The use of single-timepoint images to link administered radioiodine activity (MBq) to a prescribed lesion radiation-absorbed dose (cGy): a regression-based prediction interval tool for the management of well-differentiated thyroid cancer patients.

PURPOSE: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124I PET. METHODS: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUVmax > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUVmax and activity in microcurie per gram, from a single imaging timepoint. RESULTS: In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUVmax was the best predictor of lesion radiation dose and permitted calculation of the 131I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals. CONCLUSIONS: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center. TRIAL REGISTRATION: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.

Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy.

PURPOSE: The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness. EXPERIMENTAL DESIGN: Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio. RESULTS: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. CONCLUSIONS: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy.

Assessment of salivary gland function after 177Lu-PSMA radioligand therapy: Current concepts in imaging and management.

Prostate specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. Radioligand therapy using beta-emitting Lutetium-177 (177Lu)-labeled-PSMA-617, a radiolabeled small molecule, has gained attention as a novel targeted therapy for metastatic prostate cancer, given its high affinity and long tumor retention, and rapid blood pool clearance. In March 2022, the United States Food and Drug administration has granted approval to the targeted 177Lu-PSMA-617 therapy for treatment of patients with PSMA-positive metastatic castration resistant prostate cancer, who have been previously treated with an androgen-receptor pathway inhibitor and taxane-based chemotherapy. Studies have demonstrated the adverse effects of this treatment, mainly encountered due to radiation exposure to non-target tissues. Salivary glands show high PSMA-ligand uptake and receive increased radiation dose secondary to accumulation of 177Lu-PSMA-617. This predisposes the glands to radiation-mediated toxicity. The exact mechanism, scope and severity of radiation-mediated salivary gland toxicity are not well understood, however, the strategies for its prevention and treatment are under evaluation. This review will focus on the current knowledge about salivary gland impairment post 177Lu labeled PSMA-based radioligand therapies, diagnostic methodologies, and imaging with emphasis on salivary gland scintigraphy. The preventive strategies and known treatment options would also be briefly highlighted.

Treatment Response and Clinical Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors to Lutetium-177-DOTATATE.

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.

Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. Methods: Patients with BRAFV600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive iodine (131I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Predicting malignancy in patients with adrenal tumors using 18 F-FDG-PET/CT SUVmax.

BACKGROUND AND OBJECTIVES: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) parameters may help distinguish malignant from benign adrenal tumors, but few have been externally validated or determined based on definitive pathological confirmation. We determined and validated a threshold for 18 F-FDG-PET/CT maximum standard uptake value (SUVmax) in patients who underwent adrenalectomy for a nonfunctional tumor. METHODS: Database review identified patients with 18 F-FDG-PET/CT images available (training cohort), or only SUVmax values (validation cohort). Discriminative accuracy was assessed by area under the curve (AUC), and the optimal cutoff value estimated by maximally selected Wilcoxon rank statistics. RESULTS: Of identified patients (n = 171), 86 had adrenal metastases, 20 adrenal cortical carcinoma, and 27 adrenal cortical adenoma. In the training cohort (n = 96), SUVmax was significantly higher in malignant versus benign tumors (median 8.3 vs. 3.0, p < .001), with an AUC of 0.857. Tumor size did not differ. The optimal cutoff SUVmax was 4.6 (p < .01). In the validation cohort (n = 75), this cutoff had a sensitivity of 75% and specificity 55%. CONCLUSIONS: 18 F-FDG-PET/CT SUVmax was associated with malignancy. Validation indicated that SUVmax ≥ 4.6 was suggestive of malignancy, while lower values did not reliably predict benign tumor.

Thyroid Cancer Bone Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort.

Bone metastasis (BM) in differentiated thyroid cancer (DTC) is the second most common site of metastasis after lung. Bone metastases are associated with worse prognosis in DTC. In this study, we examined risk factors for overall survival in patients with BM and for the first time explore the pattern of genomic alterations in DTC BM. PATIENTS AND METHODS: A Health Insurance Portability and Accountability Act (HIPAA) compliant, institutional review board-approved retrospective evaluation of the medical record was performed for all patients treated at a single institution for thyroid cancer over a 16-year period. Seventy-four patients met inclusion criteria. Multiple prognostic factors including age, sex, genes, radioactive iodine, and radiation or kinase inhibitor therapies were analyzed. Univariate and multivariate analyses were performed. RESULTS: Treatment with external beam radiation was found to significantly increase survival (P = 0.03). The 5-year survival rate was 59% and median survival was 92 months. Patients who developed bone metastasis earlier tend to live longer (P = 0.06). The presence of TERT and BRAF mutations did not significantly worsen the prognosis (P = 0.10). CONCLUSION: Patients with DTC can benefit from early treatment with external beam radiation therapy, especially those who develop bone metastasis within 3 years of primary TC diagnosis. Kinase inhibitor treatment tended to prolong survival but not in a statistically significant manner. Sex, age, and TERT or BRAF genetic mutations did not significantly affect the prognosis.

Thyroid Cancer Brain Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort.

