Hot Topics in Research: Preventive Neuroradiology in Brain Aging and Cognitive Decline.

Preventive neuroradiology is a new concept supported by growing literature. The main rationale of preventive neuroradiology is the application of multimodal brain imaging toward early and subclinical detection of brain disease and subsequent preventive actions through identification of modifiable risk factors. An insightful example of this is in the area of age-related cognitive decline, mild cognitive impairment, and dementia with potentially modifiable risk factors such as obesity, diet, sleep, hypertension, diabetes, depression, supplementation, smoking, and physical activity. In studying this link between lifestyle and cognitive decline, brain imaging markers may be instrumental as quantitative measures or even indicators of early disease. The purpose of this article is to provide an overview of the major studies reflecting how lifestyle factors affect the brain and cognition aging. In this hot topics review, we will specifically focus on obesity and physical activity.

Visual-statistical interpretation of (18)F-FDG-PET images for characteristic Alzheimer patterns in a multicenter study: inter-rater concordance and relationship to automated quantitative evaluation.

BACKGROUND AND PURPOSE: The role of (18)F-FDG-PET in the diagnosis of Alzheimer disease is increasing and should be validated. The aim of this study was to assess the inter-rater variability in the interpretation of (18)F-FDG-PET images obtained in the Japanese Alzheimer's Disease Neuroimaging Initiative, a multicenter clinical research project. MATERIALS AND METHODS: This study analyzed 274 (18)F-FDG-PET scans (67 mild Alzheimer disease, 100 mild cognitive impairment, and 107 normal cognitive) as baseline scans for the Japanese Alzheimer's Disease Neuroimaging Initiative, which were acquired with various types of PET or PET/CT scanners in 23 facilities. Three independent raters interpreted all PET images by using a combined visual-statistical method. The images were classified into 7 (FDG-7) patterns by the criteria of Silverman et al and further into 2 (FDG-2) patterns. RESULTS: Agreement among the 7 visual-statistical categories by at least 2 of the 3 readers occurred in >94% of cases for all groups: Alzheimer disease, mild cognitive impairment, and normal cognitive. Perfect matches by all 3 raters were observed for 62% of the cases by FDG-7 and 76 by FDG-2. Inter-rater concordance was moderate by FDG-7 (κ = 0.57) and substantial in FDG-2 (κ = 0.67) on average. The FDG-PET score, an automated quantitative index developed by Herholz et al, increased as the number of raters who voted for the AD pattern increased (ρ = 0.59, P < .0001), and the FDG-PET score decreased as those for normal pattern increased (ρ = -0.64, P < .0001). CONCLUSIONS: Inter-rater agreement was moderate to substantial for the combined visual-statistical interpretation of (18)F-FDG-PET and was also significantly associated with automated quantitative assessment.

Integrating imaging findings in evaluating the post-chemotherapy brain.

Cognitive complaints following cancer and cancer therapy are common. Many studies have investigated the effects of chemotherapy on the brain. However, the mechanisms for the associated cognitive impairment are not well understood. Some studies have also included brain imaging to investigate potential neurological substrates of cognitive changes. This review examines recent neuroimaging studies on cancer- and chemotherapy-related cognitive dysfunction in non-central nervous system cancers and compares findings across imaging modalities. Grey matter volume reductions and decreases in white matter integrity are seen after exposure to adjuvant chemotherapy for breast cancer, and functional studies have illuminated both hypo- and hyperactivations in many of the same regions months to years following therapy. These comparisons can assist in further characterizing the dysfunction reported by patients and contribute to a better understanding of the mechanisms involved.

The association between pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints following adjuvant chemotherapy for breast cancer.

