A convolutional neural network with self-attention for fully automated metabolic tumor volume delineation of head and neck cancer in [Formula: see text]F]FDG PET/CT.

PURPOSE: PET-derived metabolic tumor volume (MTV) and total lesion glycolysis of the primary tumor are known to be prognostic of clinical outcome in head and neck cancer (HNC). Including evaluation of lymph node metastases can further increase the prognostic value of PET but accurate manual delineation and classification of all lesions is time-consuming and prone to interobserver variability. Our goal, therefore, was development and evaluation of an automated tool for MTV delineation/classification of primary tumor and lymph node metastases in PET/CT investigations of HNC patients. METHODS: Automated lesion delineation was performed with a residual 3D U-Net convolutional neural network (CNN) incorporating a multi-head self-attention block. 698 [Formula: see text]F]FDG PET/CT scans from 3 different sites and 5 public databases were used for network training and testing. An external dataset of 181 [Formula: see text]F]FDG PET/CT scans from 2 additional sites was employed to assess the generalizability of the network. In these data, primary tumor and lymph node (LN) metastases were interactively delineated and labeled by two experienced physicians. Performance of the trained network models was assessed by 5-fold cross-validation in the main dataset and by pooling results from the 5 developed models in the external dataset. The Dice similarity coefficient (DSC) for individual delineation tasks and the primary tumor/metastasis classification accuracy were used as evaluation metrics. Additionally, a survival analysis using univariate Cox regression was performed comparing achieved group separation for manual and automated delineation, respectively. RESULTS: In the cross-validation experiment, delineation of all malignant lesions with the trained U-Net models achieves DSC of 0.885, 0.805, and 0.870 for primary tumor, LN metastases, and the union of both, respectively. In external testing, the DSC reaches 0.850, 0.724, and 0.823 for primary tumor, LN metastases, and the union of both, respectively. The voxel classification accuracy was 98.0% and 97.9% in cross-validation and external data, respectively. Univariate Cox analysis in the cross-validation and the external testing reveals that manually and automatically derived total MTVs are both highly prognostic with respect to overall survival, yielding essentially identical hazard ratios (HR) ([Formula: see text]; [Formula: see text] vs. [Formula: see text]; [Formula: see text] in cross-validation and [Formula: see text]; [Formula: see text] vs. [Formula: see text]; [Formula: see text] in external testing). CONCLUSION: To the best of our knowledge, this work presents the first CNN model for successful MTV delineation and lesion classification in HNC. In the vast majority of patients, the network performs satisfactory delineation and classification of primary tumor and lymph node metastases and only rarely requires more than minimal manual correction. It is thus able to massively facilitate study data evaluation in large patient groups and also does have clear potential for supervised clinical application.

18F-FDG PET/CT-derived total lesion glycolysis predicts abscess formation in patients with surgically confirmed infective endocarditis: Results of a retrospective study at a tertiary center.

BACKGROUND: Abnormal activity of 18F-FDG PET/CT is a major Duke criterion in the diagnostic work-up of infective prosthetic valve endocarditis (IE). We hypothesized that quantitative lesion assessment by 18F-FDG PET/CT-derived standard maximum uptake ratio (SURmax), metabolic volume (MV), and total lesion glycolysis (TLG) might be useful in distinct subgroups of IE patients (e.g. IE-related abscess formation). METHODS: All patients (n = 27) hospitalized in our tertiary IE referral medical center from January 2014 to October 2018 with preoperatively performed 18F-FDG PET/CT and surgically confirmed IE were included into this retrospective analysis. RESULTS: Patients with surgically confirmed abscess formation (n = 10) had significantly increased MV (by ~ fivefold) and TLG (by ~ sevenfold) as compared to patients without abscess (n = 17). Receiver operation characteristics (ROC) analyses demonstrated that TLG (calculated as MV × SURmean, i.e. TLG (SUR)) had the most favorable area under the ROC curve (0.841 [CI 0.659 to 1.000]) in predicting IE-related abscess formation. This resulted in a sensitivity of 80% and a specificity of 88% at a cut-off value of 14.14 mL for TLG (SUR). CONCLUSION: We suggest that 18F-FDG PET/CT-derived quantitative assessment of TLG (SUR) may provide a novel diagnostic tool in predicting endocarditis-associated abscess formation.

A convolutional neural network for fully automated blood SUV determination to facilitate SUR computation in oncological FDG-PET.

