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Introduction: Lutetium-177 (177Lu)-DOTATATE received FDA approval in 2018 to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs). Little data are available on response and outcomes for well-differentiated (WD) high-grade (HG) NETs treated with 177Lu-DOTATATE. Materials and Methods: Patients with WD HG NETs treated with 177Lu-DOTATATE at MSK from 2018 to 2020 were identified. Demographics, response (RECIST 1.1), and progression-free survival (PFS) were determined. Next-generation sequencing (NGS) was performed in the archival tumor. Results: Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22–56). Thirteen patients (68%) completed all four 177Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7–20.9). Most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; G3/4, 1 patient, 5%), anemia (7 patients, 37%; G3/4, 2 patients, 11%), leukopenia (6 patients, 32%; G3/4, 0 patients), and liver function test elevation (4 patients, 21%; G3/4, 0 patients). NGS results were available from 13/19 tumors (68%). The most observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations identified. Conclusion: We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with 177Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations.

Dose selection details, T cell activation/exhaustion flow assay and multiplex cytokine measurements.

Best overall response by RECIST 1.1 and PCWG2 for bone.

Supplemental Figure 2. Tumor PU-H71 retention at 24 hours post-injection (quantified by standard uptake value) is not explained by plasma radiotracer exposure (quantified by plasma AUC from 10 min to 4 h post-injection, see Methods), as indicated by Spearman Test R-value.

Tumor PU-H71 retention at 24 hours post-injection (quantified by standard uptake value) is not explained by plasma radiotracer exposure (quantified by plasma AUC from 10 min to 4 h post-injection, see Methods), as indicated by Spearman Test R-value.

Supplemental Figure 1. Tumor retention of PU-H71 tracer varied considerably between patients. Tumor retention expressed as tumor:bloodpool SUV ratio (y-axis) measured on PET at 4 and 24 hours post tracer-injection.

Purpose:Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855.Patients and Methods:Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria.Results:Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82–302 days) and three patients with mCRPC (25%; duration, 50–124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase.Conclusions:LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.

Assessment of tumor associated macrophage depletion using macrophage gene signature. The downward trend (pre vs post, indicating depletion of TAMs) of the gene signature did not appear pronounced in any of the patient samples except for patient C.

Supplementary figures and methods

PET detects subcentimeter PU-H71 retention by breast cancer metastases. 65-year-old female with stage IV breast cancer, off-treatment. 124I-PU-H71 PET (right), CT (left), and fusion PET/CT (middle) images show corresponding axial planes of chest, obtained 24 hours post-injection. Tracer has cleared from blood (asterisk, aorta) with sustained PU-H71 retention by biopsy-proven subcentimeter pulmonary metastasis (arrow) and left internal mammary and mediastinal nodal metastases (arrowheads).

Purpose:124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging.Experimental Design:Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, Results:124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects.Conclusions:Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.

PET detects PU-H71 retention by lymphoma. 62-year-old female with non-Hodgkin lymphoma. 124I-PU-H71 fusion PET/CT (left), CT (middle), and F-18 FDG fusion PET/CT (right) images show corresponding axial planes of chest. 124I-PU-H71 PET/CT obtained 24 hours post-injection. Mediastinal lymphomatous adenopathy (arrowhead) demonstrates PU-H71 avidity and FDG avidity.

Purpose: Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855. Patients and Methods: Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria. Results: Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82–302 days) and three patients with mCRPC (25%; duration, 50–124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase. Conclusions: LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.

Purpose: 124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. Experimental Design: Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, Results: 124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects. Conclusions: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.

Fluoride-18 sodium fluoride (18F-NaF) localizes in microcalcifications in atheroma. The microcalcifications may aggregate, passing the resolution threshold to visualize on computed tomography (CT). We evaluated serial NaF positron emission tomography (PET)-CT scans to determine the temporal relationship between vascular NaF uptake and CT evident calcification in the abdominal aorta. Prostate cancer patients who had at least 3 NaF PET-CT scans over at least 1.5 years were retrospectively enrolled. Regions of interest were traced in the abdominal aorta on both PET and CT images, excluding skeletal NaF activity. The maximum standardized uptake value (SUVmax) of NaF and the density and volume of calcium (exceeding 130 HU) were summed and divided by the number of slices to produce the SUVmax/slice and the mm3·slice−1 of calcium. Of 437 patients, 45 patients met criteria. NaF uptake waxed and waned between scans, while the calcium volume plateaued or increased over time. NaF uptake correlated with calcium volume on the baseline scan (P = .60

