Tumor-absorbed-dose estimates versus response in tositumomab therapy of previously untreated patients with follicular non-Hodgkin's lymphoma: preliminary report.

I-131-radiolabeled tositumomab (Anti-B1 Antibody), in conjunction with unlabeled tositumomab, was employed in a phase II clinical trial for the therapy of 76 previously-untreated follicular-non-Hodgkin's-lymphoma patients at the University of Michigan Cancer Center. For all patients, conjugate-view images were obtained at six to eight time points on seven consecutive days after a tracer infusion of the antibody. A SPECT image set was obtained on day two or three after the therapy infusion for 57 of the patients. Of these, 55 are suitable for dosimetric evaluation. To date, we have completed analysis and response characterization of 20 patients from the subset of 55. All 20 patients had either a complete response (CR) or a partial response (PR). Conjugate-views provided a time-activity curve for a composite of nearby, individual tumors. These tumors were unresolved in the anterior-posterior projection. Pre-therapy CT provided volume estimates. Therapy radiation dose was computed for the composite tumor by standard MIRD methods. Intra-therapy SPECT allowed the calculation of a separate dose estimate for each individual tumor associated with the composite tumor. Average dose estimates for each patient were also calculated. The 30 individual tumors in PR patients had a mean radiation dose of (369 +/- 54) cGy, while the 56 individual tumors in CR patients had a mean radiation dose of (720 +/- 80) cGy. According to a mixed ANOVA analysis, there was a trend toward a significant difference between the radiation dose absorbed by individual tumors for PR patients and that for CR patients. When the radiation dose depended on only the patient response, the p value was 0.04. When the radiation dose depended on the pre-therapy volume of the individual tumor as well as on the patient response, the p value was 0.06. Since the patient response was complete in 75% of the patients, the analysis of the total cohort of 55 evaluable patients is needed to have a larger number of PR patients to better test the trend toward a significant difference. A pseudo-prediction analysis for patient-level dose and response was also carried out. The positive predictive value and the negative predictive value were 73% and 80%, respectively when a patient's average radiation dose was used. The predictive values were 73% and 60%, respectively, when the patient's average base-10 logarithm of radiation dose was used. A complete overlap for the dose range of CR patients compared to that for PR patients precluded higher predictive values. In conclusion, there was a trend toward a significant difference in the radiation dose between CR and PR patients, but it was only moderately predictive of response.

Initial results for Hybrid SPECT--conjugate-view tumor dosimetry in 131I-anti-B1 antibody therapy of previously untreated patients with lymphoma.

UNLABELLED: A study of the use of 131I-labeled anti-B1 monoclonal antibody, proceeded by an unlabeled predose, for therapy of previously untreated non-Hodgkin's lymphoma patients has recently been completed at the University of Michigan, Ann Arbor. More than half of the patients treated were imaged intratherapy with SPECT to separate apparently large tumors, unresolved by conjugate views, into individual ones specified by CT scan. The dosimetry of these tumors is reported here. METHODS: The activity-quantification procedure used 3-dimensional CT-to-SPECT fusion so that attenuation maps could be computed from CT and that volumes of interest could be drawn on the CT slices and transferred to the SPECT images. Daily conjugate-view images after a tracer dose of labeled anti-B1 antibody followed by an unlabeled predose provided the shape of the time-activity curve for the calculation of therapy dosimetry. Reconstructed SPECT counts that were within a volume of interest were converted to activity by using a background-and-radius-adaptive conversion factor. Activities were increased for tumors less than 200 g using a recovery-coefficient factor derived from activity measurements for a set of spheres with volumes ranging from 1.6 to 200 cm3. The calculated tumor radiation absorbed dose was based, in part, on the CT volume and on the intratherapy-SPECT activity. RESULTS: The mean of the radiation dose values for 131 abdominal or pelvic tumors in 31 patients was 616 cGy with a standard deviation of +/- 50 cGy. The largest dose was 40 Gy and the smallest dose was 73 cGy. The mean volume for the tumors was 59.2 +/- 11.2 cm3. The correlation coefficient between absorbed dose and tumor volume was small (r2 = 0.007), and the slope of the least-squares fit represented a decrease of only 36.4 cGy per 100 cm3 increase in volume. This small slope may reflect a characteristic of anti-B1 antibody therapy that is important for its success. The mean absorbed dose per unit administered activity was 1.83 +/- 0.145 Gy/GBq. The largest value was 12.6 Gy/GBq, and the smallest value was 0.149 Gy/GBq. The mean dose for 9 axillary tumors in 5 patients was significantly lower than the average dose for abdominal and pelvic tumors (P = 0.01). Therefore, axillary tumors should be grouped separately in assessing dose-response relationships. Anecdotal patient results tended to verify the validity of using the shape of the conjugate-view time-activity curve for the average SPECT-intratherapy curve. However, there was also an indication that the shape varies somewhat for individual tumors with respect to time to peak. CONCLUSION: Hybrid SPECT-conjugate-view dosimetry provided radiation absorbed dose estimates for the individual patient tumors that were resolved by CT.

Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience.

CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine (131)I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P =.005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine (131)I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL. (Blood. 2000;96:1259-1266)

Metabolic response of non-Hodgkin's lymphoma to 131I-anti-B1 radioimmunotherapy: evaluation with FDG PET.

UNLABELLED: 131I-anti-B1 (CD20) radioimmunotherapy (RIT) is a promising approach for treatment of non-Hodgkin's lymphoma (NHL). We assessed the tumor metabolic response to RIT using FDG PET. METHODS: We examined 14 patients with NHL, who were given first a tracer dose of 131I-anti-B1 and then RIT, each preceded by infusion of unlabeled anti-B1. In 8 of 14 patients, PET was performed at baseline and 33-70 d after RIT. The other 6 patients underwent PET at baseline, 6-7 d after the tracer dose, and 5-7 d after RIT to estimate the early response to tracer dose and RIT. To assess tumor FDG uptake, standardized uptake value normalized for lean body mass (SUV-lean) was measured 1 h after FDG injection. RESULTS: After RIT, complete response was observed in 6 patients, partial response in 6, and no response in 2. At 33-70 d after RIT, mean SUV-lean of 6 responders markedly declined to 41% of the baseline value (P < 0.002). Soon after tracer dose and after RIT, mean SUV-lean of the other 6 responders decreased to 79% and 62% of the baseline values, respectively (P < 0.05). In 2 nonresponders, SUV-lean did not significantly decline from the baseline value at 37 d after RIT. CONCLUSION: FDG PET metabolic data obtained 1-2 mo after RIT correlate well with the ultimate best response of NHL to RIT, more significantly than the early data after tracer dose or RIT. FDG uptake in NHL may decline gradually after RIT in responding patients.

I-131 anti-B1 therapy/tracer uptake ratio using a new procedure for fusion of tracer images to computed tomography images.

In patients with non-Hodgkin's lymphoma being treated by I-131-radiolabeled anti-B1 monoclonal antibody, we test the hypothesis that the activity taken up in tumors during therapy is the same as that observed during tracer evaluation, except for scaling by the ratio of administered activities. Chemotherapy-relapsed patients are imaged only with planar conjugate views, whereas previously untreated patients are imaged with planar conjugate views and with single-photon emission computed tomography (SPECT). The SPECT tracer activity quantification requires computed tomography (CT) to SPECT image fusion, for which we devised a new procedure: first, the tracer SPECT images are fused to the therapy SPECT images. Then, that transformation is combined with the therapy SPECT-to-CT transformation. We also use (a) the same volumes of interest defined on CT for both tracer and therapy image sets, and (b) a SPECT counts-to-activity conversion factor that adapts to background and rotation radius. We define R as the ratio of therapy activity percentage of infused dose over tracer activity percentage of infused dose at 2-3 days after monoclonal antibody infusion. For 31 chemotherapy-relapsed patients, the R ratio for 60 solitary or composite tumors averages 0.931 +/- 0.031. The hypothesis of R being 1 is rejected with greater than 95% confidence. However, the difference from 1 is only 7.4%. The range of R is 0.43-1.55. For seven previously untreated patients, R averages 1.050 +/- 0.050 for 24 solitary tumors evaluated by SPECT. For six of these patients, R averages 0.946 +/- 0.098 for one of these solitary tumors and for five composite tumors, evaluated by conjugate views. Both results agree with the hypothesis that R is 1. The range of R for the SPECT tumors is 0.71 +/- 0.03 to 1.82 +/- 0.53, and for the conjugate view tumors, it is 0.70-1.35. Plots of R versus tumor volume yield small correlation coefficients. That from SPECT approaches a statistically significant difference from zero correlation (P = 0.06). In summary, on average, the tumor percentage of infused dose following tracer administration is predictive of therapeutic percentage of infused dose within 8%. For greater accuracy with individual tumors, however, an intratherapy evaluation is probably necessary because the range of R is large.

