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Objective. 177 Lu-based targeted radionuclide therapy (TRT) has become an important cancer treatment option in recent years, in particular in the treatment of advanced prostate cancer and metastasized neuroendocrine tumors. Although it is known from conventional radiotherapy that the temporal dynamics of the dose-rate can be of relevance for tumor cell survival, the analysis of TRT efficacy usually considers only the absorbed dose. Thus, the aim of this theoretical analysis is to shed light on the possible effects of the pattern of dose-rate in TRT on tumor control probability (TCP). Approach. For this purpose, TCP is studied numerically in a typical four-cycle treatment regime based on the mechanistic lethal-potentially lethal model and the Zaider-Minerbo model for TCP including repopulation of tumor cells. Main results. It is shown that the dose-rate pattern in TRT can have a substantial effect on TCP even though the absorbed dose in the tumor lesion is unchanged. These dose-rate effects are particularly evident when repair of potentially lethal lesions is slow. Significance. The results indicate that in some situations in the analysis of the efficacy of TRT it is necessary to consider the full dose-rate pattern instead of the absorbed dose alone. This can be highly relevant for optimization and further development of TRTs. In particular, it could be of relevancy in studying the efficacy of newly emerging treatment concepts that combine the use of TRT and drugs that inhibit DNA damage repair., (Creative Commons Attribution license.)

Radioligand therapy is a targeted cancer therapy that delivers radiation to tumor cells based on the expression of specific markers on the cell surface. It has become an important treatment option in metastasized neuroendocrine tumors and advanced prostate cancer. The analysis of absorbed doses in radioligand therapies has gained much attention and remains a challenging task due to individual pharmacokinetics. As an alternative to the often used sum of exponential functions in intra-therapeutic dosimetry, a basic compartmental model for the pharmacokinetics of radioligands is described and analyzed in this paper. In its simplest version, the model behavior is determined by the uptake capacity and the association constant and can be solved analytically. The model is extended with rates for excretion from the source compartment and externalization from the lesion compartment. Numerical calculations offer an insight into the quantitative effects of the model parameters on the absorbed dose in the tumor lesion. This analysis helps understanding the importance of clinically relevant factors, e.g. the effect on absorbed doses of modified radioligands that bind to albumin. Using clinical data, the potential application in intra-therapeutic dosimetry is illustrated and compared to the bi-exponential function which lacks a mechanistical basis. While the compartmental model is found to constitute a feasible alternative in these examples, this has to be confirmed by further clinical studies., (Creative Commons Attribution license.)

In this retrospective study, PET/CT data from 59 patients with suspected giant cell arteritis (GCA) were reviewed using the Deauville criteria to determine an optimal cut-off between PET positivity and negativity. Seventeen standardised vascular regions were analysed per patient by three investigators blinded to clinical information. Statistical analysis included ROC curves with areas under the curve (AUC), Cohen's and Fleiss' kappa (κ) to calculate sensitivity, specificity, accuracy, and agreement. According to final clinician's diagnosis and the revised 2017 ACR criteria GCA was confirmed in 29 of 59 (49.2 %) patients. With a diagnostic cut-off ≥ 4 (highest tracer uptake of a vessel wall exceeds liver uptake) for PET positivity, all investigators achieved high accuracy (range, 89.8-93.2%) and AUC (range, 0.94-0.97). Sensitivity and specificity ranged from 89.7-96.6% and 83.3-96.7%, respectively. Agreement between the three investigators suggested 'almost perfect agreement' (Fleiss' κ = 0.84) A Deauville score of ≥4 as threshold for PET positivity yielded excellent results with high accuracy and almost perfect inter-rater agreement, suggesting a standardized, reproducible, and reliable score in diagnosing GCA. However, the small sample size and reference standard could lead to biases. Therefore, verification in a multicentre study with a larger patient cohort and prospective setting is needed.

