Impact of 68Ga-PSMA PET/CT on radiation treatment planning of prostate cancer patients.

AIM: This study aimed to assess the impact of 68Ga-PSMA PET/CT on radiation treatment (RT) planning in prostate cancer patients with salvage (sRT) or definitive (dRT) radiotherapy. METHODS: 38 patients (27 sRT, median PSA 0.79 ng/ml (range 0.06-12.1); 11 dRT, median PSA 4.35 ng/ml (range 1.55-55.5) underwent 68Ga-PSMA PET/CT before RT. Influence of 68Ga-PSMA PET/CT on the extent of planning target volume (PTV) and addition of PET-based boosts were assessed. Median follow up was 12 months (range 3-24). RESULTS: 68Ga-PSMA PET/CT showed positive findings in 23/38 patients (8/23: local recurrence (LR), 11/23: nodal metastasis, 1/23: LR and nodal, 2/23: solitary bone metastasis, 1/23: oligometastatic nodal/ bone metastases). In sRT primary PTV was changed in 16/27 patients extending the PTV to the lymphatic drainage (10/16), PSMA-positive LR (3/16), bone metastases (2/16) and both nodal/bone metastases (1/16). PET-based increase of primary PTV was 116%. PET-based boosts were administered in 19/27 patients (8/19: local, 10/19: nodal, 1/19: both), median boost volume was 31.3 cm3 (range 17.2-80.2) (local) and 19.7 cm3 (range 3.0-109.3) (nodal). PTV was changed in 1/11 (9%) of dRT patients (extension of primary PTV to the lymphatic drainage (RT volume of 644.5 cm3), additional nodal boost (volume of 2.7 cm3, 23.1 Gy)). All patients showed biochemical response (mean PSA decrease 88.8 +/- 14.0%). Nadir PSA was reached 10 months (range 1-17) after end of RT (median 0.07 ng/ml, range 0.002-3.96). Within a median 12 months follow-up (range 3-22/8-24 in sRT/dRT), median PSA was 0.05 ng/ml (range 0.002-8.5) (sRT) and 0.26 ng/ml (range 0.02-2.68) (dRT). CONCLUSIONS: 68Ga-PSMA PET/CT influenced sRT planning in almost 63% and dRT in 9% of patients by change of PTV and additional boosts.

GRPr Theranostics: Current Status of Imaging and Therapy using GRPr Targeting Radiopharmaceuticals.

Addressing molecular targets, that are overexpressed by various tumor entities, using radiolabeled molecules for a combined diagnostic and therapeutic (theranostic) approach is of increasing interest in oncology. The gastrin-releasing peptide receptor (GRPr), which is part of the bombesin family, has shown to be overexpressed in a variety of tumors, therefore, serving as a promising target for those theranostic applications. A large amount of differently radiolabeled bombesin derivatives addressing the GRPr have been evaluated in the preclinical as well as clinical setting showing fast blood clearance and urinary excretion with selective GRPr-binding. Most of the available studies on GRPr-targeted imaging and therapy have evaluated the theranostic approach in prostate and breast cancer applying bombesin derivatives tagged with the predominantly used theranostic pair of 68Ga/177Lu which is the focus of this review.

Imaging of Prostate Cancer.