PURPOSE: Brain metastases (BMs) in patients with differentiated thyroid cancer (DTC) are rare but associated with poor prognosis. We examined risk factors for overall survival (OS) in this population and explored the pattern of genomic alterations. METHODS: Single-institution, retrospective review of all patients with DTC from January 2000 to November 2016 identified 79 patients for analysis. Multiple prognostic factors, including age, gender, distal metastasis (DM), diagnosis time, DM sites, BM diagnosis time, BM number and size, genomic sequencing data, craniectomy, external beam radiation therapy, and kinase inhibitor therapies, were evaluated. Univariate and multivariate analyses were performed. RESULTS: Median survival after BM was 18 months. One- and 3-year survival rates were 63% and 33%, respectively. Univariate analysis identified 4 covariates correlated with prolonged survival: time between DTC diagnosis and BM for less than 3 years (P = 0.01), time from initial DM diagnosis to BM for 22 months or less (P = 0.03), 3 BM sites or fewer (P = 0.002), and craniectomy (P = 0.05). Multivariate model revealed 3 variables associated with OS: DTC diagnosis to BM time of less than 3 years (P = 0.04), craniectomy (P = 0.06), and patients with fewer than 3 BM sites (P = 0.06). The majority of patients with BM had a telomerase reverse transcriptase promoter mutation, However, mutational status was not an independent predictor of survival. CONCLUSIONS: For BM from DTC, time interval between DTC diagnosis and BM, number of BM sites, and craniectomy were independently associated with OS. Further studies are needed to define the role of genomic mutations in advanced cancer.

Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers.

CONTEXT: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). OBJECTIVES: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). DESIGN: This was a pilot trial that enrolled from June 2014 to January 2016. SETTING: Academic cancer center. PATIENTS: Patients with RAIR, BRAF mutant thyroid cancer. INTERVENTION: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. MAIN OUTCOME MEASURE: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. RESULTS: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). CONCLUSIONS: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

Enchondroma of Tibia as Potential False-positive Finding on 68Ga-DOTATOC PET/CT Scan.

A 70-year-old man with a history of carcinoid tumor of small bowel was referred for Ga-DOTATOC study to evaluate the extent of disease. PET/CT scan revealed known metastatic disease in the liver, with other sites of involvement including pancreas, peritoneum, and bones. In addition, moderately intense uptake was noted in proximal right tibia and further correlation on CT showed metaphyseal lesion with "rings and arcs" calcification suggestive of enchondroma. This case highlights the possibility of overexpression of somatostatin receptors in enchondromas, which has been little explored in literature.

Incidental Detection of Medullary Thyroid Carcinoma by 68Ga-DOTATATE PET/CT in a Patient With Neuroendocrine Tumor Liver Metastases.

Ga-DOTATATE, a positron-emitting somatostatin analog, has been approved by the Food and Drug Administration for imaging neuroendocrine tumors (NETs). The presence of a second primary malignancy is common in NETs; however, synchronous primary malignancy in the thyroid has rarely been reported. The value of Ga-DOTATATE in medullary thyroid cancer is being investigated and is currently recommended for use when treatment with somatostatin analogs is an option. We present a 55-year-old man with abdominal pain associated with well-differentiated NET liver metastases and incidental medullary thyroid carcinoma demonstrated on a Ga-DOTATATE PET/CT.

Redifferentiating Thyroid Cancer: Selumetinib-enhanced Radioiodine Uptake in Thyroid Cancer.

In a recent article, we reported a restorative therapeutic intervention that turned individual thyroid cancer lesions into more efficient tissues for taking up radioactive iodine (RAI), resulting in clinically significant and durable responses. A group of Iodine-131 refractory thyroid cancer patients were treated with the MEK tyrosine kinase inhibitor (TKI) selumetinib, and RAI uptake was restored in a subset of patients. We employed Iodine-124 positron emission tomography to measure radiation absorbed dose, on a lesion by lesion basis. The process can be thought of as a re-differentiation of the cancer toward a more nearly normal state most like the tissue from which the cancer arose. Remarkably, in its own way, a change was detected within a few weeks of treatment, restoring uptake with therapeutically effective levels of RAI and in some patients, previously completely refractory to radioiodine treatment. In this article, we summarize the basic work that led to this seminal study, and make the case for lesional dosimetry in thyroid cancer with Iodine-124 as a new optimal radiotracer for precision medicine in patients with well differentiated thyroid cancer.

Ga-68 DOTATOC PET/CT-Guided Biopsy and Cryoablation with Autoradiography of Biopsy Specimen for Treatment of Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by small benign tumors of mesenchymal origin also known as phosphaturic mesenchymal tumors mixed connective tissue variant. Excellent prognosis is expected with eradication of the culprit tumor. These small tumors are notoriously difficult to localize with conventional imaging studies; this often leads to an extensive work up and prolonged morbidity. We report a patient with clinical diagnosis of TIO whose culprit tumor was localized with Ga-68 DOTATOC PET/CT and MRI. Biopsy and cryoablation were performed under Ga-68 DOTATOC PET/CT guidance. Autoradiography of the biopsy specimen was performed and showed in situ correlation between Ga-68 DOTATOC uptake and histopathology with millimeter resolution.

