Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma.

OBJECTIVE: Patients with non-acquired immunodeficiency syndrome-related primary central nervous system lymphomas have the potential to achieve durable complete responses without radiotherapy, with treatment using enhanced chemotherapy delivery with blood-brain barrier disruption (BBBD). Reported 5-year survival rates with combined chemotherapy and radiotherapy were generally only 9 to 22% and were associated, in one study, with an overall 32% incidence of overt dementia and ataxia, which are dramatically increased among patients more than 60 years of age. METHODS: At the Oregon Health Sciences University, 111 consecutive patients with non-acquired immunodeficiency syndrome-related central nervous system lymphomas were prospectively treated with methotrexate-based, BBBD-enhanced chemotherapy and underwent formal neuropsychological evaluations. Of those, 74 patients had no systemic lymphoma and had received no prior irradiation; those 74 patients are described in this report. RESULTS: The estimated 5-year survival rate for this group was 42%, and the median survival time was 40.7 months. Overall, 48 patients (65%) exhibited complete responses and 36 patients continued to exhibit complete responses after 1 year of BBBD-enhanced chemotherapy. Of those 36 patients, none demonstrated evidence of cognitive loss in neuropsychological tests and/or clinical examinations. CONCLUSION: BBBD-enhanced chemotherapy delivery, without subsequent radiotherapy, resulted in favorable survival and cognitive outcomes for patients with primary central nervous system lymphomas who had not previously undergone irradiation. A cooperative multicenter study of intravenous chemotherapy without radiotherapy versus BBBD-enhanced chemotherapy would address the feasibility and necessity of performing a Phase III study for these rare central nervous system malignancies.

The potential for complete and durable response in nonglial primary brain tumors in children and young adults with enhanced chemotherapy delivery.

PURPOSE: Radiographic tumor response and survival were evaluated in the pediatric and young adult population with germ cell tumor, primary CNS lymphoma, or primitive neuroectodermal tumor receiving intra-arterial carboplatin- or methotrexate-based chemotherapy with osmotic blood-brain barrier disruption (BBBD). PATIENTS AND METHODS: Thirty-four patients with histologically confirmed germ cell tumor (n = 9), primary CNS lymphoma (n = 9), or primitive neuroectodermal tumor (n = 16) were treated at the Oregon Health Sciences University from August 1981 through April 1995. Ages ranged from 1 to 30 years (mean, 18 years). Prior treatments included cranial radiation (n = 10) and chemotherapy (n = 18). All patients underwent extensive baseline neuropsychological evaluation and follow-up evaluation upon completion of the protocol, except for two patients who declined follow-up assessment. RESULTS: Six hundred and forty-five BBBD procedures were performed with no mortality. Significant complications included one episode of tonsillar herniation with no neurologic sequelae, 4% incidence of seizures, and 3% incidence of sepsis or granulocytopenic fever. Ototoxicity was seen in 61% of patients who received carboplatin chemotherapy. Eighty-two percent of the patients had an objective response to treatment, including 62% with complete response and 20% with partial response. For most patients, cognitive functioning was maintained or improved at follow-up; this pattern was statistically significant. Three of the test scores for the seven patients who did not receive radiation therapy showed a cognitive decline of at least one standard deviation. Among the nine patients who received radiation therapy before or after BBBD chemotherapy, 11 test scores showed a decline in cognitive function at one standard deviation or more. DISCUSSION: Durable responses were seen in patients with germ cell tumor and primary CNS lymphoma when treated with BBBD. Primitive neuroectodermal tumor requires post-chemotherapy radiotherapy for a durable response to be attained. Ototoxicity was a major form of toxicity in the patients who received carboplatin, but with the recent introduction of sodium thiosulfate, this problem has been markedly alleviated. Favorable cognitive outcomes appeared more likely for patients treated solely with BBBD chemotherapy and not with radiotherapy. Trends in the results for this sample are similar to those of previous research showing that radiotherapy is associated with cognitive decline. Current alternatives to enhanced drug delivery after BBBD include bone marrow transplantation; however, the increment in drug delivery is less, the number of courses is limited, and the morbidity and mortality are greater for bone marrow transplant than for BBBD. The current results suggest that in future trials, irradiation may not be needed in lymphoma and may not be necessary in some CNS germ cell tumors and that more focal radiotherapy should be further assessed in localized primitive neuroectodermal tumors.

Paced Auditory Serial Addition Test: adult norms and moderator variables.

This study examined the performance of a sample of 821 healthy job applicants on the Paced Auditory Serial Addition Test (PASAT). Subjects had previously passed basic academic skills tests and physical examinations and were deemed free of cognitive impairment and medical illness. They were also motivated to perform well on cognitive tests. Gender, ethnicity, and education were not significant moderator variables in our subjects. Age and IQ did significantly affect PASAT test results. Normative data are stratified by age and WAIS-R Full Scale IQ scores to be useful to those who administer the PASAT in clinical practice.

Non-AIDS primary CNS lymphoma: first example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy.