BACKGROUND: Prostate cancer is the most common type of solid tumor in men and the second most common cause of cancer-related death in males in Germany. The conventional strategy for its primary detection, i.e., systematic ultrasound-guided prostate biopsy in men who have elevated PSA levels and/or positive findings on digital rectal examination, fails to reveal all cases. The same is true of the use of conventional computed tomography (CT), magnetic resonance imaging (MRI), and skeletal scintigraphy for the early detection of recurrences and distant metastases. METHODS: This review is based on pertinent publications retrieved by a selective search, including the German clinical practice guideline on prostate cancer and systematic review articles. RESULTS: Prospective multicenter trials have shown that the detection of clinically significant prostate cancer is markedly improved with multiparametric MRI (mpMRI) and MR/TRUS fusion biopsy (TRUS = transrectal ultrasonography), compared to conventional systematic biopsy. A recent Cochrane review showed that the rate of overdiagnosis of low-risk prostate cancer was reduced with mpMRI and MR/TRUS fusion biopsy compared with conventional systematic biopsy (95/1000 vs. 139/1000), and that clinically significant prostate cancer was more reliably detected (sensitivity 72% vs. 63%), albeit with slightly lower specificity (96% vs. 100%). Prostate- specific membrane antigen (PSMA) hybrid imaging improves the detection of lymphogenic and bony metastases in patients with high-risk prostate cancer. PSMA hybrid imaging is most commonly used to detect biochemical recurrences. A metaanalysis showed that the detection rate depends on the PSA concentration: 74.1% overall, 33.7% with PSA <0.2 ng/mL, and 91.7% with PSA ≥= 2.0 ng/mL. CONCLUSION: The appropriate use of mpMRI and MR/TRUS fusion biopsy improves the initial detection of prostate cancer as well as the assessment of the prognosis. PSMA hybrid imaging is useful for the staging of high-risk patients and for the detection of recurrences. These methods are now recommended in the German clinical practice guideline on prostate cancer as well as in guidelines from other countries.

Semi-automated Analysis of Ventilation-Perfusion Single-Photon Emission Tomography in the Diagnosis of Pulmonary Embolism - Does it add extra value?

AIM: Diagnosis of pulmonary embolism using V/P-SPECT may include the application of advanced image-processing techniques to identify V/P-mismatches. Aim of this study was to evaluate the benefit in clinical decision making in the diagnosis of pulmonary embolism.by whether adding to conventional reading a software that automatically calculates and visualizes the ventilation/perfusion-quotient pixel by pixel. METHODS: 63 consecutive patients with a clinical suspicion of PE who underwent V/P-SPECT were included in this retrospective study. Images were randomly ordered both for standard as well as for software-assisted reading using V/P-quotients. Studies were read independently by 2 experienced and 2 inexperienced raters. Diagnostic performance and observer agreement of all readers and both reading methods were determined. RESULTS: Expert observers consistently achieved a high diagnostic accuracy both in conventional as well as in software-assisted reporting (sensitivity: 0.94 vs. 0.94, specificity: 0.96 vs. 0.97, LR+: 17.32 vs. 28.86, LR- stayed constant at 0.06). For inexperienced readers, diagnostic performance improved: sensitivity raised from 0.74 to 0.85 and specificity from 0.86 to 0.95, LR+ raised from 5.20 to 15.69, LR- decreased from 0.31 to 0.16. Inter-rater reliability (Fleiss' κ) improved from 0.63 to 0.86 by using V/P quotient. CONCLUSION: Benefit from a software-tool that calculates V/P-ratio automatically is only small when used by experienced physicians If inexperienced readers use the software, the diagnostic accuracy increases. Images generated by automated calculation of V/P-mismatches are easy to read and their use might help to standardize and objectify interpretation of V/P-SPECT in the diagnosis of PE.

Antifibrogenic effects of vitamin D derivatives on mouse pancreatic stellate cells.

