Breast Tumor Characterization Using [18F]FDG-PET/CT Imaging Combined with Data Preprocessing and Radiomics.

Background: This study investigated the performance of ensemble learning holomic models for the detection of breast cancer, receptor status, proliferation rate, and molecular subtypes from [18F]FDG-PET/CT images with and without incorporating data pre-processing algorithms. Additionally, machine learning (ML) models were compared with conventional data analysis using standard uptake value lesion classification. Methods: A cohort of 170 patients with 173 breast cancer tumors (132 malignant, 38 benign) was examined with [18F]FDG-PET/CT. Breast tumors were segmented and radiomic features were extracted following the imaging biomarker standardization initiative (IBSI) guidelines combined with optimized feature extraction. Ensemble learning including five supervised ML algorithms was utilized in a 100-fold Monte Carlo (MC) cross-validation scheme. Data pre-processing methods were incorporated prior to machine learning, including outlier and borderline noisy sample detection, feature selection, and class imbalance correction. Feature importance in each model was assessed by calculating feature occurrence by the R-squared method across MC folds. Results: Cross validation demonstrated high performance of the cancer detection model (80% sensitivity, 78% specificity, 80% accuracy, 0.81 area under the curve (AUC)), and of the triple negative tumor identification model (85% sensitivity, 78% specificity, 82% accuracy, 0.82 AUC). The individual receptor status and luminal A/B subtype models yielded low performance (0.46-0.68 AUC). SUVmax model yielded 0.76 AUC in cancer detection and 0.70 AUC in predicting triple negative subtype. Conclusions: Predictive models based on [18F]FDG-PET/CT images in combination with advanced data pre-processing steps aid in breast cancer diagnosis and in ML-based prediction of the aggressive triple negative breast cancer subtype.

Sequential [18F]FDG-[18F]FMISO PET and Multiparametric MRI at 3T for Insights into Breast Cancer Heterogeneity and Correlation with Patient Outcomes: First Clinical Experience.

The aim of this study was to assess whether sequential multiparametric 18[F]fluoro-desoxy-glucose (18[F]FDG)/[18F]fluoromisonidazole ([18F]FMISO) PET-MRI in breast cancer patients is possible, facilitates information on tumor heterogeneity, and correlates with prognostic indicators. In this pilot study, IRB-approved, prospective study, nine patients with ten suspicious breast lesions (BIRADS 5) and subsequent breast cancer diagnosis underwent sequential combined [18F]FDG/[18F]FMISO PET-MRI. [18F]FDG was used to assess increased glycolysis, while [18F]FMISO was used to detect tumor hypoxia. MRI protocol included dynamic breast contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI). Qualitative and quantitative multiparametric imaging findings were compared with pathological features (grading, proliferation, and receptor status) and clinical endpoints (recurrence/metastases and disease-specific death) using multiple correlation analysis. Histopathology was the standard of reference. There were several intermediate to strong correlations identified between quantitative bioimaging markers, histopathologic tumor characteristics, and clinical endpoints. Based on correlation analysis, multiparametric criteria provided independent information. The prognostic indicators proliferation rate, death, and presence/development of recurrence/metastasis correlated positively, whereas the prognostic indicator estrogen receptor status correlated negatively with PET parameters. The strongest correlations were found between disease-specific death and [18F]FDGmean (R=0.83, p < 0.01) and between the presence/development of metastasis and [18F]FDGmax (R=0.79, p < 0.01), respectively. This pilot study indicates that multiparametric [18F]FDG/[18F]FMISO PET-MRI might provide complementary quantitative prognostic information on breast tumors including clinical endpoints and thus might be used to tailor treatment for precision medicine in breast cancer.

PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2- Early Invasive Breast Cancer: a Molecular Imaging Study Using [18F]FDG PET/CT.

