Personalized <Superscript>177</Superscript>Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study

Purpose

Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course.

Methods

Thirty-six patients underwent 122 fixed-IA ¹⁷⁷Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6?±?2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2?±?5.5, 1.3?±?0.8, and 114?±?66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle.

Results

In the P-PRRT regime, cumulative IA could have been increased to 43.7?±?16.5 GBq over four induction cycles (10.9?±?5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5?±?2.5, 1.63?±?0.61, and 163.4?±?85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68–2.64-fold; P?=?0.0013).

Conclusion

By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity.

     

Long-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with <Superscript>177</Superscript>Lu-D OTATATE

Purpose

Lu-DOTATATE (Lu-PRRT) is a valid therapeutic option in differentiated pancreatic neuroendocrine tumors (P-NETs). FDG PET seems to be an important prognostic factor in P-NETs. We evaluated the efficacy of Lu-PRRT and the role of FDG PET in 60 patients with advanced P-NETs.

Methods

From March 2008 to June 2011, 60 consecutive patients with P-NETs were enrolled in the study. Follow-up lasted until March 2016. Eligible patients were treated with two different total cumulative activities (18.5 or 27.8 GBq in 5 cycles every 6–8 weeks), according to kidney and bone marrow parameters.

Results

Twenty-eight patients received a mean full activity (FA) of 25.9 GBq and 32 a mean reduced activity (RA) of 18.5 GBq. The disease control rate (DCR), defined as the sum of CR+PR+SD was 85.7 % in the FA group and 78.1 % in the RA group. Median progression-free survival (mPFS) was 53.4 months in the FA group and 21.7 months in the RA group (P?=?0.353). Median overall survival (mOS) was not reached (nr) in FA patients and was 63.8 months in the RA group (P?=?0.007). Fifty-five patients underwent an FDG PET scan before Lu-PRRT, 32 (58 %) showing an increased FDG uptake in tumor sites. mPFS was 21.1 months in FDG PET-positive patients and 68.7 months in the FDG PET-negative group (P?<?0.0002), regardless of the total activity administered.

Conclusion

Both FA and RA are active in patients undergoing Lu-PRRT. However, an FA of 27.8 GBq of Lu-PRRT prolongs PFS and OS compared to an RA of 18.5 GBq. Our results indicate that FDG PET is an independent prognostic factor in this patient setting.

     

Pre-dosing with lilotomab prior to therapy with <Superscript>177</Superscript>Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients

Purpose

¹⁷⁷Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses.

Methods

Two of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m² BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq ¹⁷⁷Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student’s t tests were used for all statistical analyses.

Results

Organs with distinct uptake of ¹⁷⁷Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1–4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p?=?0.04) and arm 4 (p?=?0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p?<?0.01).Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1–4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p?=?0.05 and p?=?0.02). No statistically significant difference between arms 1 and 4 was found.

Conclusions

RM is the primary dose-limiting organ for ¹⁷⁷Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m² was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab.

     

<Superscript>18</Superscript>F-FDG PET/MRI evaluation of retroperitoneal fibrosis: a simultaneous multiparametric approach for diagnosing active disease

Purpose

The aim of this study was to evaluate integrated ¹⁸F-FDG PET/MRI as a one-stop diagnostic procedure in the assessment of (active) idiopathic retroperitoneal fibrosis (RPF)

Methods

A total of 22 examinations comprising a PET/CT scan followed by a PET/MRI scan in 17 patients (13 men, 4 women, age 58?±?11 years) with histopathologically confirmed RPF at diagnosis or during follow-up under steroid therapy were analysed in correlation with laboratory inflammation markers (ESR, CRP). The patient cohort was subdivided into two groups: 6 examinations in untreated and 16 in treated patients. Tissue formations in typically periaortic localization suggestive of RPF were visually and quantitatively evaluated. The PET analysis included the assessment of SUVmax and a qualitative score for FDG uptake in RPF tissue in relation to the uptake in the liver. MRI analysis included evaluation of the T2-weighted image signal intensity, contrast enhancement and diffusion restriction (ADC values). Mean values were compared using the Mann-Whitney U test. ADC, SUVmax and ESR values were correlated using Pearson’s correlation.

