Repeatability of hypoxia PET imaging using [<Superscript>18</Superscript>F]HX4 in lung and head and neck cancer patients: a prospective multicenter trial

Purpose

Hypoxia is an important factor influencing tumor progression and treatment efficacy. The aim of this study was to investigate the repeatability of hypoxia PET imaging with [¹⁸F]HX4 in patients with head and neck and lung cancer.

Methods

Nine patients with lung cancer and ten with head and neck cancer were included in the analysis (NCT01075399). Two sequential pretreatment [¹⁸F]HX4 PET/CT scans were acquired within 1 week. The maximal and mean standardized uptake values (SUV_max and SUV_mean) were defined and the tumor-to-background ratios (TBR) were calculated. In addition, hypoxic volumes were determined as the volume of the tumor with a TBR >1.2 (HV_1.2). Bland Altman analysis of the uptake parameters was performed and coefficients of repeatability were calculated. To evaluate the spatial repeatability of the uptake, the PET/CT images were registered and a voxel-wise comparison of the uptake was performed, providing a correlation coefficient.

Results

All parameters of [¹⁸F]HX4 uptake were significantly correlated between scans: SUV_max (r?=?0.958, p?<?0.001), SUV_mean (r?=?0.946, p?<?0.001), TBR_max (r?=?0.962, p?<?0.001) and HV_1.2 (r?=?0.995, p?<?0.001). The relative coefficients of repeatability were 15 % (SUV_mean), 17 % (SUV_max) and 17 % (TBR_max). Voxel-wise analysis of the spatial uptake pattern within the tumors provided an average correlation of 0.65?±?0.14.

Conclusion

Repeated hypoxia PET scans with [¹⁸F]HX4 provide reproducible and spatially stable results in patients with head and neck cancer and patients with lung cancer. [¹⁸F]HX4 PET imaging can be used to assess the hypoxic status of tumors and has the potential to aid hypoxia-targeted treatments.

     

Molecular response assessed by <Superscript>68</Superscript>Ga-DOTANOC and survival after <Superscript>90</Superscript>Y microsphere therapy in patients with liver metastases from neuroendocrine tumours

Purpose

We investigated the prognostic role of ⁶⁸Ga-DOTANOC in patients affected by hepatic metastases from neuroendocrine tumours (NET) undergoing ⁹⁰Y radioembolization (⁹⁰Y-RE).

Methods

A group of 15 consecutive patients with unresectable NET liver metastases underwent ⁶⁸Ga-DOTANOC PET at baseline and 6 weeks after ⁹⁰Y-RE. Molecular response was defined as a reduction of >50 % in the tumour-to-spleen ratio (ΔT/S). The patients were divided into two groups (responders with ΔT/S >50 % and nonresponders with ΔT/S <50 %) Patients were followed up by imaging and laboratory tests every 3 months until death or for at least 36 months following ⁹⁰Y-RE. Statistical analysis was performed to identify factors predicting overall survival (OS) and progression-free survival (PFS).

Results

A decrease in T/S ratio was seen in all patients on ⁶⁸Ga-DOTANOC PET scans performed after ⁹⁰Y-RE. Nine patients were classified as responders and six as nonresponders. The mean OS in all patients was 31.0 months. Responders had a significantly (p?<?0.001) longer OS (mean 36.0?±?2.5 months) and PFS (mean 29.7?±?3.4 months) than nonresponders. In a multivariate analysis, none of the other examined variables including age, unilobar vs. bilobar locations, bilirubin levels, radiological response or the presence of extrahepatic disease significantly predicted patient outcome.

Conclusion

Molecular response assessed with ⁶⁸Ga-DOTANOC PET might be a useful predictor of survival in patients affected by NET liver metastases treated with ⁹⁰Y-RE.

     

Nephrotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate

Purpose

After peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with ⁹⁰Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]-Octreotate (¹⁷⁷Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with ⁹⁰Y-radiolabelled somatostatin analogues.

Methods

The annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.

Results

Of the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5?–?3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (±?SD) was 108?±?5 ml/min and the estimated average annual decrease in CLR (±?SD) was 3.4?±?0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1?±?4.9 Gy.

Conclusion

Nephrotoxicity in patients treated with ¹⁷⁷Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with ⁹⁰Y-labelled somatostatin analogues, does not seem valid for PRRT with ¹⁷⁷Lu-octreotate.

