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Background Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration-resistant tumors. Lutetium-177-labeled anti-PSMA monoclonal antibody J591 (177 Lu-J591) targets prostate cancer with efficacy and dose-response/toxicity data when delivered as a single dose. Dose fractionation may allow higher doses to be administered safely. Method Men with metastatic castration-resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose-escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses of 177 Lu-J591 2 weeks apart. 177 Lu-J591 imaging was performed after treatment, but no selection for PSMA expression was performed before enrollment. Phase 2 patients had circulating tumor cell (CTC) counts assessed before and after treatment. Results Forty-nine men received fractionated doses of 177 Lu-J591 ranging from 20 to 45 mCi/m2 ×2 two weeks apart. The dose-limiting toxicity in phase 1 was neutropenia. The RP2Ds were 40 mCi/m2 and 45 mCi/m2 ×2. At the highest RP2D (45 mCi/m2 ×2), 35.3% of patients had reversible grade 4 neutropenia, and 58.8% of patients had thrombocytopenia. This dose showed a greater decrease in prostate-specific antigen (PSA) levels and longer survival (87.5% with any PSA decrease, 58.8% with >30% decrease, 29.4% with >50% decrease; median survival, 42.3 months [95% confidence interval, 19.9-64.7]). Fourteen of 17 (82%) patients with detectable CTCs experienced a decrease in CTC count. Overall, 79.6% of patients had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses. Conclusion Fractionated administration of 177 Lu-J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA decrease, overall survival, and toxicity (dose-limiting myelosuppression) increased with higher doses.

BACKGROUND AND PURPOSE Dopamine and glutamate reciprocally regulate each other in some of the neurocircuits affected by Parkinson's disease (PD). The objective of this pilot study was to explore relationships between these neurotransmitter systems with positron emission tomography. METHODS The sample consisted of nine patients with PD and eight healthy volunteers (HVs). Dynamic images of the brain were acquired after the IV administration of ∼370 MBq (10 mCi) of [11 C]PE2i, a dopamine transporter (DaT) imaging agent, and ∼185 MBq (∼5 mCi) of [18 F]FPEB, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist. Multiple volumes of interest were semiautomatically placed on contemporaneously acquired MRI scans. Nondisplaceable binding potentials (BPND ) were calculated with the Logan reference tissue model using cerebellar white matter as the reference region. RESULTS The findings showed that average [18 F]FPEB BPND values were slightly more than 20% higher in PD than HVs in several mesocortical regions, including the bilateral putamen (P = .01), hippocampus (P = .02), and amygdala (P = .05). Average [11 C]PE2i BPND was significantly reduced by about half or more in patients with PD in the bilateral caudate (P < .001) and putamen (P < .001). CONCLUSIONS mGluR5 seems upregulated in strategic dopaminergic brain regions adversely affected by PD. The findings seem to confirm that DaT tracers are better discriminatory biomarkers for diagnosing PD; however, mGluR5 tracers might deserve further exploration as potential biomarkers of response in clinical trials.

Author(s): Kang, Yeona; Mozley, P David; Verma, Ajay; Schlyer, David; Henchcliffe, Claire; Gauthier, Susan A; Chiao, Ping C; He, Bin; Nikolopoulou, Anastasia; Logan, Jean; Sullivan, Jenna M; Pryor, Kane O; Hesterman, Jacob; Kothari, Paresh J; Vallabhajosula, Shankar | Abstract: BACKGROUND AND PURPOSE:Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [11 C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials. METHODS:The sample consisted of 20 participants with PD and 19 HVs. Two independent teams analyzed the data to compare the volume of distribution calculated using image-derived input functions (IDIFs), and binding potentials calculated using the Logan reference region model. RESULTS:With all methods, the higher signal-to-background in patients resulted in lower variability and better repeatability than in controls. We were able to use noninvasive techniques showing significantly increased uptake of PK in multiple brain regions of participants with PD compared to HVs. CONCLUSION:Although not necessarily reflecting absolute values, these noninvasive image analysis methods can discriminate between PD patients and HVs. We see a difference of 24% in the substantia nigra between PD and HV with a repeatability coefficient of 13%, showing that it will be possible to estimate responses in longitudinal, within subject trials of novel neuroprotective drugs.

Introduction Cerebrospinal fluid (CSF) molecular exchange with brain interstitial fluid (ISF) and periphery is implicated in neurological disorders but needs better quantitative clinical assessment approaches. Methods Following intrathecal (ITH) dosing via lumbar puncture, Technetium‐99 m (99mTc‐) diethylenetriaminepentaacetic acid (DTPA) imaging was used to quantify neuraxial spread, CSF‐brain molecular exchange, and CSF‐peripheral clearance in 15 normal human volunteers. The effect of experimental convection manipulation on these processes was also assessed. Results Rostral cranial 99mTc‐DTPA exposures were influenced by the volume of artificial CSF in the formulation. Signal translocation to the cranial cisterns and the brain parenchyma was observable by 3 hours. 99mTc‐DTPA penetrated cortical ISF but showed lower signal in deeper structures. Urinary 99mTc‐DTPA signal elimination was accelerated by higher formulation volumes and mechanical convection. Discussion Widely used for detecting CSF leaks, ITH 99mTc‐DTPA imaging can also become a useful clinical biomarker for measuring molecular exchange physiology between the CSF, brain, and periphery.