PURPOSE: The standardized uptake value (SUV) is widely used for quantitative evaluation in oncological FDG-PET but has well-known shortcomings as a measure of the tumor's glucose consumption. The standard uptake ratio (SUR) of tumor SUV and arterial blood SUV (BSUV) possesses an increased prognostic value but requires image-based BSUV determination, typically in the aortic lumen. However, accurate manual ROI delineation requires care and imposes an additional workload, which makes the SUR approach less attractive for clinical routine. The goal of the present work was the development of a fully automated method for BSUV determination in whole-body PET/CT. METHODS: Automatic delineation of the aortic lumen was performed with a convolutional neural network (CNN), using the U-Net architecture. A total of 946 FDG PET/CT scans from several sites were used for network training (N = 366) and testing (N = 580). For all scans, the aortic lumen was manually delineated, avoiding areas affected by motion-induced attenuation artifacts or potential spillover from adjacent FDG-avid regions. Performance of the network was assessed using the fractional deviations of automatically and manually derived BSUVs in the test data. RESULTS: The trained U-Net yields BSUVs in close agreement with those obtained from manual delineation. Comparison of manually and automatically derived BSUVs shows excellent concordance: the mean relative BSUV difference was (mean ± SD) = (- 0.5 ± 2.2)% with a 95% confidence interval of [- 5.1,3.8]% and a total range of [- 10.0, 12.0]%. For four test cases, the derived ROIs were unusable (< 1 ml). CONCLUSION: CNNs are capable of performing robust automatic image-based BSUV determination. Integrating automatic BSUV derivation into PET data processing workflows will significantly facilitate SUR computation without increasing the workload in the clinical setting.

Combined tumor plus nontumor interim FDG-PET parameters are prognostic for response to chemoradiation in squamous cell esophageal cancer.

We have investigated the prognostic value of two novel interim 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters in patients undergoing chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): one tumor parameter (maximal standardized uptake ratio rSUR) and one normal tissue parameter (change of FDG uptake within irradiated nontumor-affected esophagus ∆SUVNTO ). PET data of 134 European and Chinese patients were analyzed. Parameter establishment was based on 36 patients undergoing preoperative CRT plus surgery, validation was performed in 98 patients receiving definitive CRT. Patients received PET imaging prior and during fourth week of CRT. Clinical parameters, baseline PET parameters, and interim PET parameters (rSUR and ∆SUVNTO ) were analyzed and compared to event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM). Combining rSUR and ∆SUVNTO revealed a strong prognostic impact on EFS, OS, LRC and FFDM in patients undergoing preoperative CRT. In the definitive CRT cohort, univariate analysis with respect to EFS revealed several staging plus both previously established interim PET parameters as significant prognostic factors. Multivariate analyses revealed only rSUR and ∆SUVNTO as independent prognostic factors (p = 0.003, p = 0.008). Combination of these parameters with the cutoff established in preoperative CRT revealed excellent discrimination of patients with a long or short EFS (73% vs. 17% at 2 years, respectively) and significantly discriminated all other endpoints (OS, p < 0.001; LRC, p < 0.001; FFDM, p = 0.02), even in subgroups. Combined use of interim FDG-PET derived parameters ∆SUVNTO and rSUR seems to have predictive potential, allowing to select responders for definitive CRT and omission of surgery.

Confirmation of the prognostic value of pretherapeutic tumor SUR and MTV in patients with esophageal squamous cell carcinoma.

PURPOSE: The prognosis for patients with inoperable esophageal carcinoma is still poor and the reliability of individual therapy outcome prediction based on clinical parameters is not convincing. In a recent publication, we were able to show that PET can provide independent prognostic information in such a patient group and that the tumor-to-blood standard uptake ratio (SUR) can improve the prognostic value of tracer uptake values. The present investigation addresses the question of whether the distinctly improved prognostic value of SUR can be confirmed in a similar patient group that was examined and treated at a different site. METHODS: 18F-FDG PET/CT was performed in 147 consecutive patients (115 male, 32 female, mean age: 62 years) with newly diagnosed esophageal squamous cell carcinoma prior to definitive radiochemotherapy. In the PET images, the metabolic active volume (MTV) of the primary tumor was delineated with an adaptive threshold method. For the resulting ROIs, SUVmax and total lesion glycolysis (TLG = MTV × SUVmean) were computed. The blood SUV was determined by manually delineating the aorta in the low-dose CT. SUR values were computed as ratio of tumor SUV and blood SUV. Univariate Cox regression and Kaplan-Meier analysis with respect to overall survival (OS), distant-metastases-free survival (DM), and locoregional control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. RESULTS: Univariate Cox regression revealed MTV, TLG, and SURmax as significant prognostic factors for OS. MTV as well as TLG were significant prognostic factors for LRC while SURmax showed only a trend for significance. None of the PET parameters was prognostic for DM. In univariate analysis, SUVmax was not prognostic for any of the investigated clinical endpoints. In multivariate analysis (T-stage, N-stage, MTV, and SURmax), MTV was an independent prognostic factor for OS and showed a trend for significance for LRC. SURmax was not an independent predictor for OS or LRC. When including the PET parameters separately in multivariate analysis, MTV as well as SURmax were prognostic factors for OS indicating that SURmax is independent from the clinical parameters but not from MTV. In addition, MTV was an independent prognostic factor for LRC in this separate analysis. CONCLUSIONS: Our study revealed a clearly improved prognostic value of tumor SUR compared to tumor SUV and confirms our previously published findings regarding OS. Furthermore, SUR delivers prognostic information beyond that provided by the clinical parameters alone, but does not add prognostic information beyond that provided by MTV in this patient group. Therefore, our results suggest that pretherapeutic MTV is the parameter of choice for PET-based risk stratification in the considered setting but further investigations are necessary to demonstrate that this suggestion is correct.

