Predicting the Efficacy of SBRT for Lung Cancer with 18F-FDG PET/CT Radiogenomics.

PURPOSE: to develop a radiogenomic model on the basis of 18F-FDG PET/CT radiomics and clinical-parameter EGFR for predicting PFS stratification in lung-cancer patients after SBRT treatment. METHODS: A total of 123 patients with lung cancer who had undergone 18F-FDG PET/CT examination before SBRT from September 2014 to December 2021 were retrospectively analyzed. All patients' PET/CT images were manually segmented, and the radiomic features were extracted. LASSO regression was used to select radiomic features. Logistic regression analysis was used to screen clinical features to establish the clinical EGFR model, and a radiogenomic model was constructed by combining radiomics and clinical EGFR. We used the receiver operating characteristic curve and calibration curve to assess the efficacy of the models. The decision curve and influence curve analysis were used to evaluate the clinical value of the models. The bootstrap method was used to validate the radiogenomic model, and the mean AUC was calculated to assess the model. RESULTS: A total of 2042 radiomics features were extracted. Five radiomic features were related to the PFS stratification of lung-cancer patients with SBRT. T-stage and overall stages (TNM) were independent factors for predicting PFS stratification. AUCs under the ROC curve of the radiomics, clinical EGFR, and radiogenomic models were 0.84, 0.67, and 0.86, respectively. The calibration curve shows that the predicted value of the radiogenomic model was in good agreement with the actual value. The decision and influence curve showed that the model had high clinical application values. After Bootstrap validation, the mean AUC of the radiogenomic model was 0.850(95%CI 0.849-0.851). CONCLUSIONS: The radiogenomic model based on 18F-FDG PET/CT radiomics and clinical EGFR has good application value in predicting the PFS stratification of lung-cancer patients after SBRT treatment.

Emerging PET Tracers in Cardiac Molecular Imaging.

18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) represent emerging PET tracers used to assess atherosclerosis-related inflammation and molecular calcification, respectively. By localizing to sites with high glucose utilization, FDG has been used to assess myocardial viability for decades, and its role in evaluating cardiac sarcoidosis has come to represent a major application. In addition to determining late-stage changes such as loss of perfusion or viability, by targeting mechanisms present in atherosclerosis, PET-based techniques have the ability to characterize atherogenesis in the early stages to guide intervention. Although it was once thought that FDG would be a reliable indicator of ongoing plaque formation, micro-calcification as portrayed by NaF-PET/CT appears to be a superior method of monitoring disease progression. PET imaging with NaF has the additional advantage of being able to determine abnormal uptake due to coronary artery disease, which is obscured by physiologic myocardial activity on FDG-PET/CT. In this review, we discuss the evolving roles of FDG, NaF, and other PET tracers in cardiac molecular imaging.

Efficacy and Failure Patterns of Early SBRT to the Primary Tumor in Advanced EGFR-Mutation-Positive Lung Cancer with EFGR-TKI Treatment: A Prospective, Single Arm, Phase II Study.

Early stereotactic body radiation therapy (SBRT) to the primary tumor combined with epidermal growth factor receptor tyrosine kinase inhibitor (EFGR-TKI) treatment may increase progression-free survival (PFS) by delaying resistance in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). In this prospective, single arm, phase II study, patients with advanced NSCLC were treated with EGFR-TKI (icotinib 125 mg tid or gefitinib 250 mg qd) for one month followed by SBRT (40-60 Gy/5-8 F/5-10 d) to the primary tumor with concurrent EGFR-TKI until disease progression. The primary endpoint was PFS and the patterns of failure. Overall survival (OS) and adverse effects (AEs) were secondary endpoints. Overall, 41 advanced NSCLC patients with EGFR mutations received treatment with 24.42 months of median follow-up time. On average, SBRT was initiated 1.49 months after EGFR-TKI administration. Tumors were found to have an average shrinkage rate of 42.50%. Median PFS was 15.23 months (95% CI 13.10-17.36), while median OS was 27.57 months (95% CI 23.05-32.09). Thirty-three patients were found to have disease progression, of which new site failure (NF) (22 patients, 66.66%) was the most common pattern, followed by original site failure (OF) (7 patients, 21.21%) and simultaneous OF/NF (ONF) (4 patients, 12.12%). There were no Aes equal to or greater than grade 3, with the most frequent AE being radiation pneumonitis. Therefore, administering therapy targeted at the primary tumor using early SBRT after EGFR-TKI initiation is a new potentially safe and effective approach to treat EGFR-mutant advanced NSCLC.