PURPOSE: Radiographic tumor response and survival were evaluated in patients receiving methotrexate-based chemotherapy with osmotic blood-brain barrier disruption with or without antecedent cranial radiation. PATIENTS AND METHODS: Fifty-eight non-AIDS patients (38 males, 20 females) with histologically confirmed primary central nervous system lymphoma, primarily large cell or immunoblastic, were treated at the Oregon Health Sciences University from January 1982 through March 1992. Group 1 patients (n=19) received cranial radiation prior to referral; Group 2 (n=39) received initial blood-brain barrier disruption chemotherapy. Ages ranged from 5 to 71 years (median, 57); Karnofsky performance status was 40% to 100% on inclusion (median, 80) and all underwent extensive baseline neuropsychological evaluation. RESULTS: There was no significant difference in patient characteristics between the two groups. In 15 evaluable Group I patients, 14 demonstrated objective response and 7 of 14 (50%) achieved complete response. In Group 2, 34 of 35 evaluable patients demonstrated objective response, including 29 of 34 with complete response. Estimated median survival times for Group 1 and Group 2 patients were 16 and 41 months, respectively. Currently, 19 Group 2 patients and 2 Group 1 patients are alive. Extensive neuropsychological follow-up (up to 7 years from baseline) was completed in 23 patients, which demonstrated preservation or improved cognitive function in those receiving initial chemotherapy and blood-brain barrier disruption, most notably in patients older than 60 years. CONCLUSIONS: A plateau in survival curves suggests that a portion of primary central nervous system lymphoma patients may be cured with chemotherapy and blood-brain barrier disruption without the neurologic sequelae associated with cranial radiation.

MR and cognitive testing of patients undergoing osmotic blood-brain barrier disruption with intraarterial chemotherapy.

PURPOSE: To determine whether osmotic blood-brain barrier disruption is associated with MR abnormalities or cognitive deterioration and, if so, whether the MR findings correlate with cognitive test results. METHODS: Fifteen brain tumor patients who had a complete tumor response (nine central nervous system lymphoma, three germ cell and two astrocytoma, and one primitive neuroectodermal tumor) treated with blood-brain barrier disruption procedures (318 total procedures) with intraarterial chemotherapy were included. MR images were evaluated for the development of white matter hyperintensity, vascular lesions, or atrophy. Cognitive testing was performed to assess deterioration caused by this therapy. RESULTS: In two patients white matter hyperintensity developed, in two small vascular lesions developed, and in one mild atrophy developed. One infarct was asymptomatic and the second one resulted in mild dysesthesia in one upper extremity. No patient showed diminished cognitive function on the posttherapy evaluation. CONCLUSION: In patients undergoing blood-brain barrier disruption with intraarterial chemotherapy, new abnormalities on MR imaging may develop. These patients maintain the same level of cognitive and neurologic function and MR findings do not correlate with the results of cognitive testing.

Comparison of the Auditory-Verbal Learning Test (AVLT) and California Verbal Learning Test (CVLT) in a sample of normal subjects.

Compared performance on Rey Auditory-Verbal Learning Test and California Verbal Learning Test. Slightly higher scores were obtained on CVLT variables. No significant differences were found for order of test administration. Results were interpreted to show minimal practice effects for different list-learning tests administered in the same test battery.

Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy.

PURPOSE: To examine behavioral dimensions of treatment outcomes for patients receiving cranial irradiation. Radiation encephalopathy is one of these and refers to significant cognitive and emotional dysfunction following radiation therapy to the brain. Issues of definition, estimated incidence, pathophysiologic mechanisms, and recommended research designs are reviewed in relationship to functional neurobehavioral outcomes. PATIENTS AND METHODS: Twenty-nine studies of adults receiving therapeutic cranial irradiation (TCI) involving 748 patients and 18 studies of prophylactic cranial irradiation (PCI) involving 368 patients are reviewed. Assessment of patient outcomes are summarized for research published since 1980, with specific attention to adverse changes in cognitive and emotional functioning. RESULTS: Analyses revealed that 213 TCI patients and 100 PCI patients showed encephalopathy attributed to radiation. Manifestations of the late delayed effects of radiotherapy on brain function are related to patient age, total dose of irradiation, fraction sizes, and timing of chemotherapy. Radiation encephalopathy appears to be more common than the pathologic tissue injury of radiation necrosis. Accurate diagnosis of these neurobehavioral sequelae can require follow-up over a period of years with sensitive assessment procedures. CONCLUSIONS: It is likely that the true incidence of treatment-related side effects of cranial irradiation in adults who survive more than 6 months without brain tumor growth or recurrence has been significantly underestimated. Research designs that include formal neuropsychologic assessment in conjunction with other neurodiagnostic tests can provide more comprehensive evaluation of long-term neurobehavioral outcomes.

Psychological assessment of quality of life following liver transplantation.