Increased evidence for the prognostic value of FDG uptake on late-treatment PET in non-tumour-affected oesophagus in irradiated patients with oesophageal carcinoma.

PURPOSE: 18F-FDG uptake in irradiated non-tumour-affected oesophagus (NTO) on restaging PET is a potential surrogate for the measurement of radiation-induced inflammation. Radiation-induced inflammation itself has been shown to be of high prognostic relevance in patients undergoing preoperative radiochemotherapy (RCT) for locally advanced oesophageal cancer. We assessed the prognostic relevance of FDG uptake in the NTO in an independent cohort of patients treated with definitive RCT. METHODS: This retrospective evaluation included 72 patients with oesophageal squamous cell carcinoma treated with definitive RCT with curative intent. All patients underwent pretreatment and restaging FDG PET after receiving a radiation dose of 40-50 Gy. Standardized uptake values (SUVmax/SUVmean), metabolic tumour volume (MTV) and relative changes from pretreatment to restaging PET (∆SUVmax/∆SUVmean) were determined within the tumour and NTO. Univariate Cox regression with respect to overall survival (OS), local control (LC), distant metastases (DM) and treatment failure (TF) was performed. Independence of parameters was tested by multivariate Cox regression. RESULTS: ∆SUVmax NTO and MTV were prognostic factors for all investigated clinical endpoints (OS, LC, DM, TF). Inclusion of clinical and PET tumour parameters in multivariate analysis showed that ∆SUVmax NTO was an independent prognostic factor. Furthermore, multivariate analysis of ∆SUVmax NTO using previously published cut-off values from preoperatively treated patients revealed that ∆SUVmax NTO was independent prognostic factor for OS (HR = 1.88, p = 0.038), TF (HR = 2.11, p = 0.048) and DM (HR = 3.02, p = 0.047). CONCLUSION: NTO-related tracer uptake during the course of treatment in patients with oesophageal carcinoma was shown to be of high prognostic relevance. Thus, metabolically activity of NTO measured in terms of ∆SUVmax NTO is a potential candidate for future treatment individualization (i.e. organ preservation).

Pretherapeutic FDG-PET total metabolic tumor volume predicts response to induction therapy in pediatric Hodgkin's lymphoma.

BACKGROUND: Standardized treatment in pediatric patients with Hodgkin's lymphoma (HL) follows risk stratification by tumor stage, erythrocyte sedimentation rate and tumor bulk. We aimed to identify quantitative parameters from pretherapeutic FDG-PET to assist prediction of response to induction chemotherapy. METHODS: Retrospective analysis in 50 children with HL (f:18; m:32; median age, 14.8 [4-18] a) consecutively treated according to EuroNet-PHL-C1 (n = 42) or -C2 treatment protocol (n = 8). Total metabolic tumor volume (MTV) in pretherapeutic FDG-PET was defined using a semi-automated, background-adapted threshold. Metabolic (SUVmax, SUVmean, SUVpeak, total lesion glycolysis [MTV*SUVmean]) and heterogeneity parameters (asphericity [ASP], entropy, contrast, local homogeneity, energy, and cumulative SUV-volume histograms) were derived. Early response assessment (ERA) was performed after 2 cycles of induction chemotherapy according to treatment protocol and verified by reference rating. Prediction of inadequate response (IR) in ERA was based on ROC analysis separated by stage I/II (1 and 26 patients) and stage III/IV disease (7 and 16 patients) or treatment group/level (TG/TL) 1 to 3. RESULTS: IR was seen in 28/50 patients (TG/TL 1, 6/12 patients; TG/TL 2, 10/17; TG/TL 3, 12/21). Among all PET parameters, MTV best predicted IR; ASP was the best heterogeneity parameter. AUC of MTV was 0.84 (95%-confidence interval, 0.69-0.99) in stage I/II and 0.86 (0.7-1.0) in stage III/IV. In patients of TG/TL 1, AUC of MTV was 0.92 (0.74-1.0); in TG/TL 2 0.71 (0.44-0.99), and in TG/TL 3 0.85 (0.69-1.0). Patients with high vs. low MTV had IR in 86 vs. 0% in TG/TL 1, 80 vs. 29% in TG/TL 2, and 90 vs. 27% in TG/TL 3 (cut-off, > 80 ml, > 160 ml, > 410 ml). CONCLUSIONS: In this explorative study, high total MTV best predicted inadequate response to induction therapy in pediatric HL of all pretherapeutic FDG-PET parameters - in both low and high stages as well as the 3 different TG/TL. TRIAL REGISTRATION: Ethics committee number: EA2/151/16 (retrospectively registered).

