Effects of verapamil on ventricular tachycardias possibly caused by reentry, automaticity, and triggered activity.

To define the role of verapamil in the treatment of ventricular tachycardia (VT), we studied 21 patients with chronic recurrent VT. Electrophysiologic studies were performed before and during intravenous infusion of verapamil (0.15 mg/kg followed by 0.005 mg/kg per min). On the basis of the mode of VT initiation and termination, we identified three groups of patients: (a) 11 patients had VT suggestive of reentry, as VT could be initiated with ventricular extrastimulation and terminated with overdrive ventricular pacing. Verapamil did not affect the inducibility and cycle length of VT. (b) 7 patients had VT suggestive of catecholamine-sensitive automaticity as VT could not be initiated with programmed electrical stimulation but could be provoked by isoproterenol infusion. Moreover, the VT could not be converted to a sustained sinus rhythm with overdrive ventricular pacing and it resolved only with discontinuing isoproterenol infusion. Verapamil exerted no effects on VT. (c) 3 patients had VT with electrophysiologic characteristics suggestive of triggered activity related to delayed afterdepolarizations. Characteristically, after attaining a range of cycle lengths, the sinus, atrial or ventricular paced rhythm could initiate VT without ventricular extrastimulation. The first beat of VT invariably occurred late in the cardiac cycle with a premature coupling interval 0-80 ms shorter than the preceding QRS cycle length; the premature coupling interval gradually decreased as the sinus, atrial or ventricular paced cycle length progressively shortened. Of note, verapamil completely suppressed VT inducibility in these three patients. These observations lead us to suggest that verapamil does not affect VT caused by reentry and catecholamine-sensitive automaticity but is effective in suppressing VT caused by triggered activity related to delayed afterdepolarizations in humans.

Cerebrovascular response to acute hypocapnic and eucapnic hypoxia in normal man.

Alterations in human cerebral blood flow and related blood constituents were studied during exposure to acute hypoxia. Observations were made during serial inhalation of decreasing O(2) concentrations with and without maintenance of normocarbia, during 8 min inhalation of 10% O(2), and after hyperventilation at an arterial P(O2) of about 40 mm Hg. In the range of hypoxemia studied, from normal down to arterial P(O2) of about 40 mm Hg, the magnitude of the cerebral vasodilator response to hypoxia appeared to be largely dependent upon the coexisting arterial CO(2) tension. The mean slope of the increase in cerebral blood flow with decreasing arterial O(2) tension rose more quickly (P < 0.05) when eucapnia was maintained when compared with the slope derived under similar hypoxic conditions without maintenance of eucapnia. When 12 subjects inhaled 10% oxygen, cerebral blood flow rose to more than 135% of control in four whose mean decrease in arterial CO(2) tension was - 2.0 mm Hg. The remaining eight had flows ranging from 97 to 120% of control, and their mean decrease in CO(2) tension was - 5.1 mm Hg. When mean arterial P(O2) was 37 mm Hg, hyperventilation was carried out in 10 subjects. Arterial P(O2) increased insignificantly, arterial P(CO2) declined from 34 to 27 mm Hg (P < 0.05), and cerebral blood flow which had been 143% of control decreased to 109%, a figure not significantly different from control.These data demonstrate the powerful counterbalancing constrictor effects of modest reductions in CO(2) tension on the vasodilator influence of hypoxia represented by arterial P(O2) reductions to about 40 mm Hg. Indeed, mild hyperventilation completely overcame the vasodilator effect provided by an arterial O(2) tension as low as 40 mm Hg. The effects of hypoxia on the control of the cerebral circulation must be analyzed in terms of the effects of any associated changes in CO(2) tension.

Human brain tumor transplantation into nude mice.