Results

MRI analysis revealed restricted diffusion in 100 % and 56 %, hyperintense T2 signal in 100 % and 31 %, and contrast enhancement in the periaortic tissue formation suggestive of RPF in 100 % and 62.5 % in the untreated and treated patients, respectively. In the qualitative and quantitative PET analysis, statistically significant differences were found for mean FDG uptake scores (2.5?±?0.8 in untreated patients and 1.1?±?0.9 in treated patients) and mean SUVmax (7.8?±?3.5 and 4.1?±?2.2, respectively). A strong correlation was found between the ADC values and SUVmax (Pearson r? ??0.65, P?=?0.0019), and between ESR and CRP values and SUVmax (both r?=?0.45, P?=?0.061).

Conclusion

Integrated ¹⁸F-FDG PET/MRI shows high diagnostic potential as a one-stop diagnostic procedure for the assessment of (active) RPF providing multiparametric supportive information.

     

Texture analysis of <Superscript>18</Superscript>F-FDG PET/CT to predict tumour response and prognosis of patients with esophageal cancer treated by chemoradiotherapy

Purpose

This retrospective study was done to examine whether the heterogeneity in primary tumour F-18-fluorodeoxyglucose (¹⁸F-FDG) distribution can predict tumour response and prognosis of patients with esophageal cancer treated by chemoradiotherapy (CRT).

Methods

The enrolled 52 patients with esophageal cancer underwent ¹⁸F-FDG-PET/CT studies before CRT. SUVmax, SUVmean, metabolic tumour volume (MTV, SUV?≥?2.5), total lesion glycolysis (TLG) and six heterogeneity parameters assessed by texture analysis were obtained. Patients were classified as responders or non-responders according to Response Evaluation Criteria in Solid Tumors. Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method. Prognostic significance was assessed by Cox proportional hazards analysis.

Results

Thirty four non-responders showed significantly higher MTV (p?=?0.006), TLG (p?=?0.007), intensity variability (IV; p?=?0.003) and size-zone variability (SZV; p?=?0.004) than 18 responders. The positive and negative predictive values for non-responders were 77 % and 69 % in MTV, 76 % and 100 % in TLG, 78 % and 67 % in IV and 78 % and 82 % in SZV, respectively. Although PFS and OS were significantly shorter in patients with high MTV (PFS, p?=?0.018; OS, p?=?0.014), TLG (PFS, p?=?0.009; OS, p?=?0.025), IV (PFS, p?=?0.013; OS, p?=?0.007) and SZV (PFS, p?=?0.010; OS, p?=?0.007) at univariate analysis, none of them was an independent factor, while lymph node status, stage and tumour response status were independent factors at multivariate analysis.

Conclusion

Texture features IV and SZV, and volumetric parameters MTV and TLG can predict tumour response, but all of them have limited value in prediction of prognosis of patients with esophageal cancer treated by CRT.

     

Preliminary feasibility study on differential diagnosis between radiation-induced cerebral necrosis and recurrent brain tumor by means of [<Superscript>18</Superscript>F]fluoro-borono-phenylalanine PET/CT

Objectives

A previous study reported that a differential diagnosis between glioblastoma progression and radiation necrosis by 4-borono-2-[¹⁸F]-fluoro-phenylalanine ([¹⁸F]FBPA) PET can be made based on lesion-to-normal ratio of [¹⁸F]FBPA accumulation. Two-dimensional data acquisition mode PET alone system, with in-plane resolution of 7.9 mm and axial resolution of 13.9 mm, was used. In the current study, we aimed to confirm the differential diagnostic capability of [¹⁸F]FBPA PET/CT with higher PET spatial resolution by three-dimensional visual inspection and by measuring mean standardized uptake value (SUVmean), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion (TL) [¹⁸F]FBPA uptake.

Methods

Twelve patients of glioma (9), malignant meningioma (1), hemangiopericytoma (1), and metastatic brain tumor (1) were enrolled. All had preceding radiotherapy. High-resolution three-dimensional data acquisition mode PET/CT with in-plane resolution of 4.07 mm and axial resolution of 5.41 mm was employed for imaging. Images were three-dimensionally analyzed using the PMOD software. SUVmean and SUVmax of lesion and normal brain were measured. Lesion MTV and TL FBPA uptake were calculated. The diagnostic accuracy of [¹⁸F]FBPA PET/CT in detecting recurrence (n?=?6) or necrosis (n?=?6) was verified by clinical follow-up.

