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This paper describes the preclinical validation of the radioligand [ 11 C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α 2C R) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α 2C R. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [ 3 H]ORM-13070. BAY 292 bound to the same binding site as [ 3 H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α 2C R. In non-human primates in vivo , [ 11 C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α 2C R. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC 50 for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [ 11 C]ORM-13070 as a PET-radioligand for the study of α 2C R in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DPB, IP, TP and WP are employees of Bayer AG and may own shares or share options. MD was employee of Bayer AG at the time of conducting the study and data analysis. The study was funded by Bayer AG.ALA, CCC, DRB, EAR, KRZ, LAW are full-time employees of Invicro LLC.

A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

Introduction: Fatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development. Companion molecular imaging probes are needed, however, to assess FAAH inhibition in the nervous system in vivo. We report here the synthesis and in vivo evaluation of [(18)F]PF-9811, a novel PET ligand for non-invasive imaging of FAAH in the brain., Methods: The potency and selectivity of unlabeled PF-9811 were determined by activity-based protein profiling (ABPP) both in vitro and in vivo. [(18)F]PF-9811 was synthesized in a 3-step, one-pot reaction sequence, followed by HPLC purification. Biological evaluation was performed by biodistribution and dynamic PET imaging studies in male rats. The specificity of [(18)F]PF-9811 uptake was evaluated by pre-administration of PF-04457845, a potent and selective FAAH inhibitor, 1h prior to radiotracer injection., Results: Biodistribution studies show good uptake (SUV~0.8 at 90 min) of [(18)F]PF-9811 in rat brain, with significant reduction of the radiotracer in all brain regions (37%-73% at 90 min) in blocking experiments. Dynamic PET imaging experiments in rat confirmed the heterogeneous uptake of [(18)F]PF-9811 in brain regions with high FAAH enzymatic activity, as well as statistically significant reductions in signal following pre-administration of the blocking compound PF-04457845., Conclusions: [(18)F]PF-9811 is a promising PET imaging agent for FAAH. Biodistribution and PET imaging experiments show that the tracer has good uptake in brain, regional heterogeneity, and specific binding as determined by blocking experiments with the highly potent and selective FAAH inhibitor, PF-04457845., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The 18F isotope of fluoro-2-deoxy-D-glucose (FDG) is a radiotracer commonly used in positron emission tomography (PET) for determining regional metabolic activity in the brain. However, in rats and many other species with nictitating membranes, harderian glands located just behind the eyes aggressively incorporate 18F-FDG to the extent that PET images of the brain become obscured. This radioactive spillover, or 'partial volume error,' combined with the limited spatial resolution of microPET scanners (1.5 to 2 mm) may markedly reduce the ability to quantify neuronal activity in frontal brain structures. Theoretically, surgical removal of the harderian glands before 18F-FDG injection would eliminate the confounding uptake of the radioactive tracer and thereby permit visualization of glucose metabolism in the frontal brain. We conducted a pilot study of unilateral harderian gland adenectomy, leaving the contralateral gland intact for comparison. At 1 wk after surgery, each rat was injected intravenously with 18F-FDG, and 40 min later underwent brain microPET for 20 min. Review of the resulting images showed that the frontal cortex on the surgical side was defined more clearly, with only background 18F-FDG accumulation in the surgical bed. Activity in the frontal cortex on the intact side was obscured by intense accumulation of 18F-FDG in the harderian gland. By reducing partial volume error, this simple surgical procedure may become a valuable tool for visualization of the frontal cortex of rat brain by 18F-FDG microPET imaging.

Purpose: This study evaluated in a phantom model and verified in patients with lung cancer whether the use of an internal positron-emitting labeled marker could localize a critical structure by positron emission tomography (PET) imaging and verify multimodality image registration., Materials and Methods: An initial device and method were developed to demonstrate by dedicated PET the location of the normal esophagus in a phantom and in three patients using a column of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) solution between proximal and distal gas phases in polyurethane tubing. The device was assessed for possible loss of radioactivity. PET, CT and PET-CT fusion imaging followed., Results: X-rays of the marker device showed a continuous fluid column. No leakage of contents was detected. The internal marker in the phantom and in patients allowed visualization by PET of the esophagus, and verified an image registration algorithm., Conclusions: A positron-emitting internal marker was constructed, demonstrated to retain tracer, and shown to be capable of verifying an image registration algorithm and identifying a critical structure, the esophagus, by PET in a phantom and in patients.