AIM: To study the molecular effects of three different D-vitamins, vitamin D2, vitamin D3 and calcipotriol, in pancreatic stellate cells (PSCs). METHODS: Quiescent PSCs were isolated from mouse pancreas and activated in vitro by seeding on plastic surfaces. The cells were exposed to D-vitamins as primary cultures (early-activated PSCs) and upon re-culturing (fully-activated cells). Exhibition of vitamin A-containing lipid droplets was visualized by oil-red staining. Expression of α-smooth muscle actin (α-SMA), a marker of PSC activation, was monitored by immunofluorescence and immunoblot analysis. The rate of DNA synthesis was quantified by 5-bromo-2'-deoxyuridine (BrdU) incorporation assays. Real-time PCR was employed to monitor gene expression, and protein levels of interleukin-6 (IL-6) were measured by ELISA. Uptake of proline was determined using 18F-proline. RESULTS: Sustained culture of originally quiescent PSCs induced cell proliferation, loss of lipid droplets and exhibition of stress fibers, indicating cell activation. When added to PSCs in primary culture, all three D-vitamins diminished expression of α-SMA (to 32%-39% of the level of control cells; P < 0.05) and increased the storage of lipids (scores from 1.97-2.15 on a scale from 0-3; controls: 1.49; P < 0.05). No such effects were observed when Dvitamins were added to fully-activated cells, while incorporation of BrdU remained unaffected under both experimental conditions. Treatment of re-cultured PSCs with Dvitamins was associated with lower expression of IL-6 (-42% to -49%; P < 0.05; also confirmed at the protein level) and increased expression of the vitamin D receptor gene (209%-321% vs controls; P < 0.05). There was no effect of Dvitamins on the expression of transforming growth factor-ß1 and collagen type 1 (chain α1). The lowest uptake of proline, a main component of collagen, was observed in calcipotriol-treated PSCs. CONCLUSION: The three D-vitamins inhibit, with similar efficiencies, activation of PSCs in vitro, but cannot reverse the phenotype once the cells are fully activated.

Application of in vivo imaging techniques to monitor therapeutic efficiency of PLX4720 in an experimental model of microsatellite instable colorectal cancer.

OBJECTIVES: Patient-derived tumor cell lines are a powerful tool to analyze the sensitivity of individual tumors to specific therapies in mice. An essential prerequisite for such an approach are reliable quantitative techniques to monitor tumor progression in vivo. METHODS: We have employed HROC24 cells, grown heterotopically in NMRI Foxn1nu mice, as a model of microsatellite instable colorectal cancer to investigate the therapeutic efficiencies of 5'-fluorouracil (5'-FU) and the mutant BRAF inhibitor PLX4720, a vemurafenib analogue, by three independent methods: external measurement by caliper, magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG). RESULTS: Repeated measure ANOVA by a general linear model revealed that time-dependent changes of anatomic tumor volumes measured by MRI differed significantly from those of anatomic volumes assessed by caliper and metabolic volumes determined by PET/CT. Over the investigation period of three weeks, neither 5'-FU, PLX4720 nor a combination of both drugs affected the tumor volumes. Also, there was no drug effect on the apparent diffusion constant (ADC) value as detected by MRI. Interestingly, however, PET/CT imaging showed that PLX4720-containing therapies transiently reduced the standardized uptake value (SUV), indicating a temporary response to treatment. CONCLUSIONS: 5'-FU and PLX4720 were largely ineffective with respect to HROC24 tumor growth. Tumoral uptake of 18F-FDG, as expressed by the SUV, proved as a sensitive indicator of small therapeutic effects. Metabolic imaging by 18F-FDG PET/CT is a suitable approach to detect effects of tumor-directed therapies early and even in the absence of morphological changes.

Comparison of [(11)C]Choline ([(11)C]CHO) and [(18)F]Bombesin (BAY 86-4367) as Imaging Probes for Prostate Cancer in a PC-3 Prostate Cancer Xenograft Model.