Six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a relatively newly identified target in prostate cancer. We evaluated the ability of PET/CT with (89)Zr-DFO-MSTP2109A, an antibody that recognizes STEAP1, to detect lesions in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Nineteen mCRPC patients were prospectively imaged using approximately 185 MBq/10 mg of (89)Zr-DFO-MSTP2109A. (89)Zr-DFO-MSTP2109A PET/CT images obtained 4–7 d after injection were compared with bone and CT scans. Uptake in lesions was measured. Fifteen patients were treated with an antibody–drug conjugate (ADC) based on MSTP2109A; ADC treatment–related data were correlated with tumor uptake by PET imaging. Bone or soft-tissue biopsy samples were evaluated. Results: No significant toxicity occurred. Excellent uptake was observed in bone and soft-tissue disease. Median SUV(max) was 20.6 in bone and 16.8 in soft tissue. Sixteen of 17 lesions biopsied were positive on (89)Zr-DFO-MSTP2109A, and all sites were histologically positive (1 on repeat biopsy). Bayesian analysis resulted in a best estimate of 86% of histologically positive lesions being true-positive on imaging (95% confidence interval, 75%–100%). There was no correlation between SUV(max) tumor uptake and STEAP1 immunohistochemistry, survival after ADC treatment, number of ADC treatment cycles, or change in prostate-specific antigen level. Conclusion: (89)Zr-DFO-MSTP2109A is well tolerated and shows localization in mCRPC sites in bone and soft tissue. Given the high SUV in tumor and localization of a large number of lesions, this reagent warrants further exploration as a companion diagnostic in patients undergoing STEAP1-directed therapy.

Up to 90% of men with metastatic castration-resistant prostate cancer (mCRPC) will have a distribution of disease that includes bone metastases demonstrated on a Technetium-99m (99mTc-MDP) bone scan. The Prostate Cancer Working Group 2 and 3 Consensus Criteria standardized the criteria for assessing progression based on the development of new lesions. These criteria have been recognized by regulatory authorities for drug approval. The bone scan index (BSI) is a method to quantitatively measure the burden of bony disease, and can assess both disease progression and regression. The automated BSI (aBSI) is a method of computer analysis to assess BSI, and is being qualified as a clinical trials endpoint. Manual searching was used to identify the literature on BSI and aBSI. We summarize the most relevant aspects of the retrospective and prospective studies evaluating aBSI measurements, and provide a critical discussion on the potential advantages and caveats of aBSI. The development of neural artificial networks (EXINI boneBSI) to automatically determine the BSI reduces the turnaround time for assessing BSI with high reproducibility and accuracy. Several studies showed that the concordance between aBSI and BSI, as well as the interobserver concordance of aBSI, was >0.95. In a phase 3 assessment of aBSI, a doubling value increased the risk of death in 20%, pre-treatment aBSI values independently correlated with overall survival (OS) and time to symptomatic progression. Retrospective studies suggest that a decrease in aBSI after treatment may correlate with higher survival when compared with increasing aBSI. aBSI provides a quantitative measurement that is feasible, reproducible, and in analyses to date correlates with OS and symptomatic progression. These findings support the aBSI to risk-stratify men with mCRPC for clinical trial enrollment. Future studies quantifying aBSI change over time as an intermediate endpoint for evaluating new systemic therapies are needed.

Integration of artificial intelligence (AI) applications within clinical workflows is an important step for leveraging developed AI algorithms. In this report, generalizable components for deploying AI systems into clinical practice are described that were implemented in a clinical pilot study using lymphoscintigraphy examinations as a prospective use case (July 1, 2019–October 31, 2020). Deployment of the AI algorithm consisted of seven software components, as follows: (a) image delivery, (b) quality control, (c) a results database, (d) results processing, (e) results presentation and delivery, (f) error correction, and (g) a dashboard for performance monitoring. A total of 14 users used the system (faculty radiologists and trainees) to assess the degree of satisfaction with the components and overall workflow. Analyses included the assessment of the number of examinations processed, error rates, and corrections. The AI system processed 1748 lymphoscintigraphy examinations. The system enabled radiologists to correct 146 AI results, generating real-time corrections to the radiology report. All AI results and corrections were successfully stored in a database for downstream use by the various integration components. A dashboard allowed monitoring of the AI system performance in real time. All 14 survey respondents “somewhat agreed” or “strongly agreed” that the AI system was well integrated into the clinical workflow. In all, a framework of processes and components for integrating AI algorithms into clinical workflows was developed. The implementation described could be helpful for assessing and monitoring AI performance in clinical practice. Keywords: PACS, Computer Applications-General (Informatics), Diagnosis © RSNA, 2021

Many effective forms of treatment are currently available for cancer patients including surgery, systemic therapy (e.g. chemotherapy, immunotherapy), bone marrow and stem cell transplants, and radiation therapy. Each of these therapeutic categories confers substantial benefit and some degree of cardiovascular risk. Careful attention is warranted especially in patients with known heart disease.

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 ).