Background: Tumor hypoxia measured by dedicated tracers like [ 18 F]fluoromisonidazole (FMISO) is a well-established prognostic factor in head and neck squamous cell carcinomas (HNSCC) treated with definitive chemoradiation (CRT). However, prevalence and characteristics of positron emission tomography (PET) measured hypoxia in patients with relapse after previous irradiation is missing. Here we report imaging findings of a prospective pilot study in HNSCC patients treated with re-irradiation. Methods: In 8 patients with recurrent HNSCC, diagnosed at a median of 18 months after initial radiotherapy/CRT, [ 18 F]fluorodeoxyglucose (FDG)-PET/CT (n=8) and FMISO-PET/MRI (n=7) or FMISO-PET/CT (n=1) were performed. Static FMISO-PET was performed after 180 min. MRI sequences in PET/MRI included diffusion-weighted imaging with apparent diffusion coefficient (ADC) values and contrast enhanced T1w imaging (StarVIBE). Lesions (primary tumor recurrence, 4; cervical lymph node, 1; both, 3) were delineated on FDG-PET and FMISO-PET data using a background-adapted threshold-based method. SUV max and SUV mean in FDG- and FMISO-PET were derived, as well as maximum tumor-to-muscle ratio (TMR max ) and hypoxic volume with 1.6-fold muscle SUV mean (HV 1.6 ) in FMISO-PET. Intensity of lesional contrast enhancement was rated relative to contralateral normal tissue. Average ADC values were derived from a 2D region of interest in the tumor. Results: In FMISO-PET, median TMR max was 1.7 (range: 1.1-1.8). Median HV 1.6 was 0.05 ml (range: 0-7.3 ml). Only in 2/8 patients, HV 1.6 was ≥1.0 ml. In FDG-PET, median SUV max was 9.3 (range: 5.0-20.1). On contrast enhanced imaging four lesions showed decreased and four lesions increased contrast enhancement compared to non-pathologic reference tissue. Median average ADC was 1,060 ×10 6 mm 2 /s (range: 840-1,400 ×10 6 mm 2 /s). Conclusions: This pilot study implies that hypoxia detectable by FMISO-PET may not be as prevalent as expected among loco-regional recurrent, HPV negative HNSCC. ADC values were only mildly reduced, and contrast enhancement was variable. The results require confirmation in larger sample sizes., Competing Interests: Competing interests: Dr. Amthauer reports personal fees from SIRTEX Medical Europe, grants from GE Healthcare, grants and personal fees from Novartis; Dr. Walter-Rittel has reported personal fees from Bayer Health Care; both outside the submitted work; all other authors have declared no competing interests exist., (Copyright: © 2021 Rogasch J et al.)

Background: Tumor hypoxia measured by dedicated tracers like [ 18 F]fluoromisonidazole (FMISO) is a well-established prognostic factor in head and neck squamous cell carcinomas (HNSCC) treated with definitive chemoradiation (CRT). However, prevalence and characteristics of positron emission tomography (PET) measured hypoxia in patients with relapse after previous irradiation is missing. Here we report imaging findings of a prospective pilot study in HNSCC patients treated with re-irradiation. Methods: In 8 patients with recurrent HNSCC, diagnosed at a median of 18 months after initial radiotherapy/CRT, [ 18 F]fluorodeoxyglucose (FDG)-PET/CT (n=8) and FMISO-PET/MRI (n=7) or FMISO-PET/CT (n=1) were performed. Static FMISO-PET was performed after 180 min. MRI sequences in PET/MRI included diffusion-weighted imaging with apparent diffusion coefficient (ADC) values and contrast enhanced T1w imaging (StarVIBE). Lesions (primary tumor recurrence, 4; cervical lymph node, 1; both, 3) were delineated on FDG-PET and FMISO-PET data using a background-adapted threshold-based method. SUV max and SUV mean in FDG- and FMISO-PET were derived, as well as maximum tumor-to-muscle ratio (TMR max ) and hypoxic volume with 1.6-fold muscle SUV mean (HV 1.6 ) in FMISO-PET. Intensity of lesional contrast enhancement was rated relative to contralateral normal tissue. Average ADC values were derived from a 2D region of interest in the tumor. Results: In FMISO-PET, median TMR max was 1.7 (range: 1.1-1.8). Median HV 1.6 was 0.05 ml (range: 0-7.3 ml). Only in 2/8 patients, HV 1.6 was ≥1.0 ml. In FDG-PET, median SUV max was 9.3 (range: 5.0-20.1). On contrast enhanced imaging four lesions showed decreased and four lesions increased contrast enhancement compared to non-pathologic reference tissue. Median average ADC was 1,060 ×10 6 mm 2 /s (range: 840-1,400 ×10 6 mm 2 /s). Conclusions: This pilot study implies that hypoxia detectable by FMISO-PET may not be as prevalent as expected among loco-regional recurrent HNSCC. ADC values were only mildly reduced, and contrast enhancement was variable. The results require confirmation in larger sample sizes., Competing Interests: Competing interests: Dr. Amthauer reports personal fees from SIRTEX Medical Europe, grants from GE Healthcare, grants and personal fees from Novartis; Dr. Walter-Rittel has reported personal fees from Bayer Health Care; both outside the submitted work; all other authors have declared no competing interests exist., (Copyright: © 2020 Rogasch J et al.)