Unlabelled: A study of the use of (131)I-labeled tositumomab, preceded by an unlabeled tositumomab predose, for therapy of 76 previously untreated non-Hodgkin's lymphoma patients has been completed at the University of Michigan. Fifty-two of the 76 treated patients were imaged once during therapy with SPECT to assist in dosimetric estimation. In this article, the patient's average tumor dose, estimated by a hybrid method using that SPECT, is compared with the same statistic estimated by pretherapy conjugate views., Methods: The SPECT activity-quantification procedure used 3-dimensional CT-to-SPECT image registration. Daily pretherapy conjugate-view images provided the shape of the time-activity curve for the hybrid dose estimation., Results: With the hybrid method, the mean of the patient's average tumor dose over 8 patients using only their axillary tumors (162 cGy) was very significantly lower (P < 0.0001) than the mean over 47 patients using only their evaluated chest, abdominal, and pelvic tumors (624 cGy) for unknown reasons. Excluding axillary tumors as a best case for prediction, there still was considerable overlap in the distribution of a patient's average tumor dose over 38 patients who went on to a complete response (CR) and that from 9 patients who went on to a partial response (PR) using either method. However, a high value of the patient's average tumor dose was correctly associated with a CR for 15 of 16 patients (94%) with hybrid SPECT and for 9 of 12 patients (75%) with conjugate views. Also, the mean of the patient's average tumor dose for the CR patients was larger than the mean for PR patients; the P value was 0.18 with hybrid SPECT and 0.25 with conjugate views. A multiple logistic regression analysis combining the dose, tumor burden, and level of lactate dehydrogenase as explanatory variables for response did not yield statistical significance with either method., Conclusion: Patients with evaluated tumors that receive the highest tumor radiation dose are most likely to achieve a CR. Dosimetry based on a combination of pretherapy conjugate views and intratherapy SPECT provides somewhat better correspondence between the patient's average tumor dose and his or her degree of response compared with dosimetry from pretherapy conjugate views alone. Statistical significance for the correspondence is not reached either with the dosimetric method or with either method in combination with the tumor burden and level of lactate dehydrogenase.

The aim of this study was to determine the relationship between tumor blood flow and glucose utilization in women with untreated primary breast carcinomas. Noninvasive determinations of blood flow and glucose utilization with positron emission tomography (PET) were performed in 101 regions of tumor from nine women with untreated primary breast carcinoma. [(15)O]H(2)O PET scans of tumor blood flow were compared with fluorine-18 fluoro-2-deoxy- D-glucose (FDG) PET scans of tumor glucose metabolism. Modeling of multiple parameters was undertaken and flow and glucose utilization compared. Mean whole-tumor blood flow was 14.9 ml dl(-1) min(-1), but ranged from 7.6 to 29.2 ml dl(-1) min(-1). Mean whole-tumor standardized uptake value corrected for lean body mass, SUV-lean (50-60 min), was 2.32+/-0.19 while mean K(i) was 1.2 ml dl(-1) min(-1) for FDG. SUV-lean and blood flow were strongly correlated (r=0.82, P=0.007) as were K(1) for FDG and flow (r=0.84, P=0.004). In these women with untreated breast cancers, FDG uptake (SUV-lean) and tumor blood flow are strongly correlated. The slope of FDG uptake versus blood flow appears higher at low flow rates, suggesting the possible presence of areas of tumor hypoxia.

Expressions of HKII and Glut-1 were studied in untreated primary human breast cancers by immunohistochemistry. 79% of the breast cancers were HKII-positive and 61% were Glut-1-positive. Average positive malignant cell areas were 66 +/- 41% for HKII and 29 +/- 36% for Glut-1. HKII staining was cytoplasmic, suggesting mitochondrial localization with no variations in staining intensities. Glut-1 staining was heterogeneous, cytoplasmic and membranous and varied with histology and tumor stage. Cells expressing HKII did not always express Glut-1 and vice versa. Increased FDG-uptake appeared to be associated with increased Glut-1 expression (P = 0.021), but not with HKII expression (p = 0.6).FDG uptake in breast cancer tissue appears to be associated with the extent of immunodetectable expression of Glut-1, but not that of HKII, and FDG uptake may differ between individual tumors depending on tumor stage and histology.