     

<Superscript>18</Superscript>F-FDG uptake by rectal cancer is similar in mucinous and nonmucinous histological subtypes

Purpose

PET/CT has been considered limited for the evaluation of mucinous colorectal tumors due to low ¹⁸F-FDG uptake. The aim of our study was to compare PET/CT variables in mucinous (MC) and nonmucinous (NMC) rectal adenocarcinomas.

Methods

Consecutive patients with cT2-4N0-2M0 rectal cancer included in a prospective clinical trial were reviewed. PET/CT was performed for primary baseline staging. Visual and quantitative analysis included SUVmax and SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). PET/CT parameters were compared according to histological subtypes.

Results

Overall, 73 patients were included (18 mucinous and 55 nonmucinous). SUVmax values were similar between MC and NMC (19.7 vs. 16.6; p = 0.5). MTV and TLG values were greater in the MC group (103.9 vs. 54.1; p = 0.007 and 892.5 vs. 358.8; p = 0.020) due to larger tumor volumes of MC.

Conclusions

Metabolic parameters at baseline PET/CT for patients with rectal cancer are similar in mucinous and nonmucinous histological subtypes.

     

Utility of <Superscript>18</Superscript>F-fluoroestradiol (<Superscript>18</Superscript>F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy

Background

Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. ¹⁸F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes ¹⁸F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen.

Methods

Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with ¹⁸F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with ¹⁸F-FES 1–5 days post administration of Z-endoxifen.

Results

Statistically significant changes (p?=?0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration.

Conclusion

F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

     

Individualised <Superscript>177</Superscript>Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry

Purpose

To present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED).

Method

Treatment was given with repeated cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE at 8-12-week intervals. Detailed dosimetry was performed in all patients after each cycle using a hybrid method (SPECT?+?planar imaging). All patients received treatment up to a renal BED of 27?±?2 Gy (α/β?=?2.6 Gy) (Step 1). Selected patients were offered further treatment up to a renal BED of 40?±?2 Gy (Step 2). Renal function was followed by estimation and measurement of the glomerular filtration rate (GFR).

Results

Fifty-one patients were included in the present analysis. Among the patients who received treatment as planned, the median number of cycles in Step 1 was 5 (range 3-7), and for those who completed Step 2 it was 7 (range 5-8); 73% were able to receive >4 cycles. Although GFR decreased in most patients after the completion of treatment, no grade 3-4 toxicity was observed. Patients with a reduced baseline GFR seemed to have an increased risk of GFR decline. Five patients received treatment in Step 2, none of whom exhibited a significant reduction in renal function.

Conclusions

Individualising PRRT using renal dosimetry seems feasible and safe and leads to an increased number of cycles in the majority of patients. The trial will continue as planned.

     

Recommended administered activities for <Superscript>68</Superscript>Ga-labelled peptides in paediatric nuclear medicine

Purpose

The aim of this study was to establish a method for determining administered activities for ⁶⁸Ga-labelled peptides. Dose calculations were based on the weight-independent effective dose model proposed by the EANM paediatric dosage card for use in paediatric nuclear medicine.

Methods

Previously published time-integrated activity coefficients for ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTATOC and ⁶⁸Ga-pentixafor were used to calculate age-independent effective doses. Consequently, the corresponding weight-dependent effective dose coefficients were rescaled according to the formalism of the EANM dosage card to determine the radiopharmaceutical class of  ⁶⁸Ga-labelled peptides (“multiples”) and to calculate the baseline activities based on an upper limit for administered activity (185 MBq) in an adult.

Results

All calculated normalization factors suggest that the ⁶⁸Ga-labelled peptides are class “B” radiopharmaceuticals. The baseline activity for all compounds is 12.8 MBq. In analogy to ¹⁸F-fluoride, we recommend a minimum activity of 14 MBq.

Conclusion

For paediatric nuclear medicine applications involving ⁶⁸Ga-labelled peptides, we suggest determining administered activities based on the formalism proposed in this work. The corresponding effective doses from these procedures will remain age-independent.

     

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.

     

Radiation dosimetry of <Superscript>68</Superscript>Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing

Purpose

The clinical introduction of ⁶⁸Ga-PSMA-11 (“HBED-CC”) ligand targeting the prostate-specific membrane antigen (PSMA) has been regarded as a significant step forward in the diagnosis of prostate cancer (PCa). In this study, we provide human dosimetry and data on optimal timing of PET imaging after injection.