Background: in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET), the mTOR inhibitor everolimus is associated with significant improvement in progression-free survival (PFS). This study evaluated the lesional asphericity (ASP) in pretherapeutic somatostatin receptor (SSR) imaging as the first imaging-based prognostic marker for PFS., Methods: this retrospective bicentric cohort study included 30 patients (f = 13, median age, 66.5 (48-81) years) with pretherapeutic [ 111 In-DTPA 0 ]octreotide scintigraphy (Octreoscan ® ). ASP of functional volumes of up to three leading lesions per patient ( n = 74) was calculated after semiautomatic, background-adapted segmentation. Uni- and multivariable Cox regression regarding PFS for clinical factors and the maximum ASP per patient was obtained., Results: all 30 patients showed metachronous or progressive liver metastases. ASP, primary tumor site, metastases pattern, and prior peptide receptor radionuclide therapy (PRRT) were significantly associated with PFS in univariable Cox regression. Only ASP > 12.9% (hazard ratio (HR), 3.33; p = 0.024) and prior PRRT (HR, 0.35; p = 0.043) remained significant in multivariable Cox. Median PFS was 6.7 months for ASP > 12.9% (95% confidence interval (CI), 2.1-11.4 months) versus 14.4 (12.5-16.3) months for ASP ≤ 12.9% (log-rank, p = 0.028)., Conclusion: pretherapeutic ASP of SSR positive lesions independently predicted PFS for treatment with everolimus in GEP-NET. ASP may supplement risk-benefit assessment before patient inclusion to treatment.