Reevaluation of the standardized uptake value for FDG: variations with body weight and methods for correction.

PURPOSE: To reevaluate the relationships between standardized uptake values (SUVs) and body weight by using positron emission tomography (PET) with 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG). MATERIALS AND METHODS: FDG PET scanning was performed in 138 female patients with known or suspected primary breast cancers. SUVs in blood and tumor (n = 79) were calculated by using body weight (SUVbw), ideal body weight (SUVibw), lean body mass (SUVlbm), and body surface area (SUVbsa) on images obtained 50-60 minutes after the injection of FDG. RESULTS: There was a strong positive correlation between the blood SUVbw and body weight (r = 0.705, P < .001). The blood SUVibw reduced the weight dependence but showed a negative correlation with body weight (r = -0.296, P < .001). Both the blood SUVibm and SUVbsa eliminated the weight dependence and showed no correlation with body weight (r = -0.010, P = .904 and r = 0.106, P = .215, respectively). Although there was a wide variance in the tumor SUVbw, it showed a weak but significant positive correlation with body weight (r = 0.207, P = .033). Plots of the tumor SUVlbm and SUVbsa versus body weight showed relatively flat slopes. CONCLUSION: SUVlbm and SUVbsa are weight-independent indices for FDG uptake, and SUVlbm appears to be more appropriate for quantifying FDG uptake to avoid overestimation of glucose utilization in obese patients.

Splenic fluorodeoxyglucose uptake increased by granulocyte colony-stimulating factor therapy: PET imaging results.

UNLABELLED: Using PET, we investigated the change in 18F-fluorordeoxyglucose (FDG) uptake in the spleen after granulocyte colony-stimulating factor (G-CSF) treatment. METHODS: Forty-two FDG PET scans in 12 patients with locally advanced breast cancer who received G-CSF treatment were studied (12 baseline, 10 during G-CSF, 20 after G-CSF treatment). The PET images obtained at 50-60 and 60-70 min after intravenous FDG (370 MBq) injection were assessed visually and were compared with those before G-CSF treatment. For a semiquantitative index of FDG uptake, we determined the standardized uptake value calculated on the basis of predicted lean body mass (SUL) on these images, and we calculated the SUL ratios normalized to their baseline SUL values. RESULTS: During G-CSF treatment (n = 10), 9 scans (90%) showed increased splenic FDG uptake (3 slightly, 6 substantially). After G-CSF treatment (n = 20), 13 (65%) showed no change, 7 (35%) showed slightly increased uptake, but no case showed substantially increased FDG uptake in the spleen (P = 0.0003). Out of 30 PET scans obtained during and after G-CSF treatment, 16 (53%) showed increased FDG uptake in the spleen (10 slightly, 6 substantially), whereas 26 (87%) showed increased bone marrow FDG uptake (14 slightly, 12 substantially). The FDG uptake in other normal organs (liver, blood and lung) showed no change during or after G-CSF treatment. Similar to the change in the bone marrow, the SULs in the spleen significantly increased during G-CSF treatment (baseline, 1.50+/-0.31, versus during G-CSF, 2.69+/-0.84; P = 0.0004), then decreased after discontinuation of G-CSF (1.65+/-0.23). There was a significant correlation between the SUL ratios in the spleen and those in the bone marrow (r = 0.778, P < 0.0001), whereas there were no correlations between those in other organs and those in the bone marrow. CONCLUSION: Substantially increased FDG uptake was observed in the spleen during and after G-CSF treatment, although this change was less frequent and not as marked as the change observed in the bone marrow. The recognition and understanding of this phenomenon will be increasingly important when interpreting FDG PET images in cancer patients to avoid confusing this normal phenomenon with pathological splenic (tumor) involvement.

Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer.