Effects of systematic partial volume errors on the estimation of gray matter cerebral blood flow with arterial spin labeling MRI.

OBJECTIVE: Partial volume (PV) correction is an important step in arterial spin labeling (ASL) MRI that is used to separate perfusion from structural effects when computing the mean gray matter (GM) perfusion. There are three main methods for performing this correction: (1) GM-threshold, which includes only voxels with GM volume above a preset threshold; (2) GM-weighted, which uses voxel-wise GM contribution combined with thresholding; and (3) PVC, which applies a spatial linear regression algorithm to estimate the flow contribution of each tissue at a given voxel. In all cases, GM volume is obtained using PV maps extracted from the segmentation of the T1-weighted (T1w) image. As such, PV maps contain errors due to the difference in readout type and spatial resolution between ASL and T1w images. Here, we estimated these errors and evaluated their effect on the performance of each PV correction method in computing GM cerebral blood flow (CBF). MATERIALS AND METHODS: Twenty-two volunteers underwent scanning using 2D echo planar imaging (EPI) and 3D spiral ASL. For each PV correction method, GM CBF was computed using PV maps simulated to contain estimated errors due to spatial resolution mismatch and geometric distortions which are caused by the mismatch in readout between ASL and T1w images. Results were analyzed to assess the effect of each error on the estimation of GM CBF from ASL data. RESULTS: Geometric distortion had the largest effect on the 2D EPI data, whereas the 3D spiral was most affected by the resolution mismatch. The PVC method outperformed the GM-threshold even in the presence of combined errors from resolution mismatch and geometric distortions. The quantitative advantage of PVC was 16% without and 10% with the combined errors for both 2D and 3D ASL. Consistent with theoretical expectations, for error-free PV maps, the PVC method extracted the true GM CBF. In contrast, GM-weighted overestimated GM CBF by 5%, while GM-threshold underestimated it by 16%. The presence of PV map errors decreased the calculated GM CBF for all methods. CONCLUSION: The quality of PV maps presents no argument for the preferential use of the GM-threshold method over PVC in the clinical application of ASL.

Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments.

Experimental evidence has associated receptor tyrosine kinase EphB4 with tumor angiogenesis also in malignant melanoma. Considering the limited in vivo data available, we have conducted a systematic multitracer and multimodal imaging investigation in EphB4-overexpressing and mock-transfected A375 melanoma xenografts. Tumor growth, perfusion, and hypoxia were investigated by positron emission tomography. Vascularization was investigated by fluorescence imaging in vivo and ex vivo. The approach was completed by magnetic resonance imaging, radioluminography ex vivo, and immunohistochemical staining for blood and lymph vessel markers. Results revealed EphB4 to be a positive regulator of A375 melanoma growth, but a negative regulator of tumor vascularization. Resulting in increased hypoxia, this physiological characteristic is considered as highly unfavorable for melanoma prognosis and therapy outcome. Lymphangiogenesis, by contrast, was not influenced by EphB4 overexpression. In order to distinguish between EphB4 forward and EphrinB2, the natural EphB4 ligand, reverse signaling a specific EphB4 kinase inhibitor was applied. Blocking experiments show EphrinB2 reverse signaling rather than EphB4 forward signaling to be responsible for the observed effects. In conclusion, functional expression of EphB4 is considered a promising differentiating characteristic, preferentially determined by non-invasive in vivo imaging, which may improve personalized theranostics of malignant melanoma.

Individualized risk assessment in neuroblastoma: does the tumoral metabolic activity on 123I-MIBG SPECT predict the outcome?

PURPOSE: Risk-adapted treatment in children with neuroblastoma (NB) is based on clinical and genetic factors. This study evaluated the metabolic tumour volume (MTV) and its asphericity (ASP) in pretherapeutic 123I-MIBG SPECT for individualized image-based prediction of outcome. METHODS: This retrospective study included 23 children (11 girls, 12 boys; median age 1.8 years, range 0.3-6.8 years) with newly diagnosed NB consecutively examined with pretherapeutic 123I-MIBG SPECT. Primary tumour MTV and ASP were defined using semiautomatic thresholds. Cox regression analysis, receiver operating characteristic analysis (cut-off determination) and Kaplan-Meier analysis with the log-rank test for event-free survival (EFS) were performed for ASP, MTV, laboratory parameters (including urinary homovanillic acid-to-creatinine ratio, HVA/C), and clinical (age, stage) and genetic factors. Predictive accuracy of the optimal multifactorial model was determined in terms of Harrell's C and likelihood ratio χ 2. RESULTS: Median follow-up was 36 months (range 7-107 months; eight patients showed disease progression/relapse, four patients died). The only significant predictors of EFS in the univariate Cox regression analysis were ASP (p = 0.029; hazard ratio, HR, 1.032 for a one unit increase), MTV (p = 0.038; HR 1.012) and MYCN amplification status (p = 0.047; HR 4.67). The mean EFS in patients with high ASP (>32.0%) and low ASP were 21 and 88 months, respectively (p = 0.013), and in those with high MTV (>46.7 ml) and low MTV were 22 and 87 months, respectively (p = 0.023). A combined risk model of either high ASP and high HVA/C or high MTV and high HVA/C best predicted EFS. CONCLUSIONS: In this exploratory study, pretherapeutic image-derived and laboratory markers of tumoral metabolic activity in NB (ASP, MTV, urinary HVA/C) allowed the identification of children with a high and low risk of progression/relapse under current therapy.