Feasibility of Global Assessment of Bone Metastases in Prostate Cancer with 18F-Sodium Fluoride-PET/Computed Tomography.

18F-sodium fluoride (NaF) PET/computed tomography (CT) allows detection of bone metastases in patients with prostate cancer (PCa). The aim of this study was to test the feasibility of assessing global metastatic bone disease in patients with PCa by using a threshold-based PET segmentation technique. This retrospective analysis was performed in 32 patients with PCa with known bone metastases who underwent NaF-PET/CT imaging. An adaptive contrast-oriented thresholding technique was used to segment NaF avid lesions. The mean metabolic volumetric product (MVPmean), partial volume-corrected MVPmean (cMVPmean), and metabolically active volume (MAV) were calculated. Lesional values were summed within each patient to obtain the global PET disease burden. Pearson correlation analysis was used to assess the associations between global NaF-PET/CT metrics and clinical biomarkers of metastatic disease activity. Global MVPmean, cMVPmean, and MAV were significantly correlated with alkaline phosphatase (ALP) levels (p < 0.05). No correlation was observed between global NaF-PET/CT measures and prostate-specific antigen (PSA) levels. Global assessment is a feasible method to quantify metastatic bone disease activity in patients with PCa. Convergent validity was supported by demonstrating a significant correlation between NaF-PET/CT parameters and blood ALP levels.

Assessing Coronary Artery and Aortic Calcification in Patients with Prostate Cancer Using 18F-Sodium Fluoride PET/Computed Tomography.

The aim of this study was to assess coronary artery and aortic calcification in healthy controls, angina pectoris patients, and prostate cancer patients using 18F-sodium fluoride PET/computed tomography (NaF-PET/CT). A retrospective analysis compared 33 prostate cancer patients with 33 healthy subjects and 33 patients with angina pectoris. Increased target-to-background ratio (TBR) of the coronary arteries, ascending aorta, aortic arch, and descending aorta was observed in cancer patients compared to healthy controls but not compared to angina pectoris patients. These results demonstrate the feasibility of assessing vascular microcalcification with NaF-PET/CT, with significant differences in uptake according to comorbidities.

Application of 18F-NaF-PET/CT in assessing age-related changes in the cervical spine.

Background: Cervical spondylosis is the degeneration of cervical spine often associated with aging and neck pain. As the degenerative changes are coupled with altered osteoblastic activity, imaging modalities sensitive to such molecular changes could be valuable for clinical assessment, disease prophylaxis, and monitoring early therapy response. In this study, we examined the role of 18F-sodium fluoride-positron emission tomography/computed tomography (18F-NaF-PET/CT) in detecting age-associated changes in the cervical spine of an adult population with broad age spectrum. Methods: In this retrospective cross-sectional study, we analyzed 18F-NaF-PET/CT scans of 88 control volunteers (43 females, 45 males) with age ranging from 21 to 75 years (mean =44.6, standard deviation, 14.0) divided into younger (21-45 years) and older (46-75 years) age groups. A semi-automated global assessment technique was used to measure 18F-NaF uptake in C2-C4 and C5-C7 vertebrae of the subjects. Furthermore, a CT-based scoring system was devised to measure the degree of structural degeneration. Results: There was a significant difference in 18F-NaF uptake of the younger and older groups at the C5-C7 vertebrae for both females (younger: mean =4.13, 95% CI: 3.72-4.55; older: mean = 4.80, 95% CI: 4.40-5.20; P=0.005) and males (younger: mean =3.66, 95% CI: 3.24-4.09; older: mean =4.22, 95% CI: 3.80-4.64; P=0.009), but not at the C2-C4 vertebrae. Furthermore, there was a positive correlation between the degree of degeneration and 18F-NaF uptake at both C2-C4 and C5-C7 spinal segments of both sexes. Conclusions: Aging is associated with increased 18F-NaF uptake in the cervical spine, which may be associated with osteoblastic activity coupled with degeneration. Our study alludes to the potential role of 18F-NaF-PET/CT in evaluating age-related degeneration and osteoarthritis of the spine.