PURPOSE: In PIK3CA mutant breast cancer, downstream hyperactivation of the PI3K/AKT/mTOR pathway may be associated with increased glycolysis of cancer cells. The purpose of this study was to investigate the functional association of PIK3CA mutational status and tumor glycolysis in invasive ER+/HER2- early breast cancer. PROCEDURES: This institutional review board-approved retrospective study included a dataset of 67 ER+/HER2- early breast cancer patients. All patients underwent 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/X-ray computed tomography ([18F]FDG PET/CT) and clinico-pathologic assessments as part of a prospective study. For this retrospective analysis, pyrosequencing was used to detect PIK3CA mutations of exons 4, 7, 9, and 20. Tumor glucose metabolism was assessed semi-quantitatively with [18F]FDG PET/CT using maximum standardized uptake values (SUVmax). SUVmax values were corrected for the partial volume effect, and metabolic tumor volume was calculated using the volume of interest automated lesion growing function 2D tumor size, i.e., maximum tumor diameter was assessed on concurrent pre-treatment contrast-enhanced magnetic resonance imaging. RESULTS: PIK3CA mutations were present in 45 % of all tumors. Mutations were associated with a small tumor diameter (p < 0.01) and with low nuclear grade (p = 0.04). Glycolytic activity was positively associated with nuclear grade (p = 0.01), proliferation (p = 0.002), regional lymph node metastasis (p = 0.015), and metabolic tumor volume (p = 0.001) but not with tumor size/T-stage. In invasive ductal carcinomas, median SUVmax was increased in PIK3CA-mutated compared to wild-type tumors; however, this increase did not reach statistical significance (p = 0.05). Multivariate analysis of invasive ductal carcinomas revealed [18F]FDG uptake to be independently associated with PIK3CA status (p = 0.002) and nuclear tumor grade (p = 0.046). Size, volume, and regional nodal status had no influence on glycolytic activity. PIK3CA mutational status did not influence glycolytic metabolism in lobular carcinomas. Glycolytic activity and PIK3CA mutational status had no significant influence on recurrence-free survival or disease-specific survival. CONCLUSIONS: In ER+/HER2- invasive ductal carcinomas of the breast, glucose uptake is independently associated with PIK3CA mutations. Initial data suggest that [18F]FDG uptake reflects complex genomic alterations and may have the potential to be used as candidate biomarker for monitoring therapeutic response and resistance mechanisms in emerging therapies that target the PI3K/AKT/mTOR pathway.

Diffusion-weighted imaging of breast lesions: Region-of-interest placement and different ADC parameters influence apparent diffusion coefficient values.

OBJECTIVES: To investigate the influence of region-of-interest (ROI) placement and different apparent diffusion coefficient (ADC) parameters on ADC values, diagnostic performance, reproducibility and measurement time in breast tumours. METHODS: In this IRB-approved, retrospective study, 149 histopathologically proven breast tumours (109 malignant, 40 benign) in 147 women (mean age 53.2) were investigated. Three radiologists independently measured minimum, mean and maximum ADC, each using three ROI placement approaches:1 - small 2D-ROI, 2 - large 2D-ROI and 3 - 3D-ROI covering the whole lesion. One reader performed all measurements twice. Median ADC values, diagnostic performance, reproducibility, and measurement time were calculated and compared between all combinations of ROI placement approaches and ADC parameters. RESULTS: Median ADC values differed significantly between the ROI placement approaches (p < .001). Minimum ADC showed the best diagnostic performance (AUC .928-.956), followed by mean ADC obtained from 2D ROIs (.926-.94). Minimum and mean ADC showed high intra- (ICC .85-.94) and inter-reader reproducibility (ICC .74-.94). Median measurement time was significantly shorter for the 2D ROIs (p < .001). CONCLUSIONS: ROI placement significantly influences ADC values measured in breast tumours. Minimum and mean ADC acquired from 2D-ROIs are useful for the differentiation of benign and malignant breast lesions, and are highly reproducible, with rapid measurement. KEY POINTS: • Region of interest placement significantly influences apparent diffusion coefficient of breast tumours. • Minimum and mean apparent diffusion coefficient perform best and are reproducible. • 2D regions of interest perform best and provide rapid measurement times.

Quantitative Assessment of Breast Parenchymal Uptake on 18F-FDG PET/CT: Correlation with Age, Background Parenchymal Enhancement, and Amount of Fibroglandular Tissue on MRI.