PurposeStarting from a broad-based needs assessment and utilizing an image analysis algorithm (IAA) developed at our institution, the purpose of this study was to define generalizable building blocks necessary for the integration of any IAA into a clinical practice.MethodsAn IAA was developed in our institution to process lymphoscintigraphy exams. A team of radiologists defined a set of building blocks for integration of this IAA into clinical workflow. The building blocks served the following roles: (1) Timely delivery of images to the IAA, (2) quality control, (3) IAA results processing, (4) results presentation & delivery, (5) IAA error correction, (6) system performance monitoring, and (7) active learning. Utilizing these modules, the lymphoscintigraphy IAA was integrated into the clinical workflow at our institution. System performance was tested over a 1 month period, including assessment of number of exams processed and delivered, and error rates and corrections.ResultsFrom June 26-July 27, 2019, the building blocks were used to integrate IAA results from 132 lymphoscintigraphy exams into the clinical workflow, representing 100% of the exams performed during the time period. The system enabled radiologists to correct 21 of the IAA results. All results and corrections were successfully stored in a database. A dashboard allowed the development team to monitor system performance in real-time.ConclusionsWe describe seven building blocks that optimize the integration of IAAs into clinical workflow. The implementation of these building blocks in this study can be used to inform development of more robust, standards-based solutions.

Optimal clinical development of new cancer therapies targeting tumor vasculature requires new target-specific response assays. This clinical study examined the test-retest repeatability of SPECT as an in vivo assay of angiogenic hepatic tumor microvasculature using an intraarterial infusion ofPatients with primary or secondary cancerous liver tumors with HAI pump-catheter implants placed for HAI chemotherapy underwent hepatic SPECT after separate arterial infusions of 37 and 185 MBq ofTest-retest HAI pump SPECT yielded highly repeatable measurements in quantitative indexes of tumor microvasculature. Variability in repeat test-retest measurements was small relative to the range of observed measurements between different tumors. The total hepatic tumor microvascular MAA accumulation (percentage injected dose) proved most repeatable, with test-retest value quotients near unity (quotients: median, 1.10 ± 0.09 [SD]; range, 1.03-1.32; 95% CI, 1.07-1.19) and 1.6% CR. Tumor MAA uptake values ranged from 5% to 18% injected dose.This article describes the precision of HAI SPECT as a quantitative biomarker of tumor microvasculature under conditions of repeatability. The results support clinical testing of HAI SPECT as a radiologic response biomarker for angiotropic tumor therapy.

Fluoride-18 sodium fluoride (Prostate cancer patients who had at least 3 NaF PET-CT scans over at least 1.5 years were retrospectively enrolled. Regions of interest were traced in the abdominal aorta on both PET and CT images, excluding skeletal NaF activity. The maximum standardized uptake value (SUVOf 437 patients, 45 patients met criteria. NaF uptake waxed and waned between scans, while the calcium volume plateaued or increased over time. NaF uptake correlated with calcium volume on the baseline scan (P = .60, .0001Abdominal aortic NaF uptake varied over time. NaF uptake on the baseline scans and high NaF uptake on the serial scans preceded an increase in calcium volume, especially by 1.0-1.5 years. Persistently high NaF uptake was associated with a greater increment in calcium volume than patients with transiently elevated or persistently low fluoride uptake.

Six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a newly identified target in prostate cancer. The use of radiolabeled STEAP1-targeting antibodies with positron emission tomography (PET) may allow for detection of sites of metastatic prostate cancer and may refine patient selection for antigen-directed therapies. This was a prospective study in seven patients with metastatic castration-resistant prostate cancer who had at least one archival biopsy that was STEAP1-positive by immunohistochemistry. Patients received intravenous injections of ~185 MBq and 10 mg of [(89)Zr]Zr-DFO-MSTP2109A, a humanized IgG1 monoclonal antibody directed against STEAP1. PET/CT images, blood samples, and whole-body counts were monitored longitudinally in six patients. Here we report on safety, biodistribution, pharmacokinetics, dose estimates to normal tissues, and initial tumor targeting for this group of patients. There was no significant acute or sub-acute toxicity. Favorable biodistribution and enhanced lesion uptake (in both bone and soft tissue) was observed on imaging using a mass of 10 mg of DFO-MSTP2109A. The best lesion discrimination was seen at the latest imaging time, a median of six days post-administration. Pharmacokinetics showed a median serum T (1/2) Beta of 198 h, volume of central compartment of 3.54 L (similar to plasma volume), and clearance of 19.7 mL/h. The median biologic T ½ for whole-body retention was 469 h. The highest mean absorbed doses to normal organs (mGy/MBq) were 1.18, 1.11, 0.78, 0.73, and 0.71 for liver, heart wall, lung, kidney, and spleen, respectively. Excellent targeting of metastatic prostate sites in both bone and soft tissue was observed, with an optimal imaging time of six days post-administration. The liver and heart were the normal organs that experienced the highest absorbed doses. The pharmacokinetics were similar to other antibodies without major cross-reactivity with normal tissues. A more detailed analysis of lesion targeting in a larger patient population with correlation to immunohistology and standard imaging modalities has been reported.