Gaucher disease (GD) is frequently associated with reduced plasma levels of low density lipoproteins, presumably due to increased catabolism of LDL. The purpose of this study was to determine the distribution of Tc-99m LDL (Tc-LDL) in Gaucher patients, and compare the findings to bone marrow distribution. Four patients with non-neuropathic Gaucher disease (type 1) underwent baseline whole body imaging at 4 and 24 h after injection of dialyzed autologous LDL labeled with 10-20 mCi Tc-99m-pertechnetate. Three of the four patients were treated with macrophage-targeted alglucerase (Ceredase). The LDL studies were compared to concurrent bone marrow scans performed with 10 mCi Tc-99m sulfur colloid (Tc-SC). Follow-up Tc-LDL and Tc-SC scans were obtained 12-14 months later. Tc-LDL activity was abnormally increased in the spleen and long bones of the upper and lower extremities. Liver activity was also increased. Prominent blood pool activity 4 h after injection mostly cleared on the 24-hour images. The distribution of Tc-SC was congruent with Tc-LDL activity. All patients had mild-to-moderate hepatomegaly and peripheral bone marrow expansion. One patient had been previously splenectomized and the remaining three had moderate-to-severe splenomegaly. Two of the three treated patients showed regression of peripheral bone marrow activity with therapy, along with a comparable decrease in Tc-LDL uptake. Our study with Tc-LDL and Tc-SC suggests that in patients with Gaucher disease native LDL is taken up by the reticuloendothelial system (RES) of the spleen and bone marrow in addition to increased uptake by the liver. This abnormal uptake (presumably by macrophages of the RES) may account for accelerated LDL catabolism and reduced plasma levels of LDL. Serial LDL studies can be performed, allowing for longitudinal follow-up after drug or enzyme therapies.

BACKGROUND The accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET; dual-head camera with attenuation correction) and Ga-67 scintigraphy was compared to identify disease sites in patients with Hodgkin disease (HD) and intermediate and high-grade non-Hodgkin lymphoma (NHL) at initial diagnosis or clinical recurrence. METHODS Fifty-one contemporaneous FDG-PET and Ga-67 scintigraphies were performed on patients with NHL (35 intermediate grade, 3 high grade) or HD (13 patients). Sites of disease were correlated on a site-by-site basis on FDG-PET and Ga-67 images. Tumor-to-background (T/B) ratios were obtained for both techniques. Discordant FDG-PET and Ga-67 findings were correlated with computed tomography findings or clinical evaluation including repeat FDG-PET scans obtained after therapy. RESULTS Fluorodeoxyglucose positron emission tomography was positive at all 158 sites in 51 patients compared with 113 sites in 41 positive studies with Ga-67 scintigraphy (single positron emission computed tomography [SPECT] and/or planar images). In 44 patients who had complete Ga-67 SPECT data on all tumor sites, FDG-PET was positive at 126 sites and Ga-67 SPECT was positive at 81 sites. Ga-67 SPECT failed to demonstrate disease at 45 sites (35.7%). In 10 of 44 patients, Ga-67 SPECT completely failed to detect any disease at 22 of 45 sites (17.5%) and partially identified disease sites at 23 of 45 sites (18.2%) in 11 patients regardless of the tumor site and histology. In these patients, the lesions measured between 0.6 and 14.0 cm by CT. Fluorodeoxyglucose positron emission tomography revealed higher stage disease in 13 patients compared with Ga-67 imaging. Tumor-to-background ratios were statistically different between the two techniques with higher ratios obtained with FDG-PET (P < 0.0001). CONCLUSIONS In imaging aggressive lymphoma and HD before therapy, FDG-PET has significantly higher site and patient sensitivity than Ga-67 scintigraphy (100% vs. 71.5% and 100% vs. 80.3%, respectively). The change in disease stage by FDG-PET may result in a change in therapy strategy. Cancer 2002;94:879–88. © 2002 American Cancer Society. DOI 10.1002/cncr.10336

Arachidonic acid (AA) is involved in signal transduction, neuroinflammation, and production of eicosanoid metabolites. The AA brain incorporation coefficient (K*) is quantifiable in vivo using [11 C]AA positron emission tomography, although repeatability remains undetermined. We evaluated K* estimates obtained with population-based metabolite correction (PBMC) and image-derived input function (IDIF) in comparison to arterial blood-based estimates, and compared repeatability. Eleven healthy volunteers underwent a [11 C]AA scan; five repeated the scan 6 weeks later, simulating a pre- and post-treatment study design. For all scans, arterial blood was sampled to measure [11 C]AA plasma radioactivity. Plasma [11 C]AA parent fraction was measured in 5 scans. K* was quantified using both blood data and IDIF, corrected for [11 C]AA parent fraction using both PBMC (from published values) and individually measured values (when available). K* repeatability was calculated in the test-retest subset. K* estimates based on blood and individual metabolites were highly correlated with estimates using PBMC with arterial input function (r = 0.943) or IDIF (r = 0.918) in the subset with measured metabolites. In the total dataset, using PBMC, IDIF-based estimates were moderately correlated with arterial input function-based estimates (r = 0.712). PBMC and IDIF-based K* estimates were ∼6.4% to ∼11.9% higher, on average, than blood-based estimates. Average K* test-retest absolute percent difference values obtained using blood data or IDIF, assuming PBMC for both, were between 6.7% and 13.9%, comparable to other radiotracers. Our results support the possibility of simplified [11 C]AA data acquisition through eliminating arterial blood sampling and metabolite analysis, while retaining comparable repeatability and validity.

BACKGROUND AND PURPOSE Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient’s seizure focus as identified by ictal and interictal 18Ffluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci.