Multicenter PET image harmonization using generative adversarial networks.

PURPOSE: To improve reproducibility and predictive performance of PET radiomic features in multicentric studies by cycle-consistent generative adversarial network (GAN) harmonization approaches. METHODS: GAN-harmonization was developed to harmonize whole-body PET scans to perform image style and texture translation between different centers and scanners. GAN-harmonization was evaluated by application to two retrospectively collected open datasets and different tasks. First, GAN-harmonization was performed on a dual-center lung cancer cohort (127 female, 138 male) where the reproducibility of radiomic features in healthy liver tissue was evaluated. Second, GAN-harmonization was applied to a head and neck cancer cohort (43 female, 154 male) acquired from three centers. Here, the clinical impact of GAN-harmonization was analyzed by predicting the development of distant metastases using a logistic regression model incorporating first-order statistics and texture features from baseline 18F-FDG PET before and after harmonization. RESULTS: Image quality remained high (structural similarity: left kidney ≥ 0.800, right kidney ≥ 0.806, liver ≥ 0.780, lung ≥ 0.838, spleen ≥ 0.793, whole-body ≥ 0.832) after image harmonization across all utilized datasets. Using GAN-harmonization, inter-site reproducibility of radiomic features in healthy liver tissue increased at least by ≥ 5 ± 14% (first-order), ≥ 16 ± 7% (GLCM), ≥ 19 ± 5% (GLRLM), ≥ 16 ± 8% (GLSZM), ≥ 17 ± 6% (GLDM), and ≥ 23 ± 14% (NGTDM). In the head and neck cancer cohort, the outcome prediction improved from AUC 0.68 (95% CI 0.66-0.71) to AUC 0.73 (0.71-0.75) by application of GAN-harmonization. CONCLUSIONS: GANs are capable of performing image harmonization and increase reproducibility and predictive performance of radiomic features derived from different centers and scanners.

A Prognostic Risk Score for Prostate Cancer Based on PSMA PET-derived Organ-specific Tumor Volumes.

Background Prostate-specific membrane antigen (PSMA) PET has high specificity in localizing primary tumors and metastases in patients with prostate cancer, but the individual overall survival probability is still difficult to estimate. Purpose To develop a prognostic risk score using PSMA PET-derived organ-specific total tumor volumes for predicting overall survival in patients with prostate cancer. Materials and Methods Men with prostate cancer who underwent PSMA PET/CT from January 2014 to December 2018 were evaluated retrospectively. All patients from center A were split into training (80%) and internal validation (20%) cohorts. Randomly selected patients from center B were used for external validation. Organ-specific tumor volumes were automatically quantified from PSMA PET scans by a neural network. A prognostic score was selected using multivariable Cox regression guided by the Akaike information criterion (AIC). The final prognostic risk score fitted on the training set was applied to both validation cohorts. Results A total of 1348 men (mean age, 70 years ± 8 [SD]) were included, with 918 patients in the training cohort, 230 in the internal validation cohort, and 200 in the external validation cohort. The median follow-up time was 55.7 months (IQR, 46.7-65.1 months; >4 years; 429 deaths occurred). A body weight-adjusted prognostic risk score integrating total, bone, and visceral tumor volumes obtained high C index values in the internal (0.82) and external (0.74) validation cohorts, as well as in patients with castration-resistant (0.75) and hormone-sensitive (0.68) disease. The fit of the statistical model for the prognostic score was improved compared with a model containing total tumor volume only (AIC, 3324 vs 3351; likelihood ratio test, P < .001). Calibration plots ascertained good model fit. Conclusion The newly developed risk score that included prostate-specific membrane antigen PET-derived organ-specific tumor volumes had good model fit for predicting overall survival in both internal and external validation cohorts. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Civelek in this issue.

Radiogenomic markers enable risk stratification and inference of mutational pathway states in head and neck cancer.

PURPOSE: Head and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population. METHODS: In this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid in vivo imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC. RESULTS: Radiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone. CONCLUSION: Using the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.

Direct Patlak Reconstruction of [68Ga]Ga-PSMA PET for the Evaluation of Primary Prostate Cancer Prior Total Prostatectomy: Results of a Pilot Study.