Purpose: Positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been used for various cancers, but reproducibility of common utilized semi-quantitative parameters, such as the maximal single pixel standardized uptake value (SUV) and effective glycolytic volume (EGV), remains unknown. Knowledge of precision is essential for applying these parameters to treatment monitoring. The purpose of this investigation was to assess the precision of PET results obtained by repeated examinations of patients with untreated lung cancer., Patients and Methods: Ten patients with lung cancer underwent two PET examinations within a week with no intervening treatment. The reproducibility of three parameters:((1) maximal SUV of 1 x 1 pixel anywhere in the tumor, calculated on the basis of predicted lean body mass [SULmax]; (2) highest average SUV at 4 x 4 pixels in the tumor adjusted by predicted lean body mass [SULmean]; and (3) EGV calculated by multiplying SUL by tumor volume), using PET images obtained at 50-60 min post-injection, were examined. Plasma glucose, insulin and free fatty acid levels were also monitored., Results: The SULmax, SULmean, and EGV were measured with a mean +/- S.D. difference of 11.3% +/- 8.0, 10.1% +/- 8.2, and 10.1% +/- 8.0%, respectively. By multiplying SUL by plasma glucose concentration, the mean differences were slightly reduced to 7.2% +/- 5.8, 6.7% +/- 6.2, and 9.5% +/- 8.2, respectively., Conclusion: These data indicate that commonly used semi-quantitative indices of glucose metabolism on PET show high reproducibly. This supports their use in sequential quantitative analysis in PET, such as in treatment response monitoring.

Purpose: The aim of this work is to compare the accuracy of non-attenuation-corrected (NAC) and attenuation-corrected (AC) PET images using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) in assessment of the axilla in patients with newly-diagnosed, untreated, primary breast cancers, and to determine the frequency of extra-axillary findings., Patients and Methods: FDG-PET was performed in 36 patients with breast cancer one hour following the intravenous injection of approximately 370 MBq of FDG. Patients were imaged prior to axillary dissection to prospectively confirm the presence or absence of axillary metastases. NAC and AC images were separately and independently reviewed in a blinded fashion by two readers. Imaging results were compared with final diagnoses obtained by surgery and pathology., Results: Ninety-six positive axillary lymph nodes in 15 patients were histopathologically confirmed by surgery. The average areas under the ROC curve for NAC and AC image were 0.682 and 0.721, respectively. In patient-based analysis, the sensitivity in interpreting NAC images for the presence of metastases was low (53.3%) and comparable to that of AC images (46.7%). The specificity of NAC image was high (85.7%), but tended to be lower than that in AC (95.2%). The overall diagnostic accuracy for detecting axillary involvement in AC images (75.0%) was comparable to that of NAC images (72.2%). Extra-axillary disease was found in three patients., Conclusion: NAC images were comparable to AC images, although there were more false positive results with the NAC images. While AC PET has high specificity in this application, it appears insufficiently sensitive to use these methods to avoid axillary tissue sampling, when negative. Extra-axillary findings, while infrequent, may be quite important. Examination of both NAC and AC images is advised when assessing possible metastatic breast cancer to the axilla using PET.

Background: A Phase II study of previously untreated patients with malignant low grade follicular lymphoma given a combination of unlabeled tositumomab and tositumomab labeled with iodine-131 has recently been completed. The responses of these patients have been characterized, and for some of them tumor dosimetry during therapy has been estimated not only by pretherapy tracer conjugate views but also by a hybrid method., Methods: Available patients were studied if they had had a pelvic or abdominal tumor evaluation by single photon emission computed tomography (SPECT) and achieved a partial response. A tumor outlined on the iodine-131 conjugate-view images was called a composite tumor. Its volume estimate came from multiple, not necessarily contiguous, regions of interest (ROI) on the pretherapy computed tomography (CT) scan. Its radiation dose was estimated from the weeklong series of pretherapy images and standard Medical Internal Radiation Dose methods. Computed tomography ROI were also grouped into smaller, contiguous volumes that defined individual tumors. Their radiation doses were estimated by the hybrid method. This method employed the activity measured for each individual tumor by a single intratherapy SPECT scan, as well as the tumor's volume, to individually normalize the composite time-activity curve as appropriate. The individual normalization factors then converted the composite radiation dose to radiation doses for individual tumors. Reduction in tumor volume was calculated for both composite and individual tumors at 12 weeks posttherapy., Results: For 14 composite tumors in 10 patients, the median pretherapy volume was 170 cm(3). Application of a sigmoidal curve function to the plot of volume reduction versus radiation absorbed dose resulted in degeneration of the curve into a straight line with a negative slope. There was no statistical significance in the relationship (P = 0.73). For 43 individual tumors, the median pretherapy tumor volume was 26 cm(3). The plot of volume reduction versus dose was fairly well fit by a sigmoidal curve, and the relationship approached statistical significance (P = 0.06). The representation assigned 56% of the shrinkage to the effects of unlabeled tositumomab. For the subset of individual tumors with a pretherapy volume less than 10 cm(3) from 6 patients (n = 15), the relationship was significant (P = 0.03). The sigmoidal representation assigned only 12% of the shrinkage to unlabeled tositumomab, as contrasted with 72% for tumors with pretherapy volume greater than 10 cm(3)., Conclusions: For patients who attained a partial response, analysis of individual tumors by a hybrid dosimetric method led to a dependence between volume reduction at 12 weeks and radiation dose that tended to be significant. The same was not true with dosimetry of composite tumors based on pretherapy conjugate views alone. It appeared that volume reductions from both unlabeled antibody and radiation dose were important in tositumomab therapy of lymphoma patients, with unlabeled antibody relatively more important for larger tumors., (Copyright 2002 American Cancer Society.)

