Anatomic patterns of relapse and progression following treatment with 131 I-MIBG in relapsed or refractory neuroblastoma.

OBJECTIVES: Patients with metaiodobenzylguanidine (MIBG)-avid relapsed or refractory neuroblastoma after initial therapy may exhibit transient responses to salvage treatment with iodine-131 metaiodobenzylguanidine (131 I-MIBG). It is unclear whether disease progression following 131 I-MIBG treatment occurs in previously involved versus new anatomic sites of disease. Understanding this pattern of relapse will inform the use of consolidation therapy following 131 I-MIBG administration. METHODS: Patients with relapsed or refractory metastatic MIBG-avid neuroblastoma or ganglioneuroblastoma, who received single-agent 131 I-MIBG, had stable or responding disease 6-8 weeks following 131 I-MIBG, but subsequently experienced disease progression were included. MIBG scans were reviewed to establish anatomic and temporal evolution of MIBG-avid disease. RESULTS: A total of 84 MIBG-avid metastatic sites were identified immediately prior to MIBG therapy in a cohort of 12 patients. At first progression, a total of 101 MIBG-avid sites were identified, of which 69 (68%) overlapped with pre-treatment disease sites, while 32 (32%) represented anatomically new disease areas. Eight of 12 patients had one or more new MIBG-avid sites at first progression. Of the 69 involved sites at progression that overlapped with pre-treatment disease, 11 represented relapsed sites that had cleared following MIBG therapy, two were persistent but increasingly MIBG-avid, and 56 were stably persistent. CONCLUSIONS: Previously involved anatomic disease sites predominate at disease progression following 131 I-MIBG treatment. Nevertheless, the majority of patients progressed in at least one new anatomic disease site. This suggests that consolidation focal therapies targeting residual disease sites may be of limited benefit in preventing systemic disease progression following 131 I-MIBG treatment of relapsed or refractory neuroblastoma.

124I-MIBG PET/CT to Monitor Metastatic Disease in Children with Relapsed Neuroblastoma.

The metaiodobenzylguanidine (MIBG) scan is one of the most sensitive noninvasive lesion detection modalities for neuroblastoma. Unlike 123I-MIBG, 124I-MIBG allows high-resolution PET. We evaluated 124I-MIBG PET/CT for its diagnostic performance as directly compared with paired 123I-MIBG scans. Methods: Before 131I-MIBG therapy, standard 123I-MIBG imaging (5.2 MBq/kg) was performed on 7 patients, including whole-body (anterior-posterior) planar imaging, focused-field-of-view SPECT/CT, and whole-body 124I-MIBG PET/CT (1.05 MBq/kg). After therapy, 2 of 7 patients also completed 124I-MIBG PET/CT as well as paired 123I-MIBG planar imaging and SPECT/CT. One patient underwent 124I-MIBG PET/CT only after therapy. We evaluated all 8 patients who showed at least 1 123I-MIBG-positive lesion with a total of 10 scans. In 8 pairs, 123I-MIBG and 124I-MIBG were performed within 1 mo of each other. The locations of identified lesions, the number of total lesions, and the curie scores were recorded for the 123I-MIBG and 124I-MIBG scans. Finally, for 5 patients who completed at least 3 PET/CT scans after administration of 124I-MIBG, we estimated the effective dose of 124I-MIBG. Results:123I-MIBG whole-body planar scans, focused-field-of-view SPECT/CT scans, and whole-body 124I-MIBG PET scans found 25, 32, and 87 total lesions, respectively. There was a statistically significant difference in lesion detection for 124I-MIBG PET/CT versus 123I-MIBG planar imaging (P < 0.0001) and 123I-MIBG SPECT/CT (P < 0.0001). The curie scores were also higher for 124I-MIBG PET/CT than for 123I-MIBG planar imaging and SPECT/CT in 6 of 10 patients. 124I-MIBG PET/CT demonstrated better detection of lesions throughout the body, including the chest, spine, head and neck, and extremities. The effective dose estimated for patient-specific 124I-MIBG was approximately 10 times that of 123I-MIBG; however, given that we administered a very low activity of 124I-MIBG (1.05 MBq/kg), the effective dose was only approximately twice that of 123I-MIBG despite the large difference in half-lives (100 vs. 13.2 h). Conclusion: The first-in-humans use of low-dose 124I-MIBG PET for monitoring disease burden demonstrated tumor detection capability superior to that of 123I-MIBG planar imaging and SPECT/CT.