To examine relationships following adjuvant chemotherapy between circulating pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints in early stage breast cancer patients. 33 breast cancer patients who had completed initial treatment (surgery, ± radiation, 23 chemotherapy, 10 no chemotherapy) obtained resting (18)F-FDG PET/CT brain imaging at baseline and 1 year later. Pro-inflammatory cytokine markers (IL-1ra, sTNF-RII, CRP, and IL-6) and cognitive complaints were also assessed at both time points. At baseline, consistent correlations were seen between the left medial frontal and right inferior lateral anterior temporal cortices and inflammatory markers within the chemotherapy group, and not in the no chemotherapy group. After 1 year, correlations persisted in the medial frontal cortex and the temporal cortex, the latter shifting superiorly. Both of these regional correlations demonstrated the highest levels of significance when looking across the 1 year time frame (IL-1ra: peak voxel p < 0.0005; cluster size p < 0.0005, p = 0.001 after correction (medial prefrontal), p < 0.0005; cluster size p = 0.001, p = 0.029 corr. (anterior temporal), sTNF-RII: p < 0.0005; cluster size p = 0.001, p = 0.040 corr. (medial prefrontal)). Positive correlations were also seen within the chemotherapy group between baseline memory complaints and the medial frontal (p < 0.0005; cluster size p < 0.0005, p < 0.0005 corr.) and anterior temporal (p < 0.0005; cluster size p < 0.0005, p = 0.002 corr.) cortices at baseline and 1 year later. Metabolism in the medial prefrontal cortex and anterior temporal cortex was found to correlate with both memory complaints and cytokine marker levels in chemotherapy patients.

Does tumor necrosis factor-alpha (TNF-α) play a role in post-chemotherapy cerebral dysfunction?

Post-chemotherapy treated cancer patients frequently report cognitive difficulties. The biology of this phenomenon is poorly understood, with uncertainty about possible direct toxic effects on the brain, secondary effects from systemic inflammation, host factors/genetic predisposition to cognitive complaints, or hormonal changes influencing cognitive function. To elucidate possible mechanisms associated with post-treatment cognitive dysfunction among breast cancer survivors, in 2007 we established a prospective, longitudinal, observational cohort study of early stage breast cancer patients, recruited at the end of initial treatments (primary treatment exposure included surgery, ± radiation, ± chemotherapy), and prior to the initiation of adjuvant endocrine therapy. We assessed cognitive complaints, neuropsychological (NP) test performance, markers of inflammation, and brain imaging at baseline, 6 months and 12 months after enrollment. In this analysis of data from the first 93 patients enrolled in the cohort study, we focus on the relationship of circulating levels of proinflammatory cytokines to cerebral functioning and chemotherapy exposure. Among the proinflammatory cytokines tested (IL-1 ra, sTNF-RII, CRP, and IL-6) at baseline, only sTNF-RII was increased among chemotherapy exposed patients, with a significant decline in the year after treatment (p=0.003). Higher baseline sTNF-RII in chemotherapy patients was significantly associated with increased memory complaints. In chemotherapy exposed patients, the longitudinal decline in sTNF-RII was significantly correlated with fewer memory complaints over 12 months (r=-0.34, p=0.04). Higher baseline sTNF-RII was also associated with relatively diminished brain metabolism in the inferior frontal cortex (r=-0.55, p=0.02), as well as relatively increased inferior frontal metabolism after 1 year, in chemotherapy-exposed subjects. These preliminary findings suggest that post-chemotherapy increases in TNF-α may be playing an important role in the manifestations of cognitive complaints in breast cancer survivors.

Assessment of dementia risk in aging adults using both FDG-PET and FDDNP-PET imaging.