Background parenchymal enhancement (BPE), and the amount of fibroglandular tissue (FGT) assessed with MRI have been implicated as sensitive imaging biomarkers for breast cancer. The purpose of this study was to quantitatively assess breast parenchymal uptake (BPU) on 18F-FDG PET/CT as another valuable imaging biomarker and examine its correlation with BPE, FGT, and age. METHODS: This study included 129 patients with suspected breast cancer and normal imaging findings in one breast (BI-RADS 1), whose cases were retrospectively analyzed. All patients underwent prone 18F-FDG PET/CT and 3-T contrast-enhanced MRI of the breast. In all patients, interpreter 1 assessed BPU quantitatively using SUVmax Interpreters 1 and 2 assessed amount of FGT and BPE in the normal contralateral breast by subjective visual estimation, as recommended by BI-RADS. Interpreter 1 reassessed all cases and repeated the BPU measurements. Statistical tests were used to assess correlations between BPU, BPE, FGT, and age, as well as inter- and intrainterpreter agreement. RESULTS: BPU on 18F-FDG PET/CT varied among patients. The mean BPU SUVmax ± SD was 1.57 ± 0.6 for patients with minimal BPE, 1.93 ± 0.6 for mild BPE, 2.42 ± 0.5 for moderate BPE, and 1.45 ± 0.3 for marked BPE. There were significant (P < 0.001) moderate to strong correlations among BPU, BPE, and FGT. BPU directly correlated with both BPE and FGT on MRI. Patient age showed a moderate to strong indirect correlation with all 3 imaging-derived tissue biomarkers. The coefficient of variation for quantitative BPU measurements with SUVmax was 5.6%, indicating a high reproducibility. Interinterpreter and intrainterpreter agreement for BPE and FGT was almost perfect, with a κ-value of 0.860 and 0.822, respectively. CONCLUSION: The results of our study demonstrate that BPU varied among patients. BPU directly correlated with both BPE and FGT on MRI, and BPU measurements were highly reproducible. Patient age showed a strong inverse correlation with all 3 imaging-derived tissue biomarkers. These findings indicate that BPU may serve as a sensitive imaging biomarker for breast cancer prediction, prognosis, and risk assessment.

Influence of fat-water separation and spatial resolution on automated volumetric MRI measurements of fibroglandular breast tissue.

The aim of this study was to investigate the influence of fat-water separation and spatial resolution in MRI on the results of automated quantitative measurements of fibroglandular breast tissue (FGT). Ten healthy volunteers (age range, 28-71 years; mean, 39.9 years) were included in this Institutional Review Board-approved prospective study. All measurements were performed on a 1.5-T scanner (Siemens, AvantoFit) using an 18-channel breast coil. The protocols included isotropic (Di) [TR/TE1 /TE2 = 6.00 ms/2.45 ms/2.67 ms; flip angle, 6.0°; 256 slices; matrix, 360 × 360; 1 mm isotropic; field of view, 360°; acquisition time (TA) = 3 min 38 s] and anisotropic (Da) (TR/TE1 /TE2 = 10.00 ms/2.39 ms/4.77 ms; flip angle, 24.9°; 80 slices; matrix 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm(3) ; field of view, 360°; TA = 1 min 25 s) T1 three-dimensional (3D) fast low-angle shot (FLASH) Dixon sequences, and a T1 3D FLASH sequence with the same resolution (T1 ) without (TR/TE = 11.00 ms/4.76 ms; flip angle, 25.0°; 80 slices; matrix, 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm(3) ; field of view, 360°; TA = 50 s) and with (TR/TE = 29.00 ms/4.76 ms; flip angle, 25.0°; 80 slices; matrix, 360 × 360; voxel size, 0.7 × 0.7 × 2.0 mm(3) ; field of view, 360°; TA = 2 min 35 s) fat saturation. Repeating volunteer measurements after 20 min and repositioning were used to assess reproducibility. An automated and quantitative volumetric breast density measurement system was used for FGT calculation. FGT with Di, Da and T1 measured 4.6-63.0% (mean, 30.6%), 3.2-65.3% (mean, 32.5%) and 1.7-66.5% (mean, 33.7%), respectively. The highest correlation between different MRI sequences was found with the Di and Da sequences (R(2) = 0.976). Coefficients of variation (CVs) for FGT calculation were higher in T1 (CV = 21.5%) compared with Dixon (Di, CV = 5.1%; Da, CV = 4.2%) sequences. Dixon-type sequences worked well for FGT measurements, even at lower resolution, whereas the conventional T1 -weighted sequence was more sensitive to decreasing resolution. The Dixon fat-water separation technique showed superior repeatability of FGT measurements compared with conventional sequences. A standard dynamic protocol using Dixon fat-water separation is best suited for combined diagnostic purposes and prognostic measurements of FGT. Copyright © 2016 John Wiley & Sons, Ltd.

Diagnostic accuracy of (18)F-FDG PET/CT compared with that of contrast-enhanced MRI of the breast at 3 T.