Role of Molecular Imaging with PET/MR Imaging in the Diagnosis and Management of Brain Tumors.

Gliomas are the most common primary brain tumors. Hybrid PET/MR imaging has revolutionized brain tumor imaging, allowing for noninvasive, simultaneous assessment of morphologic, functional, metabolic, and molecular parameters within the brain. Molecular information obtained from PET imaging may aid in the detection, classification, prognostication, and therapeutic decision making for gliomas. 18F-fluorodeoxyglucose (FDG) has been widely used in the setting of brain tumor imaging, and multiple techniques may be employed to optimize this methodology. More recently, a number of non-18F-FDG-PET radiotracers have been applied toward brain tumor imaging and are used in clinical practice.

Prognostic significance of conventional and volumetric PET parameters with and without partial volume correction in the assessment of head and neck squamous cell carcinoma.

BACKGROUND: The optimal quantification of PET in assessment of head and neck squamous cell carcinoma (HNSCC) is still under development. The effect of partial volume correction (PVC) on the evaluation of survival in the HNSCC patients has not been investigated yet. METHODOLOGY: Pretreatment 18F-FDG-PET/CT scans of a selected group of 57 patients with advanced stage HNSCC were collected. Conventional (SUVmean and SUVmax) and volumetric [total lesion glycolysis (TLG) and metabolic tumor volume (MTV)] PET metrics were calculated. The ROVER software (ABX GmbH, Radeberg, Germany) automatically applied PVC to the PET metrics. Cox proportional hazards regression model calculated hazard ratio (HR) for assessment of predictive parameters of progression-free survival (PFS). RESULTS: In multivariate Cox regression analysis, including age, gender, race, human papillomavirus status, and stage, the only significant predictors of PFS were the volumetric PET parameters (TLG: HR, 1.003; 95% CI, 1.001-1.005; P = 0.02), pvcTLG (HR, 1.002; 95% CI, 1.001-1.004; P = 0.01) and MTV (HR, 1.050; 95% CI, 1.024-1.077; P < 0.01). The partial volume-corrected values were significantly higher than the noncorrected values (Wilcoxon sign test; P < 0.05). However, there was not a statistically significant difference between the nonpartial volume corrected and partial volume-corrected PET metrics for assessment of PFS. CONCLUSION: Volumetric PET metrics were predictors of PFS in Cox regression analysis. Applying PVC could not significantly improve the accuracy of PET metrics for assessment of PFS.

A review of different methods used for quantification and assessment of FDG-PET/CT in multiple myeloma.

The quantification of positron emission tomography/computed tomography (PET/CT) in multiple myeloma (MM) is challenging. Different methods of PET/CT quantification for assessment of fluorodeoxyglucose (FDG) uptake in myeloma patients have been suggested. This is the first review article that focuses on the advantages and disadvantages of each approach. Use of the maximum standardized uptake value (SUVmax) showed some promise in prognostic stratification of MM patients. However, it is affected by noise and time of flight and is subject to high variability. Volumetric PET metrics such as total lesion glycolysis and metabolic tumor volume are other proposed approaches. The high number of osteolytic lesions in MM patients makes this approach difficult in clinical practice. In addition, evaluation of small focal lesions is subject to partial volume correction. CT-based segmentation for assessment of FDG radiotracer is recently introduced. The methodologies are highly reproducible, but the clinical values of the approaches are unclear and still under investigation. We also discuss the Italian Myeloma criteria for PET Use (IMPeTUs), which is a qualitative approach, as a point of comparison. The reproducibility of IMPeTUs depends heavily on the level of user experience. We recommend further studies for assessing the prognostic significance of CT-threshold approaches in the assessment of MM patients.