To investigate the use of kinetic parameters derived from direct Patlak reconstructions of [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) to predict the histological grade of malignancy of the primary tumor of patients with prostate cancer (PCa). Thirteen patients (mean age 66 ± 10 years) with a primary, therapy-naïve PCa (median PSA 9.3 [range: 6.3-130 µg/L]) prior radical prostatectomy, were recruited in this exploratory prospective study. A dynamic whole-body [68Ga]Ga-PSMA-11 PET/CT scan was performed for all patients. Measured quantification parameters included Patlak slope (Ki: absolute rate of tracer consumption) and Patlak intercept (Vb: degree of tracer perfusion in the tumor). Additionally, the mean and maximum standardized uptake values (SUVmean and SUVmax) of the tumor were determined from a static PET 60 min post tracer injection. In every patient, initial PSA (iPSA) values that were also the PSA level at the time of the examination and final histology results with Gleason score (GS) grading were correlated with the quantitative readouts. Collectively, 20 individual malignant prostate lesions were ascertained and histologically graded for GS with ISUP classification. Six lesions were classified as ISUP 5, two as ISUP 4, eight as ISUP 3, and four as ISUP 2. In both static and dynamic PET/CT imaging, the prostate lesions could be visually distinguished from the background. The average values of the SUVmean, slope, and intercept of the background were 2.4 (±0.4), 0.015 1/min (±0.006), and 52% (±12), respectively. These were significantly lower than the corresponding parameters extracted from the prostate lesions (all p < 0.01). No significant differences were found between these values and the various GS and ISUP (all p > 0.05). Spearman correlation coefficient analysis demonstrated a strong correlation between static and dynamic PET/CT parameters (all r ≥ 0.70, p < 0.01). Both GS and ISUP grading revealed only weak correlations with the mean and maximum SUV and tumor-to-background ratio derived from static images and dynamic Patlak slope. The iPSA demonstrated no significant correlation with GS and ISUP grading or with dynamic and static PET parameter values. In this cohort of mainly high-risk PCa, no significant correlation between [68Ga]Ga-PSMA-11 perfusion and consumption and the aggressiveness of the primary tumor was observed. This suggests that the association between SUV values and GS may be more distinctive when distinguishing clinically relevant from clinically non-relevant PCa.

Added value of quantitative, multiparametric 18F-FDG PET/MRI in the locoregional staging of rectal cancer.

PURPOSE: The purpose of this study was to determine whether multiparametric positron emission tomography/magnetic resonance imaging (mpPET/MRI) can improve locoregional staging of rectal cancer (RC) and to assess its prognostic value after resection. METHODS: In this retrospective study, 46 patients with primary RC, who underwent multiparametric 18F-fluorodeoxyglucose (FDG) PET/MRI, followed by surgical resection without chemoradiotherapy, were included. Two readers reviewed T- and N- stage, mesorectal involvement, sphincter infiltration, tumor length, and distance from anal verge. In addition, diffusion-weighted imaging (DWI) and PET parameters were extracted from the multiparametric protocol and were compared to radiological staging as well as to the histopathological reference standard. Clinical and imaging follow-up was systematically assessed for tumor recurrence and death. RESULTS: Locally advanced rectal cancers (LARC) exhibited significantly higher metabolic tumor volume (MTV, AUC 0.74 [95% CI 0.59-0.89], p = 0.004) and total lesion glycolysis (TLG, AUC 0.70 [95% CI 0.53-0.87], p = 0.022) compared to early tumors. T-stage was associated with MTV (AUC 0.70 [95% CI 0.54-0.85], p = 0.021), while N-stage was better assessed using anatomical MRI sequences (AUC 0.72 [95% CI 0.539-0.894], p = 0.032). In the multivariate regression analysis, depending on the model, both anatomical MRI sequences and MTV/TLG were capable of detecting LARC. Combining anatomical MRI stage and MTV/TLG led to a superior diagnostic performance for detecting LARC (AUC 0.81, [95% CI 0.68-0.94], p < 0.001). In the survival analysis, MTV was independently associated with overall survival (HR 1.05 [95% CI 1.01-1.10], p = 0.044). CONCLUSION: Multiparametric PET-MRI can improve identification of locally advanced tumors and, hence, help in treatment stratification. It provides additional information on RC tumor biology and may have prognostic value.

Accuracy of PET quantification in [68Ga]Ga-pentixafor PET/MR imaging of carotid plaques.