Results

All parameters showed significantly higher values for tumor recurrence than for necrosis. SUVmean in recurrence was 2.95?±?0.84 vs 1.18?±?0.24 in necrosis (P?=?0.014); SUVmax in recurrence was 4.63?±?1.23 vs 1.93?±?0.44 in necrosis (P?=?0.014); MTV in recurrence was 44.92?±?28.93 mL vs 10.66?±?8.46 mL in necrosis (P?=?0.032); and mean TL FBPA uptake in recurrence was 121.01?±?50.48 g vs 12.36?±?9.70 g in necrosis (P?=?0.0029).

Conclusion

In this preliminary feasibility study, we confirmed the possibility of differentiating tumor recurrence from radiation necrosis in patients with irradiated brain tumors by [¹⁸F]FBPA PET/CT using indices of SUVmean, SUVmax, MTV, and TL ¹⁸FBPA uptake.

     

The <Superscript>68</Superscript>Ga/<Superscript>177</Superscript>Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUV<Subscript>max</Subscript> values and absorbed dose estimates

Introduction

A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods

Ten consecutive mCRPC patients were selected for ¹⁷⁷Lu-PSMA617 therapy on the basis of PSMA-targeted ⁶⁸Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging (⁶⁸Ga-PSMA-HBED-CC and ¹⁸F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1?±?0.3 GBq, range 5.4–6.5 GBq) given intravenously over 30 minutes, 9?±?1 weeks apart. PET/CT scans were compared to ¹⁷⁷Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed.

Results

¹⁷⁷Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4?±?1.9 Gy/GBq; range 1.1–7.2 Gy/GBq), lymph node (2.6?±?0.4 Gy/GBq; range 2.3–2.9 Gy/GBq) as well as liver (2.4?±?0.8 Gy/GBq; range 1.7–3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18?±?0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased ¹⁷⁷Lu-PSMA617 and ⁶⁸Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p?<?0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions.

Conclusion

Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following ¹⁷⁷Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study.

     

Prospective dosimetry with <Superscript>99m</Superscript>Tc-MDP in metabolic radiotherapy of bone metastases with <Superscript>153</Superscript>Sm-EDTMP

Purpose

On the basis of the encouraging results achieved in several clinical trials and its proven therapeutic efficacy, ¹⁵³Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP) has become widely used to palliate pain from bone metastases. The results reported in the literature have led the product suppliers (QUADRAMET®, Schering) to suggest administering a fixed activity per kilogram (37 MBq/kg). However, considering the observed extreme inter-patient variability of skeletal uptake of ¹⁵³Sm-EDTMP, a real therapy optimization would require the individualization of the activity to be administered on a dosimetric basis. This should be planned taking into account the generally accepted 2-Gy dose constraint to the haematopoietic red marrow, the critical organ in palliative treatments with beta-emitting, bone-seeking radiopharmaceuticals.

Methods

Seven to 14 days before treatment with ¹⁵³Sm-EDTMP, 44 patients underwent ^99mTc-methylene diphosphonate (MDP) total-body bone scan with two scans (the first within 10 min of injection, the second after 6 h). The percentage bone uptake (Tc_%) was evaluated as the ratio between total counts at 6 h, adjusted for decay, and total counts at the first scan. Tc_% was then compared to Sm_% similarly derived from 10-min and 24-h whole-body scans. Tc_% and Sm_% were compared both with and without Brenner’s method for soft tissue uptake.

Results

The correlation between Tc_% and Sm_% was R ²?=?0.81 and R ²?=?0.88 with and without soft tissue correction, respectively. The difference between their average values was statistically significant (Sm_%?=?64.3?±?15.2, Tc_%?=?56.2?±?16.0; p?=?0.017) with soft tissue correction, while was not statistically significant (Sm_%?=?68.2?±?15.5, Tc_%?=?66.9?±?14.0; p?=?0.670) without soft tissue correction.

Conclusions

The rate of retention of ^99mTc-MDP in bone provides a reliable estimate of the ¹⁵³Sm-EDTMP rate of retention. The proposed method can be usefully adopted for prospective dosimetry seeing its extreme simplicity, and it requires no special investment in terms of human or instrumental resources. This allows an optimization of administered ¹⁵³Sm-EDTMP activity.

     

Quantification of myocardial blood flow with <Superscript>82</Superscript>Rb positron emission tomography: clinical validation with <Superscript>15</Superscript>O-water

Purpose

Quantification of myocardial blood flow (MBF) with generator-produced ⁸²Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate ⁸²Rb-measured MBF in relation to that measured using ¹⁵O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD).