Seven human brain tumors were transplanted into the brains (6/7 takes) and subcutaneous tissues (7/7 takes) of athymic nude mice. Compared to experimental animal brain tumors, these tumors, taken directly from patients in the operating room and transplanted, grew more slowly in the mice; their growth rates following explant generally paralleled those in the patients. A rough correlation was seen between the degree of the tumor's malignancy and both successful take and rate of growth following explant. The tumors' growth rates increased during serial transplantation after explant. Two tumors developed into long-term serial lines; both came from gliosarcomas. Preliminary chemotherapy experiments with these two lines demonstrated different chemosensitivities. One line was very sensitive to the nitrosoureas and resistant to procarbazine; the other line was more sensitive to procarbazine than to the nitrosoureas. This model permits study of the biologic behavior of human brain tumors growing intracerebrally and subcutaneously in nude mice.

Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-Ommaya methotrexate administration in patients with meningeal carcinomatosis.

Serum and cerebrospinal fluid (CSF) concentrations of citrovorum factor (CF) and 5-methyltetrahydrofolic acid (5-MTHFA) were measured after i.v. infusion of leucovorin (50 or 100 mg/sq m) in seven patients undergoing treatment for meningeal carcinomatosis by intra-Ommaya reservoir injection of methotrexate (MTX). Serum CF levels rapidly rose after leucovorin administration as did 5-MTHFA, its conversion product. A small amount of CF entered the CSF, but peak CSF 5-MTHFA increased about 10-fold. The concentration X time (C X t) of additional 5-MTHFA in the CSF was greater [114.4 +/- 36.1 (S.E.) microgram/ml X min] after 100-mg/sq m doses of leucovorin than after 50 mg/sq m [14.2 +/- 4.3 micrograms/ml X min] (p less than 0.05). The CSF MTX concentration exceeded CSF 5-MTHFA by 2 to 3 logs throughout the 48 hr of observation, while serum 5-MTHFA and CF exceeded serum MTX by 0.5 to 2 logs. This study demonstrates that leucovorin administered i.v. to patients receiving intra-Ommaya MTX does not increase CSF concentrations of "rescue" folate above those of CSF MTX and are unlikely to interfere with MTX action against meningeal tumor. On the other hand, i.v. leucovorin does permit serum "rescue" folate to operate, thus reducing the systemic toxicity that may follow intraventricular administration of MTX.

Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture.

Six karyotypically distinct clonal cell lines isolated from each of two freshly resected human malignant gliomas were examined for heterogeneity of morphology, in vitro growth rate, and chemosensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea and cis-diamminedichloroplatinum (II). Each clone was identified karyotypically as having come from the parent tumor. The karyotypic deviations were primarily numerical; chromosome numbers ranged from hypodiploid to near-tetraploid. Three morphological types were recognized: astrocyte-like; squamous-like; and fibroblast-like. The growth rates differed among the clones; the doubling times ranged from 48 to 84 hr in those from one tumor and from 72 to 252 hr in the other. Chemosensitivity was measured by cytotoxicity and/or colony-forming assay. In both assays and in both tumors, heterogeneity of chemosensitivity response to both drugs was demonstrated among the different clones from the same tumor. Dose-response curves from some clones differed statistically (log-probit analysis) from those of others, and when the curves were parallel, their 50% effective doses often differed. For the cytotoxicity assay, the 50% effective doses of BCNU ranged from 43 to 94 microgram/ml and for cis-diamminedichloroplatinum (II), from 29 to 340 microgram/ml. For the colony-forming assay, the 50% effective doses of 1,3-bis(2-chloroethyl)-1-nitrosourea ranged from 4.5 to 7.0 microgram/ml and for cis-diamminedichloroplatinum (II), from 0.35 to 1.40 microgram/ml. No correlation was evident between the chromosome number, morphology, growth rates, or chemosensitivities of the clones. These results identified heterogeneity of chemosensitivity among cellular subpopulations in human malignant gliomas.

Pharmacokinetics of tumor cell exposure to [14C]methotrexate after intracarotid administration without and with hyperosmotic opening of the blood-brain and blood-tumor barriers in rat brain tumors: a quantitative autoradiographic study.