AIM: The aim of this study was to evaluate and correct for partial-volume-effects (PVE) on [68Ga]Ga-Pentixafor uptake in atherosclerotic plaques of the carotid arteries, and the impact of ignoring bone in MR-based attenuation correction (MR-AC). METHODS: Twenty [68Ga]Ga-pentixafor PET/MR examinations including a high-resolution T2-TSE MR of the neck were included in this study. Carotid plaques located at the carotid bifurcation were delineated and the anatomical information was used for partial-volume-correction (PVC). Mean and max tissue-to-background ratios (TBR) of the [68Ga]Ga-Pentixafor uptake were compared for standard and PVC-PET images. A potential influence of ignoring bone in MR-AC was assessed in a subset of the data reconstructed after incorporating bone into MR-AC and a subsequent comparison of standardized-uptake values (SUV). RESULTS: In total, 34 atherosclerotic plaques were identified. Following PVC, mean and max TBR increased by 77 and 95%, respectively, when averaged across lesions. When accounting for bone in the MR-AC, SUV of plaque changed by 0.5%. CONCLUSION: Quantitative readings of [68Ga]Ga-pentixafor uptake in plaques are strongly affected by PVE, which can be reduced by PVC. Including bone information into the MR-AC yielded no clinically relevant effect on tracer quantification.

Prediction of response and survival after standardized treatment with 7400 MBq 177Lu-PSMA-617 every 4 weeks in patients with metastatic castration-resistant prostate cancer.

BACKGROUND AND AIMS: [177Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) is a new therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). However, identification of reliable prognostic factors is hampered by heterogeneous treatment regimens applied in previous studies. Hence, we sought clinical factors able to predict response and survival to PSMA-RLT in a homogenous group of patients, all receiving 7400 MBq every 4 weeks. PATIENTS AND METHODS: Data of 61 patients (mean age 71.6 ± 6.9 years, median basal PSA 70.7 [range 1.0-4890 µg/L]), pretreated with abiraterone/enzalutamide (75.4%) and docetaxel/cabazitaxel (68.9%), received three cycles of PSMA-RLT (mean 7321 ± 592 MBq) at four weekly intervals and were analyzed retrospectively. General medical conditions and laboratory parameters of every patients were regularly assessed. Response to therapy was based on PSA levels 1 month after the 3rd cycle. Binary logistic regression test and Kaplan-Meier estimates were used to evaluate predictors and overall survival (OS). RESULTS: Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels. Baseline hemoglobin (Hb) significantly predicted PSA reductions of ≥ 50% 4 weeks after receiving the 3rd PSMA-RLT (P = 0.01, 95% CI: 1.09-2.09) with an AUC of 0.68 (95% CI: 0.54-0.81). The levels of basal Hb and basal PSA were able to predict survival of patients, both P < 0.05 (relative risk 1.51 and 0.79, 95% CI: 1.09-2.09 and 0.43-1.46), respectively. In comparison to patients with reduced basal Hb, patients with normal basal Hb levels lived significantly longer (median survival not reached vs. 89 weeks, P = 0.016). Also, patients with basal PSA levels ≤ 650 µg/L had a significantly longer survival than patients with basal PSA levels > 650 µg/L (median survival not reached vs. 97 weeks, P = 0.031). Neither pretreatments with abiraterone/enzalutamide or docetaxel/cabazitaxel nor distribution of metastasis affected survival and rate of response to PSMA-RLT. CONCLUSION: Basal Hb level is an independent predictor for therapy response and survival in patients receiving PSMA-RLT every 4 weeks. Both baseline PSA ≤ 650 µg/L and normal Hb levels were associated with longer survival.

Clinical outcome of standardized 177Lu-PSMA-617 therapy in metastatic prostate cancer patients receiving 7400 MBq every 4 weeks.

PURPOSE: [177Lu]Lu-PSMA-617 radio-ligand therapy (PSMA-RLT) is emerging in patients with an advanced metastatic castration-resistant prostate cancer (mCRPC). Here, we aimed to estimate the results of PSMA-RLT in terms of response, progression-free survival (PFS), and overall survival (OS) in patients receiving a highly standardized treatment regimen due to mCRPC. The toxicity of PSMA-RLT has also been evaluated. PATIENTS AND METHODS: Fifty-four patients (mean age 72 ± 7 years, median PSA at time of initial therapy 66 [range 1.0-4890 µg/L]), receiving three PSMA-RLT cycles (mean 7315 ± 573 MBq) at four weekly intervals, were included in this retrospective analysis. Hematological and biochemical parameters were regularly determined in every patient. Kaplan-Meier estimates were used to assess PFS and OS and a Cox proportional hazard model was used to analyze significant associations. Treatment response was based on PSA measurements 4 weeks after the 3rd treatment. RESULTS: The majority of patients were previously treated with abiraterone/enzalutamide (69%) and docetaxel/cabazitaxel (67%). In total, 79% of the patients showed a decrease in PSA (median PSA decrease from 66 to 19.8, range 0.7-4563 µg/L, P < 0.001) 1 month after the 3rd therapy cycle. Among them, 58% and 35% demonstrated a PSA-decline of > 50% and > 80%, respectively. Median OS was 119 weeks; median PFS was 25 weeks. Patients presenting with a PSA decline had significantly longer PFS (27 vs. 15 weeks, P < 0.0001) and OS (median survival not reached vs. 52 weeks, P < 0.001) than patients with no PSA reduction. Moreover, patients with reduction in PSA levels ≥ 50% (median survival not reached vs. 52 weeks, P < 0.0001) and ≥ 80% (median survival not reached vs. 87 weeks, P = 0.008) lived significantly longer. While hemoglobin did not change during treatment, levels of platelets (236 ± 71 g/L vs. 193 ± 67 g/L) and leucocytes (6.5, range 2.9-13.7 g/L vs. 4.8, range 1.5-12.3 g/L) decreased significantly, both P < 0.001. Two grade 3 leukocytopenia and one grade 3 anemia were observed. CONCLUSION: Intense PSMA-RLT regime with four weekly intervals between the cycles is well-tolerated and offers favorable response rates, PFS, and survival rates for patients with mCRPC.