Background Cardiac magnetic resonance ( CMR) differentiates neoplasm from thrombus via contrast enhancement; positron emission tomography ( PET) assesses metabolism. The relationship between CMR contrast enhancement and metabolism on PET is unknown. Methods and Results The population included 121 cancer patients undergoing CMR and 18 F‐fluorodeoxyglucose ( 18 F‐ FDG) – PET , including 66 with cardiac masses and cancer‐matched controls. Cardiac mass etiology (neoplasm, thrombus) on CMR was defined by late gadolinium enhancement; PET was read blinded to CMR for diagnostic performance, then colocalized to measure FDG avidity. Of CMR ‐evidenced thrombi (all nonenhancing), none were detected by PET . For neoplasm, PET yielded reasonable sensitivity (70–83%) and specificity (75–88%). Lesions undetected by PET were more likely to be highly mobile ( P =0.001) despite similar size ( P =0.33). Among nonmobile neoplasms, PET sensitivity varied in relation to extent of CMR ‐evidenced avascularity; detection of diffusely enhancing or mixed lesions was higher versus predominantly avascular neoplasms (87% versus 63%). Colocalized analyses demonstrated 2‐ to 4‐fold higher FDG uptake in neoplasm versus thrombus ( P FDG uptake decreased stepwise when neoplasms were partitioned based on extent of avascularity on late gadolinium enhancement CMR ( P ≤0.001). Among patients with neoplasm, signal‐to‐noise ratio on late gadolinium enhancement CMR moderately correlated with standardized uptake values on PET ( r =0.42–0.49, P CMR ‐evidenced neoplasm versus controls (hazard ratio: 1.99 [95% CI, 1.1–3.6]; P =0.03) despite nonsignificant differences when partitioned via FDG avidity (hazard ratio: 1.56 [95% CI, 0.85–2.74]; P =0.16). Among FDG‐positive neoplasms detected concordantly with CMR , mortality risk versus cancer‐matched controls was equivalently increased (hazard ratio: 2.12 [95% CI, 1.01–4.44]; P =0.047). Conclusions CMR contrast enhancement provides a criterion for neoplasm that parallels FDG ‐evidenced metabolic activity and stratifies prognosis. Extent of tissue avascularity on late gadolinium enhancement CMR affects cardiac mass identification by FDG ‐ PET .

Up to 90% of men with metastatic castration-resistant prostate cancer (mCRPC) will have a distribution of disease that includes bone metastases demonstrated on a Technetium-99m (Manual searching was used to identify the literature on BSI and aBSI. We summarize the most relevant aspects of the retrospective and prospective studies evaluating aBSI measurements, and provide a critical discussion on the potential advantages and caveats of aBSI.The development of neural artificial networks (EXINI boneBSI) to automatically determine the BSI reduces the turnaround time for assessing BSI with high reproducibility and accuracy. Several studies showed that the concordance between aBSI and BSI, as well as the interobserver concordance of aBSI, was0.95. In a phase 3 assessment of aBSI, a doubling value increased the risk of death in 20%, pre-treatment aBSI values independently correlated with overall survival (OS) and time to symptomatic progression. Retrospective studies suggest that a decrease in aBSI after treatment may correlate with higher survival when compared with increasing aBSI.aBSI provides a quantitative measurement that is feasible, reproducible, and in analyses to date correlates with OS and symptomatic progression. These findings support the aBSI to risk-stratify men with mCRPC for clinical trial enrollment. Future studies quantifying aBSI change over time as an intermediate endpoint for evaluating new systemic therapies are needed.

Castration-resistant prostate cancer (CRPC) is the lethal form of prostate cancer, and more than 26,000 men will die from this disease in 2016. The pathophysiology of CRPC is clearly multifactorial, but most often, androgen receptor (AR) upregulation is associated with its earliest beginnings and the AR increase is part of the multimolecular complex including downstream effector proteins linked to AR (AR-axis) responsible for rapid proliferation and malignant features of the malignant cell. In both animal models and patients, glycolysis (Warburg effect) is also an early manifestation of CRPC transformation. At Memorial Sloan Kettering Cancer Center, we have focused our energies on imaging studies of the AR-axis in CRPC, using 18F-FDG, 18F-16β-fluoro-5α-dihydrotestosterone (18F-FDHT), and a variety of radiolabeled antibodies targeting downstream effectors, such as prostate-specific membrane antigen (PSMA). Small-molecular-weight PSMA-targeting agents are not part of this review. In this review, we will focus on molecular imaging of the AR-axis in metastatic CRPC (mCRPC) and discuss our personal experience with these tracers. Our goal is to put these radiopharmaceuticals in the context of mCRPC biology and diagnosis (e.g., 18F-FDHT).

OBJECTIVE. The purpose of this study was to compare the diagnostic performance of 18F-FDG PET/CT and conventional imaging for staging and follow-up of pediatric osteosarcoma and skeletal Ewing sarcoma. MATERIALS AND METHODS. We calculated sensitivity, specificity, and accuracy of PET/CT and conventional imaging (CT, MRI, bone scanning) for sites of disease and number of lesions. Diagnostic benefit, defined as better characterization of lesions, was evaluated on a per-scan basis, comparing PET/CT and conventional imaging. RESULTS. A total of 412 lesions were characterized by imaging in 64 patients (20, osteosarcoma; 44, Ewing sarcoma). For osteosarcoma patients PET/CT was available only at follow-up, where it proved more accurate than conventional imaging for the detection of bone lesions (accuracy, 95% vs 67% for CT and 86% for MRI) and complementary to CT in evaluating lung nodules (sensitivity, 84% vs 94%; specificity, 79% vs 71%) with diagnostic benefit in 18% of examinations. In patients with Ewing sa...

