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.

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.

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.

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.

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.

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.

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.

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.

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.

Molecular Imaging of endometrial sentinel lymph nodes utilizing fluorescent-labeled Tilmanocept during robotic-assisted surgery in a porcine model.

Molecular imaging with a fluorescent version of Tilmanocept may permit an accurate and facile detection of sentinel nodes of endometrial cancer. Tilmanocept accumulates in sentinel lymph nodes (SLN) by binding to a cell surface receptor unique to macrophages and dendritic cells. Four female Yorkshire pigs underwent cervical stromal injection of IRDye800-Tilmanocept, a molecular imaging agent tagged with near-infrared fluorescent dye and radiolabeled with gallium-68 and technetium-99m. PET/CT scans 1.5 hours post-injection provided pre-operative SLN mapping. Robotic-assisted lymphadenectomy was performed two days after injection, using the FireFly imaging system to identify nodes demonstrating fluorescent signal. After removal of fluorescent nodes, pelvic and periaortic node dissections were performed. Nodes were assayed for technetium-99m activity, and SLNs were established using the "10%-rule", requiring that the radioactivity of additional SLNs be greater than 10% of the "hottest" SLN. Thirty-four nodal samples were assayed ex vivo for radioactivity. All the SLNs satisfying the "10%-rule" were detected using the FireFly system. Five fluorescent nodes were detected, corresponding with preoperative PET/CT scan. Three pigs had one SLN and one pig had two SLNs, with 100% concordance between fluorescence and radioactivity. Fluorescent-labeled Tilmanocept permits real-time intraoperative detection of SLNs during robotic-assisted lymphadenectomy for endometrial cancer in a porcine model. When radiolabeled with gallium-68, Tilmanocept allows for preoperative localization of SLNs using PET/CT, and shows specificity to SLNs with persistent fluorescent signal, detectable using the FireFly system, for two days post-injection. In conclusion, these findings suggest that a phase I trial in human subjects is warranted, and that a long-term goal of an intra-operative administration of non-radioactive fluorescent-labeled Tilmanocept is possible.

TP53 mutations and number of alterations correlate with maximum standardized uptake value (SUVmax) determined by positron emission tomography/computed tomography (PET/CT) [18F] fluorodeoxyglucose (18F-FDG PET).

BACKGROUND: Our study explored the relationship between the molecular changes in cancer and the maximum standardized uptake value (SUVmax) determined by positron emission tomography/computed tomography (PET/CT) with [18F] fluorodeoxyglucose (18F-FDG). RESULTS: A higher SUVmax correlated with TP53 alterations, but not with histologic diagnosis or other gene/pathway mutations or copy number alterations. In data from breast, lung and colon cancer, patients with the highest SUVmax show more genomic anomalies compared to those with the lowest SUVmax (P < 0.005). CONCLUSIONS: A higher SUVmax on 18F-FDG PET/CT is associated with TP53 tumor suppressor gene anomalies and the presence of more genomic anomalies. Since TP53 alterations and high SUVmax both correlate with a poor prognosis, the underlying mechanism/implications of this association merit further study. METHODS: Overall, 176 patients with diverse cancers had a tumor biopsy within 6 months after a PET/CT image for SUVmax measurement. The biopsy was interrogated by next generation sequencing (182 to 315 genes). TP53, EGFR, ALK, MYC, MET and FGF/FGFR genes and DNA repair, PI3K/Akt/mTOR (PAM), MEK, CYCLIN, and WNT pathway genes were analyzed.

Feasibility of atlas-based active bone marrow sparing intensity modulated radiation therapy for cervical cancer.

BACKGROUND: To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients. METHODS: We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training (n=32) or test (n=30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABMAtlas) vs. the individual's PET (ABMCustom). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABMAtlas, or ABMCustom were compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality. RESULTS: ABMAtlas and ABMCustom volumes were not significantly different (p=0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABMCustom, ABMAtlas-sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABMCustom (mean ABMCustom dose 29.4Gy vs. 27.1Gyvs. 26.9Gy, respectively; p=0.10); however, PTV coverage and bowel sparing were slightly reduced. CONCLUSIONS: Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity.