Using quantitative autoradiography, we investigated the entry over 90 min of [14C]methotrexate (MTX) into C6 gliomas implanted bilaterally into Wistar rat brains. The [14C]MTX was administered into the right carotid artery, yielding ipsilateral "arterial" brain and tumor concentrations and contralateral "systemic" concentrations. In a separate group of tumor-bearing rats, mannitol 1.6 M was given into the right carotid artery prior to administering the [14C]MTX to disrupt the blood-brain barrier on the ipsilateral side. [14C]MTX tissue concentrations were measured in regions of 50 x 50 x 20 microns in tumor, peritumoral brain tissue (brain adjacent to tumor), and cerebral cortex. In the nonmannitol experiments, tissue concentrations from the rats at each time interval were fitted using a nonlinear curve fitting program, and the pharmacokinetic values of influx and efflux of [14C]MTX into the three compartments were calculated. The influx rate constant K1 for [14C]MTX ranged from 1.3 to 8.2 microliters/g/min in the tumor. Influx rate constants in the cortex were 1.3-1.9 microliters/g/min and in the brain adjacent to tumor were 1.7-2.8 microliters/g/min. The efflux rate constant k2 was approximated for each tissue but was less reliable than the K1 values. The k2 for tumor, brain adjacent to tumor, and cortex was always higher than the corresponding K1. Peak [14C]MTX concentrations in the tumor were highest after arterial infusion with hyperosmolar barrier disruption, lower after arterial administration without barrier modification, and lowest after systemic administration. However, cortical [14C]MTX concentration was also highest after arterial administration with barrier modification and higher than the highest tumor concentration. Furthermore, tissue exposure (concentration x time) was also highest in the cortex after barrier disruption. The [14C]MTX concentration x time (micrograms/min/g x 90 min +/- SEM) ratio between tumor and cortex after systemic administration was 33.4 +/- 4.1:15.7 +/- 1.9; after arterial administration it was 96.3 +/- 11.7:30.3 +/- 3.1; after arterial administration with barrier disruption it was 266.6 +/- 28.8:311.2 +/- 15.9. The greatest tumor:cortex ratio (3.1:1) occurred with arterial drug administration without barrier disruption. Disrupting the barrier enough to permit increased tumor exposure actually increased cortical exposure to a greater degree. The resulting poorer therapeutic ratio would not appear to support this technique in humans, at least for neurotoxic drugs.

Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine.

We tested the hypothesis that the level of the DNA repair protein O6-alkylguanine-DNA alkyltransferase in brain tumors was correlated with resistance to carmustine (BCNU) chemotherapy. Alkyltransferase levels in individual cells in sections from 167 primary brain tumors treated with BCNU were quantitated with an immunofluorescence assay using monoclonal antibodies against human alkyltransferase. Patients with high levels of alkyltransferase had shorter time to treatment failure (P = 0.05) and death (P = 0.004) and a death rate 1.7 times greater than patients with low alkyltransferase levels. Furthermore, the size of the subpopulation of cells with high levels of alkyltransferase was correlated directly with drug resistance. For all tumors the variables most closely correlated with survival, in order of importance, were age, tumor grade, and alkyltransferase levels. For glioblastoma multiforme, survival was more strongly correlated with alkyltransferase levels than with age. These results should encourage prospective studies to evaluate alkyltransferase levels as a method, for identifying brain tumor patients with the best likelihood of response to BCNU chemotherapy.

The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group.