UNLABELLED: PET imaging of malignant tumors with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) as a tracer is a noninvasive diagnostic and prognostic tool that measures tumor metabolism. In this study, we assessed the relationships between FDG uptake and the expression of facilitative glucose transporters, the sizes of populations of proliferating cells and infiltrating macrophages in patients with primary non-small cell lung cancers (NSCLC). METHODS: FDG uptake and the expression of five glucose transporters and the proportions of proliferating cell and macrophage populations were studied in paraffin sections from untreated primary lung cancers by immunohistochemistry. The patients were imaged with FDG PET before surgery. RESULTS: All tumors could be detected by FDG PET. Uptake was correlated with tumor size (P = 0.004). FDG uptake was lower in adenocarcinomas (ACs) than in squamous cell carcinomas (SQCs) (P = 0.03) or large cell carcinomas (P = 0.002) [standardized uptake value corrected for lean body mass (SUL) = 5.42 +/- 2.77, 8.04 +/-3.25 and 10.42 +/- 4.54, respectively]. Glut-1 expression was significantly higher than that of any other transporter. All tumors tested (n = 23) were Glut-1-positive (70.8% +/- 26.1% of tumor cell area was positive and staining intensity was 2.8 +/- 1.2). Glut-1 expression was higher in SQCs (78% +/- 17.8% and 3.5 +/-0.6) than in ACs (47.5% +/- 30.3% and 1.6 +/- 1.1; P = 0.044 for positive tumor cell area and P = 0.005 for staining intensity). Proliferating cells constituted 15.3% +/- 13.1% of the cancer cells, and the average number of macrophages was 7.8% +/- 6.3%; neither correlated with FDG uptake. CONCLUSION: In this population of patients with NSCLC, Glut-1 is the major glucose transporter expressed. Both FDG uptake and Glut-1 expression appear to be associated with tumor size. No association was found between FDG uptake and either macrophage or proliferative cell populations.

Germ cell tumor: differentiation of viable tumor, mature teratoma, and necrotic tissue with FDG PET and kinetic modeling.

PURPOSE: To evaluate the feasibility of positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in patients with germ cell tumor (GCT) to monitor treatment and differentiate residual masses after chemotherapy. MATERIALS AND METHODS: Twenty-six FDG PET studies were performed in 21 patients with GCT, FDG uptake of tumors was interpreted visually, and the lean standardized uptake value (SUVlean) was determined. Tumor kinetic rate constants (K1, k2, k3) and net rate of FDG phosphorylation (K = [K1.k3]/[k2 + k3]) in tumors were calculated from the dynamic data by means of a three-compartment model, assuming k4 = 0. RESULTS: Viable tumors (n = 10) showed intense FDG uptake and could easily be differentiated visually from mature teratoma (n = 6) and necrosis or scar (n = 10). The SUVlean of residual viable tumors (4.51 +/- 1.34 [mean +/- SD]) was higher than that of mature teratoma (1.38 +/- 0.71) and necrosis or scar (1.05 +/- 0.29) (P < .05). Although neither the visual interpretation nor SUVlean differentiated mature teratoma from necrosis or scar, there were statistically significant differences in the kinetic rate constants K1 and K between mature teratoma and necrosis or scar as follows: K1, 0.113 mL/min/g +/- 0.026 versus 0.036 mL/min/g +/- 0.005 (P < .05); K, 0.005 mL/min/g +/- 0.003 versus 0.0008 mL/min/g +/- 0.0001 (P < .05). CONCLUSION: FDG PET with kinetic analysis appears to be a promising method for management of disease in patients with GCT after treatment.

Rapid detection of human infections with fluorine-18 fluorodeoxyglucose and positron emission tomography: preliminary results.