PURPOSE: To compare the diagnostic accuracy of prone (18)F-FDG PET/CT with that of contrast-enhanced MRI (CE-MRI) at 3 T in suspicious breast lesions. To evaluate the influence of tumour size on diagnostic accuracy and the use of maximum standardized uptake value (SUVMAX) thresholds to differentiate malignant from benign breast lesions. METHODS: A total of 172 consecutive patients with an imaging abnormality were included in this IRB-approved prospective study. All patients underwent (18)F-FDG PET/CT and CE-MRI of the breast at 3 T in the prone position. Two reader teams independently evaluated the likelihood of malignancy as determined by (18)F-FDG PET/CT and CE-MRI independently. (18)F-FDG PET/CT data were qualitatively evaluated by visual interpretation. Quantitative assessment was performed by calculation of SUVMAX. Sensitivity, specificity, diagnostic accuracy, area under the curve and interreader agreement were calculated for all lesions and for lesions <10 mm. Histopathology was used as the standard of reference. RESULTS: There were 132 malignant and 40 benign lesions; 23 lesions (13.4%) were <10 mm. Both (18)F-FDG PET/CT and CE-MRI achieved an overall diagnostic accuracy of 93%. There were no significant differences in sensitivity (p = 0.125), specificity (p = 0.344) or diagnostic accuracy (p = 1). For lesions <10 mm, diagnostic accuracy deteriorated to 91% with both (18)F-FDG PET/CT and CE-MRI. Although no significant difference was found for lesions <10 mm, CE-MRI at 3 T seemed to be more sensitive but less specific than (18)F-FDG PET/CT. Interreader agreement was excellent (κ = 0.85 and κ = 0.92). SUVMAX threshold was not helpful in differentiating benign from malignant lesions. CONCLUSION: (18)F-FDG PET/CT and CE-MRI at 3 T showed equal diagnostic accuracies in breast cancer diagnosis. For lesions <10 mm, diagnostic accuracy deteriorated, but was equal for (18)F-FDG PET/CT and CE-MRI at 3 T. For lesions <10 mm, CE-MRI at 3 T seemed to be more sensitive but less specific than (18)F-FDG PET/CT. Quantitative assessment using an SUVMAX threshold for differentiating benign from malignant lesions was not helpful in breast cancer diagnosis.

Improved differentiation of benign and malignant breast tumors with multiparametric 18fluorodeoxyglucose positron emission tomography magnetic resonance imaging: a feasibility study.

PURPOSE: To assess whether multiparametric (18)fluorodeoxyglucose positron emission tomography magnetic resonance imaging (MRI) (MP (18)FDG PET-MRI) using dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted imaging (DWI), three-dimensional proton MR spectroscopic imaging (3D (1)H-MRSI), and (18)FDG-PET enables an improved differentiation of benign and malignant breast tumors. EXPERIMENTAL DESIGN: Seventy-six female patients (mean age, 55.7 years; range, 25-86 years) with an imaging abnormality (BI-RADS 0, 4-5) were included in this Institutional Review Board (IRB)-approved study. Patients underwent fused PET-MRI of the breast with (18)FDG-PET/CT and MP MRI at 3T. The likelihood of malignancy was assessed for all single parameters, for MP MRI with two/three parameters, and for MP (18)FDG PET-MRI. Histopathology was used as the standard of reference. Appropriate statistical tests were used to assess sensitivity, specificity, and diagnostic accuracy for each assessment combination. RESULTS: There were 53 malignant and 23 benign breast lesions. MP (18)FDG PET-MRI yielded a significantly higher area under the cure (AUC) of 0.935 than DCE-MRI (AUC, 0.86; P = 0.044) and the combination of DCE-MRI and another parameter (AUC, 0.761-0.826; P = 0.013-0.020). MP (18)FDG PET-MRI showed slight further improvement to MP MRI with three parameters (AUC, 0.925; P = 0.317). Using MP (18)FDG PET-MRI there would have been a reduction of the unnecessary breast biopsies recommended by MP imaging with one or two parameters (P = 0.002-0.011). CONCLUSION: This feasibility study shows that MP (18)FDG PET-MRI enables an improved differentiation of benign and malignant breast tumors when several MRI and PET parameters are combined. MP (18)FDG PET-MRI may lead to a reduction in unnecessary breast biopsies.

Molecular imaging for the characterization of breast tumors.