Methods

MBF was measured at rest and during adenosine-induced hyperaemia with ⁸²Rb and ¹⁵O-water PET in 33 participants (22 control subjects, aged 30?±?13 years; 11 CAD patients without transmural infarction, aged 60?±?13 years). A one-tissue compartment ⁸²Rb model with ventricular spillover correction was used. The ⁸²Rb flow-dependent extraction rate was derived from ¹⁵O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson’s correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin’s concordance correlation ρ _c (measuring both precision and accuracy) were used.

Results

Over the entire MBF range (0.66–4.7 ml/min/g), concordance was excellent for MBF (r?=?0.90, [⁸²Rb–¹⁵O-water] mean difference?±?SD?=?0.04?±?0.66 ml/min/g, LoA?=??1.26 to 1.33 ml/min/g, ρ _c?=?0.88) and MFR (range 1.79–5.81, r?=?0.83, mean difference?=?0.14?±?0.58, LoA?=??0.99 to 1.28, ρ _c?=?0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53?±?0.74 vs. 3.62?±?0.68 ml/min/g, p?=?0.002, for ¹⁵O-water; 2.53?±?1.01 vs. 3.82?±?1.21 ml/min/g, p?=?0.013, for ⁸²Rb) and this was paralleled by a lower MFR (2.65?±?0.62 vs. 3.79?±?0.98, p?=?0.004, for ¹⁵O-water; 2.85?±?0.91 vs. 3.88?±?0.91, p?=?0.012, for ⁸²Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p?>?0.31).

Conclusion

Quantification of MBF with ⁸²Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using ¹⁵O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. ⁸²Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routine.

     

Automatic calculation of myocardial external efficiency using a single <Superscript>11</Superscript>C-acetate PET scan

Background

Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed (MVO₂) by the left ventricular mass (LVM). We developed a fully automated method for estimating MEE based on a single ¹¹C-acetate PET scan without ECG-gating.

Methods and Results

Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO₂ was calculated using washout of ¹¹C -acetate activity. FCO and LVM were calculated automatically using dynamic PET and parametric image formation. FCO and LVM were also obtained using cardiac magnetic resonance (CMR) in all subjects. The correlation between MEE_PET-CMR and MEE_PET was high (r = 0.85, P < 0.001) without significant bias. MEE_PET was 23.6 ± 4.2% for controls and was lowered in AVS (17.2 ± 4.3%, P < 0.001) and in MVR (18.0 ± 5.2%, P = 0.004). MEE_PET was strongly associated with both NYHA class (P < 0.001) and the magnitude of valvular dysfunction (mean aortic gradient: P < 0.001, regurgitant fraction: P = 0.009).

Conclusion

A single ¹¹C-acetate PET yields accurate and automated MEE results on different scanners. MEE might provide an unbiased measurement of the phenotypic response to valvular disease.

     

Coronary CT angiography in obese patients using 3<Superscript>rd</Superscript> generation dual-source CT: effect of body mass index on image quality

Objectives

To evaluate the image quality of coronary CT angiography (CCTA) in obese patients using a 3^rd generation, dual-source CT scanner.

Methods

We retrospectively evaluated 102 overweight and obese patients who had undergone CCTA. Studies were performed with 3^rd generation dual-source CT, prospectively ECG-triggered acquisition at 120 kV, and automated tube current modulation. Advanced modeled iterative reconstruction was used. Patients were divided into three BMI groups: 1)25–29.9 kg/m²; 2)30–39.9 kg/m²; 3)?≥?40 kg/m². Vascular attenuation in the coronary arteries was measured. Contrast-to-noise ratio (CNR) was calculated. Image quality was subjectively evaluated using five-point scales.

Results

Image quality was considered diagnostic in 97.6 % of examinations. CNR was consistently adequate in all groups but decreased for groups 2 and 3 in comparison to group 1 as well as for group 3 compared to group 2 (p?=?0.001, respectively). Subjective image quality was significantly higher in group 1 compared to group 3 (attenuation proximal: 4.8?±?0.4 vs. 4.4?±?0.6, p?=?0.011; attenuation distal: 4.5?±?0.7 vs. 4.0?±?0.8, p?=?0.019; noise: 4.7?±?0.6 vs. 3.8?±?0.7, p?<?0.001). The mean effective dose was 9.5?±?3.9 mSv for group 1, 11.4?±?4.7 mSv for group 2 and 14.0?±?6.4 mSv for group 3.