Longitudinal Changes in Active Bone Marrow for Cervical Cancer Patients Treated With Concurrent Chemoradiation Therapy.

PURPOSE: To quantify longitudinal changes in active bone marrow (ABM) distributions within unirradiated (extrapelvic) and irradiated (pelvic) bone marrow (BM) in cervical cancer patients treated with concurrent chemoradiation therapy (CRT). METHODS AND MATERIALS: We sampled 39 cervical cancer patients treated with CRT, of whom 25 were treated with concurrent cisplatin (40 mg/m2) and 14 were treated with cisplatin (40 mg/m2) plus gemcitabine (50-125 mg/m2) (C/G). Patients underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and 1.5 to 6.0 months after treatment. ABM was defined as the subvolume of bone with standardized uptake value (SUV) above the mean SUV of the total bone. The primary aim was to measure the compensatory response, defined as the change in the log of the ratio of extrapelvic versus pelvic ABM percentage from baseline to after treatment. We also quantified the change in the proportion of ABM and mean SUV in pelvic and extrapelvic BM using a 2-sided paired t test. RESULTS: We observed a significant increase in the overall extrapelvic compensatory response after CRT (0.381; 95% confidence interval [CI]: 0.312, 0.449) and separately in patients treated with cisplatin (0.429; 95% CI: 0.340, 0.517) and C/G (0.294; 95% CI: 0.186, 0.402). We observed a trend toward higher compensatory response in patients treated with cisplatin compared with C/G (P=.057). Pelvic ABM percentage was reduced after CRT both in patients receiving cisplatin (P<.001) and in those receiving C/G (P<.001), whereas extrapelvic ABM percentage was increased in patients receiving cisplatin (P<.001) and C/G (P<.001). The mean SUV in pelvic structures was lower after CRT with both cisplatin (P<.001) and C/G (P<.001). The mean SUV appeared lower in extrapelvic structures after CRT in patients treated with C/G (P=.076) but not with cisplatin (P=.942). We also observed that older age and more intense chemotherapy regimens were correlated with a decreased compensatory response on multivariable analysis. In patients treated with C/G, mean pelvic bone marrow dose was found to be negatively correlated with the compensatory response. CONCLUSION: Patients have differing subacute compensatory responses after CRT, owing to variable recovery in unirradiated marrow. Intensive chemotherapy regimens appear to decrease the extrapelvic compensatory response, which may lead to increased hematologic toxicity.

Fluorescence-Based Molecular Imaging of Porcine Urinary Bladder Sentinel Lymph Nodes.

The primary objective was to test the ability of a laparoscopic camera system to detect the fluorescent signal emanating from sentinel lymph nodes (SLNs) approximately 2 d after injection and imaging of a positron-emitting molecular imaging agent into the submucosa of the porcine urinary bladder. Methods: Three female pigs underwent a submucosal injection of the bladder with fluorescent-tagged tilmanocept, radiolabeled with both 68Ga and 99mTc. One hour after injection, a pelvic PET/CT scan was acquired for preoperative SLN mapping. Approximately 36 h later, robotic SLN mapping was performed using a fluorescence-capable camera system. After identification of the fluorescent lymph nodes, a pelvic lymph node dissection was completed with robotic assistance. All excised nodal packets (n = 36) were assayed for 99mTc activity, which established a lymph node as an SLN. 99mTc activity was also used to calculate the amount of dye within each lymph node. Results: All of the SLNs defined by the ex vivo γ-well assay of 99mTc activity were detected by fluorescence mode imaging. The time between injection and robotic SLN mapping ranged from 32 to 38 h. A total of 5 fluorescent lymph nodes were detected; 2 pigs had 2 fluorescent lymph nodes and 1 pig exhibited a single lymph node. Four of the 5 SLNs exhibited increased SUVs of 12.4-139.0 obtained from PET/CT. The dye content of the injection sites ranged from 371 to 1,441 pmol, which represented 16.5%-64.1% of the injected dose; the amount of dye within the SLNs ranged from 8.5 to 88 pmol, which was equivalent to 0.38%-3.91% of the administered dose. Conclusion: Fluorescent-labeled 68Ga-tilmanocept allows for PET imaging and real-time intraoperative detection of SLNs during robotic surgery.