The average age of a cancer patient is 67. Sexagenarians with cancer are likely to have comorbidities at the time of diagnosis. Cancer patients > 55 years old have an average of ∼ 2.9 comorbidities, while cancer patients older than 75 have an average of 4.2 comorbidities. The likelihood of coronary artery disease as an etiology of this comorbidity increases with the age of the patient. Cardiovascular comorbidity is present in ∼ 20% of patients with neoplasm. These comorbidities increase the risk of a serious cardiovascular event during treatment. An additional risk factor is limited work capacity. If patients cannot perform 4 METS of work, their all cause mortality is increased. Patients with cancer and known cardiovascular comorbidity or risk factors such as diabetes, hypertension, smoking history, or limited work capacity should have medical clearance prior to invasive diagnostic procedures, major surgery, mediastinal radiation, and/or potentially cardiotoxic chemotherapy. Medical clearance should include a detailed cardiovascular history and physical examination. This information will permit calculation of a clinical score (such as POSSUM) to define the risk of adverse events as a result of a major surgical procedure, blood tests to determine hematologic and renal status, and if necessary, assessment of the patients work capacity. Stress testing with imaging should be done in patients with an intermediate risk of coronary heart disease and considered in patients with limited work capacity or advanced age. In selected patients, coronary CT angiography or coronary calcium score may be a suitable evaluation. In patients with cancer of the esophagus, breast, lung, melanoma, or lymphoma, chest-CT and PET/CT studies should be carefully evaluated to detect possible pericardial or myocardial involvement.

Background Standard ventilation and perfusion ( V ˙ / Q ˙ ) scintigraphy uses planar images for the diagnosis of pulmonary embolism (PE). To evaluate whether tomographic imaging improves the diagnostic accuracy of the procedure, we compared noncontrast perfusion single-photon emission CT ( Q ˙ -SPECT)/CT scans with planar V ˙ / Q ˙ scans in patients at high risk for PE. Methods Between 2006 and 2010, most patients referred for diagnosis of PE underwent both Q ˙ -SPECT/CT scan and planar V ˙ / Q ˙ scintigraphy. All scans were reviewed retrospectively by four observers; planar scans were read with modified Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II and Prospective Investigative Study of Pulmonary Embolism Diagnosis (PISA-PED) criteria. On Q ˙ -SPECT/CT scan, any wedge-shaped peripheral perfusion defect occupying > 50% of a segment without corresponding pulmonary parenchymal or pleural disease was considered to show PE. The final diagnosis was established with a composite reference standard that included ECG, ultrasound of lower-extremity veins, D-dimer levels, CT pulmonary angiography (when available), and clinical follow-up for at least 3 months. Results One hundred six patients with cancer and mean Wells score of 4.4 had sufficient follow-up; 22 patients were given a final diagnosis of PE, and 84 patients were given a final diagnosis of no PE. According to PIOPED II, 13 studies were graded as intermediate probability. Sensitivity and specificity for PE were 50% and 98%, respectively, based on PIOPED II criteria; 86% and 93%, respectively, based on PISA-PED criteria; and 91% and 94%, respectively, based on Q ˙ -SPECT/CT scan. Seventy-six patients had additional relevant findings on the CT image of the Q ˙ -SPECT/CT scan. Conclusions Noncontrast Q ˙ -SPECT/CT imaging has a higher accuracy than planar V ˙ / Q ˙ imaging based on PIOPED II criteria in patients with cancer and a high risk for PE.

To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16β-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer.This is a retrospective study of 38 patients with castration-resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression.In 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = -0.3007; P.001; reader 2: r = -0.3147; P.001) and FDHT (reader 1: r = -0.2680; P = .001; reader 2: r = -0.3656; P.001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051-1.109; P.001) and reader 2 (HR, 1.026-1.082; P ≤ .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P = .02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38).In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival.

Purpose ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC. Patients and Methods Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [18F]fluoro-α-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose. Results Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (≥ 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at ≥ 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose. Conclusion ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.

A 64-year-old African American woman with history of stage III breast carcinoma, 3 years after complete response to therapy, presents with progressive fatigue, increasing arthralgia, and unintentional weight loss of 15 lb in 3 months. An 18F-FDG PET demonstrated new diffuse FDG avidity of the renal parenchyma, new FDG-avid foci in pancreas and lungs, and new FDG-avid lymph nodes above and below the diaphragm. While a retroperitoneal lymph node biopsy was inconclusive, a kidney biopsy resulted in diagnosis of diffuse, severe, IgG4-related tubulointerstitial nephritis. Treatment with corticosteroid led to complete resolution of the symptoms and PET findings.