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.

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)

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.

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.

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.

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.

OBJECTIVE: To compare kinetics and accumulation of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in primary lung cancer between diabetic and non-diabetic patients using positron emission tomography (PET).METHODS: Five diabetic patients and 21 non-diabetic patients underwent dynamic FDG-PET to image untreated primary lung cancers. Standardized uptake value normalized for lean body mass (SUL) was determined in tumor, blood, muscle, and lung. A 3-compartment metabolic model was applied to FDG kinetics in tumors in 24 of 26 patients.RESULTS: At the time of PET scans, serum glucose levels were elevated in 5 diabetic patients, while 21 non-diabetic patients showed normal glucose levels. In diabetic patients, tumor SUL, tumor/blood and tumor/muscle SUL ratios were significantly decreased (P < 0.02) and also tumor/lung SUL ratio declined (P = 0.064), as compared to non-diabetic patients. In addition, the rate constant for FDG phosphorylation (k3) and influx constant (Ki) in diabetic patients were significantly lower than those in non-diabetic patients (P < 0.02).CONCLUSION: In diabetic patients, the rate of FDG accumulation in tumors is decreased, and tumor targeting with FDG is impaired. Diabetes may reduce the sensitivity of FDG-PET for lung cancer detection.

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.

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.

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.

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.

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.

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.

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.

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.

PURPOSE: To determine if tumor volume, in addition to tumor metabolic activity, can be assessed noninvasively from attenuation-corrected fluorodeoxyglucose (FDG)-PET imaging using a semiautomated method.METHODS: CT and FDG-PET scanning was performed in 14 patients, eight with newly diagnosed untreated malignancies, and six patients with progressive non-Hodgkin's lymphoma (NHL). Tumor volume was determined from CT scans by summation of manually drawn regions of interest over tumor. Tumor volume was determined at FDG-PET with a semiautomated method based on quantitation of (18)F uptake and thresholding.RESULTS: Mean tumor volume was 187 +/- 189 cm(3). Tumor volume determined by means of PET and CT was strongly correlated in the patients with untreated tumors. Correlation was weaker for all patients, mainly due to one previously treated patient with a large disparity between CT and metabolically active tumor volumes at FDG-PET, presumably due to tumor necrosis.CONCLUSIONS: Tumor volume determination by FDG-PET was strongly correlated with tumor volumes determined by anatomic imaging with CT. FDG-PET appears comparable to CT in measuring untreated tumor volumes of this size. FDG-PET may be superior to anatomic techniques in assessing metabolically active tumor volume, and warrants further study in this role.

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.

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.

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.

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).

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.

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.

Purpose: To study the precision of repeated 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) uptake measurements at positron emission tomography (PET) in patients with primary lung cancer., Materials and Methods: Ten patients with untreated lung cancer underwent two dynamic FDG PET examinations after a 4-hour fast within 1 week. Kinetic modeling of tumor FDG uptake was performed on the basis of a three-compartment model. The tumor concentration of F-18 (standardized uptake value calculated on the basis of predicted lean body mass [SUV-lean]) was also measured 50-60 minutes after injection of a tracer. Blood glucose, insulin, and free fatty acid levels were monitored., Results: SUV-lean and the FDG influx constant Ki were measured with a mean +/- standard deviation difference of 10% +/- 7 and 10% +/- 8, respectively, over repeated PET scans. The mean difference was reduced to 6% +/- 6 and 6% +/- 5 by multiplying SUV-lean and Ki by plasma glucose concentration., Conclusion: SUV-lean and graphical Ki can be measured reproducibly, supporting their use in quantitative FDG PET algorithms.