Methods

Four patients with recurrent PCa were referred for ⁶⁸Ga-PSMA-11 PET/CT. Whole-body PET/CT_low-dose scans were conducted at 5 min, and 1, 2, 3, 4 and 5 h after injection of 152–198 MBq ⁶⁸Ga-PSMA-11. Organs of moderate to high uptake were used as source organs; their total activity was determined at all measured time points. Time–activity curves were created for each source organ as well as for the remainder. The radiation exposure of a ⁶⁸Ga-PSMA-11 PET was identified using the OLINDA-EXM software. In addition, tracer uptake was measured in 16 sites of metastases.

Results

The highest tracer uptake was observed in the kidneys, liver, upper large intestine, and the urinary bladder. Mean organ doses were: kidneys 0.262?±?0.098 mGy/MBq, liver 0.031?±?0.004 mGy/MBq, upper large intestine 0.054?±?0.041 mGy/MBq, urinary bladder 0.13?±?0.059 mGy/MBq. The calculated mean effective dose was 0.023?±?0.004 mSv/MBq (=0.085?±?0.015 rem/mCi). Most tumor lesions (n?=?16) were visible at 3 h p.i., while at all other time points many were not qualitatively present (10/16 visible at 1 h p.i.).

Conclusions

The mean effective dose of a ⁶⁸Ga-PSMA-11 PET is 0.023 mSv/MBq. A 3-h delay after injection was optimal timing for ⁶⁸Ga-PSMA-11 PET/CT in this patient cohort.

     

Local recurrence of prostate cancer after radical prostatectomy is at risk to be missed in <Superscript>68</Superscript>Ga-PSMA-11-PET of PET/CT and PET/MRI: comparison with mpMRI integrated in simultaneous PET/MRI

Purpose

The positron emission tomography (PET) tracer ⁶⁸Ga-PSMA-11, targeting the prostate-specific membrane antigen (PSMA), is rapidly excreted into the urinary tract. This leads to significant radioactivity in the bladder, which may limit the PET-detection of local recurrence (LR) of prostate cancer (PC) after radical prostatectomy (RP), developing in close proximity to the bladder. Here, we analyze if there is additional value of multi-parametric magnetic resonance imaging (mpMRI) compared to the ⁶⁸Ga-PSMA-11-PET-component of PET/CT or PET/MRI to detect LR.

Methods

One hundred and nineteen patients with biochemical recurrence after prior RP underwent both hybrid ⁶⁸Ga-PSMA-11-PET/CT_low-dose (1 h p.i.) and -PET/MRI (2-3 h p.i.) including a mpMRI protocol of the prostatic bed. The comparison of both methods was restricted to the abdomen with focus on LR (McNemar). Bladder-LR distance and recurrence size were measured in axial T2w-TSE. A logistic regression was performed to determine the influence of these variables on detectability in ⁶⁸Ga-PSMA-11-PET. Standardized-uptake-value (SUV_mean) quantification of LR was performed.

Results

There were 93/119 patients that had at least one pathologic finding. In addition, 18/119 Patients (15.1%) were diagnosed with a LR in mpMRI of PET/MRI but only nine were PET-positive in PET/CT and PET/MRI. This mismatch was statistically significant (p?=?0.004). Detection of LR using the PET-component was significantly influenced by proximity to the bladder (p?=?0.028). The PET-pattern of LR-uptake was classified into three types (1): separated from bladder; (2): fuses with bladder, and (3): obliterated by bladder). The size of LRs did not affect PET-detectability (p?=?0.84), mean size was 1.7?±?0.69 cm long axis, 1.2?±?0.46 cm short-axis. SUV_mean in nine men was 8.7?±?3.7 (PET/CT) and 7.0?±?4.2 (PET/MRI) but could not be quantified in the remaining nine cases (obliterated by bladder).

Conclusion

The present study demonstrates additional value of hybrid ⁶⁸Ga-PSMA-11-PET/MRI by gaining complementary diagnostic information compared to ^{the 68}Ga-PSMA-11-PET/CT_low-dose for patients with LR of PC.

     

<Superscript>18</Superscript>F-fluoromisonidazole positron emission tomography can predict pathological necrosis of brain tumors

Purpose

Tumor necrosis is one of the indicators of tumor aggressiveness. ¹⁸F-fluoromisonidazole (FMISO) is the most widely used positron emission tomography (PET) tracer to evaluate severe hypoxia in vivo. Because severe hypoxia causes necrosis, we hypothesized that intratumoral necrosis can be detected by FMISO PET in brain tumors regardless of their histopathology. We applied FMISO PET to various types of brain tumors before tumor resection and evaluated the correlation between histopathological necrosis and FMISO uptake.