Conclusion

Diagnostic image quality can be routinely obtained at CCTA in obese patients with 3^rd generation DSCT at 120 kV.

Key Points

? Diagnostic CCTA can be routinely performed in obese patients with 3 ^rd generation DSCT.? 120-kV tube voltage allows diagnostic image quality in patients with BMI?>?40 kg/m ² .? 80-ml contrast medium can be administered without significant decline in vascular attenuation.

     

Evaluation of ECG-gated [<Superscript>11</Superscript>C]acetate PET for measuring left ventricular volumes,mass, and myocardial external efficiency

Background

Noninvasive estimation of myocardial external efficiency (MEE) requires measurements of left ventricular (LV) oxygen consumption with [¹¹C]acetate PET in addition to LV stroke volume and mass with cardiovascular magnetic resonance (CMR). Measuring LV geometry directly from ECG-gated [¹¹C]acetate PET might enable MEE evaluation from a single PET scan. Therefore, we sought to establish the accuracy of measuring LV volumes, mass, and MEE directly from ECG-gated [¹¹C]acetate PET.

Methods

Thirty-five subjects with aortic valve stenosis underwent ECG-gated [¹¹C]acetate PET and CMR. List mode PET data were rebinned into 16-bin ECG-gated uptake images before measuring LV volumes and mass using commercial software and compared to CMR. Dynamic datasets were used for calculation of mean LV oxygen consumption and MEE.

Results

LV mass, volumes, and ejection fraction measured by CMR and PET correlated strongly (r = 0.86-0.92, P < .001 for all), but were underestimated by PET (P < .001 for all except ESV P = .79). PET-based MEE, corrected for bias, correlated fairly with PET/CMR-based MEE (r = 0.60, P < .001, bias ?3 ± 21%, P = .56). PET-based MEE bias was strongly associated with LV wall thickness.

Conclusions

Although analysis-related improvements in accuracy are recommended, LV geometry estimated from ECG-gated [¹¹C]acetate PET correlate excellently with CMR and can indeed be used to evaluate MEE.

     

Comparison of choline influx from dynamic <Superscript>18</Superscript>F-Choline PET/CT and clinicopathological parameters in prostate cancer initial assessment

Aim

The aim of the study was to compare the kinetic analysis of ¹⁸F-labeled choline (FCH) uptake with static analysis and clinicopathological parameters in patients with newly diagnosed prostate cancer (PC).

Materials and methods

Sixty-one patients were included. PSA was performed few days before FCH PET/CT. Gleason scoring (GS) was collected from systematic sextant biopsies. FCH PET/CT consisted in a dual phase: early pelvic list-mode acquisition (from 0 to10 min post-injection) and late whole-body acquisition (60 min post-injection). PC volume of interest was drawn using an adaptative thresholding (40% of the maximal uptake) on the late acquisition and projected onto an early static frame of 10 min and each of the 20 reconstructed frames of 30 s. Kinetic analysis was performed using an imaging-derived plasma input function. Early kinetic parameter (K1 as influx) and static parameters (early SUVmean, late SUVmean, and retention index) were extracted and compared to clinicopathological parameters.

Results

K1 was significantly, but moderately correlated with early SUVmean (r?=?0.57, p?<?0.001) and late SUVmean (r?=?0.43, p?<?0.001). K1, early SUVmean, and late SUVmean were moderately correlated with PSA level (respectively, r?=?0.36, p?=?0.004; r?=?0.67, p?<?0.001; r?=?0.51, p?<?0.001). Concerning GS, K1 was higher for patients with GS?≥?4?+?3 than for patients with GS?<?4?+?3 (median value 0.409 vs 0.272 min^??1, p?<?0.001). No significant difference was observed for static parameters.

Conclusions

FCH influx index K1 seems to be related to GS and could be a non-invasive tool to gain further information concerning tumor aggressiveness.

     

<Superscript>18</Superscript>F-FDG-PET/CT based total metabolic tumor volume change during neoadjuvant chemotherapy predicts outcome in advanced epithelial ovarian cancer

Objective

To evaluate the predictive potential of total metabolic tumor volume (MTV) reduction during neoadjuvant chemotherapy (NACT) with ¹⁸F–FDG-PET/CT in an advanced FIGO stage III/IV epithelial ovarian cancer (EOC) patient cohort.

