Multidisciplinary Approach to Chronic Thromboembolic Pulmonary Hypertension: Role of Radiologists.

Management of chronic thromboembolic pulmonary hypertension (CTEPH) should be determined by a multidisciplinary team, ideally at a specialized CTEPH referral center. Radiologists contribute to this multidisciplinary process by helping to confirm the diagnosis of CTEPH and delineating the extent of disease, both of which help determine a treatment decision. Preoperative assessment of CTEPH usually employs multiple imaging modalities, including ventilation-perfusion (V/Q) scanning, echocardiography, CT pulmonary angiography (CTPA), and right heart catheterization with pulmonary angiography. Accurate diagnosis or exclusion of CTEPH at imaging is imperative, as this remains the only form of pulmonary hypertension that is curative with surgery. Unfortunately, CTEPH is often misdiagnosed at CTPA, which can be due to technical factors, patient-related factors, radiologist-related factors, as well as a host of disease mimics including acute pulmonary embolism, in situ thrombus, vasculitis, pulmonary artery sarcoma, and fibrosing mediastinitis. Although V/Q scanning is thought to be substantially more sensitive for CTEPH compared with CTPA, this is likely due to lack of recognition of CTEPH findings rather than a modality limitation. Preoperative evaluation for pulmonary thromboendarterectomy (PTE) includes assessment of technical operability and surgical risk stratification. While the definitive therapy for CTEPH is PTE, other minimally invasive or noninvasive therapies also lead to clinical improvements including greater survival. Complications of PTE that can be identified at postoperative imaging include infection, reperfusion edema or injury, pulmonary hemorrhage, pericardial effusion or hemopericardium, and rethrombosis. ©RSNA, 2022 Online supplemental material is available for this article.

Rosai-Dorfman-Destombes (RDD) disease presenting as palindromic rheumatism.

BACKGROUND: Rosai-Dorfman-Destombes (RDD) disease, is a rare proliferative and inflammatory disorder of non-Langerhans cell histiocytes. CASE PRESENTATION: We report a 35-year-old woman, who originally presented with recurrent episodes of lower extremity joint/bone pain and chronic nasal stuffiness and congestion. Her worsening nasal congestion was due to an obstructing nasal cavity lesion which was subsequently biopsied. Pathology was consistent with RDD. 18F-FDG PET images demonstrated intense uptake in the paranasal sinuses and a large pelvic lymph node. Focal osseous lesions with intense 18F-FDG uptake were also observed in the lower extremity, corresponding to areas of peri-articular pain. Rheumatologic work-up was consistent with palindromic rheumatism. She was diagnosed with immune-related disseminated RDD, presenting as palindromic rheumatism. CONCLUSIONS: This is the first case of RDD presenting as palindromic rheumatism. RDD should be considered as a possible but rare diagnosis in young patients with sinus-related symptoms and lymphadenopathy. The disease can on rare occasions be disseminated and can also present as immune-related RDD, such as in this patient.

Perfusion Scintigraphy in Diagnosis and Management of Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of acute pulmonary embolism (PE). Because the treatment of CTEPH is markedly different from that of other types of pulmonary hypertension, lung ventilation-perfusion (V/Q) scintigraphy is recommended for the workup of patients with unexplained pulmonary hypertension. Lung V/Q scintigraphy is superior to CT pulmonary angiography for detecting CTEPH. Perfusion defect findings of CTEPH can be different from those of acute PE. Familiarity with the patterns of perfusion defects seen during the initial workup of CTEPH and the expected posttreatment changes seen at follow-up imaging is essential for accurate interpretation of V/Q scintigraphy findings. ©RSNA, 2019.

Hepatopulmonary Shunting: A Prognostic Indicator of Survival in Patients with Metastatic Colorectal Adenocarcinoma Treated with 90Y Radioembolization.