Potential and Most Relevant Applications of Total Body PET/CT Imaging.

ABSTRACT: The introduction of total body (TB) PET/CT instruments over the past 2 years has initiated a new and exciting era in medical imaging. These instruments have substantially higher sensitivity (up to 68 times) than conventional modalities and therefore allow imaging the entire body over a short period. However, we need to further refine the imaging protocols of this instrument for different indications. Total body PET will allow accurate assessment of the extent of disease, particularly, including the entire axial and appendicular skeleton. Furthermore, delayed imaging with this instrument may enhance the sensitivity of PET for some types of cancer. Also, this modality may improve the detection of venous thrombosis, a common complication of cancer and chemotherapy, in the extremities and help prevent pulmonary embolism. Total body PET allows assessment of atherosclerotic plaques throughout the body as a systematic disease. Similarly, patients with widespread musculoskeletal disorders including both oncologic and nononcologic entities, such as degenerative joint disease, rheumatoid arthritis, and osteoporosis, may benefit from the use of TB-PET. Finally, quantitative global disease assessment provided by this approach will be superior to conventional measurements, which do not reflect overall disease activity. In conclusion, TB-PET imaging may have a revolutionary impact on day-to-day practice of medicine and may become the leading imaging modality in the future.

18F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications.

In a healthy body, homeostatic actions of osteoclasts and osteoblasts maintain the integrity of the skeletal system. When cellular activities of osteoclasts and osteoblasts become abnormal, pathological bone conditions, such as osteoporosis, can occur. Traditional imaging modalities, such as radiographs, are insensitive to the early cellular changes that precede gross pathological findings, often leading to delayed disease diagnoses and suboptimal therapeutic strategies. 18F-sodium fluoride (18F-NaF)-positron emission tomography (PET) is an emerging imaging modality with the potential for early diagnosis and monitoring of bone diseases through the detection of subtle metabolic changes. Specifically, the dissociated 18F- is incorporated into hydroxyapatite, and its uptake reflects osteoblastic activity and bone perfusion, allowing for the quantification of bone turnover. While 18F-NaF-PET has traditionally been used to detect metastatic bone disease, recent literature corroborates the use of 18F-NaF-PET in benign osseous conditions as well. In this review, we discuss the cellular mechanisms of 18F-NaF-PET and examine recent findings on its clinical application in diverse metabolic, autoimmune, and osteogenic bone disorders.

A Critical Review of PET Tracers Used for Brain Tumor Imaging.

The brain is a common site for metastases as well as primary tumors. Although evaluation of these malignancies with contrast-enhanced MR imaging defines current clinical practice, 18F-fluorodeoxyglucose (FDG)-PET has shown considerable utility in this area. In addition, many other tracers targeting various aspects of tumor biology have been developed and tested. This article discusses recent developments in PET imaging and the anticipated role of FDG and other tracers in the assessment of brain tumors.

Novel Musculoskeletal and Orthopedic Applications of 18F-Sodium Fluoride PET.

PET imaging with 18F-sodium fluoride (NaF), combined with computed tomography or magnetic resonance, is a sensitive method of assessing bone turnover. Although NaF-PET is gaining popularity in detecting prostate cancer metastases to bone marrow, osseous changes represent secondary effects of cancer cell growth. PET tracers more appropriate for assessing prostate cancer metastases directly portray malignant activity and include 18F-fluciclovine and prostatic specific membrane antigen ligands. Recent studies investigating NaF-PET suggest utility in the assessment of benign musculoskeletal disorders. Emerging applications in assessing traumatic injuries, joint disease, back pain, orthopedic complications, and metabolic bone disease are discussed.

Magnetic resonance imaging-based partial volume-corrected 18F-sodium fluoride positron emission tomography in the femoral neck.