PET/MRI versus PET/CT in oncology: a prospective single-center study of 330 examinations focusing on implications for patient management and cost considerations.

PURPOSE: PET/MRI has recently been introduced into clinical practice. We prospectively investigated the clinical impact of PET/MRI compared with PET/CT, in a mixed population of cancer patients, and performed an economic evaluation of PET/MRI. METHODS: Cancer patients referred for routine staging or follow-up by PET/CT underwent consecutive PET/CT and PET/MRI, using single applications of [18F]FDG, [68Ga]Ga-DOTANOC, or [18F]FDOPA, depending on tumor histology. PET/MRI and PET/CT were rated separately, and lesions were assessed per anatomic region; based on regions, per-examination and per-patient accuracies were determined. A simulated, multidisciplinary team meeting served as reference standard and determined whether differences between PET/CT and PET/MRI affected patient management. The McNemar tests were used to compare accuracies, and incremental cost-effectiveness ratios (ICERs) for PET/MRI were calculated. RESULTS: Two hundred sixty-three patients (330 same-day PET/CT and PET/MRI examinations) were included. PET/MRI was accurate in 319/330 examinations and PET/CT in 277/330 examinations; the respective accuracies of 97.3% and 83.9% differed significantly (P < 0.001). The additional findings on PET/MRI-mainly liver and brain metastases-had implications for patient management in 21/263 patients (8.0%). The per-examination cost was 596.97 EUR for PET/MRI and 405.95 EUR for PET/CT. ICERs for PET/MRI were 14.26 EUR per percent of diagnostic accuracy and 23.88 EUR per percent of correctly managed patients. CONCLUSIONS: PET/MRI enables more appropriate management than PET/CT in a nonnegligible fraction of cancer patients. Since the per-examination cost is about 50% higher for PET/MRI than for PET/CT, a histology-based triage of patients to either PET/MRI or PET/CT may be meaningful.

Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of 177Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.

[68Ga]Pentixafor PET/MR imaging of chemokine receptor 4 expression in the human carotid artery.

PURPOSE: Type 4 chemokine receptor (CXCR4) plays an important role in immune cell migration during the atherosclerosis progression. We aimed to evaluate [68Ga]Pentixafor positron emission tomography (PET) in combination magnetic resonance imaging (MRI) for in vivo quantification of CXCR4 expression in carotid plaques. METHODS: Seventy-two patients with lymphoma were prospectively scheduled for whole body [68Ga]Pentixafor PET/MRI with an additional T2-weighted carotid sequence. Volumes of interest (VOIs) were drawn along the carotid bifurcation regions, and the maximum tissue-to-blood ratios (TBR) of [68Ga]Pentixafor uptake were calculated. Lesions were categorized into non-eccentric (n = 27), mild eccentric (n = 67), moderately (n = 41) and severely (n = 19) eccentric carotid atherosclerosis. A different cohort of symptomatic patients (n = 10) with carotid stenosis scheduled for thrombendarterectomy (TEA) was separately imaged with 3T MRI with dedicated plaque sequences (time of flight, T1-, and T2-weighted). MRI findings were correlated with histochemical assessment of intact carotid plaques. RESULTS: At hybrid PET/MRI, we observed significantly increased [68Ga]Pentixafor uptake in mildly (mean TBRmax = 1.57 ± 0.27, mean SUVmax = 2.51 ± 0.39), moderately (mean TBRmax = 1.64 ± 0.37, mean SUVmax = 2.61 ± 0.55) and severely eccentric carotids (mean TBRmax = 1.55 ± 0.26, mean SUVmax = 2.40 ± 0.44) as compared to non-eccentric carotids (mean TBRmax = 1.29 ± 0.21, mean SUVmax = 1.77 ± 0.42) (p ≤ 0.05). Histological findings from TEA confirmed that prominent CXCR4 expression was localized within inflamed atheromas and preatheromas. Co-localization of cellular CXCR4 and CD68 expression in the plaque was observed by immunofluorescence staining. CONCLUSIONS: In vivo evaluation of CXCR4 expression in carotid atherosclerotic lesions is feasible using [68Ga]Pentixafor PET/MRI. In atherosclerotic plaque tissue, CXCR4 expression might be used as a surrogate marker for inflammatory atherosclerosis.