Purpose To determine if high lung shunt fraction (LSF) is an independent prognostic indicator of poor survival in patients who undergo yttrium 90 radioembolization for unresectable liver-dominant metastatic colorectal cancer. Materials and Methods Retrospective data were analyzed from 606 patients (62% men; mean age, 62 years) who underwent radioembolization to treat liver metastases from colorectal adenocarcinoma between July 2002 and December 2011 at 11 U.S. centers. Institutional review board exemptions were granted prior to the collection of data at each site. Overall survival was estimated by using Kaplan-Meier survival and univariate Cox proportional hazards models to examine the effect of LSF on survival and to compare this to other potential prognostic indicators. Multivariate analysis was also performed to determine whether LSF is an independent risk factor for poor survival. Results LSF higher than 10% was predictive of significantly decreased survival (median, 6.9 months vs 10.0 months; hazard ratio, 1.60; P < .001) and demonstrated a mild but significant correlation to serum carcinoembryonic antigen levels and tumor-to-liver volume ratio (Pearson correlation coefficients, 0.105 and 0.113, respectively; P < .05). A progressive decrease in survival was observed as LSF increased from less than 5% to more than 20% (P < .05). LSF did not correlate with the presence of extrahepatic metastases or prior administration of bevacizumab. Conclusion Increased LSF is an independent prognostic indicator of worse survival in patients undergoing radioembolization for liver-dominant metastatic colorectal adenocarcinoma. High LSF correlates poorly to other potential markers of tumor size, such as tumor-to-liver volume ratio or serum carcinoembryonic antigen level, and does not correlate to the presence of extrahepatic metastases. © RSNA, 2016 Online supplemental material is available for this article.

Comparison of Post-injection Site Pain Between Technetium Sulfur Colloid and Technetium Tilmanocept in Breast Cancer Patients Undergoing Sentinel Lymph Node Biopsy.

BACKGROUND: No prior studies have examined injection pain associated with Technetium-99m Tilmanocept (TcTM). METHODS: This was a randomized, double-blinded study comparing postinjection site pain between filtered Technetium Sulfur Colloid (fTcSC) and TcTM in breast cancer lymphoscintigraphy. Pain was evaluated with a visual analogue scale (VAS) (0-100 mm) and the short-form McGill Pain Questionnaire (SF-MPQ). The primary endpoint was mean difference in VAS scores at 1-min postinjection between fTcSC and TcTM. Secondary endpoints included a comparison of SF-MPQ scores between the groups at 5 min postinjection and construction of a linear mixed effects model to evaluate the changes in pain during the 5-min postinjection period. RESULTS: Fifty-two patients underwent injection (27-fTcSC, 25-TcTM). At 1-min postinjection, patients who received fTcSC experienced a mean change in pain of 16.8 mm (standard deviation (SD) 19.5) compared with 0.2 mm (SD 7.3) in TcTM (p = 0.0002). At 5 min postinjection, the mean total score on the SF-MPQ was 2.8 (SD 3.0) for fTcSC versus 2.1 (SD 2.5) for TcTM (p = 0.36). In the mixed effects model, injection agent (p < 0.001), time (p < 0.001) and their interaction (p < 0.001) were associated with change in pain during the 5-min postinjection period. The model found fTcSC resulted in significantly more pain of 15.2 mm (p < 0.001), 11.3 mm (p = 0.001), and 7.5 mm (p = 0.013) at 1, 2, and 3 min postinjection, respectively. CONCLUSIONS: Injection with fTcSC causes significantly more pain during the first 3 min postinjection compared with TcTM in women undergoing lymphoscintigraphy for breast cancer.

Comparison of [(99m)Tc]tilmanocept and filtered [(99m)Tc]sulfur colloid for identification of SLNs in breast cancer patients.

BACKGROUND: The efficacy of sentinel lymph node (SLN) surgery requires targeted removal of first-draining nodes; however, frequently more nodes are removed than necessary. [(99m)Tc]tilmanocept (TcTM) is a molecular-targeted radiopharmaceutical specifically designed for SLN mapping. We evaluated technical outcomes of SLN biopsy in breast cancer patients mapped with TcTM + vital blue dye (VBD) versus filtered [(99m)Tc]sulfur colloid (fTcSC) + VBD. METHODS: There were 84 versus 115 patients in the TcTM versus fTcSC cohorts, respectively. Main measures were the number of SLNs removed per patient and factors influencing number of nodes removed. We also evaluated whether the radiotracer injected affected the proportion of positive nodes removed in node-positive patients. RESULTS: Fewer nodes were removed among patients mapped with TcTM compared to fTcSC (mean TcTM: 1.85 vs. fTcSC: 3.24, p < 0.001). Logistic regression analysis adjusted for tumor characteristics showed that injection of fTcSC (p < 0.001) independently predicted removal of greater than 3 nodes. A similar proportion of patients was identified as node-positive, whether mapped with TcTM or with fTcSC (TcTM: 24 % vs. fTcSC: 17 %, p = 0.3); however, TcTM detected a greater proportion of positive nodes among node-positive patients compared with fTcSC (0.73 vs. 0.43, p = 0.001). CONCLUSIONS: Patients undergoing SLN biopsy with TcTM required fewer SLNs to identify the same rate of node-positive patients compared with fTcSC in breast cancer patients with similar risk of axillary metastatic disease. These data suggest that a molecularly targeted mechanism of SLN identification may reduce the total number of nodes necessary for accurate axillary staging.