Increased FDG uptake on late-treatment PET in non-tumour-affected oesophagus is prognostic for pathological complete response and disease recurrence in patients undergoing neoadjuvant radiochemotherapy.

PURPOSE: Early side effects including oesophagitis are potential prognostic factors in patients undergoing radiochemotherapy (RCT) for locally advanced oesophageal cancer (LAEC). We assessed the prognostic value of 18F-fluorodeoxyglucose (FDG) uptake within irradiated non-tumour-affected oesophagus (NTO) during restaging positron emission tomography (PET) as a surrogate for inflammation/oesophagitis. METHODS: This retrospective evaluation included 64 patients with LAEC who had completed neoadjuvant RCT and had successful oncological resection. All patients underwent FDG PET/CT before and after RCT. In the restaging PET scan maximum and mean standardized uptake values (SUVmax, SUVmean) were determined in the tumour and NTO. Univariate Cox regression with respect to overall survival, local control, distant metastases and treatment failure was performed. Independence of clinically relevant parameters was tested in a multivariate Cox regression analysis. RESULTS: Increased FDG uptake, measured in terms of SUVmean in NTO during restaging was significantly associated with complete pathological remission (p = 0.002) and did not show a high correlation with FDG response of the tumour (rho < 0.3). In the univariate analysis, increased SUVmax and SUVmean in NTO was associated with improved overall survival (p = 0.011, p = 0.004), better local control (p = 0.051, p = 0.044), a lower rate of treatment failure (p < 0.001 for both) and development of distant metastases (p = 0.012, p = 0.001). In the multivariate analysis, SUVmax and SUVmean in NTO remained a significant prognostic factor for treatment failure (p < 0.001, p = 0.004) and distant metastases (p = 0.040, p = 0.011). CONCLUSIONS: FDG uptake in irradiated normal tissues measured on restaging PET has significant prognostic value in patients undergoing neoadjuvant RCT for LAEC. This effect may potentially be of use in treatment personalization.

The asphericity of the metabolic tumour volume in NSCLC: correlation with histopathology and molecular markers.

PURPOSE: Asphericity (ASP) is a tumour shape descriptor based on the PET image. It quantitates the deviation from spherical of the shape of the metabolic tumour volume (MTV). In order to identify its biological correlates, we investigated the relationship between ASP and clinically relevant histopathological and molecular signatures in non-small-cell lung cancer (NSCLC). METHODS: The study included 83 consecutive patients (18 women, aged 66.4 ± 8.9 years) with newly diagnosed NSCLC in whom PET/CT with 18F-FDG had been performed prior to therapy. Primary tumour resection specimens and core biopsies were used for basic histopathology and determination of the Ki-67 proliferation index. EGFR status, VEGF, p53 and ALK expression were obtained in a subgroup of 44 patients. The FDG PET images of the primary tumours were delineated using an automatic algorithm based on adaptive thresholding taking into account local background. In addition to ASP, SUVmax, MTV and some further descriptors of shape and intratumour heterogeneity were assessed as semiquantitative PET measures. RESULTS: SUVmax, MTV and ASP were associated with pathological T stage (Kruskal-Wallis, p = 0.001, p < 0.0005 and p < 0.0005, respectively) and N stage (p = 0.017, p = 0.003 and p = 0.002, respectively). Only ASP was associated with M stage (p = 0.026). SUVmax, MTV and ASP were correlated with Ki-67 index (Spearman's rho = 0.326/p = 0.003, rho = 0.302/p = 0.006 and rho = 0.271/p = 0.015, respectively). The latter correlations were considerably stronger in adenocarcinomas than in squamous cell carcinomas. ASP, but not SUVmax or MTV, showed a tendency for a significant association with the extent of VEGF expression (p = 0.058). In multivariate Cox regression analysis, ASP (p < 0.0005) and the presence of distant metastases (p = 0.023) were significantly associated with progression-free survival. ASP (p = 0.006), the presence of distant metastases (p = 0.010), and Ki-67 index (p = 0.062) were significantly associated with overall survival. CONCLUSION: The ASP of primary NSCLCs on FDG PET images is associated with tumour dimensions and molecular markers of proliferation and angiogenesis.

Increased evidence for the prognostic value of primary tumor asphericity in pretherapeutic FDG PET for risk stratification in patients with head and neck cancer.