Unlabelled: A method for performing 131I quantitative SPECT imaging is described which uses the superimposition of markers placed on the skin to accomplish fusion of computed tomography (CT) and SPECT image sets., Methods: To calculate mean absorbed dose after administration of one of two 131I-labeled monoclonal antibodies (Mabs), the shape of the time-activity curve is measured by daily diagnostic conjugate views, the y-axis of that curve is normalized by a quantitative SPECT measurement (usually intra-therapy), and the tumor mass is deduced from a concurrent CT volume measurement. The method is applied to six B-cell non-Hodgkin's lymphoma patients., Results: For four tumors in three patients treated with the MB1 Mab, a correlation appears to be present between resulting mean absorbed dose and disease response. Including all dosimetric estimates for both antibodies, the range for the specific absorbed dose is within that found by others in treating B-cell lymphoma patients. Excluding a retreated anti-B1 patient, the tumor-specific absorbed dose during anti-B1 therapy is from 1.4 to 1.7 mGy/MBq. For the one anti-B1 patient, where quantitative SPECT and conjugate-view imaging was carried out back to back, the quantitative SPECT-measured activity was somewhat less for the spleen and much less for the tumor than that from conjugate views., Conclusion: The quantitative SPECT plus conjugate views method may be of general utility for macro-dosimetry of 131I therapies.

We searched for methods that would enable prescriptions of the maximum tolerable doses of iodine-131 metaiodobenzylguanidine (MIBG) and iodine-125 MIBG in the treatment of patients with neuroblastoma. We correlated doses, defined in different ways, with subsequent platelet levels in treated patients to determine accurate predictors of the most frequent toxicity, thrombocytopenia. Nine patients with neuroblastoma were given 131I-MIBG (4.9-8.1 GBq or 132-220 mCi) and ten were given 125I-MIBG (8.3-30.0 GBq or 224-809 mCi) as initial treatments. These therapies were sufficiently varied that correlations could be made between indices of the doses and the subsequent toxicity as reflected in circulating platelet levels. Predictors of toxicity were: whole-body absorbed dose of radiation (cGy) calculated from pretherapy tracer doses of 131I-MIBG; GBq/kg of body weight; and GBq/m2 of body surface area. Toxicity was recorded as the nadir of the platelet level and platelet/pretherapeutic level (platelet ratio). For treatments with 131I-MIBG, the highest correlation was obtained between cGy and the log10-transformed platelet ratio (r = -0.86), but comparison of GBq/m2 and the platelet nadir (r = -0.76) or the platelet ratio (r = -0.74) or the log10 transformed platelet ratio (r = -0.73) gave comparable and statistically significant results. For treatments with 125I-MIBG, significant correlations were obtained between GBq/m2 and the platelet ratio (r = -0.81) or GBq/kg and the log10-transformed platelet ratio; the correlation between cGy and any toxicity index was low. Per administered GBq, 131I-MIBG was 2.6 times more potent than 125I-MIBG in causing a platelet ratio of 0.1.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: To study the relationship between standardized uptake values (SUVs) in normal tissues and body weight determined with positron emission tomography (PET)., Materials and Methods: SUVs were determined in 28 nondiabetic women with newly diagnosed untreated primary breast cancers. Body weights ranged from 45 to 107 kg. SUVs for lung, liver, marrow, spleen, blood, and normal breast were determined from images obtained with PET 50-60 minutes after injection of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG)., Results: There was a positive correlation between SUV and body weight for blood, (r = .75, P = .000004), liver (r = .72, P = .000081), and spleen (r = .57, P = .033), all of which had substantial F-18 activity. In heavy patients, SUVs for those normal tissues were up to twice those of lighter patients. Calculating SUV on the basis of predicted lean body mass (SUV-Lean) eliminated the weight dependence of the SUV for blood (r = .26, P = .18) and reduced weight dependence in other tissues., Conclusion: SUV-Lean is a weight-independent index for blood FDG accumulation at PET and may be more appropriate than SUV for quantifying F-18 activity in tumors.