Methods

This study included 59 brain tumor patients who underwent FMISO PET/computed tomography before any treatments. According to the pathological diagnosis, the brain tumors were divided into three groups: astrocytomas (group 1), neuroepithelial tumors except for astrocytomas (group 2), and others (group 3). Two experienced neuropathologists evaluated the presence of necrosis in consensus. FMISO uptake in the tumor was evaluated visually and semi-quantitatively using the tumor-to-normal cerebellum ratio (TNR).

Results

In visual analyses, 26/27 cases in the FMISO-positive group presented with necrosis, whereas 28/32 cases in the FMISO-negative group did not show necrosis. Mean TNRs with and without necrosis were 3.49?±?0.97 and 1.43?±?0.42 (p?<?0.00001) in group 1, 2.91?±?0.83 and 1.44?±?0.20 (p?<?0.005) in group 2, and 2.63?±?1.16 and 1.35?±?0.23 (p?<?0.05) in group 3, respectively. Using a cut-off value of TNR?=?1.67, which was calculated by normal reference regions of interest, we could predict necrosis with sensitivity, specificity, and accuracy of 96.7, 93.1, and 94.9 %, respectively.

Conclusions

FMISO uptake within the lesion indicated the presence of histological micro-necrosis. When we used a TNR of 1.67 as the cut-off value, intratumoral micro-necrosis was sufficiently predictable. Because the presence of necrosis implies a poor prognosis, our results suggest that FMISO PET could provide important information for treatment decisions or surgical strategies of any type of brain tumor.

     

Diagnostic value of combining <Superscript>11</Superscript>C-choline and <Superscript>18</Superscript>F-FDG PET/CT in hepatocellular carcinoma

Purpose

In this prospective study, our goal was to emphasize the diagnostic value of combining ¹¹C-choline and ¹⁸F-FDG PET/CT for hepatocellular carcinoma (HCC) in patients with chronic liver disease.

Methods

Thirty-three consecutive patients were enrolled. All patients were suspected to have HCC based on CT and/or MRI imaging. A final diagnosis was obtained by histopathological examination or by imaging alone according to American Association for the Study of Liver Disease criteria. All patients underwent PET/CT with both tracers within a median of 5 days. All lesions showing higher tracer uptake than normal liver were considered positive for HCC. We examined how tracer uptake was related to biological (serum α-fetoprotein levels) and pathological (differentiation status, peritumoral capsule and vascular invasion) prognostic markers of HCC, as well as clinical observations at 6 months (recurrence and death).

Results

Twenty-eight HCC, four cholangiocarcinomas and one adenoma were diagnosed. In the HCC patients, the sensitivity of ¹¹C-choline, ¹⁸F-FDG and combined ¹¹C-choline and ¹⁸F-FDG PET/CT for the detection of HCC was 75 %, 36 % and 93 %, respectively. Serum α-fetoprotein levels >200 ng/ml were more frequent among patients with ¹⁸F-FDG-positive lesions than those with ¹⁸F-FDG-negative lesions (p?<?0.05). Early recurrence (n=2) or early death (n=5) occurred more frequently in patients with ¹⁸F-FDG-positive lesions than in those with ¹⁸F-FDG-negative lesions (p?<?0.05).

Conclusion

The combined use of ¹¹C-choline and ¹⁸F-FDG PET/CT detected HCC with high sensitivity. This approach appears to be of potential prognostic value and may facilitate the selection of patients for surgical resection or liver transplantation.

     

Occupational radiation exposure of medical staff performing <Superscript>90</Superscript>Y-loaded microsphere radioembolization

Purpose

Radioembolization of liver cancer with ⁹⁰Y-loaded microspheres is increasingly used but data regarding hospital staff exposure are scarce. We evaluated the radiation exposure of medical staff while preparing and injecting ⁹⁰Y-loaded glass and resin microspheres especially in view of the increasing use of these products.

Methods

Exposure of the chest and finger of the radiopharmacist, nuclear medicine physician and interventional radiologist during preparation and injection of 78 glass microsphere preparations and 16 resin microsphere preparations was monitored. Electronic dosimeters were used to measure chest exposure and ring dosimeters were used to measure finger exposure.