Prognostic value of post-Yttrium 90 radioembolization therapy 18F-fluorodeoxyglucose positron emission tomography in patients with liver tumors.

OBJECTIVE: This study assessed the benefit of post-therapy 18F-FDG PET/CT versus CT alone in identifying malignant liver tumor progression following radioembolization with Y-90 microspheres. METHODS: 24 patients with 44 liver tumors underwent CT imaging pre-radioembolization and PET/CT post-radioembolization. Predictive value of Response Evaluation Criteria in Solid Tumors (RECIST 1.1), The World Health Organization (WHO), mRECIST and European Association for the Study of the Liver (EASL) with PET/CT versus CT alone was assessed. RESULTS: Prediction of liver malignancy progression was improved (p<0.05) for tumors labeled as non-responding based on combined PET/CT with RECIST 1.1, WHO, mRECIST, and EASL criteria compared to assessment without PET. CONCLUSIONS: The addition of post-therapy PET to routine CT in patients with hepatic tumors undergoing radioembolization may improve identification of non-responding tumors.

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.

Staging of fibrosis in experimental non-alcoholic steatohepatitis by quantitative molecular imaging in rat models.

OBJECTIVES: The aim of this study was to test the ability of hepatocyte-specific functional imaging to stage fibrosis in experimental rat models of liver fibrosis and progressive NASH. Using ROC analysis we tested the ability of a functional imaging metric to discriminate early (F1) from moderate (F2) fibrosis in the absence and presence of non-alcoholic steatohepatitis, which has not been achieved by any modality other than biopsy. METHODS: Galactosyl Human Serum Albumin (GSA) was radiolabeled with the positron-emitter, (68)Ga, and injected (i.v., 45-95 µCi, 1.5 pmol/g TBW) into 44 healthy, 19 DEN-, and 22 CDAA-treated male rats. Quantification of liver function was achieved by calculating T90, defined as the time for the liver to accumulate 90 percent of the [(68)Ga]GSA plateau value. All livers were excised immediately after imaging and prepared for a "blinded" histologic examination, which included fibrosis and fat content scores. Two sets of fibrosis scores were recorded for all of animals. The dominant fibrosis stage was recorded as the "Dominant Pattern" score and the "Maximum Pattern" score was assigned if a smaller distinct region with a higher fibrosis score was observed. RESULTS: Animals with Dominant Pattern F0-F1 liver fibrosis (D(-)=39) demonstrated significantly (P<0.0001) faster accumulation of [(68)Ga]GSA (2.40 ± 0.52 min) than those with moderate to advanced Dominant Pattern fibrosis F2 and F4 (D(+)=26) (3.48 ± 1.01 min). ROC analysis (F0-F1 vs F2-F4) produced an area under the binormal curve (AUC) of 0.867 ± 0.045. Twenty-seven of the 65 rats had small regions with higher fibrosis scores. Six of these Maximum Pattern scores reclassified the animals from D(-) to D(+). ROC analysis of F0-F1 versus F2-F4 rats without liver fat produced AUCs of 0.881 ± 0.053 for the Dominant Pattern Score and 0.944 ± 0.035 for the Maximum Pattern Score. CONCLUSIONS: PET Functional Imaging of [(68)Ga]GSA accurately discriminates early from moderate experimental fibrosis independent of steatosis grade. If validated in human studies, molecular imaging may emerge as a potential alternative to invasive liver biopsy.