Technical Note: Simplified and practical pretherapy tumor dosimetry - A feasibility study for 131 I-MIBG therapy of neuroblastoma using 124 I-MIBG PET/CT.

PURPOSE: Radiation dose calculated on tumors for radiopharmaceutical therapy varies significantly from tumor to tumor and from patient to patient. Accurate estimation of radiation dose requires multiple time point measurements using radionuclide imaging modalities such as SPECT or PET. In this report, we show our technical development of reducing the number of scans needed for reasonable estimation of tumor and normal organ dose in our pretherapy imaging and dosimetry platform of 124 I-metaiodobenzylguanidine (MIBG) positron emission tomography/computed tomography (PET/CT) for 131 I-MIBG therapy of neuroblastoma. METHODS: We analyzed the simplest kinetic data, areas of two-time point data for five patients with neuroblastoma who underwent 3 or 4 times of 124 I-MIBG PET/CT scan prior to 131 I-MIBG therapy. The data for which we derived areas were percent of injected activity (%IA) and standardized uptake value of tumors. These areas were correlated with time-integrated activity coefficients (TIACs) from full data (3 or 4 time points). TIACs are direct correlates with radiation dose as long as the volume and the radionuclide are known. RESULTS: The areas of %IAs between data obtained from all the two-time points with time points 1 and 2 (day 0 and day 1), time points 2 and 3 (day 1 and day 2), and time points 1 and 3 (day 0 and day 2) showed reasonable correlation (Pearson's correlation coefficient |r| > 0.5) with not only tumor and organ TIACs but also tumor and organ absorbed doses. The tumor and organ doses calculated using %IA areas of time point 1 and time point 2 were our best fits at about 20% individual percent difference compared to doses calculated using 3 or 4 time points. CONCLUSIONS: We could achieve reasonable accuracy of estimating tumor doses for subsequent radiopharmaceutical therapy using only the two-time point imaging sessions. Images obtained from these time points (within the 48-h after administration of radiopharmaceutical) were also viewed as useful for diagnostic reading. Although our analysis was specific to 124 I-MIBG PET/CT pretherapy imaging data for 131 I-MIBG therapy of neuroblastoma and the number of imaging datasets was not large, this feasible methodology would generally be applicable to other imaging and therapeutic radionuclides with an appropriate data analysis similar to our analysis to other imaging and therapeutic radiopharmaceuticals.

A Deep Learning Model to Predict a Diagnosis of Alzheimer Disease by Using 18F-FDG PET of the Brain.

Purpose To develop and validate a deep learning algorithm that predicts the final diagnosis of Alzheimer disease (AD), mild cognitive impairment, or neither at fluorine 18 (18F) fluorodeoxyglucose (FDG) PET of the brain and compare its performance to that of radiologic readers. Materials and Methods Prospective 18F-FDG PET brain images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (2109 imaging studies from 2005 to 2017, 1002 patients) and retrospective independent test set (40 imaging studies from 2006 to 2016, 40 patients) were collected. Final clinical diagnosis at follow-up was recorded. Convolutional neural network of InceptionV3 architecture was trained on 90% of ADNI data set and tested on the remaining 10%, as well as the independent test set, with performance compared to radiologic readers. Model was analyzed with sensitivity, specificity, receiver operating characteristic (ROC), saliency map, and t-distributed stochastic neighbor embedding. Results The algorithm achieved area under the ROC curve of 0.98 (95% confidence interval: 0.94, 1.00) when evaluated on predicting the final clinical diagnosis of AD in the independent test set (82% specificity at 100% sensitivity), an average of 75.8 months prior to the final diagnosis, which in ROC space outperformed reader performance (57% [four of seven] sensitivity, 91% [30 of 33] specificity; P < .05). Saliency map demonstrated attention to known areas of interest but with focus on the entire brain. Conclusion By using fluorine 18 fluorodeoxyglucose PET of the brain, a deep learning algorithm developed for early prediction of Alzheimer disease achieved 82% specificity at 100% sensitivity, an average of 75.8 months prior to the final diagnosis. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Larvie in this issue.

Predictors of response, progression-free survival, and overall survival using NANT Response Criteria (v1.0) in relapsed and refractory high-risk neuroblastoma.