Results

Chest exposure was very low for both products used (<10 μSv from preparation and injection). In our experience, finger exposure was significantly lower than the annual limit of 500 mSv for both products. With glass microspheres, the mean finger exposure was 13.7?±?5.2 μSv/GBq for the radiopharmacist, and initially 17.9?±?5.4 μSv/GBq for the nuclear medicine physician reducing to 13.97?±?7.9 μSv/GBq with increasing experience. With resin microspheres, finger exposure was more significant: mean finger exposure for the radiopharmacist was 295.1?±?271.9 μSv/GBq but with a reduction with increasing experience to 97.5?±?35.2 μSv/GBq for the six most recent dose preparations. For administration of resin microspheres, the greatest mean finger exposure for the nuclear medicine physician (the most exposed operator) was 235.5?±?156 μSv/GBq.

Conclusion

Medical staff performing ⁹⁰Y-loaded microsphere radioembolization procedures are exposed to safe levels of radiation. Exposure is lower than that from treatments using ¹³¹I-lipiodol. The lowest finger exposure is from glass microspheres. With resin microspheres finger exposure is acceptable but could be optimized in accordance with the ALARA principle, and especially in view of the increasing use of radioembolization.

     

Single-scan rest/stress imaging: validation in a porcine model with <Superscript>18</Superscript>F-Flurpiridaz

Purpose

¹⁸F-labeled myocardial flow agents are becoming available for clinical application but the ～2 hour half-life of ¹⁸F complicates their clinical application for rest-stress measurements. The goal of this work is to evaluate in a pig model a single-scan method which provides quantitative rest-stress blood flow in less than 15 minutes.

Methods

Single-scan rest-stress measurements were made using ¹⁸F-Flurpiridaz. Nine scans were performed in healthy pigs and seven scans were performed in injured pigs. A two-injection, single-scan protocol was used in which an adenosine infusion was started 4 minutes after the first injection of ¹⁸F-Flurpiridaz and followed either 3 or 6 minutes later by a second radiotracer injection. In two pigs, microsphere flow measurements were made at rest and during stress. Dynamic images were reoriented into the short axis view, and regions of interest (ROIs) for the 17 myocardial segments were defined in bull’s eye fashion. PET data were fitted with MGH2, a kinetic model with time varying kinetic parameters, in which blood flow changes abruptly with the introduction of adenosine. Rest and stress myocardial blood flow (MBF) were estimated simultaneously.

Results

The first 12–14 minutes of rest-stress PET data were fitted in detail by the MGH2 model, yielding MBF measurement with a mean precision of 0.035 ml/min/cc. Mean myocardial blood flow across pigs was 0.61?±?0.11 mL/min/cc at rest and 1.06?±?0.19 mL/min/cc at stress in healthy pigs and 0.36?±?0.20 mL/min/cc at rest and 0.62?±?0.24 mL/min/cc at stress in the ischemic area. Good agreement was obtained with microsphere flow measurement (slope?=?1.061?±?0.017, intercept?=?0.051?±?0.017, mean difference 0.096?±?0.18 ml/min/cc).

Conclusion

Accurate rest and stress blood flow estimation can be obtained in less than 15 min of PET acquisition. The method is practical and easy to implement suggesting the possibility of clinical translation.

     

The potential of <Superscript>223</Superscript>Ra and <Superscript>18</Superscript>F-fluoride imaging to predict bone lesion response to treatment with <Superscript>223</Superscript>Ra-dichloride in castration-resistant prostate cancer

Purpose

The aims of this study were to calculate bone lesion absorbed doses resulting from a weight-based administration of ²²³Ra-dichloride, to assess the relationship between those doses and corresponding ¹⁸F-fluoride uptake and to assess the potential of quantitative ¹⁸F-fluoride imaging to predict response to treatment.

Methods

Five patients received two intravenous injections of ²²³Ra-dichloride, 6 weeks apart, at 110 kBq/kg whole-body weight. The biodistribution of ²²³Ra in metastatic lesions as a function of time after administration as well as associated lesion dosimetry were determined from serial ²²³Ra scans. PET/CT imaging using ¹⁸F-fluoride was performed prior to the first treatment (baseline), and at week 6 immediately before the second treatment and at week 12 after baseline.