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease. METHODS: Fresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed. RESULTS: Herein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors. CONCLUSIONS: We report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST.

Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

BACKGROUND: Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance. METHODS: A total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept. RESULTS: A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept. CONCLUSION: [(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.

Glucose corrected standardized uptake value (SUVgluc) in the evaluation of brain lesions with 18F-FDG PET.

PURPOSE: To retrospectively assess the utility of (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) images of standardized uptake values corrected for blood glucose (SUV(gluc)), and to compare this to various quantitative methods to identify the presence or absence of high grade malignancy. METHODS: A retrospective review in 42 patients, found 81 central nervous system (CNS) lesions. Fifty one were malignant and 30 were benign or post treatment changes based on pathology (n = 32) and on clinical outcome (n = 49). Dynamic FDG PET scans were processed to generate parametric images of SUV(gluc), SUV, glucose metabolic rate (GMR), and lesion to cerebellum ratios (SUV(Rc)), and contralateral white matter ratios (SUV(Rw)). The SUV(gluc) was calculated from SUV(max) * BG/[100 mg/dl], where SUV(max) is the maximum SUV and BG is the blood glucose level (mg/dL). RESULTS: Using a malignant threshold for SUV(gluc) of 4.5 and GMR of 13.0 µmole/min/100 g, the accuracies were similar for the SUV(gluc) (80%) and GMR (81%) and were higher than the conventional SUV(max) (73%). The area under the receiver operating characteristic (ROC) curve for the SUV(gluc) (0.8661) was better than that for the SUV(max) (0.7955) (p < 0.02) and was similar to those of the GMR (0.8694), SUV(Rc) (0.8278), and SUV(Rw) (0.8559). CONCLUSION: These results suggest that the SUV(gluc) may assist in the interpretation of FDG PET brain images in patients with CNS lesions. The SUV(gluc) method avoids the complexity of kinetic modeling and the definition of a reference region.

Pilot study comparing SPECT perfusion scintigraphy with CT pulmonary angiography in chronic thromboembolic pulmonary hypertension.

BACKGROUND AND OBJECTIVE: The management of chronic thromboembolic pulmonary hypertension (CTEPH) is dependent on the extent of pulmonary artery obstruction, which is usually evaluated by planar perfusion scanning and CT pulmonary angiography (CTPA). We previously reported that SPECT perfusion scanning is more sensitive than planar scanning for detecting vascular obstruction in CTEPH. The purpose of this study is to compare SPECT with CTPA for detecting segmental pulmonary artery obstruction in CTEPH. METHODS: SPECT and CTPA were carried out before pulmonary endarterectomy in 12 CTEPH patients. Field experts documented the anatomical distribution of perfusion defects disclosed by SPECT, the anatomical distribution of pulmonary arterial filling defects disclosed by CTPA and the segmental anatomy of the vascular obstructions based on a review of clinical and pathology records, without knowledge of scan results. RESULTS: Clinical/pathological evaluation disclosed 140 obstructed (15.5 ± 2.5 per patient) and 40 unobstructed lung segments. SPECT scanning identified 87/140 (62%) of the obstructed and 29/40 (72%) of the unobstructed segments. By comparison, CTPA identified 67/140 (47.8%) of the obstructed and 32/40 (80%) of the unobstructed segments. Sensitivity for detecting obstructed segments was significantly higher for SPECT compared with CTPA (62 ± 4.1% vs 47.8 ± 2.9%, respectively; P = 0.03). CONCLUSIONS: SPECT is more sensitive than CTPA for identifying obstructed segments in this small sample of CTEPH patients. However, even SPECT under-represents the extent of vascular obstruction from this disease.