OBJECTIVES: 18F-sodium fluoride (NaF) is a radiotracer used in PET that reflects calcium metabolism and osteoblastic activity. In this study, we assessed the construct validity of a novel application of global assessment to measure NaF uptake in the femoral neck as a method of evaluating physiologic changes in osteoblastic metabolism with age. METHODS: Whole-body NaF-PET/computed tomography (CT) images and MRI of 24 male patients with a history of nonmetastatic prostate cancer between the ages of 36 and 82 years (67.8 ± 9.6) were analyzed. A region of interest delineated the entire femoral neck on the PET/CT image to determine the mean standardized uptake value (SUVmean). Correction for the partial volume effect was performed by measuring the volume of inert yellow bone marrow by MRI segmentation. Multiple linear regression was used to assess the relationship of uptake with age and body weight. RESULTS: The SUVmean with and without partial volume correction decreased with respect to age (P = 0.001 and P = 0.002, respectively). Body weight was not significantly related to any measured PET parameter. CONCLUSION: Our results support the use of global NaF uptake with magnetic resonance-derived partial volume correction in the femoral neck. Because osteoblastic metabolism is known to decrease with normal aging, the observed decrease in NaF uptake constitutes evidence for convergent validity, indicating that the proposed methodology likely reflects systemic osteoblastic activity. Future studies of this methodology are warranted in other instances of varying osteoblastic activity such as in metabolic bone diseases and for the evaluation of therapy targeting osteoblastic metabolism.

Total-Body PET Imaging of Musculoskeletal Disorders.

Imaging of musculoskeletal disorders, including arthritis, infection, osteoporosis, sarcopenia, and malignancies, is often limited when using conventional modalities such as radiography, computed tomography (CT), and MR imaging. As a result of recent advances in Positron Emission Tomography (PET) instrumentation, total-body PET/CT offers a longer axial field-of-view, higher geometric sensitivity, and higher spatial resolution compared with standard PET systems. This article discusses the potential applications of total-body PET/CT imaging in the assessment of musculoskeletal disorders.

Correlation of whole-bone marrow dual-time-point 18F-FDG, as measured by a CT-based method of PET/CT quantification, with response to treatment in newly diagnosed multiple myeloma patients.

The practical application of dual-time-point-imaging (DTPI) technique still remains controversial. One of the issues is that current parameters of DTPI quantification suffer from some deficiencies, mainly limited sampling of the diseased sites by confining measurements to specific locations. We aimed to examine the correlation between the percent change from early to delayed scans in whole-bone marrow (WBM) 18F-FDG uptake, as measured by a CT-based method of PET/CT quantification, and response to treatment in multiple myeloma (MM) patients. Pre-treatment 18F-FDG-PET/CT scans of 36 newly diagnosed MM patients were collected in a prospective study at 1 h and 3 h post tracer injection (NCT02187731). A threshold algorithm based on bone Hounsfield units on CT was applied to segment and quantify WBM 18F-FDG uptake. Patients were separated into two treatment groups: high-dose therapy with autologous stem cell transplant (HDT) and non-high dose therapy (non-HDT). The International Response Criteria for MM patients was used to determine each patient's response to treatment. In the HDT group, WBM 18F-FDG uptake increased significantly in patients that had a poor response to treatment, from a median of 1.31 (IQR: 1.13-1.64) at 1 h to a median of 1.85 (1.45-2.10) at 3 h. The median percent change was 37.77% (IQR: 23.47-46.4), with a range of 6.10-50.73 (P = 0.003). However, no significant change in uptake was observed in patients with a complete response (P = 0.24). The same trend was observed for the non-HDT group. WBM uptake of 18F-FDG assessed with dual-time-point imaging may have a role in predicting treatment response in MM.

Prognostic significance of 18F-sodium fluoride in newly diagnosed multiple myeloma patients.