Response assessment using 68Ga-PSMA ligand PET in patients undergoing 177Lu-PSMA radioligand therapy for metastatic castration-resistant prostate cancer.

PURPOSE: The first aim of this study was to evaluate 68Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA PET) parameters for assessment of response to 177Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC). The second aim was to investigate factors associated with overall survival (OS). METHODS: We retrospectively assessed mean standardized uptake values (SUVmean) and total tumor volumes (TTV) on PSMA PET in 38 of 55 mCRPC patients before and after RLT. PSA testing and PSMA PET/CT(MRI) imaging were performed during the 8 weeks before and the 6 weeks after RLT. PSMA PET and CT(MRI) images were reviewed separately according to the modified PET Response Criteria in Solid Tumors (mPERCIST) and RECIST1.1. The results were compared with PSA responses. Associations between OS and the RECIST evaluation and changes in SUVmean, TTV, and PSA, CRP, LDH, hemoglobin and ALP levels were determined in a univariable survival analysis. RESULTS: The median PSA level at the time of pretherapy PSMA PET/CT(MRI) was 60.8 ng/ml (IQR 15.4, 264.2 ng/ml). After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. A PSA response was seen in 18 patients (47.4%), stable disease in 12 (31.6%) and progressive disease in 8 (21.1%). Contrary to the changes in SUVmean and the RECIST evaluation, the change in TTV was significantly associated with PSA response (p = 0.15, p = 0.58, and p < 0.001, respectively). After a median follow-up of 17 months (IQR 8.0, 24.2 months), 11 patients (28.9%) had died of their prostate cancer. The changes in both TTV and PSA levels were associated with OS (HR 1.001, 95% CI 1-1.003, p = 0.04, and HR 1.004, 95% CI 1.001-1.008, p = 0.01, respectively), while the changes in SUVmean and the RECIST evaluation were not. The pre-therapy CRP level was also associated with OS (HR 1.07, 95% CI 1.009-1.14, p = 0.02). CONCLUSION: TTV on PSMA PET seems to be a reliable parameter for response assessment in mCRPC patients undergoing RLT and might overcome the limitations of RECIST in prostate cancer. Furthermore, the change in TTV was significantly associated with OS in our cohort.

Dynamic [18F]FET-PET/MRI using standard MRI-based attenuation correction methods.

AIM: To assess if tumour grading based on dynamic [18F]FET positron emission tomography/magnetic resonance imaging (PET/MRI) studies is affected by different MRI-based attenuation correction (AC) methods. METHODS: Twenty-four patients with suspected brain tumours underwent dynamic [18F]FET-PET/MRI examinations and subsequent low-dose computed tomography (CT) scans of the head. The dynamic PET data was reconstructed using the following AC methods: standard Dixon-based AC and ultra-short echo time MRI-based AC (MR-AC) and a model-based AC approach. All data were reconstructed also using CT-based AC (reference). For all lesions and reconstructions, time-activity curves (TACs) and time to peak (TTP) were extracted using different region-of-interest (ROI) and volume-of-interest (VOI) definitions. According to the most common evaluation approaches, TACs were categorised into two or three distinct curve patterns. Changes in TTP and TAC patterns compared to PET using CT-based AC were reported. RESULTS: In the majority of cases, TAC patterns did not change. However, TAC pattern changes as well as changes in TTP were observed in up to 8% and 17% of the cases when using different MR-AC methods and ROI/VOI definitions, respectively. However, these changes in TTP and TAC pattern were attributed to different delineations of the ROIs/VOIs in PET corrected with different AC methods. CONCLUSION: PET/MRI using different MR-AC methods can be used for the assessment of TAC patterns in dynamic [18F]FET studies, as long as a meaningful delineation of the area of interest within the tumour is ensured. KEY POINTS: • PET/MRI using different MR-AC methods can be used for dynamic [18F]FET studies. • A meaningful segmentation of the area of interest needs to be ensured, mandating a visual validation of the delineation by an experienced reader.