Results

Absorbed doses to metastatic bone lesions ranged from 0.6 Gy to 44.1 Gy. For individual patients, there was an average factor difference of 5.3 (range 2.5–11.0) between the maximum and minimum lesion dose. A relationship between lesion-absorbed doses and serial changes in ¹⁸F-fluoride uptake was demonstrated (r² = 0.52). A log-linear relationship was demonstrated (r² = 0.77) between baseline measurements of ¹⁸F-fluoride uptake prior to ²²³Ra-dichloride therapy and changes in uptake 12 weeks after the first cycle of therapy. Correlations were also observed between both ²²³Ra and ¹⁸F-fluoride uptake in lesions (r = 0.75) as well as between ²²³Ra absorbed dose and ¹⁸F-fluoride uptake (r = 0.96).

Conclusions

There is both inter-patient and intra-patient heterogeneity of absorbed dose estimates to metastatic lesions. A relationship between ²²³Ra lesion absorbed dose and subsequent lesion response was observed. Analysis of this small group of patients suggests that baseline uptake of ¹⁸F-fluoride in bone metastases is significantly correlated with corresponding uptake of ²²³Ra, the associated ²²³Ra absorbed dose and subsequent lesion response to treatment.

     

Diagnosis of recurrent prostate cancer with PET/CT imaging using the gastrin-releasing peptide receptor antagonist <Superscript>68</Superscript>Ga-RM2: Preliminary results in patients with negative or inconclusive [<Superscript>18</Superscript>F]Fluoroethylcholine-PET/CT

Purpose/background

[¹⁸F]fluoroethylcholine (¹⁸FECH) has been shown to be a valuable PET-tracer in recurrent prostate cancer (PCa), but still has limited accuracy. RM2 is a gastrin-releasing peptide receptor (GRPr) antagonist that binds to GRPr on PCa cells. Recent studies suggest that GRPr imaging with PET/CT is a promising technique for staging and restaging of PCa. We explore the value of GRPr-PET using the ⁶⁸Ga-labeled GRPr antagonist RM2 in a selected population of patients with biochemically recurrent PCa and a negative/inconclusive ¹⁸FECH-PET/CT.

Material and methods

In this retrospective study 16 men with biochemical PCa relapse and negative (n = 14) or inconclusive (n = 2) ¹⁸FECH-PET/CT underwent whole-body ⁶⁸Ga-RM2-PET/CT. Mean time from ¹⁸FECH-PET/CT to ⁶⁸Ga-RM2-PET/CT was 6.1 ± 6.8 months. Primary therapies in these patients were radical prostatectomy (n = 13; 81.3%) or radiotherapy (n = 3; 18.7%). 14/16 patients (87.5%) had already undergone salvage therapies because of biochemical relapse prior to ⁶⁸Ga-RM2-PET/CT imaging. Mean ± SD PSA at ⁶⁸Ga-RM2-PET/CT was 19.4 ± 53.5 ng/ml (range 1.06–226.4 ng/ml).

Results

⁶⁸Ga-RM2-PET/CT showed at least one region with focal pathological uptake in 10/16 patients (62.5%), being suggestive of local relapse (n = 4), lymph node metastases (LNM; n = 4), bone metastases (n = 1) and lung metastasis with hilar LNM (n = 1). Seven of ten positive ⁶⁸Ga-RM2 scans were positively confirmed by surgical resection and histology of the lesions (n = 2), by response to site-directed therapies (n = 2) or by further imaging (n = 3). Patients with a positive ⁶⁸Ga-RM2-scan showed a significantly higher median PSA (6.8 ng/ml, IQR 10.2 ng/ml) value than those with a negative scan (1.5 ng/ml, IQR 3.1 ng/ml; p = 0.016). Gleason scores or concomitant antihormonal therapy had no apparent impact on the detection of recurrent disease.

Conclusion

Even in this highly selected population of patients with known biochemical recurrence but negative or inconclusive ¹⁸FECH-PET/CT, a ⁶⁸Ga-RM2-PET/CT was helpful to localize PCa recurrence in the majority of the cases. Thus, ⁶⁸Ga-RM2-PET/CT deserves further investigation as a promising imaging modality for imaging PCa recurrence.

     

Molecular imaging of cholinergic processes in prostate cancer using <Superscript>11</Superscript>C-donepezil and <Superscript>18</Superscript>F-FEOBV

Purpose

High-grade prostate cancer (PC) displays parasympathetic neoneurogenesis. We investigated the binding of two PET tracers that visualize cholinergic nerves in PC tissue using autoradiography.