Improved Prognosis of Treatment Failure in Cervical Cancer with Nontumor PET/CT Radiomics.

Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts.

Single photon emission computed tomography in chronic thromboembolic pulmonary hypertension.

BACKGROUND AND OBJECTIVE: The management of chronic thromboembolic pulmonary hypertension (CTEPH) is largely dependent on the extent of obstruction in the pulmonary arteries. Planar perfusion scans are commonly used to quantify perfusion defects in CTEPH patients. However, planar scans typically under-represent the extent of vascular obstruction in CTEPH. We conducted this study to test the hypothesis that SPECT lung perfusion scans are more accurate than planar scans for determining the location and extent of perfusion defects in patients with CTEPH. METHODS: Planar ventilation scans, planar and SPECT perfusion scans were performed preoperatively in patients undergoing pulmonary thromboendarterectomy for treatment of CTEPH. Two clinical experts independently documented the segmental anatomy of the vascular obstructions by reviewing clinical records, pulmonary and CT angiograms, and surgical specimens. A nuclear medicine expert documented the segmental anatomy of the perfusion defects observed by planar and SPECT scans independently. RESULTS: Clinical/pathological evaluation disclosed 241 obstructed and 99 unobstructed lung segments in 17 patients. Sensitivity for detecting obstructed segments was significantly higher for SPECT than for planar scanning (63.5 ± 3.1% vs. 42.7 ± 3.2%, respectively; P < 0.01). Specificities of SPECT and planar scanning were not significantly different (62.6 ± 4.8% vs. 76.8 ± 4.2%, respectively; P = 0.092). CONCLUSIONS: The SPECT is more sensitive than planar perfusion scanning for identifying obstructed segments in CTEPH. However, even SPECT under-represents the true extent of the vascular occlusions in CTEPH.

Variant allele fraction of genomic alterations in circulating tumor DNA (%ctDNA) correlates with SUVmax in PET scan.

The relationship between higher variant allele fraction (VAF) of genomic alterations in circulating tumor DNA (%ctDNA), an indicator of poor outcome, and maximum standardized uptake value (SUVmax), the most commonly used semi-quantitative parameter in 18F-FDG PET/CT, has not been studied. Overall, 433 cancer patients had blood-based next generation sequencing. Maximum and sum of %ctDNA alterations (%ctDNAmax and %ctDNAsum, respectively) represent the maximum and sum of VAF, reported as a percentage. The subset of 46 eligible patients had treatment-naïve metastatic disease and PET/CT imaging, with median 13 days prior to ctDNA testing. We found a linear correlation between the maximum VAF (%ctDNAmax) (as well as the sum of the VAFs (%ctDNAsum)) and SUVmax of the most 18F-FDG-avid lesion (r=0.43, P=0.003; r=0.43, P=0.002; respectively). Our data suggest that SUVmax may be a non-invasive and readily available surrogate indicator for %ctDNA, a prognostic factor for patient survival. Since higher %ctDNA has been previously correlated with worse outcome, the relationship between SUVmax, %ctDNA and survival warrants further study.

Gated single-photon emission computed tomography myocardial perfusion imaging phase analysis as an imaging biomarker for mortality prediction in heart failure patients undergoing cardiac resynchronization therapy.