Administered measures of functional status, psychological distress, and quality of life to a consecutive series of 48 liver transplant recipients in follow-up clinic. Results showed that nearly total functional recovery was the norm. Thirty-six patients (75%) had a Karnofsky Performance Status (KPS) score of 80-100. Twelve transplant recipients had KPS scores below 80; none were employed, and most had been transplanted within 1 year. In spite of their impaired financial status, eight of these 12 reported being mostly satisfied on the self-report Quality-of-Life Scale (QLS). For the posttransplant sample as a whole, 83% were mostly satisfied with their quality of life. Pre- and posttransplant patient samples were not significantly different in reporting mild emotional distress. Results for the small subgroup with significant objective or subjective problems in achieving acceptable quality of life following liver transplantation were reviewed. Higher than normal emotional distress on the Symptom Checklist (SCL-90-R) was consistently reported by these patients. Prospective studies are needed to identify predictor variables of quality-of-life problems and to develop prevention and rehabilitation interventions.

Preirradiation osmotic blood-brain barrier disruption plus combination chemotherapy in gliomas: quantitation of tumor response to assess chemosensitivity.

Twelve adults (11 male, 1 female), diagnosed as having supratentorial gliomas, were treated with osmotic blood-brain barrier disruption and chemotherapy (intra-arterial methotrexate, 2500 mg/infusion; intravenous Cytoxan, 15 mg/kg/infusion; and oral procarbazine, 100 mg daily x 14 days) prior to radiotherapy. To assess higher cortical function, all patients underwent neuropsychological testing. Volumetric analysis of pretreatment and serial enhanced computerized tomographic scans were recorded. Four of ten patients with enhancing tumor showed radiographic tumor response, defined as 50% reduction of enhancing tumor volume. These four patients received no steroids at the time of maximum tumor response. Osmotic blood-brain barrier disruption and chemotherapy administered prior to radiotherapy can result in significant objective tumor responses with maintenance of cognitive function. It also offers a new and unique means to assess chemosensitivity, which may lead to improved treatment protocols.

Neuropsychological assessment outcomes of nonacquired immunodeficiency syndrome patients with primary central nervous system lymphoma before and after blood-brain barrier disruption chemotherapy.

The risk of neurotoxicity was evaluated in eight consecutive patients with non-acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma who had survived disease free for more than 1 year after completion of treatment with osmotic opening of the blood-brain barrier and chemotherapy (methotrexate, cytoxan, procarbazine, and decadron). Trends in neuropsychological assessment results between baseline and follow-up (1 to 7 years) were analyzed for all eight nonradiated survivors. This serial assessment design addressed the specific issue of neurotoxic risk potential of treatment, when confounding factors of tumor persistence/recurrence and cranial irradiation were ruled out. Follow-up results of an extensive battery of tests to assess higher cortical function provided evidence of the safety of chemotherapy protocol with the blood-brain barrier disruption. These findings stand in contrast to well-known cognitive risks associated with cranial radiotherapy. Long-term follow-up suggests that chemotherapy can be given in conjunction with osmotic opening of the blood-brain barrier in nonradiated patients without cognitive manifestations of neurotoxicity.

Hostility as a health risk factor: relationships with neuroticism, Type A behavior, attentional focus, and interpersonal style.

In order to investigate further the psychological construct of hostility measured on the Cook-Medley (Ho) Scale as a health risk factor, the present study examined relationships between hostility assessed on the Ho Scale and several measures of neuroticism, Type A behavior, and attentional and interpersonal style, using bivariate and hierarchical multiple regression analyses. Subjects were 204 psychologically normal, physically healthy males. Significant relationships were found between hostility, neuroticism, attentional overload, and interpersonal alienation. The present study provided normative data on several important health-related psychological dimensions in a sample of healthy normals. The findings also provided further support for the relationship between the hostility construct measured on the Ho Scale and measures of neuroticism as possible dimensions of disease-prone personality.

The effects of covert sensitization on preference for sexual stimuli: a preliminary analogue experiment.

Although covert sensitization is a widely and diversely employed clinical technique, there is no generally accepted conceptual guideline for its implementation. Consequently, there is considerable variability in the way covert sensitization procedures are employed, which may account for the reported inconsistency in its clinical effectiveness. The present study is an analogue experimental test of a conceptual account of covert sensitization that is based upon classical conditioning. The classical conditioning procedure is viewed as affecting operant target behaviors by altering the reinforcer effectiveness of target stimuli. This was explicitly tested by examining the effects of covert sensitization on subjects' preference for sexual stimuli in an operant choice paradigm. The results support the conceptual account.

Comparison of reactive and non-reactive measures of smoking cessation at follow-up.

Subjects who had completed a smoking cessation program were contacted at 3- and 4-month follow-up to assess self-reported frequency of daily cigarette smoking. Subjects were randomly assigned to a reactive or non-reactive condition of telephone contact in obtaining the self-report. In the reactive condition, the telephone caller seeking self-report identified herself as an assistant in the original smoking cessation treatment program. In the non-reactive condition the telephone caller identified herself as an employee of a firm conducting a market research survey of the use of various consumer products. There were no statistically significant differences between the conditions in either self-report of abstinence or absolute frequency of daily cigarette consumption.