Purpose 18-fluorodeoxyglucose positron emission tomography (PET) is already an integral part of staging in rhabdomyosarcoma. We investigated whether primary-site treatment response characterized by serial PET imaging at specific time points can be correlated with local control. Patients and Methods We retrospectively examined 94 patients with rhabdomyosarcoma who received initial chemotherapy 15 weeks (median) before radiotherapy and underwent baseline, preradiation, and postradiation PET. Baseline PET standardized uptake values (SUVmax) and the presence or absence of abnormal uptake (termed PET-positive or PET-negative) both before and after radiation were examined for the primary site. Local relapse-free survival (LRFS) was calculated according to baseline SUVmax, PET-positive status, and PET-negative status by the Kaplan-Meier method, and comparisons were tested with the log-rank test. Results The median patient age was 11 years. With 3-year median follow-up, LRFS was improved among postradiation PET-negative vs PET-positive patients: 94% vs 75%, P=.02. By contrast, on baseline PET, LRFS was not significantly different for primary-site SUVmax ≤7 vs >7 (median), although the findings suggested a trend toward improved LRFS: 96% for SUVmax ≤7 vs 79% for SUVmax >7, P=.08. Preradiation PET also suggested a statistically insignificant trend toward improved LRFS for PET-negative (97%) vs PET-positive (81%) patients (P=.06). Conclusion Negative postradiation PET predicted improved LRFS. Notably, 77% of patients with persistent postradiation uptake did not experience local failure, suggesting that these patients could be closely followed up rather than immediately referred for intervention. Negative baseline and preradiation PET findings suggested statistically insignificant trends toward improved LRFS. Additional study may further understanding of relationships between PET findings at these time points and outcome in rhabdomyosarcoma.

Purpose There is currently no imaging biomarker for metastatic prostate cancer. The bone scan index (BSI) is a promising candidate, being a reproducible, quantitative expression of tumor burden seen on bone scintigraphy. Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure. Patients and Methods We retrospectively examined serial bone scans from patients with castration-resistant metastatic prostate cancer (CRMPC) enrolled in four clinical trials. We calculated BSI at baseline and at 3 and 6 months on treatment and performed univariate and bivariate analyses of PSA, BSI, and survival. Results Eighty-eight patients were scanned, 81 of whom have died. In the univariate analysis, the log percent change in BSI from baseline to 3 and 6 months on treatment prognosticated for survival (hazard ratio [HR], 2.44; P = .0089 and HR, 2.54; P < .001, respectively). A doubling in BSI resulted in a 1.9-fold increase in risk of death. Log percent change in PSA at 6 months on treatment was also associated with survival (HR, 1.298; P = .013). In the bivariate analysis, change in BSI while adjusting for PSA was prognostic at 3 and 6 months on treatment (HR, 2.368; P = .012 and HR, 2.226; P = .002, respectively), but while adjusting for BSI, PSA was not prognostic. Conclusion These data furnish early evidence that on-treatment changes in BSI are a response indicator and support further exploration of bone scintigraphy as an imaging biomarker in CRMPC.

Recent advances in the understanding of castrate-resistant prostate cancer (CRPC) have lead to a growing number of experimental therapies, many of which are directed against the androgen-receptor (AR) signaling axis. These advances generate the need for reliable molecular imaging biomarkers to non-invasively determine efficacy, and to better guide treatment selection of these promising AR-targeted drugs. Methods. We draw on our own experience, supplemented by review of the current literature, to discuss the systematic development of imaging biomarkers for use in the context of CRPC, with a focus on bone scintigraphy, F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET imaging of the AR signaling axis. Results. The roadmap to biomarker development mandates rigorous standardization and analytic validation of an assay before it can be qualified successfully for use in an appropriate clinical context. The Prostate Cancer Working Group 2 (PCWG2) criteria for "radiographic" progression by bone scintigraphy serve as a paradigm of this process. Implemented by the Prostate Cancer Clinical Trials Consortium (PCCTC), these consensus criteria may ultimately enable the co-development of more potent and versatile molecular imaging biomarkers. Purported to be superior to single-photon bone scanning, the added value of Na(18)F-PET for imaging of bone metastases is still uncertain. FDG-PET already plays an integral role in the management of many diseases, but requires further evaluation before being qualified in the context of CRPC. PET tracers that probe the AR signaling axis, such as (18)F-FDHT and (89)Zr-591, are now under development as pharmacodynamic markers, and as markers of efficacy, in tandem with FDG-PET. Semi-automated analysis programs for facilitating PET interpretation may serve as a valuable tool to help navigate the biomarker roadmap. Conclusions. Molecular imaging strategies, particularly those that probe the AR signaling axis, have the potential to accelerate drug development in CRPC. The development and use of analytically valid imaging biomarkers will increase the likelihood of clinical qualification, and ultimately lead to improved patient outcomes.

