided into two groups. In Group 1, 8 control animals received intracarotid normal saline; in Group 2, 21 animals received intracarotid etoposide. SBP, ICP, and EEG were monitored continuously under general anesthesia and controlled ventilation after tracheostomy. Intravenous Evans blue dye was used for determination of BBB disruption. Although none of the Group 1 animals showed BBB disruption, 57% of the animals in Group 2 showed marked BBB disruption (3+). A slight but statistically significant increase in ICP was noted in the Group 2 animals with 3+ BBB disruption, although lesser degrees of barrier disruption (1+ or 2+) resulted in no significant alteration in ICP. The amplitude and frequency of the EEG decreased significantly ipsilateral to the side of intracarotid infusion in all animals with 3+ barrier disruption with a tendency to return toward normal within 2 hours. The degree of transient EEG change observed correlates well with the degree of barrier disruption, potentially allowing clinical determination of BBB disruption by this method.

Primary Treatment of Regional and Disseminated Pancreatic Cancer with Hexamethylmelamine, Mitomycin C and 5-Fluorouracil Infusion

Hexamethylmelamine, mitomycin C and 5-fluorouracil infusion (HexMF) achieved a median survival of 9 months for the 45 patients with either metastatic stage III or unresectable stage II carcinoma of the pancreas. Fifteen percent survived 2 years. Of 32 patients with measurable tumors, 7 had partial and 3 had minor responses (31%); an additional 44% has stable disease for 3 months or more. Response was associated with a 17-month median survival. These findings are indications for further evaluation of both dosage-intensive 5-fluorouracil infusions alone and HexMF as an alternative to streptozotocin- or adriamycin-containing regimens. Patients with nonmeasurable disease are candidates for survival-oriented phase III studies.

Effects of etoposide-induced blood-brain barrier disruption on brain water, intracranial pressure, and cerebral vasomotor tone

This study investigated the effects of hypertension and water loading on etoposide-induced, reversible blood-brain barrier disruption in a rat model. Twenty-nine animals were divided into four groups: group 1--intracarotid (i.c.) injection of saline followed in 1 h by 5 ml i.c. water; group 2--i.c. etoposide followed by i.c. water; group 3--i.c. saline followed by i.v. metaraminol to increase systemic blood pressure; group 4--i.c. etoposide followed by i.v. metaraminol. Systemic blood pressure and intracranial pressure were monitored continuously. Evans blue staining of the brain was used as a monitor of blood-brain barrier disruption. Animals were killed 1 h after either aramine or water infusion, and the brains removed and inspected for the degree of disruption. After dehydration, brain water was calculated for each hemisphere. Two-thirds of the animals infused with etoposide had evidence of barrier disruption, whereas none of the control animals infused with saline were disrupted. Neither control groups 1 or 3 showed significant change in intracranial pressure after water loading or augmentation of systemic blood pressure, respectively. Group 4 animals failed to demonstrate any significant change in intracranial pressure despite marked barrier disruption and acute hypertension (within the limits of normal autoregulation). A small but statistically significant increase in intracranial pressure was noted in group 2 animals with the greatest degree of barrier disruption. A significant increase in brain water was observed ipsilateral to etoposide infusion in only those animals with the most marked barrier disruption. These results indicate that etoposide-induced blood-brain barrier disruption caused significant increases in brain water without significant alteration of cerebral vasomotor tone or increases in intracranial pressure after water loading except in the most severe disruption. The classic untoward consequences of vasogenic edema were not encountered in the present model.

Fulminant disseminated carcinomatosis arising from squamous cell carcinoma of the tongue

Squamous cell carcinoma of the tongue tends to be an indolent disease. Tumors that present as small, localized lesions of the anterior tongue have a median five-year survival greater than 70 percent whether treated by irradiation or surgery. Distant metastases occur in only 7.5 percent. This report describes a well-differentiated T1N0M0 squamous cell carcinoma of the anterior tongue that progressed from diagnosis to death of the patient in less than nine months. At autopsy, the tumor had disseminated widely, including simultaneous metastases to all layers of the heart. It is concluded that factors other than morphology and anatomic extent at presentation may modify prognosis in squamous cell carcinoma of the tongue.

Anatomical Studies of Blood Brain Barrier Disruption Following Intracarotid Bile Salt Infusion

Experimentally induced blood brain barrier (BBB) disruption by the intracarotid infusion of the bile salt sodium dehy drocholate is under investigation in our laboratories. Although the ability of bile salts to break the BBB has been recognized for over thirty-five Years (Broman and Lindberg-Broman 1945), information concerning the anatomic features of this method of barrier disruption has been previously lacking. The goal of the present investigation is to characterize the morphologic consequences of sodium dehydrocholate induced barrier opening.