OBJECTIVE: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure patients. The purpose of this study was to assess the value of gated myocardial perfusion single-photon emission computed tomography (GMPS) phase analysis for predicting survival in heart failure patients undergoing CRT. METHODS: This retrospective cohort study evaluated heart failure patients who underwent GMPS prior to CRT. Phase histogram bandwidth (PHB) and phase SD (PSD) were calculated using GMPS data. Cox proportional hazards model was used to identify independent predictors of overall survival (OS). RESULTS: A total of 35 patients (age 65.1 ± 13.3, 27 men and 8 women), who were followed for mean of 4.1 ± 2.9 years, were enrolled in the study. PSD of greater than 45° was found to be an independent predictor of poor OS (hazard ratio = 12.63, P = 0.011) when compared with age (hazard ratio = 1.00, P = 0.922), gender (hazard ratio = 0.31, P = 0.155), NYHA class (hazard ratio = 0.45, P = 0.087), QRS duration greater than 150 ms (hazard ratio = 2.38, P = 0.401), pre-CRT left ventricular ejection fraction (LVEF) (hazard ratio = 0.95, P = 0.175) and etiology of heart failure (hazard ratio = 1.42, P = 0.641). Furthermore, PHB greater than 140° was also found to be an independent predictor of poor OS (hazard ratio = 5.63, P = 0.040) when compared with age, gender, NYHA class, QRS duration greater than 150 ms, pre-CRT LVEF and etiology of heart failure. CONCLUSIONS: PSD and PHB, measured by GMPS, may serve as biomarkers for the prediction of survival in patients undergoing CRT.

A receptor-binding radiopharmaceutical for imaging of traumatic brain injury in a rodent model: [99mTc]Tc-tilmanocept.

INTRODUCTION: Blood-brain barrier (BBB) disruption and subsequent neuro-inflammation occur following traumatic brain injury (TBI), resulting in a spectrum of human nervous system disorders. [99mTc]Tc-tilmanocept is a receptor-binding radiopharmaceutical FDA-approved for sentinel lymph node mapping. We hypothesize that after an intravenous (i.v.) injection, [99mTc]Tc-tilmanocept, will traverse a disrupted BBB and bind to CD206-bearing microglial cells. METHODS: Age-matched mice were divided into three groups: 5-days post TBI (n = 4), and 5-days post sham (n = 4), and naïve controls (n = 4). IRDye800CW-labeled [99mTc]Tc-tilmanocept (0.15 nmol per gram body weight) and FITC-labeled bovine serum albumin (FITC-BSA) were injected (i.v.) into each mouse. Mice were imaged with a high-resolution gamma camera for 45 min. Immediately after imaging, the brains were perfused with fixative, excised, imaged with a fluorescence scanner, assayed for radioactivity, and prepared for histology. RESULTS: In vivo nuclear imaging, ex vivo fluorescence imaging, ex vivo gamma well counting, and histo-microscopy demonstrated enhanced tilmanocept uptake in the TBI region. The normalized [99mTc]Tc-tilmanocept uptake value from nuclear imaging and the maximum pixel intensity from fluorescence imaging of the TBI group (1.12 ±â€¯0.12 and 2288 ±â€¯278 a.u., respectively) were significantly (P < 0.04) higher than the sham group (0.64 ±â€¯0.28 and 1708 ±â€¯101 a.u., respectively) and the naive group (0.76 ±â€¯0.24 and 1643 ±â€¯391 a.u., respectively). The mean [99mTc]Tc-tilmanocept scaled uptake in the TBI brains (0.058 ±â€¯0.013%/g) was significantly (P < 0.010) higher than the scaled brain uptake of the sham group (0.031 ±â€¯0.011%/g) and higher (P = 0.04) than the uptake of the naïve group (0.020 ±â€¯0.002%/g). Fluorescence microscopy demonstrated increased uptake of the IRDye800CW-tilmanocept and FITC-BSA in the TBI brain regions. CONCLUSION: [99mTc]Tc-tilmanocept traverses disrupted blood-brain barrier and localizes within the injured region. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [99mTc]Tc-tilmanocept could serve as an imaging biomarker for TBI-associated neuroinflammation and any disease process that involves a disruption of the blood-brain barrier.

Relative capability of MR imaging and FDG PET to depict changes associated with prodromal and early Alzheimer disease.