To assess the feasibility and accuracy of positron emission tomography (PET) in the detection of metastatic malignant melanoma, the authors studied 12 patients approximately 1 hr following a 10-mCi injection of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG). Scan findings were compared to physical examination, imaging and biopsy results. For intra-abdominal visceral and lymph node metastases, the sensitivity of FDG-PET was 100% (15/15). PET also identified three metastatic foci noted only retrospectively on CT, and two metastatic foci seen only on follow-up CT several months later. Eight additional intense foci of FDG uptake that were seen on PET have not yet been confirmed as tumors. In superficial lymph nodes, PET correctly identified seven of seven metastatic lesions (including three cases involving normal-sized lymph nodes) and correctly predicted the absence of tumor in six of six lymph node regions, for an overall accuracy of 100% (13/13). The sensitivity of the PET technique for detecting small pulmonary lesions was lower than CT but this could be due to respiratory motion or prior cancer treatment. This initial experience demonstrates the feasibility and clinical potential of FDG-PET for the detection of regional and systemically metastatic malignant melanoma, particularly in extra-pulmonary lesions.

Background: Many patients with non-Hodgkin's lymphomas are not cured by current therapies, and new approaches to treatment are needed. As part of an ongoing phase 1 study, we examined the effect of radioimmunotherapy with 131I-labeled B-cell-specific anti-CD20 monoclonal antibody in 10 patients with CD20-positive B-cell lymphomas in whom primary chemotherapy had failed., Methods and Results: Anti-B1 (anti-CD20) mouse monoclonal antibody trace-labeled with 131I (15 mg containing 5 mCi) was given intravenously at approximately one-week intervals: first, without pretreatment with unlabeled anti-B1 antibody, to all 10 patients; then, with pretreatment with 135 mg of unlabeled antibody, to 8 patients; and then, with pretreatment with 685 mg, to 2 patients. Serial quantitative gamma-camera images and measures of whole-body radioactivity were obtained after each tracer dose. All known disease sites larger than 2 cm could be imaged. The effect of a pretreatment dose of unlabeled anti-B1 antibody on targeting of the tumor with the radiolabeled antibody was variable. The pretreatment dose of unlabeled antibody that produced the highest ratio of the tumor dose to the whole-body dose in tracer studies was then used to deliver higher doses of radioactivity for radioimmunotherapy in nine patients. Three patients received doses designed to deliver 25 cGy to the whole body (two patients treated twice, six to eight weeks apart), four patients received 35 cGy (one patient treated twice), and two patients received 45 cGy (one patient treated twice); each dose contained 34 to 66 mCi of activity. Six of the nine treated patients had tumor responses, including patients with bulky or chemotherapy-resistant disease: four patients had complete remissions, and two had partial responses. Three patients had objective responses to tracer infusions before they received radioimmunotherapeutic doses. Of the four patients with complete remissions, one remained in remission for eight months and the other three continue to have no disease progression (for 11, 9, and 8 months). There was mild or no myelosuppression., Conclusions: Radioimmunotherapy with [131I]anti-B1 antibody is a promising new treatment for lymphoma.