The purpose of this study was to evaluate the feasibility of 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) and positron emission tomography (PET) for rapid detection of human infections. Eleven patients who were known or suspected to be harboring various infections were studied with FDG-PET. Dynamic scans over the putative infection sites were performed immediately after FDG (370 MBq) injection through 60 min, and static images including multiple projection images were then obtained. FDG uptake was assessed visually into four grades (0, normal; 1, probably normal; 2, probably abnormal; 3, definitely abnormal). For the semiquantitative index of FDG uptake in infections, the standardized uptake value of FDG normalized to the predicted lean body mass (SUV-lean, SUL) was determined from the images obtained at 50-60 min after FDG injection. PET results were compared with final clinical diagnoses. Eleven lesions in eight patients, which were interpreted as grade 2 or 3 by FDG-PET, were all concordant with active infectious foci. The SUL values of infections ranged from 0.97 to 6.69. In two patients, FDG-PET correctly showed no active infection. In one patient, it was difficult to detect infectious foci by FDG-PET due to substantial normal background uptake of FDG. In total, FDG-PET correctly diagnosed the presence or absence of active infection in 10 of 11 patients. Fusion images of PET with computed tomography showed the most intense FDG uptake to be within an abscess wall. In conclusion, FDG-PET appears to be a promising modality for rapid imaging of active human infections. More extensive clinical evaluation is warranted to determine the accuracy of this method.

Patient-specific whole-body dosimetry: principles and a simplified method for clinical implementation.

UNLABELLED: The purpose of this article is to describe the methods used to determine the precise, patient-specific dose (in mCi) of 131I anti-B1 antibody needed to deliver a specified whole-body radiation dose (generally 75 cGy) to patients being treated for non-Hodgkin's lymphoma. METHODS: The general principles, as well as simplified methods for dosimetry calculation, are described, and a "worked" example is provided. The approach described involves administration of a tracer dose that is used to determine the patient-specific whole-body residence time. The total-body radiation dose per unit of cumulated activity is calculated using an ellipsoid model of the human body, with an assumption of uniform distribution of radioactivity. Together, they determine the appropriate patient-specific therapeutic dose of radiolabeled antibody needed to deliver a specified total-body dose of radiation. RESULTS: Because a monoexponential whole-body effective half-time adequately describes the total-body kinetics, the patient's whole-body residence time is estimated from three whole-body radioactivity observations obtained over 6-7 days. Whole-body counts can be collected using either a thyroid probe system or a whole-body gamma camera. The residence time, in conjunction with the patient's weight, determines the desired therapeutic activity. Dose attenuations are instituted for obesity and reduced blood platelet counts. CONCLUSION: Methods for determining total-body dose of radiation, including a simplified dosimetric method based on just three data points, are described. Tables and graphs to allow such calculations are presented for radioimmunotherapy with 131I anti-B1 antibody, although they are likely to be useful in other forms of radiopharmaceutical therapy as well.

Iodine-131 anti-B1 antibody for B-cell lymphoma: an update on the Michigan Phase I experience.

UNLABELLED: Iodine-131 anti-B1 antibody radioimmunotherapy for B-cell lymphoma was previously reported to have substantial antitumor activity in B-cell non-Hodgkin's lymphoma (NHL) after failures of standard and salvage chemotherapy. In this article, the University of Michigan Phase I clinical experience is updated, with follow-up of up to 6 yr since initial treatment reported. METHODS: Thirty-four patients with CD20-expressing NHL were first studied with one or more dosimetric doses of approximately 5 mCi of 1311 anti-B1 antibody (after varying predoses of unlabeled anti-B1 antibody). They were then treated with a patient-specific radioimmunotherapeutic dose designed to deliver a specified radiation dose to the whole body of between 25 and 85 cGy. Patients were observed for toxicity and tumor response. RESULTS: Seventeen (50%) patients had low-grade NHL, 9 (26%) had low-grade transformed NHL and 8 (24%) had de novo intermediate-grade NHL. At study entry, 17 (50%) had an elevated lactate dehydrogenase level, 12 (35%) had high tumor burden and 18 (53%) had not responded to their last chemotherapy. The median number of prior NHL therapies was 4.1. Twenty-eight of 34 patients completed treatment, with 22 of 28 (79%) achieving a response and 14 of 28 (50%) achieving a complete response (CR). The median duration of response was 357 days. The median duration of response for CRs was 471 days, with 4 CRs having a duration of > 1000 days (maximum = > 1460 days). Bone marrow toxicity was dose-limiting and dependent on the total-body dose (TBD) of radiation. Thrombocytopenia appeared to be more marked in patients with prior bone marrow transplantation. The TBD of 75 cGy was established as the maximum tolerated dose in patients who had not had prior bone marrow transplantation. Duration of CR was significantly longer (p < 0.04) in patients who received a TBD of 65-75 cGy (1109 days) than it was in those who received a lower TBD of 25-60 cGy (385 days). Four of 34 (12%) patients developed detectable human antimouse antibody levels. The median survival from study entry for all patients was 1508 days (range = 63 to >2226 days). Sixteen of 17 patients who achieved a response of > or = 6 mo duration remain alive. CONCLUSION: This update of the Phase I results after 1311 anti-B1 antibody treatment for NHL indicates that CRs can be durable and that survival can be of long duration. This form of therapy for NHL should have increasing application in clinical practice after confirmation of these results in larger multicenter studies.