PURPOSE: In a previous study, we demonstrated the first evidence that the asphericity (ASP) of pretherapeutic FDG uptake in the primary tumor provides independent prognostic information in patients with head and neck cancer. The aim of this work was to confirm these results in an independent patient group examined at a different site. METHODS: FDG-PET/CT was performed in 37 patients. The primary tumor was delineated by an automatic algorithm based on adaptive thresholding. For the resulting ROIs, the metabolically active part of the tumor (MTV), SUVmax, SUVmean, total lesion glycolysis (TLG) and ASP were computed. Univariate Cox regression with respect to progression free survival (PFS) and overall survival (OS) was performed. For survival analysis, patients were divided in groups of high and low risk according to the parameter cut-offs defined in our previous work. In a second step, the cut-offs were adjusted to the present data. Univariate and multivariate Cox regression was performed for the pooled data consisting of the current and the previously described patient group (N = 68). In multivariate Cox regression, clinically relevant parameters were included. RESULTS: Univariate Cox regression using the previously published cut-off values revealed TLG (hazard ratio (HR) = 3) and ASP (HR = 3) as significant predictors for PFS. For OS MTV (HR = 2.7) and ASP (HR = 5.9) were significant predictors. Using the adjusted cutoffs MTV (HR = 2.9/3.3), TLG (HR = 3.1/3.3) and ASP (HR = 3.1/5.9) were prognostic for PFS/OS. In the pooled data, multivariate Cox regression revealed a significant prognostic value with respect to PFS/OS for MTV (HR = 2.3/2.1), SUVmax (HR = 2.1/2.5), TLG (HR = 3.5/3.6), and ASP (HR = 3.4/4.4). CONCLUSIONS: Our results confirm the independent prognostic value of ASP of the pretherapeutic FDG uptake in the primary tumor in patients with head and neck cancer. Moreover, these results demonstrate that ASP can be determined unambiguously across different sites.

Modeling magnetization transfer effects of Q2TIPS bolus saturation in multi-TI pulsed arterial spin labeling.

PURPOSE: To estimate the relaxation time changes during Q2TIPS bolus saturation caused by magnetization transfer effects and to propose and evaluate an extended model for perfusion quantification which takes this into account. METHOD: Three multi inversion-time pulsed arterial spin labeling sequences with different bolus saturation duration were acquired for five healthy volunteers. Magnetization transfer exchange rates in tissue and blood were obtained from control image saturation recovery. Cerebral blood flow (CBF) obtained using the extended model and the standard model was compared. RESULTS: A decrease of obtained CBF of 6% (10%) was observed in grey matter when the duration of bolus saturation increased from 600 to 900 ms (1200 ms). This decrease was reduced to 1.6% (2.8%) when the extended quantification model was used. Compared with the extended model, the standard model underestimated CBF in grey matter by 9.7, 15.0, and 18.7% for saturation durations 600, 900, and 1200 ms, respectively. Results for simulated single inversion-time data showed 5-16% CBF underestimation depending on blood arrival time and bolus saturation duration. CONCLUSION: Magnetization transfer effects caused by bolus saturation pulses should not be ignored when performing quantification as they can cause appreciable underestimation of the CBF.

Quantitative assessment of the asphericity of pretherapeutic FDG uptake as an independent predictor of outcome in NSCLC.

BACKGROUND: The aim of the present study was to evaluate the predictive value of a novel quantitative measure for the spatial heterogeneity of FDG uptake, the asphericity (ASP) in patients with non-small cell lung cancer (NSCLC). METHODS: FDG-PET/CT had been performed in 60 patients (15 women, 45 men; median age, 65.5 years) with newly diagnosed NSCLC prior to therapy. The FDG-PET image of the primary tumor was segmented using the ROVER 3D segmentation tool based on thresholding at the volume-reproducing intensity threshold after subtraction of local background. ASP was defined as the relative deviation of the tumor's shape from a sphere. Univariate and multivariate Cox regression as well as Kaplan-Meier (KM) analysis and log-rank test with respect to overall (OAS) and progression-free survival (PFS) were performed for clinical variables, SUVmax/mean, metabolically active tumor volume (MTV), total lesion glycolysis (TLG), ASP and "solidity", another measure of shape irregularity. RESULTS: ASP, solidity and "primary surgical treatment" were significant independent predictors of PFS in multivariate Cox regression with binarized parameters (HR, 3.66; p<0.001, HR, 2.11; p=0.05 and HR, 2.09; p=0.05), ASP and "primary surgical treatment" of OAS (HR, 3.19; p=0.02 and HR, 3.78; p=0.01, respectively). None of the other semi-quantitative PET parameters showed significant predictive value with respect to OAS or PFS. Kaplan-Meier analysis revealed a probability of 2-year PFS of 52% in patients with low ASP compared to 12% in patients with high ASP (p<0.001). Furthermore, it showed a higher OAS rate in the case of low versus high ASP (1-year-OAS, 91% vs. 67%: p=0.02). CONCLUSIONS: The novel parameter asphericity of pretherapeutic FDG uptake seems to provide better prognostic value for PFS and OAS in NCSLC compared to SUV, metabolic tumor volume, total lesion glycolysis and solidity.