Purpose: [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters have shown prognostic value in nasopharyngeal carcinomas (NPC), mostly in monocenter studies. The aim of this study was to assess the prognostic impact of standard and novel PET parameters in a multicenter cohort of patients., Methods: The established PET parameters metabolic tumor volume (MTV), total lesion glycolysis (TLG) and maximal standardized uptake value (SUVmax) as well as the novel parameter tumor asphericity (ASP) were evaluated in a retrospective multicenter cohort of 114 NPC patients with FDG-PET staging, treated with (chemo)radiation at 8 international institutions. Uni- and multivariable Cox regression and Kaplan-Meier analysis with respect to overall survival (OS), event-free survival (EFS), distant metastases-free survival (FFDM), and locoregional control (LRC) was performed for clinical and PET parameters., Results: When analyzing metric PET parameters, ASP showed a significant association with EFS (p = 0.035) and a trend for OS (p = 0.058). MTV was significantly associated with EFS (p = 0.026), OS (p = 0.008) and LRC (p = 0.012) and TLG with LRC (p = 0.019). TLG and MTV showed a very high correlation (Spearman's rho = 0.95), therefore TLG was subesequently not further analysed. Optimal cutoff values for defining high and low risk groups were determined by maximization of the p-value in univariate Cox regression considering all possible cutoff values. Generation of stable cutoff values was feasible for MTV (p<0.001), ASP (p = 0.023) and combination of both (MTV+ASP = occurrence of one or both risk factors, p<0.001) for OS and for MTV regarding the endpoints OS (p<0.001) and LRC (p<0.001). In multivariable Cox (age >55 years + one binarized PET parameter), MTV >11.1ml (hazard ratio (HR): 3.57, p<0.001) and ASP > 14.4% (HR: 3.2, p = 0.031) remained prognostic for OS. MTV additionally remained prognostic for LRC (HR: 4.86 p<0.001) and EFS (HR: 2.51 p = 0.004). Bootstrapping analyses showed that a combination of high MTV and ASP improved prognostic value for OS compared to each single variable significantly (p = 0.005 and p = 0.04, respectively). When using the cohort from China (n = 57 patients) for establishment of prognostic parameters and all other patients for validation (n = 57 patients), MTV could be successfully validated as prognostic parameter regarding OS, EFS and LRC (all p-values <0.05 for both cohorts)., Conclusions: In this analysis, PET parameters were associated with outcome of NPC patients. MTV showed a robust association with OS, EFS and LRC. Our data suggest that combination of MTV and ASP may potentially further improve the risk stratification of NPC patients., Competing Interests: Dr. Amthauer reports personal fees from SIRTEX Medical Europe, grants from GE Healthcare, grants and personal fees from Novartis, outside the submitted work; All other authors have declared that no competing interests exist. We ensure that Dr Amthauer´s fees and grants do not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose of this study was to evaluate the diagnostic performance of T1 relaxation time (T1) for differentiating prostate cancer (PCa) from benign tissue as well as high- from low-grade PCa. Twenty-three patients with suspicion for PCa were included in this prospective study. 3 T MRI including a Modified Look-Locker inversion recovery sequence was acquired. Subsequent targeted and systematic prostate biopsy served as a reference standard. T1 and apparent diffusion coefficient (ADC) value in PCa and reference regions without malignancy as well as high- and low-grade PCa were compared using the Mann-Whitney U test. The performance of T1, ADC value, and a combination of both to differentiate PCa and reference regions was assessed by receiver operating characteristic (ROC) analysis. T1 and ADC value were lower in PCa compared to reference regions in the peripheral and transition zone (p < 0.001). ROC analysis revealed high AUCs for T1 (0.92; 95%-CI, 0.87-0.98) and ADC value (0.97; 95%-CI, 0.94 to 1.0) when differentiating PCa and reference regions. A combination of T1 and ADC value yielded an even higher AUC. The difference was statistically significant comparing it to the AUC for ADC value alone (p = 0.02). No significant differences were found between high- and low-grade PCa for T1 (p = 0.31) and ADC value (p = 0.8). T1 relaxation time differs significantly between PCa and benign prostate tissue with lower T1 in PCa. It could represent an imaging biomarker for PCa.

Purpose: Contrast-enhanced-ultrasound (CEUS) has been frequently used in assessment of cystic renal lesions., Objective: The aim of this study was to investigate the Bosniak classification in CEUS compared to CT and MRI in a multi-center setting., Methods: Bosniak classification in CEUS examinations of cystic renal lesions were compared to imaging findings in computed-tomography (ceCT) and magnetic-resonance-imaging (ceMRI). Imaging results were correlated to histopathological reports. All examinations were performed by experts (EFSUMB level 3) using up-to-date CEUS examination-protocols., Results: Overall, 173 cystic renal lesions were compared to subgroups CT (n = 87) and MRI (n = 86). Using Bosniak-classification 64/87 renal cysts (73.6%) were rated equal compared to CT with upgrade of four lesions (4.6%) and downgrade of 19 lesions (21.8%) by CT (Intra-class-correlation [ICC] coefficient of 0.824 [p < 0.001]). CEUS compared to MRI, presenting different scoring especially in classes Bosniak IIF (n = 16/31) and Bosniak III (n = 16/28) with an ICC coefficient of 0.651 (p < 0.001)., Conclusion: CEUS can visualize even finest septal and small nodular wall enhancement, which may result in an upgrade of cystic lesions into a higher Bosniak class compared to CT or MRI. Thus, a modification of the Bosniak classification on CEUS may reduce unnecessary biopsies and surgery.