Purpose: To compare the diagnostic and prognostic value of [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scans (BS) in the assessment of osseous lesions in patients with progressing prostate cancer. Experimental Design: In a prospective imaging trial, 43 patients underwent FDG-PET and BS prior to experimental therapies. Bone scan index (BSI) and standardized uptake value (SUV) on FDG-PET were recorded. Patients were followed until death (n = 36) or at least 5 years (n = 7). Imaging findings were correlated with survival. Results: Osseous lesions were detected in 39 patients on BS and 32 on FDG-PET (P = 0.01). Follow-up was available for 105 FDG-positive lesions, and 84 (80%) became positive on subsequent BS. Prognosis correlated inversely with SUV (median survival 14.4 versus 32.8 months if SUVmax > 6.10 versus ≤ 6.10; P = 0.002) and BSI (14.7 versus 28.2 months if BSI > 1.27 versus < 1.27; P = 0.004). Only SUV was an independent factor in multivariate analysis. Conclusion: This study of progressive prostate cancer confirms earlier work that BSI is a strong prognostic factor. Most FDG-only lesions at baseline become detectable on follow-up BS, suggesting their strong clinical relevance. FDG SUV is an independent prognostic factor and provides complementary prognostic information. Clin Cancer Res; 16(24); 6093–99. ©2010 AACR.

Androgen receptor-signaling inhibitor (ARSi) drugs prolong life in metastatic castration-resistant prostate cancer (mCRPC), but such tumors eventually become resistant and progress. Comprehensive positron emission tomography/computed tomography (PET/CT) imaging using fluoro-2-D-deoxyglucose F 18 ([18F]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([18F]-FDHT) for androgen receptor (AR) expression determine heterogeneity of imaging phenotypes, which may be useful in distinguishing patients who will benefit from ARSi drugs from those who need alternative treatments.To test the hypothesis that PET/CT-based assessments of AR expression and glycolytic activity would reveal heterogeneity affecting prognosis.Between April 6, 2007, and October 4, 2012, patients with mCRPC underwent imaging with both [18F]-FDG and [18F]-FDHT at Memorial Sloan Kettering Cancer Center. The patients were naive to ARSi treatment with enzalutamide or abiraterone acetate and were referred during documented disease progression. Image-directed biopsy determined the presence or absence of prostate cancer at positive imaging sites.PET/CT imaging was performed with [18F]-FDHT and [18F]-FDG; select individual lesions were biopsied to correlate imaging phenotype with histologic findings.All metabolically active lesions were interpreted as [18F]-FDHT-positive (AR1) or [18F]-FDHT-negative (AR0) and as [18F]-FDG-positive (Glyc1) or [18F]-FDG-negative (Glyc0). Correlation was performed with overall survival for both individual lesion imaging phenotype as well as patient-specific imaging phenotype.The mean (SD) age of the 133 patients was 68 (8.6) years. Imaging phenotypes of 2405 PET/CT-positive lesions (median, 12.0 per patient) included 1713 (71.2%) AR1Glyc1, 386 (16.0%) AR1Glyc0, and 306 (12.7%) AR0Glyc1. On multivariate analysis, each phenotype had an independent negative impact effect on survival, most pronounced for AR0Glyc1 lesions (hazard ratio [HR], 1.11; 95% CI, 1.05-1.16; P .001), followed by AR1Glyc1 lesions (HR, 1.05; 95% CI, 1.03-1.06; P .001) and AR1Glyc0 lesions (HR, 1.03; 95% CI, 1.00-1.05; P = .048). When sorted by lesion type, 4 patient-specific groups emerged: (1) concordant, with all AR1Glyc1 (34 patients [25.6%]); (2) AR predominant, with AR1Glyc1 and varying numbers of AR1Glyc0 (33 [24.8%]); (3) Glyc predominant, with AR1Glyc1 and varying numbers of AR0Glyc1 (40 [30.1%]); and (4) mixed, with AR1Glyc1 plus a mixture of varying numbers of AR1Glyc0 and AR0Glyc1 (26 [19.5%]).Heterogeneity of PET/CT imaging phenotype has clinical relevance on a lesion and individual patient level. With regard to mCRPC lesions, most express ARs, consistent with initial benefit of ARSi drugs. On a patient basis, 49% (groups 3 and 4) had at least 1 AR0Glyc1 lesion-the imaging phenotype with the most negative effect on survival, possibly due to ARSi resistance.

Aim To report a case series in which the radiological features of the subcutaneous use of calcium hydroxylapatite (CaHa) dermal fillers are described for the first time. Materials and methods Five patients with facial hyperattenuating hypermetabolic subcutaneous lesions were identified on 2- [ 18 F]-fluoro-2-deoxy- d- glucose (FDG) positron-emission tomography/computed tomography (PET/CT), who gave a history of facial injections to augment physical appearance. Correlation with additional imaging studies was performed. Results All cases had subcutaneous high attenuation material on CT (range 280–700 HU), which was FDG avid on PET, with a standardized uptake value (SUV) range of 2.9–13.4. Magnetic resonance imaging (MRI) demonstrated a heterogeneous intermediate signal intensity subcutaneous lesion with enhancement post-gadolinium in one case. Conclusions CaHa dermal filler is hyperattenuating on CT, hypermetabolic on FDG-PET imaging, of intermediate signal intensity on MRI, and is a potential cause of a false-positive imaging study.