Two side-by-side energy windows are sometimes employed in quantitative single photon emission computed tomography (SPECT) studies. The count-rate losses at high activities for a GE400AT camera were measured in such a dual-window-acquisition mode by imaging a decaying source composed of a hot sphere within a warm cylinder. The data in each window was either kept separate or combined for purposes of dead-time correction and the paralyzable model was assumed. In addition, correction factors were derived from a "monitor" source at the edge of the camera. Finally, energy spectra for only the monitor-source region of interest and for the entire camera were obtained under both low- and high-count conditions and compared. With 99mTc (1) the spectral measurements show no peak shift but reveal pulse-pile-up spectral degradation. (2) The monitor-source corrections do not agree well with those from the model, presumably because of the differential effects of such degradation. For this camera the preferred correction method for patients is one using the model and two, effective, phantom-derived dead times for the separate data from the two windows. The two effective dead times are needed to compensate for pulse pile-up adding more counts to the lower-energy window than to the higher-energy one at high rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: This study was undertaken to evaluate the tumor targeting, toxicity, and therapeutic potential of the anti-B-cell-reactive monoclonal antibody MB-1 (anti-CD37) labeled with iodine 131 given in a nonmarrow ablative dose range in B-cell lymphoma patients who relapsed after chemotherapy., Patients and Methods: Twelve patients with MB-1-reactive tumors were infused first with 40 mg of trace-labeled (3 to 7 mCi) MB-1. Ten patients who had no serious toxicity postinfusion and who had successful tumor imaging on serial gamma scans then received at least one 40-mg radioimmunotherapy (RIT) dose (25 to 161 mCi). Tracer estimates of delivered whole-body dose (WBD) were used in prescribing a millicurie RIT dose for seven patients., Results: Eleven patients had positive tumor imaging after a tracer dose, including patients with bulky tumors and/or large tumor burdens (> or = 1 kg) +/- splenomegaly. However, overall sensitivity for the detection of known tumor sites was only 39%. In six of eight patients with dose-assessable tumors, the radiation dose to at least one tumor was 1.1 to 3.1 times higher than to any normal organ, excluding the spleen for a 40-mg tracer dose. Tracer-dose toxicities included reversible glossal edema in one patient, grade 3 hepatic transaminasemia in another, and early drops in both circulating B and T cells (with decreases in B cells more pronounced) in nearly all patients. RIT toxicity was primarily myelosuppression (especially thrombocytopenia), which had a delayed onset and protracted recovery (without significant recovery until at least 2 months post-RIT). Grade 3 myelosuppression in two of two patients who were treated at a tracer-projected 50-cGy WBD level (133 and 149 mCi) precluded further planned RIT dose escalation. Less myelosuppression was generally observed in patients who were treated at < or = 40-cGy WBD levels. Antimouse antibodies developed in two patients. Six patients had tumor responses post-RIT. Four had responses that lasted more than 1 month (2 to 6 months), which included one complete response, one partial response, one minor response, and one mixed response. Responses seemed to occur more frequently in imaged tumors than in nonimaged tumors. The most durable response occurred in a patient who had the best antibody targeting to tumor., Conclusions: Although 131I-MB-1 has limited diagnostic value, it can produce tumor responses at nonmarrow ablative RIT doses. Further studies that focus on improving tumor targeting with this or other B-cell-reactive radiolabeled antibodies and on ameliorating the myelosuppression associated with the RIT-dosing approach used in this trial are warranted.

To find a treatment that may be effective against micrometastases of advanced, stage III or IV neuroblastoma, [125I]metaiodobenzylguanidine (125I-MIBG) was used in a phase I toxicity trial. In seven patients, thrombocytopenia was encountered with absorbed whole body doses of 85-135 rad from 125I-MIBG, but the dosimetry was imprecise in predicting bone marrow injury. Three patients survived for over one year, results that may indicate efficacy of 125I-MIBG therapy.

Fourteen patients with advanced neuroblastoma, which was unresponsive to or had relapsed despite conventional therapy, were entered into a phase I/II trial of [131I]metaiodobenzylguanidine (131I-MIBG). Doses ranged from 1.85-8.14 GBq each (50-220 mCi), with cumulative doses of 1.85-24.20 GBq (50-654 mCi) in one to three doses. Side effects included mild nausea and vomiting and moderate myelosuppression which occurred in nine patients. Subjective responses occurred in five patients. Four patients had objective responses (one partial, two minor and one mixed). Two of these patients remain alive 80 and 60 months after beginning 131I-MIBG therapy. Comparison of the 131I-MIBG treated patients with 11 carefully matched control patients treated with an advanced current chemotherapy protocol (CCG 8605) was performed by means of Kaplan-Meier life table analysis. The 14% four-year survival with 131I-MIBG compared favorably with the 6% achieved by salvage chemotherapy. We thus believe 131I-MIBG may have a role in the management of neuroblastoma.

Twenty-eight patients with histologically proven metastatic or invasive, unresectable pheochromocytomas, which were shown to concentrate and retain tracer doses of [131I]metaiodobenzylguanidine (131I-MIBG), were treated with therapeutic quantities of this radiopharmaceutical. Between one and six doses ranging from 97 to 301 mCi (cumulative dose 111-916 mCi) were administered. Partial response in tumor size was achieved in 8/28 patients and partial biochemical responses in 12/28 patients. No pharmacological toxicity was observed. Mild radiation sickness (nausea, vomiting, anorexia) occurred in 21/28. Minor degrees of leukopenia and thrombocytopenia were observed in 3/28. There were three cases of hypothyroidism but no significant hepatic, renal, adrenocortical or autonomic nervous dysfunction. We conclude that therapeutic 131I-MIBG can achieve significant therapeutic responses in some cases of malignant pheochromocytoma without pharmacological toxicity and only mild radiotoxicity.