[68Ga]Pentixafor-PET/MRI for the detection of Chemokine receptor 4 expression in atherosclerotic plaques.

PURPOSE: The expression of chemokine receptor type 4 (CXCR4) was found co-localized with macrophages on the atherosclerotic vessel wall and participated in the initial emigration of leukocytes. Gallium-68 [68Ga]Pentixafor has recently been introduced for the imaging of atherosclerosis by targeting CXCR4. We sought to evaluate human atherosclerotic lesions using [68Ga]Pentixafor PET/MRI. METHODS: Thirty-eight oncology patients underwent [68Ga]Pentixafor PET/MR imaging at baseline. Maximum standardized uptake values (SUVmax) were derived from hot lesions in seven arterial segments and target-to-blood ratios (TBR) were calculated. ANOVA post-hoc and paired t test were performed for statistical comparison, Spearman's correlation coefficient between uptake ratios and cardiovascular risk factors were assessed. The reproducibility of [68Ga]Pentixafor PET/MRI was assessed in seven patients with a follow-up exanimation by Pearson's regression and Bland-Altman plots analysis. RESULTS: Thirty-four of 38 patients showed 611 focal [68Ga]Pentixafor uptake that followed the contours of the large arteries. Both prevalence and mean TBRmax were highest in the descending aorta. There were significantly higher TBR values found in men (1.9 ± 0.3) as compared to women (1.7 ± 0.2; p < 0.05). Patients with mean TBRmax > 1.7 showed a significantly higher incidence of diabetes, hypertension hypercholesterolemia and history of cardiovascular disease than patients with mean TBRmax ≤ 1.7. [68Ga]Pentixafor uptake showed a good reproducibility (r = 0.6, p < 0.01), and there was no difference between the mean TBRmax values of plaque lesions (TBRbaseline1.8 ± 0.3 vs TBRfollow-up1.8 ± 0.3) (p = 0.9). CONCLUSION: Patients with high arterial uptake showed increased incidence of cardiovascular risk factors, suggesting a potential role of [68Ga]Pentixafor in characterization of atherosclerosis.

Imaging of primary liver tumors with positron-emission tomography.

INTRODUCTION: The use of positron-emission tomography (PET) with fluorodeoxyglucose (FDG), 11C-acetate and radio-labelled choline such as 11C-choline or 18F-fluorocholine in the diagnosis of hepatocellular carcinoma (HCC), for risk stratification or therapy monitoring has emerged. This review aims to summarize the published results dealing with this issue. EVIDENCE ACQUISITION: PubMed database was searched until February 2017. Sensitivities, specificities, progression-free survival (PFS), survival and hazard ratios (HR) are reported. EVIDENCE SYNTHESIS: Seventy-one studies were included. Most studies are dealing with the diagnostic value of FDG PET (N.=21), 11C-acetate PET (N.=11), and choline PET (N.=8). The results indicate a homogenously higher sensitivity for 11C-acetate and choline PET as compared to FDG PET in the diagnosis of primary or recurrent HCC. This is particularly true for well differentiated HCC, which tend to have higher uptake of 11C-acetate and radio-labelled choline. Contrary, poorly differentiated HCC are more often FDG-positive than well differentiated HCC. Sixteen studies are evaluating the prognostic value of FDG PET for surgery or liver transplantation. The studies found a significant worse prognosis in terms of time to recurrence, PFS, and survival in FDG-positive HCC as compared to FDG-negative ones. Sixteen studies are reporting about the prognostic value of FDG PET and one about 18F-fluoroethylcholine PET for palliative treatment. Most of these studies indicate a significant shorter PFS and survival in FDG-positive HCC for various treatments. CONCLUSIONS: Whereas FDG PET has only a limited role in the diagnosis of HCC, it provides valuable prognostic information for liver surgery, transplantation and palliative treatment. 11C-acetate and choline PET have a higher sensitivity in the diagnosis of HCC.

Evaluation of fatty acid synthase in prostate cancer recurrence: SUV of [(11) C]acetate PET as a prognostic marker.