Notwithstanding the major improvements in diagnosis and therapy, coronary heart disease remains the leading cause of death in the United States. About every 26 s, an American will undergo a coronary event, and about every minute someone will die from one (American Heart Association computation based

To evaluate whether [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) response of the primary tumor after induction chemotherapy predicts outcomes in rhabdomyosarcoma (RMS).After excluding those with initial tumor resection, 107 patients who underwent FDG-PET after induction chemotherapy at Memorial Sloan Kettering Cancer Center from 2002 to 2013 were reviewed. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated according to FDG-PET response and maximum standardized uptake value (SUV) at baseline (PET1/SUV1), after induction chemotherapy (PET2/SUV2), and after local therapy (PET3/SUV3). Receiver operator characteristic curves were used to determine the optimal cutoff for dichotomization of SUV1 and SUV2 values.The SUV1 (9.5 vs ≥9.5) was predictive of PFS (P=.02) and OS (P=.02), but not LC. After 12 weeks (median) of induction chemotherapy, 45 patients had negative PET2 scans and 62 had positive scans: 3-year PFS was 72% versus 44%, respectively (P=.01). The SUV2 (1.5 vs ≥1.5) was similarly predictive of PFS (P=.005) and was associated with LC (P=.02) and OS (P=.03). A positive PET3 scan was predictive of worse PFS (P=.0009), LC (P=.05), and OS (P=.03).[(18)F]fluorodeoxyglucose positron emission tomography is an early indicator of outcomes in patients with RMS. Future prospective trials may incorporate FDG-PET response data for risk-adapted therapy and early assessment of new treatment regimens.

Standard ventilation and perfusion (V˙/Q˙) scintigraphy uses planar images for the diagnosis of pulmonary embolism (PE). To evaluate whether tomographic imaging improves the diagnostic accuracy of the procedure, we compared noncontrast perfusion single-photon emission CT (Q˙-SPECT)/CT scans with planar V˙/Q˙scans in patients at high risk for PE.Between 2006 and 2010, most patients referred for diagnosis of PE underwent both Q˙-SPECT/CT scan and planar V˙/Q˙scintigraphy. All scans were reviewed retrospectively by four observers; planar scans were read with modified Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II and Prospective Investigative Study of Pulmonary Embolism Diagnosis (PISA-PED) criteria. On Q˙-SPECT/CT scan, any wedge-shaped peripheral perfusion defect occupyinggt; 50% of a segment without corresponding pulmonary parenchymal or pleural disease was considered to show PE. The final diagnosis was established with a composite reference standard that included ECG, ultrasound of lower-extremity veins, D-dimer levels, CT pulmonary angiography (when available), and clinical follow-up for at least 3 months.One hundred six patients with cancer and mean Wells score of 4.4 had sufficient follow-up; 22 patients were given a final diagnosis of PE, and 84 patients were given a final diagnosis of no PE. According to PIOPED II, 13 studies were graded as intermediate probability. Sensitivity and specificity for PE were 50% and 98%, respectively, based on PIOPED II criteria; 86% and 93%, respectively, based on PISA-PED criteria; and 91% and 94%, respectively, based on Q˙-SPECT/CT scan. Seventy-six patients had additional relevant findings on the CT image of the Q˙-SPECT/CT scan.Noncontrast Q˙-SPECT/CT imaging has a higher accuracy than planar V˙/Q˙imaging based on PIOPED II criteria in patients with cancer and a high risk for PE.

Pancreatic involvement in neuroblastoma is extremely rare, with few cases reported in the literature. We present imaging findings of pancreatic involvement in neuroblastoma with clinical and pathologic correlation in the largest documented series to date.We prospectively reported pancreatic involvement evident on multimodality imaging in neuroblastoma patients presenting to our institution from 1997 to 2011. Lesions were classified according to location within the pancreas, and imaging features were correlated with cytogenetic and surgicopathologic findings.Neuroblastoma involving the pancreas was evident on imaging of seven of 1031 patients (mean age, 6.6 years). One patient had pancreatic involvement at presentation, and six developed pancreatic disease at relapse or disease progression. Pancreatic lesions were most frequently initially identified on concurrent CT and (123)I-metaiodobenzylguanidine scintigraphy, and additional lesions initially were found on MRI and ultrasound. Five of seven patients had focal lesions, one had diffuse pancreatic involvement, and one had pancreatic extension from contiguous disease. The distribution of lesions favored the pancreatic body and tail. All patients had International Neuroblastoma Staging System stage 3 or 4 disease, Children's Oncology Group intermediate- or high-risk disease, and unfavorable histology at initial diagnosis. For the five patients with surgical correlation, pancreatic surgical specimens revealed neuroblastoma in three cases and ganglioneuroblastoma in two cases.Although rare, pancreatic involvement in neuroblastoma occurs. Its variable imaging appearance should be considered when evaluating the retroperitoneum in patients with known or suspected neuroblastoma, particularly because increased patient survival holds the potential for uncommon patterns of recurrence.