Background: Today, the standardized uptake value (SUV) is essentially the only means for quantitative evaluation of static [ 18 F-]fluorodeoxyglucose (FDG) positron emission tomography (PET) investigations. However, the SUV approach has several well-known shortcomings which adversely affect the reliability of the SUV as a surrogate of the metabolic rate of glucose consumption. The standard uptake ratio (SUR), i.e., the uptake time-corrected ratio of tumor SUV to image-derived arterial blood SUV, has been shown in the first clinical studies to overcome most of these shortcomings, to decrease test-retest variability, and to increase the prognostic value in comparison to SUV. However, it is unclear, to what extent the SUR approach is vulnerable to observer variability of the additionally required blood SUV (BSUV) determination. The goal of the present work was the investigation of the interobserver variability of image-derived BSUV., Methods: FDG PET/CT scans from 83 patients (72 male, 11 female) with non-small cell lung cancer (N = 46) or head and neck cancer (N = 37) were included. BSUV was determined by 8 individuals, each applying a dedicated delineation tool for the BSUV determination in the aorta. Two of the observers applied two further tools. Altogether, five different delineation tools were used. With each used tool, delineation was performed for the whole patient group, resulting in 12 distinct observations per patient. Intersubject variability of BSUV determination was assessed using the fractional deviations for the individual patients from the patient group average and was quantified as standard deviation (SD is ), 95% confidence interval, and range. Interobserver variability of BSUV determination was assessed using the fractional deviations of the individual observers from the observer-average for the considered patient and quantified as standard deviations (SD p , SD d ) or root mean square (RMS), 95% confidence interval, and range in each patient, each observer, and the pooled data respectively., Results: Interobserver variability in the pooled data amounts to RMS = 2.8% and is much smaller than the intersubject variability of BSUV (SD is = 16%). Averaged over the whole patient group, deviations of individual observers from the observer average are very small and fall in the range [ - 0.96, 1.05]%. However, interobserver variability partly differs distinctly for different patients, covering a range of [0.7, 7.4]% in the investigated patient group., Conclusion: The present investigation demonstrates that the image-based manual determination of BSUV in the aorta is sufficiently reproducible across different observers and delineation tools which is a prerequisite for accurate SUR determination. This finding is in line with the already demonstrated superior prognostic value of SUR in comparison to SUV in the first clinical studies.

Introduction: Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) analyse tissue vascularization. We evaluated if CEUS can provide comparable information as DCE-MRI for the detection of prostate cancer (PCa) and prediction of its aggressiveness., Material and Methods: A post-hoc evaluation of 92 patients was performed. In each patient CEUS and DCE-MRI parameters of the most suspicious lesion identified on MRI were analysed. The predictive values for discrimination between benign lesions, low-/intermediate- and high-grade PCa were evaluated. Results of targeted biopsy served as reference standard (benign lesions, n=51; low- and intermediate-grade PCa [Gleason grade group 1 and 2], n=22; high-grade PCa [≥ Gleason grade group 3], n=19)., Results: In peripheral zone lesions of all tested CEUS parameters only time to peak (TTP CEUS ) showed significant differences between benign lesions and PCa (AUC 0.65). Of all tested DCE-MRI parameters, rate constant (K ep ) was the best discriminator of high-grade PCa in the whole prostate (AUC 0.83) and in peripheral zone lesions (AUC 0.89)., Conclusion: DCE-MRI showed a superior performance for detection of PCa and prediction of its aggressiveness. CEUS and DCE-MRI performed better in peripheral zone lesions than in transition zone lesions., Key Points: • DCE-MRI gathers information about vascularization and capillary permeability characteristics of tissues. • DCE-MRI can detect PCa and predict its aggressiveness. • CEUS also gathers information about vascularization of tissues. • For detection of PCa and prediction of aggressiveness DCE-MRI performed superiorly. • Both imaging techniques performed better in peripheral zone lesions.

Background: By the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far., Methods: Patients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0)., Result: Findings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow-up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naïve SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up., Conclusion: PSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed., Trial Registration: No trial registration was performed due to retrospective evaluation.

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.