Asphericity of pretherapeutic tumour FDG uptake provides independent prognostic value in head-and-neck cancer.

OBJECTIVE: To propose a novel measure, namely the 'asphericity' (ASP), of spatial irregularity of FDG uptake in the primary tumour as a prognostic marker in head-and-neck cancer. METHODS: PET/CT was performed in 52 patients (first presentation, n = 36; recurrence, n = 16). The primary tumour was segmented based on thresholding at the volume-reproducible intensity threshold after subtraction of the local background. ASP was used to characterise the deviation of the tumour's shape from sphere symmetry. Tumour stage, tumour localisation, lymph node metastases, distant metastases, SUVmax, SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were also considered. The association of overall (OAS) and progression-free survival (PFS) with these parameters was analysed. RESULTS: Cox regression revealed high SUVmax [hazard ratio (HR) = 4.4/7.4], MTV (HR = 4.6/5.7), TLG (HR = 4.8/8.9) and ASP (HR = 7.8/7.4) as significant predictors with respect to PFS/OAS in case of first tumour manifestation. The combination of high MTV and ASP showed very high HRs of 22.7 for PFS and 13.2 for OAS. In case of recurrence, MTV (HR = 3.7) and the combination of MTV/ASP (HR = 4.2) were significant predictors of PFS. CONCLUSIONS: ASP of pretherapeutic FDG uptake in the primary tumour improves the prediction of tumour progression in head-and-neck cancer at first tumour presentation. KEY POINTS: Asphericity (ASP) characterises the spatial heterogeneity of FDG uptake in tumours. ASP is a promising prognostic parameter in head-and-neck cancer. ASP is useful for identification of high-risk patients with head-and-neck cancer.

Deep learning based bilateral filtering for edge-preserving denoising of respiratory-gated PET.

BACKGROUND: Residual image noise is substantial in positron emission tomography (PET) and one of the factors limiting lesion detection, quantification, and overall image quality. Thus, improving noise reduction remains of considerable interest. This is especially true for respiratory-gated PET investigations. The only broadly used approach for noise reduction in PET imaging has been the application of low-pass filters, usually Gaussians, which however leads to loss of spatial resolution and increased partial volume effects affecting detectability of small lesions and quantitative data evaluation. The bilateral filter (BF) - a locally adaptive image filter - allows to reduce image noise while preserving well defined object edges but manual optimization of the filter parameters for a given PET scan can be tedious and time-consuming, hampering its clinical use. In this work we have investigated to what extent a suitable deep learning based approach can resolve this issue by training a suitable network with the target of reproducing the results of manually adjusted case-specific bilateral filtering. METHODS: Altogether, 69 respiratory-gated clinical PET/CT scans with three different tracers ( [ 18 F ] FDG, [ 18 F ] L-DOPA, [ 68 Ga ] DOTATATE) were used for the present investigation. Prior to data processing, the gated data sets were split, resulting in a total of 552 single-gate image volumes. For each of these image volumes, four 3D ROIs were delineated: one ROI for image noise assessment and three ROIs for focal uptake (e.g. tumor lesions) measurements at different target/background contrast levels. An automated procedure was used to perform a brute force search of the two-dimensional BF parameter space for each data set to identify the "optimal" filter parameters to generate user-approved ground truth input data consisting of pairs of original and optimally BF filtered images. For reproducing the optimal BF filtering, we employed a modified 3D U-Net CNN incorporating residual learning principle. The network training and evaluation was performed using a 5-fold cross-validation scheme. The influence of filtering on lesion SUV quantification and image noise level was assessed by calculating absolute and fractional differences between the CNN, manual BF, or original (STD) data sets in the previously defined ROIs. RESULTS: The automated procedure used for filter parameter determination chose adequate filter parameters for the majority of the data sets with only 19 patient data sets requiring manual tuning. Evaluation of the focal uptake ROIs revealed that CNN as well as BF based filtering essentially maintain the focal SUV max values of the unfiltered images with a low mean ± SD difference of δ SUV max CNN , STD = (-3.9 ± 5.2)% and δ SUV max BF , STD = (-4.4 ± 5.3)%. Regarding relative performance of CNN versus BF, both methods lead to very similar SUV max values in the vast majority of cases with an overall average difference of δ SUV max CNN , BF = (0.5 ± 4.8)%. Evaluation of the noise properties showed that CNN filtering mostly satisfactorily reproduces the noise level and characteristics of BF with δ Noise CNN , BF = (5.6 ± 10.5)%. No significant tracer dependent differences between CNN and BF were observed. CONCLUSIONS: Our results show that a neural network based denoising can reproduce the results of a case by case optimized BF in a fully automated way. Apart from rare cases it led to images of practically identical quality regarding noise level, edge preservation, and signal recovery. We believe such a network might proof especially useful in the context of improved motion correction of respiratory-gated PET studies but could also help to establish BF-equivalent edge-preserving CNN filtering in clinical PET since it obviates time consuming manual BF parameter tuning.