Methods

Prostatectomy tissue was subjected to autoradiography with ¹¹C-donepezil and ¹⁸F-FEOBV and correlated with Gleason scores (GS). Regions of interest on the autoradiograms were defined and quantified. Tracer binding in cancer tissue regions was compared with that in normal tissue.

Results

We included 13 patients with biopsy-verified PC. In particular, ¹¹C-donepezil uptake was higher in “high-grade” PC (GS ≥4?+?3) than in “low-grade” PC and benign hyperplasia. ¹¹C-donepezil uptake ranged from a mean of 56 % higher (GS 3?+?3) to 409 % higher (GS 4?+?4), and ¹⁸F-FEOBV uptake ranged from 67 % higher (GS 3?+?3) to 194 % higher (GS 4?+?5). The uptake of both tracers was higher in PC with a high GS than in PC with a low GS, but the difference was significant only for ¹¹C-donepezil (p?=?0.003).

Conclusion

Uptake of PET tracers binding to cholinergic nerves was markedly higher in PC with a high GS than in PC with a low GS. This finding implies that ¹¹C-donepezil PET/CT may be able to differentiate between low-grade and high-grade PC.

     

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.

     

Evaluation of <Superscript>68</Superscript>Ga-DOTA-TOC PET/CT for the detection of duodenopancreatic neuroendocrine tumors in patients with MEN1

Context

Somatostatin receptor scintigraphy with ¹¹¹In-pentetreotide (SRS) is used to detect duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). However, SRS has limited sensitivity for this purpose. Positron emission tomography/computed tomography (PET/CT) with ⁶⁸Ga-DOTA-TOC has a higher rate of sporadic dpNETs detection than SRS but there is little data for dpNETs detection in MEN1.

Purpose

To compare the performances of ⁶⁸Ga-DOTA-TOC PET/CT, SRS and contrast-enhanced computed tomography (CE-CT) to diagnose dpNETs in MEN1.

Design and setting

Single-institution prospective comparative study

Patients and methods

Nineteen consecutive MEN1 patients (aged 47?±?13 years) underwent ⁶⁸Ga-DOTA-TOC PET/CT, SRS, and CE-CT within 2 months in random order. Blinded readings of images were performed separately by experienced physicians. Unblinded analysis of CE-CT, combined with additional magnetic resonance imaging, endoscopic-ultrasound, ¹⁸F-2-fluoro-deoxy-d-glucose (¹⁸F-FDG) PET/CT or histopathology results served as reference standard for dpNETs diagnosis.

Results

The sensitivity of ⁶⁸Ga-DOTA-TOC PET/CT, SRS, and CE-CT was 76, 20, and 60 %, respectively (p?<?0.0001). All the true-positive lesions detected by SRS were also depicted on ⁶⁸Ga-DOTA-TOC PET/CT. ⁶⁸Ga-DOTA-TOC PET/CT detected lesions of smaller size than SRS (10.7?±?7.6 and 15.2?±?5.9 mm, respectively, p?<?0.03). False negatives of ⁶⁸Ga-DOTA-TOC PET/CT included small dpNETs (<10 mm) and ¹⁸F-FDG PET/CT positive aggressive dpNETs. No false positives were recorded. In addition, whole-body mapping with ⁶⁸Ga-DOTA-TOC PET/CT identified extra-abdominal MEN1-related tumors including one neuroendocrine thymic carcinoma identified by the three imaging procedures, one bronchial carcinoid undetected by CE-CT and three meningiomas undetected by SRS.

Conclusions

Owing to higher diagnostic performance, ⁶⁸Ga-DOTA-TOC PET/CT (or alternative ⁶⁸Ga-labeled somatostatin analogues) should replace ¹¹¹In-pentetreotide in the investigation of MEN1 patients.

     

<Superscript>177</Superscript>Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety,efficacy, and quality of life assessment

Purpose

The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, ¹⁷⁷Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC).

Methods

Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic⁶⁸Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly ¹⁷⁷Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and ttoxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria.

Results

The mean age of patients was 65.93?±?9.77 years (range: 38–81 years). The mean activity administered in the 31 patients was 5069?±?1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity.

Conclusion

¹⁷⁷Lu-DKFZ-PSMA-617 radionuclide therapy is a safe and effective approach in the treatment of mCRPC patients.