Novel Approaches to Thyroid Cancer Treatment and Response Assessment.

The incidence of thyroid cancer has been increasing. After total thyroidectomy of well-differentiated thyroid tumors with intermediate- or high-risk features on pathology, radioiodine remains one of the mainstays of therapy for both thyroid remnant ablation as well as for treatment of metastatic disease. SPECT/CT, a relatively new modality, has been shown to play a pivotal role predominantly in the post-therapy setting by changing the risk stratification of patients with thyroid cancer. In the case of radioiodine treatment failure, FDG-PET/CT may provide prognostic information based on extent and intensity of metabolically active metastatic sites as well as serve as an important imaging test for response assessment in patients treated with chemotherapy, targeted therapies, or radiotherapy, thereby affecting patient management in multiple ways. The role of newer redifferentiation drugs has been evaluated with the use of I-124 PET/CT.

RAI thyroid bed uptake after total thyroidectomy: A novel SPECT-CT anatomic classification system.

OBJECTIVE: Recent, more selective use of radioactive iodine (RAI) has led to reevaluation of the clinical importance of achieving complete total thyroidectomy with minimal residual normal thyroid tissue. We utilize the improved localization by post-RAI remnant ablation, single photon emission computerized tomography-computed tomography (SPECT-CT) to define specific anatomic sites of residual RAI-uptake foci after total thyroidectomy for differentiated thyroid cancer (DTC) and to provide a novel classification system relating uptake to thyroid anatomy and preservation of adjacent neural structures. STUDY DESIGN: Retrospective. METHOD: Radioactive iodine-uptake foci in thyroid bed were localized by SPECT/CT imaging at the time of RAI remnant ablation in 141 DTC patients undergoing total thyroidectomy. RESULTS: Minimal residual RAI uptake (median 0.32% at 24 hours) in the thyroid bed was detected by diagnostic planar whole body scans in 93% and by posttherapy SPECT/CT imaging in 99% of subjects. Discrete RAI uptake foci were identified on the SPECT/CT imaging at Berry's ligament (87%), at superior thyroid poles (79%), in paratracheal-lobar regions (67%), in isthmus-region (54%), and in pyramidal lobe (46%). Despite the residual foci, the nonstimulated thyroglobulin (Tg) prior to remnant ablation (with a median thyroid-stimulating hormone of 0.36 m IU/L) was < 0.6 ng/mL in 53% and < 1 ng/mL in 73% of cases. CONCLUSION: After extracapsular total thyroidectomy, highly sensitive detection tools identify microscopic residual RAI avid foci in thyroid bed in the majority of patients. These foci can be classified as 1) neural-related and 2) capsule-related. These common residual foci have no relationship to postoperative Tg, suggesting that attempts at radical removal of thyroid tissue in these locations may not be warranted. LEVEL OF EVIDENCE: 4.

Correlation of BRAFV600E Mutation and Glucose Metabolism in Thyroid Cancer Patients: An ¹8F-FDG PET Study.

UNLABELLED: There is significant interest in a better understanding of the genetic underpinnings of the increased glucose metabolic rates of cancer cells. Thyroid cancer demonstrates a broad variability of (18)F-FDG uptake as well as several well-characterized oncogenic mutations. In this study, we evaluated the differences in glucose metabolism of the BRAF(V600E) mutation versus BRAF wild-type (BRAF-WT) in patients with metastatic differentiated thyroid cancer (DTC) and poorly differentiated thyroid cancer (PDTC). METHODS: Forty-eight DTC and 34 PDTC patients who underwent (18)F-FDG PET/CT for tumor staging were identified from a database search. All patients were tested for the BRAF(V600E) mutation and assigned to 1 of 2 groups: BRAF(V600E) mutated and BRAF-WT. (18)F-FDG uptake of tumor tissue was quantified by maximum standardized uptake value (SUVmax) of the hottest malignant lesion in 6 prespecified body regions (thyroid bed, lymph nodes, lung, bone, soft tissue, and other). When there were multiple lesions in 1 of the prespecified body regions, only the 1 with the highest (18)F-FDG uptake was analyzed. RESULTS: In the DTC cohort, 24 tumors harbored a BRAF(V600E) mutation, whereas 24 tumors were BRAF-WT. (18)F-FDG uptake of BRAF(V600E)-positive lesions (median SUVmax, 6.3; n = 53) was significantly higher than that of BRAF-WT lesions (n = 39; median SUVmax, 4.7; P = 0.019). In the PDTC group, only 5 tumors were BRAF(V600E)-positive, and their (18)F-FDG uptake was not significantly different from the BRAF-WT tumors. There was also no significant difference between the SUVmax of all DTCs and PDTCs, regardless of BRAF mutational status (P = 0.90). CONCLUSION: These data suggest that BRAF(V600E)-mutated DTCs are significantly more (18)F-FDG-avid than BRAF-WT tumors. The effect of BRAF(V600E) on tumor glucose metabolism in PDTC needs further study in larger groups of patients.

Noncontrast perfusion single-photon emission CT/CT scanning: a new test for the expedited, high-accuracy diagnosis of acute pulmonary embolism.

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.