Partial volume correction in arterial spin labeling using a Look-Locker sequence.

PURPOSE: Partial volume (PV) effects are caused by limited spatial resolution and significantly affect cerebral blood flow investigations with arterial spin labeling. Therefore, accurate PV correction (PVC) procedures are required. PVC is commonly based on PV maps obtained from segmented high-resolution T1 -weighted images. Segmentation of these images is error-prone, and it can be difficult to coregister these images accurately with the single-shot ASL images such as those created by echo-planar imaging (EPI). In this paper, an alternative method for PV map generation is proposed. METHODS: The Look-Locker EPI (LL-EPI) acquisition is used for analyzing the T1 -recovery curve and for subsequent PV map generation. The new method was evaluated in five healthy volunteers (mean age 30 ± 3.7 years). RESULTS: By applying a linear regression method for PVC, a 12% decrease in regression error was reached with the new method. CONCLUSION: PV maps extraction from LL-EPI is a viable, possibly superior alternative to the standard approach based on segmentation of high-resolution T1 -weighted images.

Pulmonary blood flow increases in damaged regions directly after acid aspiration in rats.

BACKGROUND: After gastric aspiration events, patients are at risk of pulmonary dysfunction and the development of severe acute lung injury and acute respiratory distress syndrome, which may contribute to the development of an inflammatory reaction. The authors' aim in the current study was to investigate the role of the spatial distribution of pulmonary blood flow in the pathogenesis of pulmonary dysfunction during the early stages after acid aspiration. METHODS: The authors analyzed the pulmonary distribution of radiolabeled microspheres in normal (n = 6) and injured (n = 12) anesthetized rat lungs using positron emission tomography, computed tomography, and histological examination. RESULTS: Injured regions demonstrate increased pulmonary blood flow in association with reduced arterial pressure and the deterioration of arterial oxygenation. After acid aspiration, computed tomography scans revealed that lung density had increased in the injured regions and that these regions colocalized with areas of increased blood flow. The acid was instilled into the middle and basal regions of the lungs. The blood flow was significantly increased to these regions compared with the blood flow to uninjured lungs in the control animals (middle region: 1.23 [1.1; 1.4] (median [25%; 75%]) vs. 1.04 [1.0; 1.1] and basal region: 1.25 [1.2; 1.3] vs. 1.02 [1.0; 1.05], respectively). The increase in blood flow did not seem to be due to vascular leakage into these injured areas. CONCLUSIONS: The data suggest that 10 min after acid aspiration, damaged areas are characterized by increased pulmonary blood flow. The results may impact further treatment strategies, such as drug targeting.

Quantitative accuracy of attenuation correction in the Philips Ingenuity TF whole-body PET/MR system: a direct comparison with transmission-based attenuation correction.

OBJECTIVE: Evaluation of the quantitative accuracy of MR-based attenuation correction (MRAC) in the Philips Ingenuity TF whole-body PET/MR. MATERIALS AND METHODS: In 13 patients, PET emission data from the PET/MR were reconstructed using two different methods for attenuation correction. In the first reconstruction, the vendor-provided standard MRAC was used. In the second reconstruction, a coregistered transmission-based attenuation map from a second immediately preceding investigation with a stand-alone Siemens ECAT EXACT HR(+) PET scanner was used (TRAC). The two attenuation maps were compared regarding occurrence of segmentation artifacts in the MRAC procedure. Standard uptake values (SUVs) of multiple VOIs (liver, cerebellum, hot focal structures at various locations in the trunk) were compared between both reconstructed data sets. Furthermore, a voxel-wise intensity correlation analysis of both data sets in the lung and trunk was performed. RESULTS: VOI averaged SUV differences between MRAC and TRAC were as follows (relative differences, mean ± standard deviation): (+12 ± 6) % cerebellum, (-4 ± 9) % liver, (-2 ± 11) % hot focal structures. The fitted slopes of the voxel-wise correlations in the lung and trunk were 0.87 ± 0.17 and 0.95 ± 0.10 with averaged adjusted R (2) values of 0.96 and 0.98, respectively. These figures include two instances with partially erroneous lung segmentation due to artifacts in the underlying MR images. CONCLUSION: The MR-based attenuation correction implemented on the Philips Ingenuity PET/MR provides reasonable quantitative accuracy. On average, deviations from TRAC-based results are small (on the order of 10% or below) across the trunk, but due to interindividual variability of the segmentation quality, deviations of more than 20% can occur. Future improvement of the segmentation quality would help to increase the quantitation accuracy further and to reduce the inter-subject variability.