Methods

Twenty-nine primarily inoperable EOC patients underwent ¹⁸F–FDG-PET/CT before and after NACT. The pre- and post-NACT total MTV, in addition to the percentage MTV reduction during NACT, were compared with primary therapy outcome and progression-free survival (PFS). ROC-analysis determined an optimal threshold for MTV reduction identifying patients with progressive or stable disease (PD/SD) at the end of primary therapy. A multivariate analysis with residual tumor (0/>0), FIGO stage (III/IV) and MTV reduction compared to PFS was performed. The association between MTV reduction and overall survival (OS) was evaluated.

Results

The median pre- and post-NACT total MTV were 352 cm³ (range 150 to 1322 cm³) and 51 cm³ (range 0 to 417 cm³), respectively. The median MTV reduction during NACT was 89% (range 24% to 100%). Post-NACT MTV and MTV reduction associated with primary therapy outcome (MTV post-NACT p?=?0.007, MTV reduction p?=?0.001) and PFS (MTV post-NACT p?=?0.005, MTV reduction p?=?0.005). MTV reduction <85% identified the PD/SD patients (sensitivity 70%, specificity 78%, AUC 0.79). In a multivariate analysis, MTV reduction (p?=?0.002) and FIGO stage (p?=?0.003) were statistically significant variables associated with PFS. MTV reduction during NACT corresponded to OS (p?=?0.05).

Conclusion

¹⁸F–FDG-PET/CT is helpful in NACT response evaluation. Patients with total MTV reduction <85% during NACT might be candidates for second-line chemotherapy and clinical trials, instead of interval debulking surgery.

     

Pulmonary <Superscript>18</Superscript>F-FDG uptake helps refine current risk stratification in idiopathic pulmonary fibrosis (IPF)

Purpose

There is a lack of prognostic biomarkers in idiopathic pulmonary fibrosis (IPF) patients. The objective of this study is to investigate the potential of ¹⁸F-FDG-PET/ CT to predict mortality in IPF.

Methods

A total of 113 IPF patients (93 males, 20 females, mean age?±?SD: 70?±?9 years) were prospectively recruited for ¹⁸F-FDG-PET/CT. The overall maximum pulmonary uptake of ¹⁸F-FDG (SUV_max), the minimum pulmonary uptake or background lung activity (SUV_min), and target-to-background (SUV_max/ SUV_min) ratio (TBR) were quantified using routine region-of-interest analysis. Kaplan–Meier analysis was used to identify associations of PET measurements with mortality. We also compared PET associations with IPF mortality with the established GAP (gender age and physiology) scoring system. Cox analysis assessed the independence of the significant PET measurement(s) from GAP score. We investigated synergisms between pulmonary ¹⁸F-FDG-PET measurements and GAP score for risk stratification in IPF patients.

Results

During a mean follow-up of 29 months, there were 54 deaths. The mean TBR?±?SD was 5.6?±?2.7. Mortality was associated with high pulmonary TBR (p?=?0.009), low forced vital capacity (FVC; p?=?0.001), low transfer factor (TLCO; p?<?0.001), high GAP index (p?=?0.003), and high GAP stage (p?=?0.003). Stepwise forward-Wald–Cox analysis revealed that the pulmonary TBR was independent of GAP classification (p?=?0.010). The median survival in IPF patients with a TBR < 4.9 was 71 months, whilst in those with TBR?> 4.9 was 24 months. Combining PET data with GAP data (“PET modified GAP score”) refined the ability to predict mortality.

Conclusions

A high pulmonary TBR is independently associated with increased risk of mortality in IPF patients.

     

[<Superscript>18</Superscript>F]FDG PET accurately differentiates infected and non-infected non-unions after fracture fixation

Purpose

Complete fracture healing is crucial for good patient outcomes. A major complication in the treatment of fractures is non-union. The pathogenesis of non-unions is not always clear, although implant-associated infections play a significant role, especially after surgical treatment of open fractures. We aimed to evaluate the value of [¹⁸F]FDG PET in suspected infections of non-union fractures.

Methods

We retrospectively evaluated 35 consecutive patients seen between 2000 and 2015 with suspected infection of non-union fractures, treated at a level I trauma center. The patients underwent either [¹⁸F]FDG PET/CT (N?=?24), [¹⁸F]FDG PET (N?=?11) plus additional CT (N?=?8), or conventional X-ray (N?=?3). Imaging findings were correlated with final diagnosis based on intraoperative culture or follow-up.