BACKGROUND: In a previous study, positron emission tomography (PET) with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro, identified three subgroups of non-demented subjects according to FDDNP binding patterns: low global (LG) binding; high frontal, parietal, medial temporal binding (HF/PA); and high medial and lateral temporal and posterior cingulate (HT/PC) binding. In this follow-up investigation, we compared 2-deoxy-2-[F-18]fluoro- d-glucose (FDG)-PET cerebral metabolic patterns in the three FDDNP-PET binding subgroups. METHODS: Fifty-four subjects with normal aging (N = 28) or amnestic forms of mild cognitive impairment (N = 26) underwent FDDNP-PET and FDG-PET scanning. Subjects in the LG, HF/PA, and HT/PC FDDNP subgroups were compared according to visual ratings, statistical parametric mapping, and automated region of interest analyses of their FDG-PET data. RESULTS: The FDDNP-PET subgroups demonstrated different glucose metabolic patterns according to visual ratings, region of interest, and statistical parametric mapping analyses of FDG-PET data. The LG FDDNP subgroup showed no areas of significant hypometabolism relative to the other subgroups and had low Alzheimer's disease risk by FDG-PET standards. The HF/PA FDDNP subgroup demonstrated hypometabolism in bilateral inferior parietal/parietotemporal, bilateral posterior cingulate, perisylvian, mid-temporal gyrus, and dorsolateral prefrontal regions, which is a pattern suggestive of high Alzheimer's disease risk. The HT/PC FDDNP subgroup demonstrated heterogeneous FDG-PET patterns with predominant anterior frontal and anterior temporal hypometabolism, suggestive of mixed etiologies, including fronto-temporal dementia risk. CONCLUSIONS: The FDG-PET data provided independent validation that different patterns of FDDNP-PET binding in non-demented individuals may be associated with differential dementia risk.

Brain glucose metabolism in hypothyroidism: a positron emission tomography study before and after thyroid hormone replacement therapy.

CONTEXT: Hypothyroidism is frequently associated with subtle behavioral and psychiatric symptoms. The consequences of inadequate thyroid hormone availability to brain metabolism are poorly understood. OBJECTIVE: This study assessed the relationships between neuropsychiatric symptoms and changes in relative regional cerebral glucose metabolism in hypothyroid patients undergoing thyroid hormone replacement therapy. DESIGN, SETTING, AND OUTCOME MEASURE: Relative regional cerebral glucose metabolism was compared in 13 previously untreated hypothyroid patients and 10 healthy control participants. Effects of thyroid hormone replacement therapy (levothyroxine, 3 months) were assessed using neuropsychiatric measures and positron emission tomography with [(18)F]fluorodeoxyglucose. RESULTS: Before treatment, hypothyroid patients exhibited lower regional activity than control subjects in the bilateral amygdala, hippocampus, and perigenual anterior cingulate cortex (ACC), left subgenual ACC, and right posterior cingulate cortex. Severity of depressive symptoms covaried negatively with pretreatment activity in the bilateral middle frontal gyrus and right subgenual and dorsal ACC. Thyroid hormone replacement therapy abolished pretreatment group differences in regional activity, robustly increased activity in the ventral ACC, and significantly reduced both clinician-rated and self-rated behavioral and psychiatric symptoms. Increased activity within the ventral ACC was associated with reduced somatic complaints, whereas increased activity within the dorsal ACC was associated with reduced depressive symptoms. CONCLUSIONS: Reduction of the behavioral complaints during thyroid hormone therapy is associated with a restoration of metabolic activity in brain areas that are integral to the regulation of affect and cognition. The findings suggest that thyroid hormone modulates regional glucose metabolism and psychiatric symptoms in the mature brain.

Computer simulations suggest that acute correction of hyperglycaemia with an insulin bolus protocol might be useful in brain FDG PET.

AIM: FDG PET in hyperglycaemic subjects often suffers from limited statistical image quality, which may hamper visual and quantitative evaluation. In our study the following insulin bolus protocol is proposed for acute correction of hyperglycaemia (>7.0 mmol/l) in brain FDG PET. (i) Intravenous bolus injection of short-acting insulin, one I.E. for each 0.6 mmol/l blood glucose above 7.0. (ii) If 20 min after insulin administration plasma glucose is

Thyroid, brain and mood modulation in affective disorder: insights from molecular research and functional brain imaging.