PURPOSE: The New Approaches to Neuroblastoma Therapy Response Criteria (NANTRC) were developed to optimize response assessment in patients with recurrent/refractory neuroblastoma. Response predictors and associations of the NANTRC version 1.0 (NANTRCv1.0) and prognostic factors with outcome were analyzed. METHODS: A retrospective analysis was performed of patients with recurrent/refractory neuroblastoma enrolled from 2000 to 2009 on 13 NANT Phase 1/2 trials. NANTRC overall response integrated CT/MRI (Response Evaluation Criteria in Solid Tumors [RECIST]), metaiodobenzylguanidine (MIBG; Curie scoring), and percent bone marrow (BM) tumor (morphology). RESULTS: Fourteen (6.9%) complete response (CR) and 14 (6.9%) partial response (PR) occurred among 203 patients evaluable for response. Five-year progression-free survival (PFS) was 16 ± 3%; overall survival (OS) was 27 ± 3%. Disease sites at enrollment included MIBG-avid lesions (100% MIBG trials; 84% non-MIBG trials), measurable CT/MRI lesions (48%), and BM (49%). By multivariable analysis, Curie score of 0 (P < 0.001), lower Curie score (P = 0.003), no measurable CT/MRI lesions (P = 0.044), and treatment on peripheral blood stem cell (PBSC) supported trials (P = 0.005) were associated with achieving CR/PR. Overall response of stable disease (SD) or better was associated with better OS (P < 0.001). In multivariable analysis, MYCN amplification (P = 0.037) was associated with worse PFS; measurable CT/MRI lesions (P = 0.041) were associated with worse OS; prior progressive disease (PD; P < 0.001/P < 0.001), Curie score ≥ 1 (P < 0.001; P = 0.001), higher Curie score (P = 0.048/0.037), and treatment on non-PBSC trials (P = < 0.001/0.003) were associated with worse PFS and OS. CONCLUSIONS: NANTRCv1.0 response of at least SD is associated with better OS in patients with recurrent/refractory neuroblastoma. Patient and tumor characteristics may predict response and outcome. Identifying these variables can optimize Phase 1/2 trial design to select novel agents for further testing.

Quantitative and Visual Assessments toward Potential Sub-mSv or Ultrafast FDG PET Using High-Sensitivity TOF PET in PET/MRI.

PURPOSE: Newer high-performance time-of-flight (TOF) positron emission tomography (PET) systems have the capability to preserve diagnostic image quality with low count density, while maintaining a high raw photon detection sensitivity that would allow for a reduction in injected dose or rapid data acquisition. To assess this, we performed quantitative and visual assessments of the PET images acquired using a highly sensitive (23.3 cps/kBq) large field of view (25-cm axial) silicon photomultiplier (SiPM)-based TOF PET (400-ps timing resolution) integrated with 3 T-MRI in comparison to PET images acquired on non-TOF PET/x-ray computed tomography (CT) systems. PROCEDURES: Whole-body 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT was acquired for 15 patients followed by whole body PET/magnetic resonance imaging (MRI) with an average injected dose of 325 ± 84 MBq. The PET list mode data from PET/MRI were reconstructed using full datasets (4 min/bed) and reduced datasets (2, 1, 0.5, and 0.25 min/bed). Qualitative assessment between PET/CT and PET/MR images were made. A Likert-type scale between 1 and 5, 1 for non-diagnostic, 3 equivalent to PET/CT, and 5 superior quality, was used. Maximum and mean standardized uptake values (SUVmax and SUVmean) of normal tissues and lesions detected were measured and compared. RESULTS: Mean visual assessment scores were 3.54 ± 0.32, 3.62 ± 0.38, and 3.69 ± 0.35 for the brain and 3.05 ± 0.49, 3.71 ± 0.45, and 4.14 ± 0.44 for the whole-body maximum intensity projections (MIPs) for 1, 2, and 4 min/bed PET/MR images, respectively. The SUVmean values for normal tissues were lower and statistically significant for images acquired at 4, 2, 1, 0.5, and 0.25 min/bed on the PET/MR, with values of - 18 ± 28 % (p < 0.001), - 16 ± 29 % (p = 0.001), - 16 ± 31 % (p = 0.002), - 14 ± 35 % (p < 0.001), and - 13 ± 34 % (p = 0.002), respectively. SUVmax and SUVpeak values of all lesions were higher and statistically significant (p < 0.05) for 4, 2, 1, 0.50, and 0.25 min/bed PET/MR datasets. CONCLUSION: High-sensitivity TOF PET showed comparable but still better visual image quality even at a much reduced activity in comparison to lower-sensitivity non-TOF PET. Our data translates to a seven times reduction in either injection dose for the same time or total scan time for the same injected dose. This "ultra-sensitivity" PET system provides a path to clinically acceptable extremely low-dose FDG PET studies (e.g., sub 1 mCi injection or sub-mSv effective dose) or PET studies as short as 1 min/bed (e.g., 6 min of total scan time) to cover whole body without compromising diagnostic performance.