Untreated primary lung and breast cancers: correlation between F-18 FDG kinetic rate constants and findings of in vitro studies.

PURPOSE: To compare kinetic modeling of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (F-18 FDG) between untreated primary lung and untreated primary breast cancers by using positron emission tomographic (PET) findings and to correlate these findings with findings of in vitro studies. MATERIALS AND METHODS: Nineteen patients (12 men, seven women; age range, 49-82 years) with untreated primary lung cancer and 17 women with untreated primary breast cancer (age range, 26-65 years) underwent 1-hour dynamic F-18 FDG PET. A three-compartment model was applied to F-18 FDG kinetics in tumors. The standard uptake value normalized for lean body mass (SUVlean) in tumors was measured 50-60 minutes after tracer injection. In vitro, thin-layer chromatography was performed to evaluate the intracellular phosphorylation of tritiated F-18 FDG in human lung cancer and breast cancer cell lines. RESULTS: At PET, lung cancer had a significantly (P < .003) higher rate constant for F-18 FDG phosphorylation (k3) and SUVlean than did breast cancer (0.164 +/- 0.150 [standard deviation] vs 0.043 +/- 0.018 and 8.25 +/- 3.28 vs 3.17 +/- 1.08, respectively). Breast cancer showed a significant correlation between k3 and SUVlean (r = .607, P < .01), although no such correlation was observed in lung cancer. In vitro studies showed phosphorylation of F-18 FDG in breast cancer cells was less complete in hyperglycemia than it was in lung cancer cells. CONCLUSION: A much lower k3 appears to be a rate-limiting factor for F-18 FDG accumulation in breast cancer, while the higher k3 in lung cancer is probably not rate limiting for F-18 FDG accumulation.

Immunolymphoscintigraphy in breast cancer: evaluation using 131I-labeled monoclonal antibody B72.3.

Noninvasive axillary lymph node staging was investigated using [131I]murine monoclonal antibody B72.3 in 16 patients with breast cancer scheduled for axillary dissection. [131I]B72.3 was injected into ipsilateral finger webs or around the breast biopsy. Scintigraphy to 72 h and gamma-counting/immunohistochemistry of nodes were performed. Specific antibody uptake (%ID/g) and the ratio of specific:nonspecific antibody uptake were not significantly different in tumor-positive versus tumor-negative nodes, suggesting that [131I]B72.3 is unsuitable to discriminate axillary node tumor involvement.

Deadtime correction for two multihead Anger cameras in 131I dual-energy-window-acquisition mode.

Two side-by-side energy windows, one at the photopeak and one at lower energy, are sometimes employed in quantitative SPECT studies. We measured the count-rate losses at moderately high activities of 131I for two multihead Anger cameras in such a dual-window-acquisition mode by imaging a decaying source composed of two hot spheres within a warm cylinder successively over a total of 23 days. The window locations were kept fixed and the paralyzable model was assumed. In addition, for the Picker Prism 3000 XP camera, the source was viewed from three different angles separated by 120 degrees and the final results are from an average over these three angles. For the Picker camera, the fits to the data from the individual windows are good (the mean of the squared correlation coefficient equals 0.98) while for the Siemens Multispect camera fits to the data from head 1 and from the lower-energy, monitor window are relatively poor. Therefore, with the Siemens camera the data from the two windows are combined for deadtime computation. Repeated autopeaking might improve the fits. At the maximum count rate, corresponding to a total activity of 740 MBq (20 mCi) in the phantom, the multiplicative deadtime correction factor is considerably larger for the Picker than for the Siemens camera. For the Picker camera, it is 1.11, 1.12, and 1.12 for heads 1-3 with the photopeak window and 1.10 for all heads with the lower-energy monitor window. For the Siemens camera, the combined-window deadtime correction factor is 1.02 for head 1 and 1.03 for head 2. Differences between the deadtime correction factor for focal activity and for the total activity do not support the hypothesis of count misplacement between foci of activity at these count rates. Therefore, the total-image dead time correction is recommended for any and all parts of the image.

Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy.

PURPOSE: To evaluate the effect of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on bone marrow glucose metabolism in rodents and in patients, as assessed by 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) uptake measured directly or by positron-emission tomography (PET) scanning. MATERIALS AND METHODS: Groups of three rats received either daily saline, G-CSF, or GM-CSF injections for 7 days. After treatment, FDG was injected and F-18 activities in tissues measured 1 hour later. Twenty-two breast cancer patients treated with multiagent chemotherapy were sequentially studied with PET. Eleven patients received G-CSF therapy as an adjunct to chemotherapy, while 11 received chemotherapy only. The standardized uptake value-lean (SUL) of bone marrow FDG uptake was measured and compared. RESULTS: In rats, bone marrow F-18 activity was significantly higher in both CSF groups than in the saline group (G-CSF, 0.44 +/- 0.08; GM-CSF, 0.33 +/- 0.02; saline, 0.18 +/- 0.02% injected dose [ID]/g x kg; P < .05), but the other normal tissues had comparable biodistributions to controls. In breast cancer patients, the FDG uptake of bone marrow did not change with chemotherapy alone; however, marrow uptake was increased after treatment with G-CSF. The dose of G-CSF and duration of treatment were correlated with the extent of increase in FDG uptake. The SUL of bone marrow was as follows: baseline, 1.56 +/- 0.23; after one cycle, 3.13 +/- 1.40 (P < .01); after two cycles, 2.22 +/- 0.85 (P < .05); and after three cycles, 2.14 +/- 0.79 (P < .05), respectively. Although the FDG uptake of bone marrow declined after G-CSF treatment was completed, it was higher than the baseline level for up to 4 weeks postcompletion of G-CSF and the elevated marrow FDG uptake was sustained longer than the period of blood neutrophil count elevation. CONCLUSION: Substantial increases in bone marrow FDG uptake are rapidly induced by CSF treatments and should not be misinterpreted as diffuse bone marrow metastases.

Demonstration of accuracy and clinical versatility of mutual information for automatic multimodality image fusion using affine and thin-plate spline warped geometric deformations.

This paper applies and evaluates an automatic mutual information-based registration algorithm across a broad spectrum of multimodal volume data sets. The algorithm requires little or no pre-processing, minimal user input and easily implements either affine, i.e. linear or thin-plate spline (TPS) warped registrations. We have evaluated the algorithm in phantom studies as well as in selected cases where few other algorithms could perform as well, if at all, to demonstrate the value of this new method. Pairs of multimodal gray-scale volume data sets were registered by iteratively changing registration parameters to maximize mutual information. Quantitative registration errors were assessed in registrations of a thorax phantom using PET/CT and in the National Library of Medicine's Visible Male using MRI T2-/T1-weighted acquisitions. Registrations of diverse clinical data sets were demonstrated including rotate-translate mapping of PET/MRI brain scans with significant missing data, full affine mapping of thoracic PET/CT and rotate-translate mapping of abdominal SPECT/CT. A five-point thin-plate spline (TPS) warped registration of thoracic PET/CT is also demonstrated. The registration algorithm converged in times ranging between 3.5 and 31 min for affine clinical registrations and 57 min for TPS warping. Mean error vector lengths for rotate-translate registrations were measured to be subvoxel in phantoms. More importantly the rotate-translate algorithm performs well even with missing data. The demonstrated clinical fusions are qualitatively excellent at all levels. We conclude that such automatic, rapid, robust algorithms significantly increase the likelihood that multimodality registrations will be routinely used to aid clinical diagnoses and post-therapeutic assessment in the near future.

Untreated lung cancer: quantification of systematic distortion of tumor size and shape on non-attenuation-corrected 2-[fluorine-18]fluoro-2-deoxy-D-glucose PET scans.