The efficacy resulting from adjunctive use of supraphysiological doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis for refractory mood disorders. Most patients with mood disorders who receive treatment with supraphysiological doses of levothyroxine have normal peripheral thyroid hormone levels, and also respond differently to the hormone and tolerate it better than healthy individuals and patients with primary thyroid diseases. Progress in molecular and functional brain imaging techniques has provided a new understanding of these phenomena, illuminating the relationship between thyroid function, mood modulation and behavior. Thyroid hormones are widely distributed in the brain and have a multitude of effects on the central nervous system. Notably many of the limbic system structures where thyroid hormone receptors are prevalent have been implicated in the pathogenesis of mood disorders. The influence of the thyroid system on neurotransmitters (particularly serotonin and norepinephrine), which putatively play a major role in the regulation of mood and behavior, may contribute to the mechanisms of mood modulation. Recent functional brain imaging studies using positron emission tomography (PET) with [ (18)F]-fluorodeoxyglucose demonstrated that thyroid hormone treatment with levothyroxine affects regional brain metabolism in patients with hypothyroidism and bipolar disorder. Theses studies confirm that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide intriging neuroanatomic clues that may guide future research.

The usefulness of F-18 deoxyglucose whole-body positron emission tomography (PET) for re-staging of renal cell cancer.

PURPOSE: The use of whole-body PET for re-staging of renal cell carcinoma has not been investigated. The aim of the current study was to examine the diagnostic accuracy and clinical usefulness of whole-body PET imaging for re-staging of renal cell cancer. PATIENTS AND METHODS: Clinical PET was performed for re-staging in 36 patients with advanced renal cell cancer. Written reports of imaging studies (including CT, MRI, US, plain film and bone scan), patient history, and extensive chart notes were used to define the clinical stage before PET (pre-PET stage). The written PET report was used to define the clinical stage after PET (PET stage). Reports were used to determine the accuracy of PET for re-staging renal cell cancer and for defining biopsy proven lesions. Clinical parameters and biopsy proven lesions served as reference for the accuracy of PET for re-staging renal cell cancer. RESULTS: PET classified the clinical stage correctly in 32/36 patients (89%) and was incorrect in 4/36 (11%) (sensitivity and specificity: 87% and 100%). In 20 patients, 25 suspicious lesions were biopsied within 3.2 +/- 6.7 months of the PET study. Of these, 17 were malignant and 8 were benign. PET correctly classified 21/25 (84%) of the biopsied lesions (sensitivity and specificity: 88% and 75%). CONCLUSION: PET re-stages renal cell cancer with a diagnostic accuracy of 89%. Its diagnostic accuracy for classifying biopsy proven anatomic lesions as malignant or benign was 84%. These findings suggest that PET is useful in characterizing anatomic lesions of unknown significance in patients with renal cell cancer.

Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome.

CONTEXT: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined. OBJECTIVE: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia. DESIGN, SETTING, AND PATIENTS: Positron emission tomography (PET) studies of [(18)F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000. MAIN OUTCOME MEASURES: Regional distribution of [(18)F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses. RESULTS: Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001). CONCLUSION: In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.

Impact of 18F-FDG PET on managing patients with colorectal cancer: the referring physician's perspective.

UNLABELLED: Whole-body PET imaging with 18F-FDG has been used successfully to stage colorectal cancer. However, the impact of FDG PET on patient management from the referring physician's point of view has not been determined. METHODS: A questionnaire was sent to referring physicians to determine whether and how PET altered the management of colorectal cancer patients. Management changes, when present, were classified as intermodality (e.g., medical to surgical, surgical to radiation, medical to no treatment) or intramodality (e.g., altered medical, surgical, or radiotherapy approach). RESULTS: Of 60 responses from referring physicians, changes in clinical stage were reported for 25 patients (42%). Among these, the disease was upstaged in 20 patients (80%) and downstaged in 5 patients (20%). The PET findings contributed to intermodality management changes in 22 of the 60 patients (37%), intramodality changes in 11 patients (18%), a combination of management changes in 4 patients (7%), and no change in 19 patients (32%). Two of the 60 patients (3%) had other changes, and no response to this question was received for the remaining 2 patients (3%). As a result of PET findings, physicians avoided major surgery in 41% of patients for whom surgery was the intended treatment. CONCLUSION: This survey-based study of referring physicians shows that FDG PET had a major impact on the management of colorectal cancer patients and contributed to changes in clinical stage and major management decisions in >40% of patients.

Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma.

Dosimetry studies in patients with non-Hodgkin's lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received (111)In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of (111)In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2-7.8 Gy), 2.6 Gy to lungs (range 0.72-4.4 Gy), and 0.38 Gy to kidneys (range 0.07-0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8-67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T(1/2), blood AUC, plasma T(1/2), and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T(1/2), reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Regulation of myocardial blood flow response to mental stress in healthy individuals.

Mental stress testing has been proposed as a noninvasive tool to evaluate endothelium-dependent coronary vasomotion. In patients with coronary artery disease, mental stress can induce myocardial ischemia. However, even the determinants of the physiological myocardial blood flow (MBF) response to mental stress are poorly understood. Twenty-four individuals (12 males/12 females, mean age 49 +/- 13 yr, range 31-74 yr) with a low likelihood for coronary artery disease were studied. Serum catecholamines, cardiac work, and MBF (measured quantitatively with N-13 ammonia and positron emission tomography) were assessed. During mental stress (arithmetic calculation) MBF increased significantly from 0.70 +/- 0.14 to 0.92 +/- 0.21 ml x min(-1) x g(-1) (P < 0.01). Mental stress caused significant increases (P < 0.01) in serum epinephrine (26 +/- 16 vs. 42 +/- 17 pg/ml), norepinephrine (272 +/- 139 vs. 322 +/- 136 pg/ml), and cardiac work [rate-pressure product (RPP) 8,011 +/- 1,884 vs. 10,416 +/- 2,711]. Stress-induced changes in cardiac work were correlated with changes in MBF (r = 0.72; P < 0.01). Multiple-regression analysis revealed stress-induced changes in the RPP as the only significant (P = 0.0001) predictor for the magnitude of mental stress-induced increases in MBF in healthy individuals. Data from this group of healthy individuals should prove useful to investigate coronary vasomotion in individuals at risk for or with documented coronary artery disease.

Effect of mental stress on myocardial blood flow and vasomotion in patients with coronary artery disease.

UNLABELLED: In patients with coronary artery disease (CAD), mental stress may provoke ischemic electrocardiograph changes and abnormalities in regional and global left ventricular function. However, little is known about the underlying myocardial blood flow response (MBF) in these patients. METHODS: We investigated the hemodynamic, neurohumoral, and myocardial blood flow responses to mental stress in 17 patients with CAD and 17 healthy volunteers of similar age. Mental stress was induced by asking individuals to solve mathematic subtractions in a progressively challenging sequence; MBF was quantified at rest and during mental stress using 13N ammonia PET. RESULTS: Mental stress induced significant (P < 0.01) and comparable increases in rate-pressure product, measured in beats per minute x mm Hg, in both patients (from 7826 +/- 2006 to 10586 +/- 2800) and healthy volunteers (from 8227 +/- 1272 to 10618 +/- 2468). Comparable increases also occurred in serum epinephrine (58% in patients versus 52% in healthy volunteers) and norepinephrine (22% in patients versus 27% in healthy volunteers). Although MBF increased in patients (from 0.67 +/- 0.15 to 0.77 +/- 0.18 mL/min/g, P < 0.05) and healthy volunteers (from 0.73 +/- 0.13 to 0.95 +/- 0.22 mL/min/g, P < 0.001), the magnitude of flow increase was smaller in patients (14% +/- 17%) than in healthy volunteers (29% +/- 14%) (P = 0.01). The increase in MBF during mental stress correlated significantly with changes in cardiac work in healthy volunteers (r = 0.77; P < 0.001) but not in patients. CONCLUSION: Despite similar increases in cardiac work and comparable sympathetic stimulation in CAD patients and healthy volunteers, CAD patients exhibit an attenuated blood flow response to mental stress that may contribute to mental stress-induced ischemic episodes in daily life.

Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma.

PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass > or = 5 cm. RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/microL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody). CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.