Effect of Time-of-Flight and Regularized Reconstructions on Quantitative Measurements and Qualitative Assessments in Newly Diagnosed Prostate Cancer With 18F-Fluorocholine Dual Time Point PET/MRI.

Recent technical advances in positron emission tomography/magnetic resonance imaging (PET/MRI) technology allow much improved time-of-flight (TOF) and regularized iterative PET reconstruction regularized iterative reconstruction (RIR) algorithms. We evaluated the effect of TOF and RIR on standardized uptake values (maximum and peak SUV [SUVmax and SUVpeak]) and their metabolic tumor volume dependencies and visual image quality for 18F-fluorocholine PET/MRI in patients with newly diagnosed prostate cancer. Fourteen patients were administered with 3 MBq/kg of 18F-fluorocholine and scanned dynamically for 30 minutes. Positron emission tomography images were divided to early and late time points (1-6 minutes summed and 7-30 minutes summed). The values of the different SUVs were documented for dominant PET-avid lesions, and metabolic tumor volume was estimated using a 50% isocontour and SUV threshold of 2.5. Image quality was assessed via visual acuity scoring (VAS). We found that incorporation of TOF or RIR increased lesion SUVs. The lesion to background ratio was not improved by TOF reconstruction, while RIR improved the lesion to background ratio significantly ( P < .05). The values of the different VAS were all significantly higher ( P < .05) for RIR images over TOF, RIR over non-TOF, and TOF over non-TOF. In conclusion, our data indicate that TOF or RIR should be incorporated into current protocols when available.

In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis.

BACKGROUND: Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine-18-labeled 9-ß-d-arabinofuranosylguanine ([18F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant-induced arthritis (AIA) small animal model. METHODS: Using positron emission tomography-computed tomography imaging, uptake of [18F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry. RESULTS: Differential uptake of [18F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry. CONCLUSION: [18F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials.

11C-L-methyl methionine dynamic PET/CT of skeletal muscle: response to protein supplementation compared to L-[ring 13C6] phenylalanine infusion with serial muscle biopsy.

OBJECTIVE: The objective of this study was to determine if clinical dynamic PET/CT imaging with 11C-L-methyl-methionine (11C-MET) in healthy older women can provide an estimate of tissue-level post-absorptive and post-prandial skeletal muscle protein synthesis that is consistent with the more traditional method of calculating fractional synthesis rate (FSR) of muscle protein synthesis from skeletal muscle biopsies obtained during an infusion of L-[ring 13C6] phenylalanine (13C6-Phe). METHODS: Healthy older women (73 ± 5 years) completed both dynamic PET/CT imaging with 11C-MET and a stable isotope infusion of 13C6-Phe with biopsies to measure the skeletal muscle protein synthetic response to 25 g of a whey protein supplement. Graphical estimation of the Patlak coefficient Ki from analysis of the dynamic PET/CT images was employed as a measure of incorporation of 11 C-MET in the mid-thigh muscle bundle. RESULTS: Post-prandial values [mean ± standard error of the mean (SEM)] were higher than post-absorptive values for both Ki (0.0095 ± 0.001 vs. 0.00785 ± 0.001 min-1, p < 0.05) and FSR (0.083 ± 0.008 vs. 0.049 ± 0.006%/h, p < 0.001) in response to the whey protein supplement. The percent increase in Ki and FSR in response to the whey protein supplement was significantly correlated (r = 0.79, p = 0.015). CONCLUSIONS: Dynamic PET/CT imaging with 11C-MET provides an estimate of the post-prandial anabolic response that is consistent with a traditional, invasive stable isotope, and muscle biopsy approach. These results support the potential future use of 11C-MET imaging as a non-invasive method for assessing conditions affecting skeletal muscle protein synthesis.

Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine.

SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest-affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks.

The utility of radioisotope cisternography in low CSF/volume syndromes compared to myelography.

Objective The objective of this report is to compare computed tomography (CT) and magnetic resonance (MR) myelography with radioisotope cisternography (RC) for detection of spinal cerebrospinal (CSF) leaks. Methods We retrospectively reviewed 12 spontaneous intracranial hypotension (SIH) patients; CT and RC were performed simultaneously. Three patients had MR myelography. Results CT and/or MR myelography identified CSF leaks in four of 12 patients. RC detected spinal leaks in all three patients confirmed by CT myelography; RC identified the CSF leak location in two of three cases, and these were due to osteophytic spicules and/or discs. RC showed only enlarged perineural activity. Only intrathecal gadolinium MR myelography clearly identified a slow leak from a perineural cyst. In eight remaining cases, the leak site was unknown; however, two of these showed indirect signs of CSF leak on RC. CSF slow leaks from perineural cysts were the most common presumed etiology; and the cysts were best visualized on myelography. Conclusion RC is comparable to CT myelography but has spatial limitations and should be limited to atypical cases.

Radioembolization with 90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: final report of a prospective pilot study.

BACKGROUND: This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of radioembolization of liver-dominant metastatic gastrointestinal cancer using 90Y glass microspheres. METHODS: Between June 2010 and October 2013, 42 adult patients (26 men, 16 women; median age 60 years) with metastatic chemotherapy-refractory unresectable colorectal (n=21), neuroendocrine (n=11), intrahepatic bile duct (n=7), pancreas (n=2), and esophageal (n=1) carcinomas underwent 60 lobar or segmental administrations of 90Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for up to 5.5 years after radioembolization. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Time to maximum response, response duration, progression-free survival (PFS) (hepatic and extrahepatic), and overall survival (OS) were measured. RESULTS: Median target dose and activity were 109.4 Gy and 2.6 GBq per treatment session, respectively. Majority of clinical AE were grade 1 or 2 in severity. Patients with colorectal cancer had hepatic objective response rate (ORR) of 25% and a hepatic disease control rate (DCR) of 80%. Median PFS and OS were 1.0 and 4.4 months, respectively. Patients with neuroendocrine tumors (NET) had hepatic ORR and DCR of 73% and 100%, respectively. Median PFS was 8.9 months for this cohort. DCR and median PFS and OS for patients with cholangiocarcinoma were 86%, 1.1 months, and 6.7 months, respectively. CONCLUSIONS: 90Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.

Glioma FMISO PET/MR Imaging Concurrent with Antiangiogenic Therapy: Molecular Imaging as a Clinical Tool in the Burgeoning Era of Personalized Medicine.

The purpose of this article is to provide a focused overview of the current use of positron emission tomography (PET) molecular imaging in the burgeoning era of personalized medicine in the treatment of patients with glioma. Specifically, we demonstrate the utility of PET imaging as a tool for personalized diagnosis and therapy by highlighting a case series of four patients with recurrent high grade glioma who underwent 18F-fluoromisonidazole (FMISO) PET/MR (magnetic resonance) imaging through the course of antiangiogenic therapy. Three distinct features were observed from this small cohort of patients. First, the presence of pseudoprogression was retrospectively associated with the absence of hypoxia. Second, a subgroup of patients with recurrent high grade glioma undergoing bevacizumab therapy demonstrated disease progression characterized by an enlarging nonenhancing mass with newly developed reduced diffusion, lack of hypoxia, and preserved cerebral blood volume. Finally, a reduction in hypoxic volume was observed concurrent with therapy in all patients with recurrent tumor, and markedly so in two patients that developed a nonenhancing reduced diffusion mass. This case series demonstrates how medical imaging has the potential to influence personalized medicine in several key aspects, especially involving molecular PET imaging for personalized diagnosis, patient specific disease prognosis, and therapeutic monitoring.

Impact of Whole-Body Radiation Dose on Response and Toxicity in Patients With Neuroblastoma After Therapy With 131 I-Metaiodobenzylguanidine (MIBG).

BACKGROUND: (131) I-metaiodobenzylguanidine ((131) I-MIBG) is a targeted radiopharmaceutical for patients with neuroblastoma. Despite its tumor-specific uptake, the treatment with (131) I-MIBG results in whole-body radiation exposure. Our aim was to correlate whole-body radiation dose (WBD) from (131) I-MIBG with tumor response, toxicities, and other clinical factors. METHODS: This retrospective cohort analysis included 213 patients with high-risk neuroblastoma treated with (131) I-MIBG at UCSF Benioff Children's Hospital between 1996 and 2015. WBD was determined from radiation exposure rate measurements. The relationship between WBD ordered tertiles and variables were analyzed using Cochran-Mantel-Haenszel test of trend, Kruskal-Wallis test, and one-way analysis of variance. Correlation between WBD and continuous variables was analyzed using Pearson correlation and Spearman rank correlation. RESULTS: WBD correlated with (131) I-MIBG administered activity, particularly with (131) I-MIBG per kilogram (P < 0.001). Overall response rate did not differ significantly among the three tertiles of WBD. Correlation between response by relative Curie score and WBD was of borderline significance, with patients receiving a lower WBD showing greater reduction in osteomedullary metastases by Curie score (rs = 0.16, P = 0.049). There were no significant ordered trends among tertiles in any toxicity measures (grade 4 neutropenia, thrombocytopenia < 20,000/µl, and grade > 1 hypothyroidism). CONCLUSIONS: This study showed that (131) I-MIBG activity per kilogram correlates with WBD and suggests that activity per kilogram will predict WBD in most patients. Within the range of activities prescribed, there was no correlation between WBD and either response or toxicity. Future studies should evaluate tumor dosimetry, rather than just WBD, as a tool for predicting response following therapy with (131) I-MIBG.

Assessing Biological Response to Bevacizumab Using 18F-Fluoromisonidazole PET/MR Imaging in a Patient with Recurrent Anaplastic Astrocytoma.

We present our initial experience in using single modality fluoromisonidazole (FMISO) PET/MR imaging to noninvasively evaluate the biological effects induced by bevacizumab therapy in a patient treated for recurrent high grade glioma. In this index patient, bevacizumab therapy resulted in the development of nonenhancing tumor characterized by reduced diffusion and markedly decreased FMISO uptake in the setting of maintained CBF and CBV. These observations suggest that the dynamic biological interplay between tissue hypoxia and vascular normalization occurring within treated recurrent high grade glioma can be captured utilizing FMISO PET/MR imaging.

Bone remodeling after MR imaging-guided high-intensity focused ultrasound ablation: evaluation with MR imaging, CT, Na(18)F-PET, and histopathologic examination in a swine model.

PURPOSE: To serially monitor bone remodeling in the swine femur after magnetic resonance (MR) imaging-guided high-intensity focused ultrasound (HIFU) ablation with MR imaging, computed tomography (CT), sodium fluorine 18 (Na(18)F)-positron emission tomography (PET), and histopathologic examination, as a function of sonication energy. MATERIALS AND METHODS: Experimental procedures received approval from the local institutional animal care and use committee. MR imaging-guided HIFU was used to create distal and proximal ablations in the right femurs of eight pigs. The energy used at the distal target was higher (mean, 419 J; range, 390-440 J) than that used at the proximal target (mean, 324 J; range, 300-360 J). Imaging was performed before and after ablation with 3.0-T MR imaging and 64-section CT. Animals were reevaluated at 3 and 6 weeks with MR imaging (n = 8), CT (n = 8), Na(18)F-PET (n = 4), and histopathologic examination (n = 4). Three-dimensional ablation lengths were measured on contrast material-enhanced MR images, and bone remodeling in the cortex was measured on CT images. RESULTS: Ablation sizes at MR imaging 3 and 6 weeks after MR imaging-guided HIFU ablation were similar between proximal (low-energy) and distal (high-energy) lesions (average, 8.7 × 21.9 × 16.4 mm). However, distal ablation lesions (n = 8) demonstrated evidence of subperiosteal new bone formation at CT, with a subtle focus of new ossification at 3 weeks and a larger focus of ossification at 6 weeks. New bone formation was associated with increased uptake at Na(18)F-PET in three of four animals; this was confirmed at histopathologic examination in four of four animals. CONCLUSION: MR imaging-guided HIFU ablation of bone may result in progressive remodeling, with both subcortical necrosis and subperiosteal new bone formation. This may be related to the use of high energies. MR imaging, CT, and PET are suitable noninvasive techniques to monitor bone remodeling after MR imaging-guided HIFU ablation.