AIM: High levels of fatty acid synthase have shown to correlate with the aggressiveness of prostate cancer. As [(11) C]acetate exhibits a close correlation with the level of fatty acid synthase, we aimed to assess whether the SUV in [(11) C]acetate PET serves as a suitable prognostic marker in patients with recurrent prostate cancer. MATERIALS AND METHODS: In 123 consecutive patients, examined between 2010 and 2014, the maximum standardized uptake value (SUVmax) of local recurrences as well as lymph node and bone metastases was measured. Choosing the spleen as a standard for relatively high physiological uptake, a ratio of tumor to spleen uptake (SUVts) was calculated for standardizing the uptake, too. The corresponding initial Gleason scores (GS) and serum-PSA levels around the time of the performed PET/CT for each patient were retrospectively collected and PSA doubling together with PSA velocity were determined. For further analysis patients were divided with regard to their initial Gleason score (≤3 + 4 and ≥ 4 + 3). The median of PSA velocity was calculated to separate patients with a high and low PSA velocity and Mann-Whitney U or Student's t-test were used, testing for significant differences. For correlation Spearmen-Rho test was used. RESULTS: PET was positive for recurrence in 82/123 patients. PSA was significantly higher in PET-positive than in negative patients (5.9 vs. 3.2 ng/ml; P = 0.006). Initial Gleason score did not differ in PET negative and positive patients (P = 0.3), whereas PSA velocity was markedly higher in PET positive patients (0.4 vs. 0.1 ng/ml/month; P = 0.01). Median SUVmax of PET positive patients was 5.23 (mean 5.78; range 0.9-16.8) and meadian SUVts was 0.78 (mean 0.84, range 0.14-2.50). SUVts was significantly higher in patients with high PSA velocity (SUVts 0.76 vs. 0.92; P = 0.009), whereas SUVmax failed statistical significance (5.4 vs. 6.3 ng/ml/month; P = 0.08). Patients with a high SUVmax proved to have a significantly higher median Gleason score compared to low uptake 8.0 vs. 7.0; P = 0.004). Vice versa both SUVmax (GS 6: 5.0; GS 7: 5.6; GS 8: 5.7; GS 9: 6.5; r = 0.30, P = 0.008) and SUVts (GS 6: 0.63; GS 7: 0.68; GS 8: 0.85; GS 9: 0.89; r = 0.30, P = 0.006) significantly correlated with Gleason score. Patients with a Gleason score ≤ 3 + 4 had a significantly lower SUVmax (4.8 vs. 5.7; P = 0.02) and SUVts (0.67 vs. 0.85; P = 0.02) as compared to a Gleason score ≥ 4 + 3. CONCLUSION: [(11) C]acetate uptake demonstrated to correlate with initial Gleason score. Furthermore, patients with a high PSA velocity proved to have higher [(11) C]acetate uptake in tumor lesions.

Impact of (68)Ga-DOTATATE PET/CT on the surgical management of primary neuroendocrine tumors of the pancreas or ileum.

BACKGROUND: Resection is the only curative treatment in patients suffering from neuroendocrine tumors (NETs) of the ileum or the pancreas. Accurate preoperative imaging is critical for surgical planning, as even findings of small and distant metastases may profoundly influence surgical management. METHODS: (68)Ga-DOTATATE PET/CT was performed preoperatively in 44 patients suffering from NET of the ileum (n = 26) or the pancreas (n = 18) before surgery at our University Hospital. Data were analyzed retrospectively by an interdisciplinary team of nuclear medicine and visceral surgery specialists. Intended surgical management was documented before and after availability of PET/CT findings. The team judged whether the imaging findings provided additional information relevant to surgical planning. RESULTS: Imaging results altered surgical management in 9 of 44 (20 %) patients, more specifically in 3 of 26 (12 %) patients with NET of the ileum and in 6 of 18 (33 %) patients with NET of the pancreas. PET/CT findings led to a more invasive surgical approach in 6 cases (3 each of ileum and pancreas) and to a less invasive strategy in 3 patients with NET of the pancreas. Although PET/CT results did not alter management in 35 of 44 patients, somatostatin receptor imaging still provided additional information for surgery planning in more than 95 % of the cases. CONCLUSIONS: Additional information provided by (68)Ga-DOTATATE PET/CT in the preoperative workup significantly influences surgical management in one-fifth of our NET patients and, notably, one-third of those suffering from NET of the pancreas.

Towards new response criteria in neuroendocrine tumors: which changes in MRI parameters are associated with longer progression-free survival after radioembolization of liver metastases?