Results

In 13 of 35 patients (37 %), infection was proven by either positive intraoperative tissue culture (N?=?12) or positive follow-up (N?=?1). [¹⁸F]FDG PET revealed 11 true-positive, 19 true-negative, three false-positive, and two false-negative results, indicating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 85 %, 86 %, 79 %, 90 %, and 86 %, respectively. The SUV_max was 6.4?±?2.7 in the clinically infected group and 3.0?±?1.7 in the clinically non-infected group (p <0.01). The SUV_ratio was 5.3?±?3.3 in the clinically infected group and 2.6?±?1.5 in the clinically non-infected group (p <0.01).

Conclusion

[¹⁸F]FDG PET differentiates infected from non-infected non-unions with high accuracy in patients with suspected infections of non-union fractures, for whom other clinical findings were inconclusive for a local infection. [¹⁸F]FDG PET should be considered for therapeutic management of non-unions.

     

Dynamic <Superscript>18</Superscript>F-fluoride small animal PET to noninvasively assess renal function in rats

Purpose

Renal function can be quantified by both laboratory and scintigraphic methods. In the case of small animal diagnostics, scintigraphic image-based methods are ideal since they can assess split renal function, work noninvasively, and can be repeated. The aim of this study is to validate a ¹⁸F-PET-based method to quantify renal function in rats.

Materials and methods

Fluoride clearance was calculated from a dynamic whole body listmode acquisition of 60 min length in a small animal PET scanner following an i.v. injection of 15 MBq ¹⁸F-fluoride. Volumes of interest (VOIs) were placed in the left ventricle and the bladder as well as traced around the kidney contours. The respective time–activity curves (TAC) were calculated. The renal ¹⁸F-clearance was calculated by the ratio of the total renal excreted activity (bladder VOI) and the integral of the blood TAC. PET-derived renal function was validated by intraindividual measurements of creatinine clearance (n?=?23), urea clearance (n?=?23), and tubular excretion rate (TER-MAG3). The split renal function was derived from the injection of the clinically available radionuclide ^99mTc-mercaptotriglycine by blood sampling and planar renography (n?=?8).

Results

In all animals studied, PET revealed high-quality TACs. PET-derived renal fluoride clearance was linearly correlated with intraindividual laboratory measures (PET vs. creatinine: r?=?0.78; PET vs. urea: r?=?0.73; PET vs. TER-MAG3: r?=?0.73). Split function was comparable (¹⁸F-PET vs. MAG3-renography: r?=?0.98). PET-derived measures were highly reproducible.

Conclusions

¹⁸F-PET is able to noninvasively assess renal function in rats and provides a significant potential for serial studies in different experimental scenarios.

     

<Superscript>1</Superscript>H- and <Superscript>31</Superscript>P-myocardial magnetic resonance spectroscopy in non-obstructive hypertrophic cardiomyopathy patients and competitive athletes

Purpose

The clinical differentiation between athlete’s heart and mild forms of non-obstructive hypertrophic cardiomyopathy (HCM) is crucial. We hypothesized that differences do exist between the myocardial metabolism of patients with non-obstructive HCM and competitive athletes (CAs). Our aim was to evaluate myocardial metabolism with ³¹P-MRS and ¹H-MRS in HCM patients and CAs.

Materials and methods

After Ethics Committee approval, 15 CAs and 7 HCM patients were prospectively enrolled. They underwent a 1.5-T cardiac MR including electrocardiographically triggered cine images, single-voxel ¹H-MRS and multivoxel ³¹P-MRS. ¹H-MRS was performed after imaging using standard coil with the patient in the supine position; thereafter, ³¹P-MRS was performed using a dedicated coil, in the prone position. Data were reported as median and interquartile range. Mann–Whitney U test was used.

Results

In CAs, left ventricular mass index was 72 (66–83) g/m², septal thickness 10 (10–11) mm, end diastolic volume index 95 (85–102) ml/m², end systolic volume index 30 (28–32) ml/m² and ejection fraction 68% (65–69%); in HCM patients, 81 (76–111) g/m² (P = 0.052), 18 (15–21) mm (P = 0.003), 73 (58–76) ml/m² (P = 0.029), 20 (16–34) ml/m² (P = 0.274) and 68% (55–73%) (P = 1.000), respectively. At ¹H-MRS, total lipids were 35 (0–183) arbitrary units (au) for CA and 763 (155–1994) au for HCM patients (P = 0.046). At ³¹P-MRS, PCr/γATP was 5 (4–6) au for CA and 4 (2–5) au for HCM patients (P = 0.230). Examination time was 20 min for imaging only, 5 min for ¹H-MRS and 15 min for ³¹P-MRS.