The prognostic importance of tumor size was studied in 510 patients with malignant glioma (80% with glioblastoma multiforme) in the Valid Study Group of Study 80-01 of the Brain Tumor Study Group (now the Brain Tumor Cooperative Group [BTCG]). The endpoint was length of survival from randomization, which occurred within 3 weeks of definitive surgery. Following randomization, patients were scheduled to receive radiotherapy (RT) (6,020 cGy) during a 7-week period, along with continuing courses of chemotherapy. Computed tomographic (CT) scan information was available for 124 patients preoperatively, 300 patients postoperatively (preradiation), and 218 patients 9 weeks post-RT (+/- 3 weeks). Tumor size was determined as area (length x width) on the contrast-enhanced scan and survival was compared by log rank statistics. Preoperative tumor area was unrelated to survival (P = .48), but postoperative area was significantly prognostic (P less than .0001); the smaller the residual tumor, the longer the patient lived. Patients with a 75% or greater resection, as determined by measuring the difference between the preoperative and the postoperative scans, tended to have better survival, but the difference was not significant (P = .16). The post-RT area was strongly related to survival (P less than .00001). The percent change in area between the pre- and post-RT scans was also prognostic. Tumor size was of prognostic importance independent of the other known prognostic variables: age, Karnofsky performance score, and whether the tumor was glioblastoma or anaplastic astrocytoma. We conclude that the amount of tumor remaining after surgery is an important baseline variable at the start of RT, and that the tumor size 9 weeks following RT is also prognostic. Surgical resection is most important when it leaves the least amount of residual tumor.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

Electrophysiologic and hemodynamic effects of intravenous propafenone in patients with recurrent ventricular tachycardia.

Electrophysiologic and hemodynamic studies were performed before and after intravenous infusion of a new antiarrhythmic agent, propafenone, in 28 patients with recurrent ventricular tachycardia. Propafenone was given at a loading dose of 2 mg/kg in all patients. Subsequently, group A, the first 14 patients, received 1 mg/min and group B, the second 14 patients, received 2 mg/min continuous infusion. Propafenone exerted no effect on sinus nodal recovery time and sinoatrial conduction time, but significantly prolonged atrioventricular (AV) nodal and His-Purkinje conduction time and the QRS duration (respectively, 95 +/- 19, 48 +/- 10 and 120 +/- 23 ms before, and 110 +/- 28, 53 +/- 10 and 135 +/- 27 ms after; p less than 0.001). Propafenone did not change the mean arterial blood pressure but slightly increased right atrial, pulmonary artery and capillary wedge pressures resulting in mild depression of the cardiac index (2.6 +/- 0.8 liters/min per m2 before and 2.3 +/- 0.7 liters/min per m2 after; p less than 0.001). None of the patients were symptomatic from these changes. In group A, propafenone did not affect the inducibility of ventricular tachycardia except for one patient whose arrhythmia was sustained before and become nonsustained after propafenone. In group B, sustained ventricular tachycardia became noninducible in three patients and nonsustained in two patients, and nonsustained ventricular tachycardia became noninducible in one patient after propafenone. Therefore, an appropriate loading dose of intravenous propafenone such as 2 mg/kg followed by 2 mg/min infusion may be given safely and may suppress ventricular tachycardia. Propafenone may be a useful addition to currently available antiarrhythmic agents.

Infusion intravenous pyelography and renal function. Effects in patients with chronic renal insufficiency.

Acute renal failure (ARF) following infusion intravenous pyelography (IVP) has been reported in patients with chronic renal insufficiency, particularly diabetics. Renal function was evaluated before and after infusion IVP in 40 patients with chronic renal insufficiency. In 11 of 12 (92%) diabetics and 17 of 28 (61%) nondiabetics, a 25% or greater increase in serum creatinine values and/or decrease in creatinine clearance was noted after IVP despite adequate hydration in all patients. The maximum decrease in kidney function occurred within three days and usually returned to or near pre-IVP levels in seven to ten days. At least 70% of the patients had hypertension and/or evidence of vascular disease. The data suggest that preexisting vascular disease in the kidney, possibly associated with the known vasoconstricting effects of contrast media, may be an important factor in the ARF following infusion IVP.

Infusion intravenous pyelography and renal function. Effect of hypertonic mannitol in patients with chronic renal insufficiency.