PURPOSE: To evaluate the association of therapy-related changes in imaging parameters with progression-free survival (PFS) of patients with unresectable liver metastases from neuroendocrine tumors (NETLMs). MATERIALS AND METHODS: Forty-five radioembolized patients (median age: 62 years; range: 43-75) received a pre- and 3 months posttherapeutic magnetic resonance imaging (MRI) examination. The latter were evaluated for tumor size, arterial enhancement, and necrosis pattern. Influences of therapy-related changes on PFS were analyzed. Statistical analysis included Student's t-test, Wilcoxon test, Cox regression analysis, and Kaplan-Meier curves. RESULTS: The median percentage decrease in sum of diameters was 9.7% (range: 43.9% decrease to 15.4% increase). Twenty-one patients (47%) showed increased necrosis. Three parameters were associated with significantly longer PFS: a decrease of diameter (hazard ratio [HR]: 0.206; 95% confidence interval [CI]: 0.058-0.725; P = 0.0139), a decrease in tumor arterial enhancement (HR: 0.143; 95% CI: 0.029-0.696; P = 0.0160), and an increase in necrosis after 3 months (HR: 0.321; 95% CI: 0.104-0.990; P = 0.0480). Multivariate analysis revealed that changes in diameter and arterial enhancement have complementary information and are associated independently with long PFS. CONCLUSION: A decrease both in sum of diameters and arterial enhancement of metastases, as well as an increase in necrosis, are associated with significantly longer PFS after radioembolization.

Nomogram including pretherapeutic parameters for prediction of survival after SIRT of hepatic metastases from colorectal cancer.

OBJECTIVES: Pre-therapeutic prediction of outcome is important for clinicians and patients in determining whether selective internal radiation therapy (SIRT) is indicated for hepatic metastases of colorectal cancer (CRC). METHODS: Pre-therapeutic characteristics of 100 patients with colorectal liver metastases (CRLM) treated by radioembolization were analyzed to develop a nomogram for predicting survival. Prognostic factors were selected by univariate Cox regression analysis and subsequent tested by multivariate analysis for predicting patient survival. The nomogram was validated with reference to an external patient cohort (n = 25) from the Bonn University Department of Nuclear Medicine. RESULTS: Of the 13 parameters tested, four were independently associated with reduced patient survival in multivariate analysis. These parameters included no liver surgery before SIRT (HR:1.81, p = 0.014), CEA serum level ≥ 150 ng/ml (HR:2.08, p = 0.001), transaminase toxicity level ≥2.5× upper limit of normal (HR:2.82, p = 0.001), and summed computed tomography (CT) size of the largest two liver lesions ≥10 cm (HR:2.31, p < 0.001). The area under the receiver-operating characteristic curve for our prediction model was 0.83 for the external patient cohort, indicating superior performance of our multivariate model compared to a model ignoring covariates. CONCLUSIONS: The nomogram developed in our study entailing four pre-therapeutic parameters gives good prediction of patient survival post SIRT. KEY POINTS: • Four individual parameters predicted reduced survival following SIRT in CRC. • These parameters were combined into a nomogram of pre-therapeutic risk stratification. • The model provided good prediction of survival in two independent patient cohorts.

Ga-68-DOTA-TATE PET/CT for discrimination of tumors of the optic pathway.

PURPOSE: Symptomatic tumors of the optic nerve pathway may endanger vision. They are difficult to classify by imaging alone and biopsy may damage visual function. Tumor pathology influences treatment decision and a diagnostic tool with a high sensitivity and specificity would therefore be invaluable. We hypothesized that Ga-68-DOTA-TATE PET/CT may help in discriminating optic nerve tumors as uptake of somatostatin is elevated in meningiomas. MATERIAL AND METHODS: Ga-68-DOTA-TATE PET/CT was used to examine 13 patients with ambiguous, symptomatic lesions of the optic pathway for treatment planning. The presence or absence of meningioma was validated by histopathology or supplementary diagnostic work-up. RESULTS: Ga-68-DOTA-TATE PET/CT identified 10 meningiomas (en plaque = 1, optic nerve sheath = 4, sphenoidal = 5) correctly via increased SSTR (somatostatin receptor) expression (mean SUVmax (maximum standardized uptake value) = 14.3 ± 15.4). 3 tumors did not show elevated Ga-68-DOTA-TATE uptake (SUVmax = 2.1 ± 1.0). Subsumizing all clinical-radiological follow-up tools available, these lesions were classified as an intracerebral metastasis of an advanced gastric carcinoma, histologically proven inflammatory collagenous connective tissue and presumed leukemic infiltration of a newly diagnosed chronic lymphocytic leukemia. In this case series, Ga-68-DOTA-TATE PET/CT demonstrated both a sensitivity and specificity of 100%. Yet, the golden standard of histopathology was only available in a subset of patients included. CONCLUSION: Ga-68-DOTA-TATE PET/CT proved to be a valuable diagnostic tool for the correct classification of equivocal, symptomatic tumors of the anterior optic pathway requiring therapy. PET/CT results influenced therapy decision essentially in all cases.