PURPOSE: To quantify the effect sizes of regional metabolic and morphometric measures in patients with preclinical and mild Alzheimer disease (AD) to aid in the identification of noninvasive biomarkers for the early detection of AD. MATERIALS AND METHODS: The study was conducted with institutional review board approval and in compliance with HIPAA regulations. Written informed consent was obtained from each participant or participant's legal guardian. Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging data were analyzed from 80 healthy control (HC) subjects, 68 individuals with AD, and 156 with amnestic mild cognitive impairment (MCI), 69 of whom had single-domain amnestic MCI. Regions of interest (ROIs) were derived after coregistering FDG PET and MR images by using high-throughput, subject-specific procedures. The Cohen d effect sizes were calculated for 42 predefined ROIs across the brain. Statistical comparison of the largest overall effect sizes for MR imaging and PET was performed. Metabolic effect sizes were determined with and without accounting for regional atrophy. Discriminative accuracy of ROIs showing the largest effect sizes were compared by calculating receiver operating characteristic curves. RESULTS: For all disease groups, the hippocampus showed the largest morphometric effect size and the entorhinal cortex showed the largest metabolic effect size. In mild AD, the Cohen d effect size for hippocampal volume (1.92) was significantly larger (P < .05) than that for entorhinal metabolism (1.43). Regression of regional atrophy substantially reduced most metabolic effects. For all group comparisons, the areas under the receiver operating characteristic curves were significantly larger for hippocampal volume than for entorhinal metabolism. CONCLUSION: The current results show no evidence that FDG PET is more sensitive than MR imaging to the degeneration occurring in preclinical and mild AD, suggesting that an MR imaging finding may be a more practical clinical biomarker for early detection of AD.

Standardized uptake value (SUVmax) in 18F-FDG PET/CT is correlated with the total number of main oncogenic anomalies in cancer patients.

Cancer diagnosis and therapy is quickly moving from the traditional histology-based approaches to genomic stratification, providing a huge opportunity for radiogenomics, associating imaging features with genomic data. Genome sequencing is time consuming, expensive and invasive whereas 18F-FDG PET/CT is readily available, fast and noninvasive. The aim of this study was to determine the relationship between the maximum standardized uptake value (SUVmax) and the frequency of 11 common oncogenic anomalies determined by specific common genomic alterations in tissue biopsies from patients with cancer. We retrospectively studied 102 consecutive untreated patients with gastrointestinal, lung, and breast cancer who underwent 18F-FDG PET/CT imaging, shortly prior to molecular testing by a biopsy for genomic profiling that consisted of 11 common DNA alterations: (1) TP53, (2) DNA repair, (3) EGFR, (4) PI3K/AKT/MTOR (PAM) pathway including PTEN, PIK3CA, AKT, TSC, CCNB1, MTOR, FBXW2, and NF2, (5) MEK, (6) CYCLIN including CCND,CDK, CDKN, and RB, (7) WNT, (8) ALK, (9) MYC, (10) MET, and (11) FGF/FGFR. Higher SUVmax was associated with the presence of TP53 and PAM genomic anomalies (p < .05), but not the other 9 gene groups (p > .05). More importantly, SUVmax was positively correlated with total number of oncogenic anomalies (r = 0.27, p = .005). We propose higher SUVmax as an indicator for total number of common oncogenic anomalies. This finding is a step forward in noninvasive stratification of cancer patients, in terms of the overall load of oncogenic anomalies, based on their SUVmax.

Relationship between tumor mutational burden and maximum standardized uptake value in 2-[18F]FDG PET (positron emission tomography) scan in cancer patients.

PURPOSE: Deriving links between imaging and genomic markers is an evolving field. 2-[18F]FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography-computed tomography) is commonly used for cancer imaging, with maximum standardized uptake value (SUVmax) as the main quantitative parameter. Tumor mutational burden (TMB), the quantitative variable obtained using next-generation sequencing on a tissue biopsy sample, is a putative immunotherapy response predictor. We report the relationship between TMB and SUVmax, linking these two important parameters. METHODS: In this pilot study, we analyzed 1923 patients with diverse cancers and available TMB values. Overall, 273 patients met our eligibility criteria in that they had no systemic treatment prior to imaging/biopsy, and also had 2-[18F]FDG PET/CT within 6 months prior to the tissue biopsy, to ensure acceptable temporal correlation between imaging and genomic evaluation. RESULTS: We found a linear correlation between TMB and SUVmax (p < 0.001). In the multivariate analysis, only TMB independently correlated with SUVmax, whereas age, gender, and tumor organ did not. CONCLUSION: Our observations link SUVmax in readily available, routinely used, and noninvasive 2-[18F]FDG PET/CT imaging to the TMB, which requires a tissue biopsy and time to process. Since higher TMB has been implicated as a prognostic biomarker for better outcomes after immunotherapy, further investigation will be needed to determine if SUVmax can stratify patient response to immunotherapy.