In a previous prospective study, we reported that infusion intravenous pyelography (IVP) in 40 patients with chronic renal insufficiency resulted in acute renal failure (ARF) in 28 patients (70%). In an attempt to prevent this complication, we have evaluated the conditions of another group of 37 patients with chronic renal insufficiency treated in a similar manner except that each patient received 250 mL of 20% mannitol 60 minutes after infusion of the IVP dye (diatrizoate sodium, 300 mL of a 30% solution). These patients were similar to those in the previous study with regard to age, sex, renal function, and incidence of diabetes. Only eight (22%) of the 37 patients had ARF develop after infusion IVP in this study. This incidence was significantly lower compared with 70% in the previous study. We conclude that administration of hypertonic mannitol 60 minutes after administration of the radiographic contrast material is highly effective in preventing ARF after infusion IVP in patients with chronic renal insufficiency.

Xenograft of human malignant glial tumors into brains of nude mice. A histopatholgical study.

Sixteen of 21 human malignant glial tumors were successfully heterotransplanted into the brains of nude mice, and one other was transplanted into the brain after prior subcutaneous heterotransplantation. Most xenografts grew preferentially as diffusely infiltrating tumors within hemispheric white matter, generally sparing cortex and deep gray matter. The heterogeneity of most in vivo human tumors gave way to a tumor of generally uniform cell type while growing in nude mice. From six human tumors, all glioblastomas, there emerged histologic patterns or cell forms that were not evident in the original tumor. Tumors from 15 patients were treated with standard chemotherapeutic agents while growing in nude mouse brains. The most common morphologic change induced in tumors by several agents was a distinctive giant cell change characterized by large bizarre nuclei and abundant cytoplasm. It is concluded that the human brain-tumor-nude-mouse xenograft model offers morphological parallels with the clinical situation, but selects for growth only some of the many subpopulations of the human tumor. Such selection imposes restriction on the clinical inferences that may be drawn from this model.

Meningeal carcinomatosis: development of an experimental model.

An experimental model of meningeal carcinomatosis has been produced by intracisternal inoculation of Walker 256 carcinoma cell suspension into Wistar rats. The tumor grows rapidly and is fatal in about 15 days if 10(6) cells are injected. The histopathological pattern observed is similar to that seen in diffuse leptomeningeal involvement of systemic cancer in human beings. The model will be useful for investigating the pathophysiology of the neurological disability produced by meningeal carcinomatosis and the efficacy of chemotherapeutic agents.

Neurological complications of antineoplastic therapy.

Increasingly vigorous chemotherapy of cancer including primary and metastatic central nervous system disease has resulted in prolonged good-quality survival. However, there has been an associated increase in neurotoxicity from both radiation therapy and chemotherapy. All classes of chemotherapeutic agents contain drugs that are potentially neurotoxic, often only at high doses. Mechlorethamine, the first nitrogen mustard, is not neurotoxic at conventional dosage, but at high doses, it may produce both an acute and a delayed encephalopathy. Methotrexate administered intrathecally often induces reversible aseptic meningitis, but chronic administration, either intrathecally or high-dose intravenously, may produce fatal leukoencephalopathy. 5-Fluorouracil at high dosage may cause cerebellar ataxia, but may also do so at low dosage when combined with thymidine infusions. Cytosine arabinoside at high dosage may also produce cerebellar ataxia. Vincristine produces a peripheral neuropathy, and less commonly causes both autonomic and cranial neuropathy. The enzyme L-asparaginase can produce a dose-related reversible encephalopathy. BCNU, now the mainstay of glioma chemotherapy, may combine with radiation to produce long-term cerebral atrophy. Both intracarotid and high-dose intravenous BCNU administration may cause encephalopathy. Several other chemotherapeutic agents have also been reported to cause neurotoxicity under certain circumstances.

Treatment of Cataplexy with Clomipramine.