The spectral-fitting method of correction for gamma-ray Compton scattering within objects separates the unscattered and scattered components of locally measured energy spectra. Here, we employ a third-order polynomial for the scattering and an approximately constant fitting window. A scatter fraction, defined as total scattered over total unscattered counts within a 20% window, is calculated for each point in our Anger camera images. These scatter fractions are tested against those from Monte-Carlo simulation for 99mTc and against results from semiconductor detector measurements for 131I. A radioactive sphere at several locations within a non-radioactive cylinder and the inverse are imaged for the testing. For one case, reproducibility of the spectral-fitting scatter fraction as a function of the number of unscattered counts within the 20% acceptance window was also determined. With 99mTc, for all cases, the agreement between spectral fitting and the standard estimation method is within 16%. With 131I, for the 'hot' sphere at two locations, the agreement is within 21%. For the 'hot' sphere at the third location (off the cylinder axis towards the camera), the dependence of scatter fraction on transverse distance is good although the absolute values are too large. Scatter fraction reproducibility is within 10% for 1000 or more counts. Therefore, further testing of spectral fitting and initial application to realistic clinical images seem to be in order.

The dosimetry for two, similarly sized tumours in a lymphoma patient being treated with non-bone marrow ablative, monoclonal antibody therapy is reported. The 45-year-old man was infused with 2.48 GBq (67 mCi) of 131I-labelled MB-1. Prior to therapy, a time series of diagnostic conjugate-view images and a radionuclide transmission scan were obtained and processed to obtain time-activity curves. Starting 2 days after the therapeutic infusion of radioactivity, a second conjugate-view time series was obtained. At that time, a quantitative single-photon emission tomography (SPET) acquisition was also carried out. Pre- and post-therapy X-ray computed tomography scans demonstrated a percentage reduction in volume for the right tumour which was 3.8 times that for the left tumour. In contrast, diagnostic conjugate views by themselves estimated the absorbed dose to be the same for the two tumours. Addition of therapy conjugate-view data increased the right-over-left ratio but only to 1.22. Normalizing either time-activity series by the intra-therapy SPET results increased the ratio to greater than 1.5. We assume here that a differential dose is correct according to the differential tumour shirnkage. One can further assume that the largest ratio corresponds most certainly to the most accurate dosimetric method. Other assumptions are possible. While additional study is essential, data from this patient suggest that the preferred dosimetric method is intra-therapy SPET normalization of either time series.

Three children with Stage III neuroblastoma were treated with [125I]MIBG in a phase I toxicity study. Concepts of the treatment were: in small tumors, the absorbed dose of radiation from MIBG labeled with 131I is reduced but the absorbed dose from [125I]MIBG is less affected; and many recurrences of neuroblastoma arise from small tumors. Two patients exhibited only modest thrombocytopenia and leukopenia, the most sensitive indices of radiation toxicity, after receiving 261 and 407 mCi, and 83 and 104 rad of whole-body radiation. One patient died of progressive neuroblastoma; the other two patients have stable disease over 30 mo after treatment. Per millicurie given, [125I]MIBG imparts about one-fourth the radiation dose of [131I]MIBG to the whole body. Iodine-125-MIBG can be given in doses that impart over 100 rad of whole-body radiation and that exceed 400 mCi before toxicity becomes limiting, even in small children.

Autoradiolysis of therapeutic doses of monoclonal antibodies can occur rapidly, limits their shelf life and makes onsite radiolabeling a near-necessity. We evaluated freezing of three different 131I-labeled murine monoclonal antibodies at -70 degrees C, immediately following radiolabeling, as a method of diminishing autoradiolysis, and of preserving immunoreactivity. Freezing greatly limits the ability of radiation-induced free radicals to diffuse in solution and thus produce radiolytic damage. By freezing at -70 degrees C autoradiolytic damage of immunoreactivity of three different 131I monoclonal antibodies could be largely eliminated, in contrast to the 80-90% losses in immunoreactivity seen with storage at 4 degrees C for a period of 1 to 12 days. Reduced in vitro deiodination rates are also seen for frozen antibodies. Limited studies with 125I-labeled antibodies indicate autoradiolysis does occur, though at a slower rate per mCi than for 131I, and that this process is also retarded by freezing. Freezing may be valuable while quality control procedures are performed following radiolabeling as well as if temporary storage or shipment of radioantibodies prior to patient dosing is undertaken. While the approach should be validated for each antibody studied, freezing of therapeutic doses of monoclonal antibodies appears to be a simple and effective approach to the problem of autoradiolysis.