Glucose-corrected standardized uptake value (SUVgluc) is the most accurate SUV parameter for evaluation of pulmonary nodules.

Standardized uptake values (SUVs) of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) are widely used to help characterize pulmonary nodules. The purpose of this study is to assess the accuracy of the SUV corrected by blood glucose levels (SUVgluc), compared to four other commonly used semi-quantitative methods: maximal SUV normalized to body weight (SUVmax), ratio of SUV of nodule to cerebellum (SUVcer), SUV normalized to body surface area (SUVbsa) and SUV normalized to body mass index (SUVbmi). 52 patients with lung nodules had FDG PET scans, consecutively imaged between 7/1/2015 and 6/7/2016. Histopathologic result of the nodules, obtained within two months after the FDG PET scan, demonstrated 10 benign and 42 malignant lung nodules. The SUVgluc was defined as SUVmax × blood glucose level/100. The average SUVmax was 2.8 for benign nodules and 7.7 for malignant nodules. No significant difference in the receiver operating characteristic (ROC) area under the curves (AUCs) were found between the SUVmax (0.84) and the SUVcer (0.87) or SUVbsa (0.86), or SUVbmi (0.86) with p-values greater than 0.05; however, the ROC AUC for the SUVgluc (0.90) was larger than that for the SUVmax with p-value of 0.03. These results suggest that SUVgluc may assist in more accurately representing the glucose metabolism of malignant lung nodules by accounting for the patient's blood glucose level (BGL). The simplicity of the SUVgluc method avoids an additional reference ROI, uses preexisting clinical data, i.e. pre-injection blood glucose level, and retains the familiar SUV reference values.

Molecular Imaging of the Glomerulus via Mesangial Cell Uptake of Radiolabeled Tilmanocept.

An unmet need for the clinical management of chronic kidney disease is a predictive tool of kidney function during the first decade of the disease, when there is silent loss of glomerular function. The objective of this study was to demonstrate receptor-mediated binding of tilmanocept to CD206 within the kidney and provide evidence of kinetic sensitivity of this binding to renal function. Methods: Rats were positioned in a PET scanner with the liver and kidneys within the field of view. After an intravenous injection of 68Ga-IRDye800-tilmanocept, using 1 of 2 scaled molar doses (0.02 nmol/g, n = 5; or 0.10 nmol/g, n = 5), or coinjection (n = 3) of 68Ga-IRDye800-tilmanocept (0.10 nmol/g) and unlabeled tilmanocept (5.0 nmol/g), or a negative control, 68Ga-IRDye800-DTPA-galactosyl-dextran (0.02 nmol/g, n = 5), each animal was imaged for 20 min followed by a whole-body scan. Frozen kidney sections were stained for podocytes and CD206 using immunofluorescence. Molecular imaging of diabetic db/db mice (4.9 wk, n = 6; 7.3 wk, n = 4; 13.3 wk, n = 6) and nondiabetic db/m mice (n = 6) was performed with fluorescence-labeled 99mTc-tilmanocept (18.5 MBq, 2.6 nmol). Thirty minutes after injection, blood, liver, kidneys, and urine were assayed for radioactivity. Renal time-activity curves were generated. Results: Rat PET whole-body images and time-activity curves of 68Ga-IRDye800-tilmanocept demonstrated receptor-mediated renal accumulation with evidence of glomerular uptake. Activity within the renal cortex persisted during the 40-min study. Histologic examination demonstrated colocalization of CD206 and IRDye800-tilmanocept within the glomerulus. The glomerular accumulation of the coinjection and the negative control studies were significantly less than the CD206-targeted agent. The db/db mice displayed a multiphasic renal time-activity curve with high urinary bladder accumulation; the nondiabetic mice exhibited renal uptake curves dominated by a single phase with low bladder accumulation. Conclusion: This study demonstrated receptor-mediated binding to the glomerular mesangial cells and kinetic sensitivity of tilmanocept to chronic renal disease. Given the role of mesangial cells during the progression of diabetic nephropathy, PET or SPECT renal imaging with radiolabeled tilmanocept may provide a noninvasive quantitative assessment of glomerular function.