Conclusions

We observed a significant increase of myocardial lipids, but a preserved PCr/γATP ratio in the metabolism of HCM patients compared with competitive CAs.

     

Feasibility of dynamic stress <Superscript>201</Superscript>Tl/rest <Superscript>99m</Superscript>Tc-tetrofosmin single photon emission computed tomography for quantification of myocardial perfusion reserve in patients with stable coronary artery disease

Purpose

We evaluated the feasibility of dynamic stress ²⁰¹Tl/rest ^99mTc-tetrofosmin SPECT imaging using a cardiac camera equipped with cadmium-zinc-telluride detectors for the quantification of myocardial perfusion reserve (MPR).

Methods

Subjects with stable known or suspected coronary artery disease (CAD) who had undergone or were scheduled to undergo fractional flow reserve (FFR) measurement were prospectively enrolled. Dynamic stress ²⁰¹Tl/rest ^99mTc-tetrofosmin SPECT imaging was performed using a dedicated multiple pinhole SPECT camera with cadmium-zinc-telluride detectors. MPR was derived using Corridor4DM software.

Results

A total of 34 subjects were enrolled (25 men and 9 women; mean age 60.4 years). FFR was measured in 65 coronary arteries with intermediate lesions. The average global MPR was 2.58?±?1.03. Global MPR was associated with the extent of CAD (P?=?0.028) and global summed stress score (r?=??0.60, P?<?0.001). Regional MPR showed a significant correlation with diameter stenosis (r?=??0.57, P?<?0.001), minimum lumen diameter (r?=?0.50, P?<?0.001), summed stress score (r?=??0.52, P?<?0.001) and FFR (r?=?0.52, P?<?0.001). The area under the receiver operating characteristic curve of MPR for the diagnosis of functionally significant stenosis (FFR ≤0.8) was 0.79 (P?<?0.001). The sensitivity and specificity of regional MPR were 67% and 83%, respectively, using a cut-off value of 2.0.

Conclusion

Dynamic stress ²⁰¹Tl/rest ^99mTc-tetrofosmin SPECT imaging and quantification of MPR is feasible in patients with stable CAD. The preliminary results of this study in a small number of patients require confirmation in a larger cohort to determine their implications for bolstering the role of SPECT imaging in the diagnosis and risk prediction of CAD.

     

Left ventricular function in response to dipyridamole stress: head-to-head comparison between <Superscript>82</Superscript>Rubidium PET and <Superscript>99m</Superscript>Tc-sestamibi SPECT ECG-gated myocardial perfusion imaging

Purpose

Myocardial perfusion imaging (MPI) with ^99mTc-sestamibi (sestamibi) SPECT and rubidium-82 (⁸²Rb) PET both allow for combined assessment of perfusion and left ventricular (LV) function. We sought to compare parameters of LV function obtained with both methods using a single dipyridamole stress dose.

Materials and methods

A group of 221 consecutive patients (65.2?±?10.4 years, 52.9% male) underwent consecutive sestamibi and ⁸²Rb MPI after a single dipyridamole stress dose. Sestamibi and ⁸²Rb summed rest (SRS), stress (SSS) and difference (SDS) scores, and LV end-diastolic (EDV) and end-systolic (ESV) volumes and left ventricular ejection fraction (LVEF) were compared.

Results

Bland-Altman analysis showed that with increasing ESV and EDV the difference between the two perfusion tracers increased both at rest and post-stress. The mean difference in EDV and ESV between the two perfusion tracers at rest could both be independently explained by the ⁸²Rb SDS and the sestamibi SRS. The combined models explained approximately 30% of the variation in these volumes between the two perfusion tracers (R²?=?0.261, p?=?0.005; R²?=?0.296, p?<?0.001, for EDV and ESV respectively). However, the mean difference in LVEF between sestamibi and ⁸²Rb showed no significant trend post-stress (R²?=?0.001, p?=?0.70) and only a modest linear increase with increasing LVEF values at rest (R²?=?0.032, p?=?0.009).

Conclusions

Differences in left ventricular volumes between sestamibi and ⁸²Rb MPI increase with increasing volumes. However, these differences did only marginally affect LVEF between sestamibi and ⁸²Rb. In clinical practice these results should be taken into account when comparing functional derived parameters between sestamibi and ⁸²Rb MPI.