The authors quantitatively evaluated possible distortions of tumor size and shape introduced on non-attenuation-corrected 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scans obtained in primary lung cancer tumors. Primary lung cancer tumors in 21 patients were measured on x-ray computed tomography (CT), attenuation-corrected FDG PET, and non-attenuation-corrected FDG PET scans. Apparent anteroposterior tumor dimensions on non-attenuation-corrected FDG PET scans were significantly larger (P = .0007; mean difference, 30%) than on attenuation-corrected FDG PET or CT scans (P = .05; mean difference, 28%). Left-to-right tumor dimensions on non-attenuation-corrected FDG PET scans were significantly smaller than on attenuation-corrected FDG PET scans (P = .03; mean difference, 8.5%) but were not significantly different from those on CT scans (P = .3).

Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma.

PURPOSE: The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for radioimmunotherapy, treatment using radiolabeled antibodies. We conducted a phase I dose-escalation trial to assess the toxicity, tumor targeting, and efficacy of nonmyeloablative doses of an anti-CD20 monoclonal antibody (anti-B1) labeled with iodine-131 (131I) in 34 patients with B-cell lymphoma who had failed chemotherapy. PATIENTS AND METHODS: Patients were first given tracelabeled doses of 131I-labeled anti-B1 (15 to 20 mg, 5 mCi) to assess radiolabeled antibody biodistribution, and then a radioimmunotherapeutic dose (15 to 20 mg) labeled with a quantity of 131I that would deliver a specified centigray dose of whole-body radiation predicted by the tracer dose. Whole-body radiation doses were escalated from 25 to 85 cGy in sequential groups of patients in 10-cGy increments. To evaluate if radiolabeled antibody biodistribution could be optimized, initial patients were given one or two additional tracer doses on successive weeks, each dose preceded by an infusion of 135 mg of unlabeled anti-B1 one week and 685 mg the next. The unlabeled antibody dose resulting in the most optimal tracer biodistribution was also given before the radioimmunotherapeutic dose. Later patients were given a single tracer dose and radioimmunotherapeutic dose preceded by infusion of 685 mg of unlabeled anti-B1. RESULTS: Treatment was well tolerated. Hematologic toxicity was dose-limiting, and 75 cGy was established as the maximally tolerated whole-body radiation dose. Twenty-eight patients received radioimmunotherapeutic doses of 34 to 161 mCi, resulting in complete remission in 14 patients and a partial response in eight. All 13 patients with low-grade lymphoma responded, and 10 achieved a complete remission. Six of eight patients with transformed lymphoma responded. Thirteen of 19 patients whose disease was resistant to their last course of chemotherapy and all patients with chemotherapy-sensitive disease responded. The median duration of complete remission exceeds 16.5 months. Six patients remain in complete remission 16 to 31 months after treatment. CONCLUSION: Nonmyeloablative radioimmunotherapy with 131I-anti-B1 is associated with a high rate of durable remissions in patients with B-cell lymphoma refractory to chemotherapy.

Enhanced FDG-PET tumor imaging with correlation-coefficient filtered influx-constant images.

UNLABELLED: Although FDG is an excellent PET tumor imaging agent, residual tracer activity in normal structures such as blood vessels and the liver can impair the detection of small or modestly tracer-avid tumors. Since tumors generally have a continuous influx of FDG over time while normal tissues generally show tracer efflux, we produced and optimized correlation-coefficient constrained influx-constant "parametric" images to maximize tumor visualization but minimize background and artifacts for FDG-PET cancer imaging. METHODS: Influx-constant image sets were generated in 17 patients with various cancers for a range of correlation-coefficient constraint values. Quantitative evaluation of the parametric PET images was performed. RESULTS: Image noise was reduced 70% (mean) with no loss of tumor signal for r > or = 0.90 constraint versus no constraint. Higher (0.95-0.99) constraints improved tumor-to-normal ratios but resulted in some loss of tumor signal. Mild constraints (0-0.85) produced more background artifacts than higher constraints, though all correlation constraints improved tumor-to-normal ratios over the single 50-60-min acquisition frame. CONCLUSION: Correlation-coefficient filtered parametric imaging, especially with an r-value constraint of > or = 0.90, enhances tumor-to-normal contrast for FDG-PET and appears promising for improving lesion detectability.