Patient-specific dosimetry using pretherapy [¹²4I]m-iodobenzylguanidine ([¹²4I]mIBG) dynamic PET/CT imaging before [¹³¹I]mIBG targeted radionuclide therapy for neuroblastoma.

PURPOSE: Iodine-131-m-iodobenzylguanidine ([(131)I]mIBG)-targeted radionuclide therapy (TRT) is a standard treatment for recurrent or refractory neuroblastoma with response rates of 30-40 %. The aim of this study is to demonstrate patient-specific dosimetry using quantitative [(124)I]mIBG positron emission tomography/X-ray computed tomography (PET/CT) imaging with a GEometry ANd Tracking 4 (Geant4)-based Monte Carlo method for better treatment planning. PROCEDURES: A Monte Carlo dosimetry method was developed using the Geant4 toolkit with voxelized anatomical geometry and source distribution as input. The presegmented hybrid computational human phantoms developed by the University of Florida and the National Cancer Institute (UF/NCI) were used as a surrogate to characterize the anatomy of a given patient. S values for I-131 were estimated by the phantoms coupled with Geant4 and compared with those estimated by OLINDA|EXM and MCNPX for the newborn model. To obtain patient-specific biodistribution of [(131)I]mIBG, a 10-year-old girl with relapsed neuroblastoma was imaged with [(124)I]mIBG PET/CT at four time points prior to the planned [(131)I]mIBG TRT. The organ- and tumor-absorbed doses of the clinical case were estimated with the Geant4 method using the modified UF/NCI 10-year-old phantom with tumors and the patient-specific residence time. RESULTS: For the newborn model, the Geant4 S values were consistent with the MCNPX S values. The S value ratio of the Geant4 method to OLINDA|EXM ranged from 0.08 to 6.5 of all major organs. The [(131)I]mIBG residence time quantified from the pretherapy [(124)I]mIBG PET/CT imaging of the 10-year-old patient was mostly comparable to those previously reported. Organ-absorbed dose for the salivary glands was 98.0 Gy, heart wall 36.5 Gy, and liver 34.3 Gy, while tumor-absorbed dose ranged from 143.9 to 1,641.3 Gy in different sites. CONCLUSIONS: Patient-specific dosimetry for [(131)I]mIBG TRT was accomplished using pretherapy [(124)I]mIBG PET/CT imaging and a Geant4-based Monte Carlo dosimetry method. The Geant4 method with quantitative pretherapy imaging can provide dose estimates to normal organs and tumors with more realistic simulation geometry, and thus may improve treatment planning for [(131)I]mIBG TRT.

Likelihood of bone recurrence in prior sites of metastasis in patients with high-risk neuroblastoma.

PURPOSE/OBJECTIVES: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. METHODS AND MATERIALS: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. RESULTS: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. CONCLUSIONS: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore, they raise the hypothesis that metastatic sites appearing to clear with induction chemotherapy may also benefit from radiotherapeutic treatment modalities (external beam radiation or (131)I-MIBG).

90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: a pilot study.

PURPOSE: This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of treatment of liver-dominant metastatic gastrointestinal cancer using (90)Y glass microspheres. METHODS: Between June 2010 and November 2012, 30 adult patients (22 men, eight women; median age 61 years) with metastatic chemotherapy-refractory unresectable colorectal (n = 15), neuroendocrine (n = 9), intrahepatic cholangiocarcinoma (n = 3), pancreas (n = 2), and esophageal (n = 1) carcinomas underwent 45 lobar or segmental administrations of (90)Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for 6 months after each treatment. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1. Time to maximum response, response duration, progression-free survival (hepatic and extrahepatic), and overall survival were measured. RESULTS: Median target dose and activity were 111.6 Gy and 2.5 GBq per treatment session, respectively. All but three clinical AE were grade 1 or 2 in severity. Serious AE included an unplanned hospital admission for carcinoid crisis, grade 3 vomiting, and grade 4 gastric ulcer. Patients with colorectal cancer had hepatic objective response rate (ORR) of 27 % and a disease control rate (DCR) of 73 %. Median progression-free and overall survival were 1.0 and 4.9 months, respectively. Patients with neuroendocrine tumors had hepatic ORR and DCR of 78 % and 100 %, respectively. Median progression-free survival was 18.5 months for this cohort. CONCLUSIONS: Y glass microspheres device has a favorable safety profile and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.