Recently, molecular imaging, using various techniques, has been assessed for breast imaging. Molecular imaging aims to quantify and visualize biological, physiological, and pathological processes at the cellular and molecular levels to further elucidate the development and progression of breast cancer and the response to treatment. Molecular imaging enables the depiction of tumor morphology, as well as the assessment of functional and metabolic processes involved in cancer development at different levels. To date, molecular imaging techniques comprise both nuclear medicine and radiological techniques. This review aims to summarize the current and emerging functional and metabolic techniques for the molecular imaging of breast tumors.

False aneurysm after balloon dilation of a calcified innominate artery stenosis.

PURPOSE: To describe the occurrence of a false aneurysm after percutaneous transluminal angioplasty of a severely calcified, high-grade stenosis of the brachiocephalic trunk. CASE REPORT: A 68-year-old patient was admitted with cerebrovascular insufficiency, right upper extremity ischemia, and recurrent amaurosis fugax. Magnetic resonance arteriography (MRA) and duplex ultrasound revealed a severely calcified, high-grade stenosis of the innominate artery. Balloon dilation of this lesion was performed with minimal morphological success. After dilation, the patient suffered a reversible ischemic neurological deficit, from which he recovered completely. The patient's symptoms improved, but after 3 weeks he was re-admitted with palsy of the recurrent laryngeal nerve. An MRA showed a false aneurysm at the dilation site. Open surgery was performed, and the patient received a bifurcated aorto-subclavian-carotid bypass graft. He was discharged free of his preoperative symptoms. CONCLUSIONS: This case illustrates the potential hazards of angioplasty of severely calcified stenoses of the supra-aortic vessels.

External beam radiation for prevention of intimal hyperplasia in peripheral arterial bypasses.

PURPOSE: Neointimal hyperplasia is one of the limiting factors in infrainguinal prosthetic vascular grafting. We conducted a pilot study to assess the possible role of radiotherapy for the prevention of this proliferating cellular process. METHODS AND MATERIALS: Ten patients (7 men, 3 women; median age: 73 years) suffering from critical leg ischemia were treated by infrainguinal revascularization using 6-mm polytetrafluoroethylene. Postoperative radiation therapy of the anastomotic sites started within 24 h. A dose of 20.4 Gy was delivered in 12 fractions in 2.5 weeks by external beam radiation with electrons. The target volume was defined as the clip-marked anastomotic region plus a 1.5-cm safety margin in each direction. RESULTS: Radiation therapy was technically feasible in all cases without radiation-related side effects. In one patient, radiotherapy had to be terminated prematurely, because of a hematoma at the distal anastomotic site with consequent skin necrosis. One patient developed an occlusion of a suprainguinal graft without anastomotic stenosis after 9 months; 2 other grafts occluded at 12-month intervals. At a median follow-up of 16 months, the remaining 6 patients had no signs of restenosis. CONCLUSIONS: The restenosis rate of peripheral vascular grafts after external beam radiation was lower than expected without additional treatment. The value of this approach will now be determined in a randomized prospective trial.

Preliminary observations on the need for control angiography after peripheral endovascular brachytherapy using a centering balloon.

PURPOSE: To examine the need for completion angiography after endovascular femoropopliteal brachytherapy using a centering catheter. METHODS: Nine consecutive patients (7 men; mean age 68 years, range 53-79) were enrolled in a double-blinded multicenter randomized trial of endovascular brachytherapy after femoropopliteal balloon angioplasty. All patients underwent postdilation angiography, after which the centering catheter was placed in the dilated segment. The patients were randomized and transferred to the radiotherapy unit; the centering catheter was inflated only in patients randomized to receive brachytherapy (18 Gy of gamma radiation delivered to the target site 2 mm from an iridium-192 source axis). Because the local ethics committee required angiography after any interventional procedure (not stipulated in the study protocol), our patients were taken back to the angiosuite for angiography. RESULTS: There were no complications of angioplasty or centering catheter introduction. In the 5 patients randomized to brachytherapy, the median inflation time of the centering catheter was 12.1 minutes (range 9.1-13.3). The completion angiogram following brachytherapy showed peripheral embolization in 2 patients and lesion recoil that required redilation in another; all the complications were confined to the treatment group. CONCLUSIONS: Three of 5 patients who received brachytherapy via a centering catheter demonstrated sequelae on postradiation angiography. Therefore, as in any other peripheral vascular intervention, completion angiography after brachytherapy seems to be essential in preventing delayed diagnosis of procedural complications.