Focal bone lesions and fractures due to weakened bone are associated with higher morbidity and mortality of multiple myeloma (MM) patients. 18F-sodium fluoride (18F-NaF) is a sensitive PET radiotracer for detection of abnormal bone metabolism and, therefore, is particularly suited to assess the degree of bone involvement in MM patients. We aimed to investigate the prognostic significance of metabolic active volume (MAV) of 18F-NaF-avid lesions in MM patients. In addition to MAV, conventional methods of PET quantification, namely SUVmean and SUVmax, were measured in each patient for the purpose of comparison. Thirty-seven newly diagnosed MM patients were included. PET imaging was performed after intravenous administration of 200 MBq NaF. Active bone lesions and fractures on whole-body 18F-NaF-PET/CT scans were identified. An adaptive thresholding algorithm automatically calculated the total MAV, SUVmean and SUVmax for each patient (ROVER, ABX, Radeberg, Germany). The patients were followed for a median of 39.8 months after treatment (range: 17.8-55.4). The overall survival (OS) of patients with 18F-NaF-MAV value > 38.65 (36.36% [N of Events/Total N: 4/11]) was significantly shorter than that of patients with 18F-NaF-MAV value < 38.65 (3.85% [1/26]; P = 0.002). In multivariate forward stepwise (conditional LR) Cox regression analysis of prognostic factors of OS (including 18F-NaF-MAV (> 38.65 or < 38.65), age, gender, beta-2 microglobulin, and revised international staging system), 18F-NaF-MAV remained the only significant factor (HR: 14.39, P = 0.02). The results for PFS were not significant. Moreover, Kaplan-Meier analyses of conventional methods of PET quantification did not reveal any statistically significant log-rank p-values. MM patients with high 18F-NaF-MAV had shorter overall survival, compared to those with low 18F-NaF-MAV levels (NCT02187731).

Association of triglyceride to high density lipoprotein ratio with global cardiac microcalcification to evaluate subclinical coronary atherosclerosis in non-diabetic individuals.

OBJECTIVE: Triglycerides (TG) to high density lipoprotein (HDL) ratio has been proposed as a marker of insulin resistance and atherosclerosis. We hypothesize that TG/HDL ratio correlates positively with global cardiac microcalcification as assessed by NaF-PET/CT as a surrogate marker for coronary atherosclerosis in healthy non-diabetic individuals. METHOD: We identified 68 healthy, non-diabetic individuals (age 41.7 ± 13.5 years; 35/33 female/male) from the CAMONA trial. All underwent PET/CT imaging 90 minutes after NaF injection (2.2 Mbq/Kg). Global cardiac average SUVmean (aSUVmean) was calculated by a trained physician for each individual. Fasting plasma lipid profile (total cholesterol (TC), low-density lipoprotein (LDL), HDL, and TG) and fasting plasma glucose were recorded. TG/HDL ratio was calculated for every individual. Univariate and multivariate linear regression models were used to assess the association between TG/HDL ratio and global cardiac aSUVmean. RESULT: On univariate analysis, there was a positive linear association of TG/HDL ratio and global cardiac aSUVmean (r=0.244, B=0.047, P=0.045). On multivariate analysis adjusted for age, gender, systolic blood pressure, diastolic blood pressure, smoking status, total cholesterol, low-density lipoprotein, and fasting plasma glucose, TG/HDL ratio was found to be independently associated with global cardiac aSUVmean (B=0.060, 95% CI: 0.007-0.114, P=0.027). CONCLUSION: There was a positive correlation between TG/HDL ratio with global cardiac microcalcification assessed by NaF-PET/CT imaging.

PET/MR Imaging in Musculoskeletal Precision Imaging - Third wave after X-Ray and MR.

18F-Fluorodeoxyglucose PET has been used to evaluate a wide array of inflammatory and neoplastic pathologies. MR imaging has great soft tissue resolution and high accuracy for detection of edema. Combining PET with MR imaging offers substantial advantages in musculoskeletal imaging. Specifically, evidence demonstrates the potential of imaging of bone marrow, soft tissue, and synovia by PET/MR imaging. Because of inherent limitations of 1H-MR to image cortical bone, there are some challenges; however, the use of 18F-sodium fluoride for PET/MR imaging could change the landscape. This article reviews the literature regarding PET/MR imaging in identification and management of many musculoskeletal diseases.