A new antodepressant drug, clomipramine hydrochloride, closely related to imipramine hydrochloride, was used to treat four patients suffering from cataplexy, sleep paralysis, and hypnagogic hallucinations. Attacks of cataplexy were associated with rapid-eye-movement (REM) electroencephalographic patterns. Cloripramine, in doses of 25 to 75 mg/day, completely stopped all attacks of cataplexy, sleep paralysis, and hypnagogic hallucinations within 48 hours of initial therapy. The patients have been free of symptoms for periods of 10 to 21 months. Side effects included impotence in the male patients, but no hematologic, cardiovascular, hepatic, or renal toxic effects were observed. Available evidence suggests that such drugs inhibit those brain stem systems that control the toxic components of REM sleep.

Current therapy for brain tumors: back to the future.

In the last 30 years, while considerable progress has been made in laboratory research of malignant gliomas, fewer clinical breakthroughs can be highlighted. Laboratory research has improved our understanding of the biology, and especially the molecular genetics of this disease. Unfortunately, these successes highlight the difficulties in translating laboratory results into substantive clinical improvements. In part, these difficulties stem from a schizophrenic view of the development and evolution of brain tumors. We believe either that (1) brain tumors are local and therefore the most important research should have as its goal local control, or (2) brain tumors are diffuse, which is to say that the cells rapidly grow beyond their initial locus, and our research goal is the prevention or treatment of the advancing tumor front. Clearly both hypotheses have merit and, in fact, almost certainly, both are true. The question becomes, should we devote our research energies to one hypothesis at the exclusion of the other?

Treatment of malignant glioma. A controlled study of chemotherapy and irradiation.

Thirty-three patients with malignant glioma were randomly divided into two groups after extensive tumor resection. Those in group A received, every five to eight weeks, a course of chemotherapy consisting of intravenously administered carmustine, 80 mg/sq m/day for three days, and vincristine sulfate, 1.4mg/sq m on days 1 and 8. Patients in group B were treated identically and received radiation therapy (RT) as well, 4,500 rads whole brain plus 1,500 rads to the side of the tumor. The median survival time of group A was 30 weeks, while that of group B was 44.5 weeks, but the overall survival curves were not significantly different. The median survival times exceeded the 17 weeks reported elsewhere in comparable patients not receiving postoperative therapy. Estimates of the quality of survival suggested (1) the two groups were not comparable following randomization, possibly influencing the results; and (2) postoperative radiation and chemotherapy do not increase morbidity and offer a longer period than other treatments during which patients' conditions remain stable or improve.

Experimental spinal cord compression by epidural neoplasm.

We have developed an experimental model of spinal cord compression in rats. Tumor injected anterior to the T-12 vertebral body grows through the intervertebral foramina to compress the cord and produces paraplegia in 3 to 4 weeks. Evidence for vasogenic edema in spinal cord compressed by tumor includes increased water content, leakage of horseradish peroxidase into gray matter, and histologic evidence of edema. The vascular supply to the cord overlying the tumor appears to be compromised. Both spinal cord edema and clinical symptoms are lessened by treating symptomatic animals with dexamethasone.

Enhancement of CNS penetration of methotrexate by hyperosmolar intracarotid mannitol or carcinomatous meningitis.

Intracarotid (i.c.) hyperosmolar mannitol enhances central nervous system (CNS) penetration of intravenous (i.v.) methotrexate (MTX) in normal adult rats. A fivefold augmentation in the CSF:serum and ipsilateral brain:serum MTX concentration ratios was observed 1 hour after drug administration. Intravenous mannitol had no such effect. Rats with meningeal carcinomatosis have a partial defect in blood-brain barrier function, and the CSF:serum MTX concentration ratio was 4.6 times higher in these animals than in normal rats prior to mannitol therapy. Intracarotid hyperosmolar mannitol further augmented the blood-brain barrier permeability to intravenous MTX. Intracarotid mannitol increased the therapeutic effect of MTX, since rats with meningeal carcinomatosis that received i.v. MTX and i.c. mannitol experienced a slight enhancement in survival.