Horace Norrell

Leukoencephalopathy following the administration of methotrexate into the cerebrospinal fluid in the treatment of primary brain tumors

Four children having recurrent primary malignant posterior fossa tumors de‐developed a leukoencephalopathy during treatment with methotrexate administered via a ventriculocisternal catheter. Symptoms and signs, including visual disturbances; seizures, quadriparesis, and organic dementia appeared from 3 to 15 months following the initiation of methotrexate therapy. At autopsy all four patients had severe leukoencephalopathy, chiefly involving die central white matter of the cerebral hemispheres; one patient had no residual tumor. All patients had received earlier irradiation, but the lesions within the brain are believed not to represent irradiation necrosis. It is postulated that the changes occurring within the brain are secondary to the disturbances in brain folic acid metabolism produced by the methotrexate; this effect may have been accentuated by the blockage of the cerebrospinal fluid pathways, the delayed effects of irradiation, or the administration of anticonvulsants. Intrathecal methotrexate is capable of eradicating certain intracranial malignancies, but its administration must be more judicious in order to avoid lethal complications.

Persistent potency of a secondary (conditioned) reinforcer following withdrawal of morphine from physically dependent rats

Abstract1.On 9 nights (2000-0800) over a 25-day period, an anise-flavored aqueous solution of etonitazene, 5 mcg/ml, was provided as the sole drinking fluid for one group of physically dependent rats (MFETZ) maintained on morphine, 200 mg/kg i.p. once daily at 0800 (hence acutely abstinent each night) and for one group of saline-injected rats (SFETZ), while only anise-flavored water was available to comparable physically dependent (MFH2O) and saline-injected (SFH2O) groups.2.Beginning 3 days after abrupt and permanent termination of morphine or saline injections, all rats were tested at intervals over a period of 287 days on nocturnal (2000-0800) choice drinking from 2 tubes (positions alternated), one contained anise-flavored water and the other, plain water.3.Analyses of variance on the mean volumes of each of the two fluids consumed by each rat over blocks of choice-drinking tests revealed that through the VIIth test (137th post-injection day), MFETZ drank more anise-flavored water than any other group while there were no significant differences among the groups as regards consumption of plain water.4.The evidence indicates that the potency of secondary reinforcers so generated can persist long after morphine withdrawal. Some implications for problems of relapse and treatment of opioid addicts are discussed.

Brain tumor chemotherapy with intrathecal methotrexate

Two patients harboring recurrent posterior fossa tumors were treated with intrathecal methotrexate. The patient with an ependymoma responded dramatically and, when he died of a leukoencephalopathy 2 years later, no evidence of intracranial tumor remained. A medulloblastoma in the second patient responded to methotrexate but became moderately drug resistant and spread to bone. In this case, concomitant use of intrathecal methotrexate and systemic citrovorum factor offered no apparent advantage. Relevant literature relating to methotrexate and tumor kinetics is reviewed. In the light of present knowledge, brain tumors selected for intrathecal methotrexate should be treated weekly for an indefinite period of time. The need for additional information regarding the behavior of citrovorum factor in the central nervous system is acknowledged.

Cryohypophysectomy in the management of advanced prostatic canger

Twenty patients with metastatic carcinoma of the prostate underwent stereo‐taxic trans‐sphenoidal cryohypophysectomy. Of the 19 patients surviving the operative procedure, 12 (63%) benefited. Seven patients (37%) experienced objective remissions, whereas 5 (26%) had subjective responses alone. The mean survival of those who responded was 11.5 months as compared with 3.8 months for those who did not. Mean duration of the remission was 7 months. Autopsies revealed a 90% or greater destruction of the anterior lobe of the pituitary in 5 of 7 cases. The calculated amount of residual anterior pituitary tissue varied from 0 to 49%; there was little correlation between the completeness of hypophysectomy and the quality or duration of the response. Complications included death in one patient, cerebrospinal fluid rhinorrhea in 3, and diabetes insipidus (transient) in 7. Cryohypophysectomy is an effective technique of pituitary ablation capable of providing a high overall remission rate in metastatic prostatic cancer.

Limbic system and opioid addiction in the rat.

Abstract Statistical comparisons of means in groups of morphine-dependent (or post-dependent) rats with and without bilteral lesions in the cingulum, the dorsomedial thalamic nucleus, the anterior temporal lobe (amygdaloid complex and ventral hippocampus), or the septum, and in nondependent rats with and without such lesions, revealed no significant lesion effects on specific signs of the 24-hr primary morphine-abstinence syndrome in this species: decreased water intake; increased “no-choice” drinking of a 5-μg/ml aqueous solution of a potent opioid (etonitazene); increased “wet dog” shake frequency; fall in colonic temperature. Lesions in the cingulum attenuated one sign of the secondary (protracted) morphine-abstinence syndrome (increased 24-hr water consumption). None of the lesions altered the suppressive effects on the primary morphine-abstinence syndrome of “no-choice” etonitazene-drinking or of intraperitoneal injection of morphine. None of the lesions prevented “relapse” of postdependent rats, as measured by comparisons of mean volumes of etonitazene (5-μg/ml) and water consumed in “choice” trials 9–72 days after permanent withdrawal of morphine.

A clinicopathologic analysis of cryohypophysectomy in patients with advanced cancer

Serial sections of the sella turcica were obtained in 18 autopsy specimens of patients with advanced breast and prostatic carcinoma who had undergone extensive endocrine testing before and after cryoablation of the pituitary gland. Cryohypophysectomy, a techinque which requires neither craniotomy nor general anesthesia, resulted in 90 percent or greater destruction of the anterior lobe of the pituitary in 11 cases; destruction was complete in 3 cases. Persistence of human growth hormone following cryohypophysectomy was the most reliable indication of residual anterior pituitary function, but even this was an unreliable index when less than 10 percent of the pituitary gland remained viable. Withdrawal of corticosteroids resulting in an adrenal crisis following operation proved a poor technique to determine the adequacy of pituitary destruction. Length and extent of tumor remission did not seem to be dependent upon the degree of pituitary destruction. Based upon our experience with 60 patients having cryohypophysectomy for advanced carcinoma, CSF rhinorrhea and persistent diabetes insipidus each occurred in 10 percent of the cases.