PURPOSE: Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressing new imaging targets. The aim of this study was to compare the properties of [(18)F]Bombesin (BAY 86-4367) as an innovative biomarker for prostate cancer imaging targeting the gastrin-releasing peptide receptor and [(11)C]Choline ([(11)C]CHO) in a human prostate tumor mouse xenograft model by small animal PET/X-ray computed tomography (CT). PROCEDURES: We carried out a dual-tracer small animal PET/CT study comparing [(18)F]Bombesin and [(11)C]CHO. The androgen-independent human prostate tumor cell line PC-3 was implanted subcutaneously in the flanks of nu/nu NMRI mice (n = 10) (PET/CT measurements of two [(11)C]Choline mice could not be analyzed due to technical reasons). [(18)F]Bombesin and [(11)C]CHO PET/CT imaging was performed about 3-4 weeks after the implantation of PC-3 cells on two separate days. After the intravenous tail vein injection of 14 MBq [(18)F]Bombesin and 37 MBq [(11)C]CHO, respectively, a dynamic study over 60 min was acquired in list mode using an Inveon animal PET/CT scanner (Siemens Medical Solutions). The sequence of [(18)F]Bombesin and [(11)C]CHO was randomized. Image analysis was performed using summed images as well as dynamic data. To calculate static and dynamic tumor-to-muscle (T/M), tumor-to-blood (T/B), liver-to-blood (L/B), and kidney-to-blood (K/B) ratios, 4 × 4 × 4 mm(3) volumes of interest (VOIs) of tumor, muscle (thigh), liver, kidney, and blood derived from transversal slices were used. RESULTS: The mean T/M ratio of [(18)F]Bombesin and [(11)C]CHO was 6.54 ± 2.49 and 1.35 ± 0.30, respectively. The mean T/B ratio was 1.83 ± 0.79 for [(18)F]Bombesin and 0.55 ± 0.10 for [(11)C]CHO. The T/M ratio as well as the T/B ratio for [(18)F]Bombesin were significantly higher compared to those for [(11)C]CHO (p < 0.001, respectively). Kidney and liver uptake was statistically significantly lower for [(18)F]Bombesin (K/B 3.41 ± 0.81, L/B 1.99 ± 0.38) compared to [(11)C]CHO [K/B 7.91 ± 1.85 (p < 0.001), L/B 6.27 ± 1.99 (p < 0.001)]. The magnitudes of the time course of T/M and T/B ratios (T/M and T/Bdyn ratios) were statistically significantly different (showing a higher uptake of [(18)F]Bombesin compared to [(11)C]CHO); additionally, also the change of the T/M and T/B ratios over time was significantly different between both tracers in the dynamic analysis (p < 0.001, respectively). Furthermore, there was a statistically significantly different change of the K/B and L/B ratios over time between the two tracers in the dynamic analysis (p = 0.026 and p < 0.001, respectively). CONCLUSIONS: [(18)F]Bombesin (BAY 86-4367) visually and semi-quantitatively outperforms [(11)C]CHO in the PC-3 prostate cancer xenograft model. [(18)F]Bombesin tumor uptake was significantly higher compared to [(11)C]CHO. [(18)F]Bombesin showed better imaging properties compared to the clinically utilized [(11)C]CHO due to a higher tumor uptake as well as a lower liver and kidney uptake.

Comparison of [¹¹C]choline ([¹¹C]CHO) and S(+)-ß-methyl-[¹¹C]choline ([¹¹C]SMC) as imaging probes for prostate cancer in a PC-3 prostate cancer xenograft model.

PURPOSE: Carbon-11- and fluorine-18-labeled choline derivatives have been introduced as promising tracers for prostate cancer imaging. However, due to limited specificity and sensitivity, there is a need for new tracers with higher sensitivity and specificity for diagnosing prostate cancer to improve tracer uptake and enhance imaging contrast. The aim of this study was to compare the properties of [(11)C]choline ([(11)C]CHO) with S(+)-ß-methyl-[(11)C]choline ([(11)C]SMC) as tracer for prostate cancer imaging in a human prostate tumor mouse xenograft model by small-animal positron emission tomography/X-ray computed tomography (PET/CT). PROCEDURES: We carried out a dual-tracer small-animal PET/CT study comparing [(11)C]CHO and [(11)C]SMC. The androgen-independent human prostate tumor cell line PC3 was implanted subcutaneously in the flanks of Naval Medical Research Institute (NMRI) (nu/nu) mice (n = 11). Mice-6 weeks post-xenograft implantation-were injected with 37 MBq [(11)C]CHO via the tail vein. On a separate day, the mice were injected with 37 MBq [(11)C]SMC. Dynamic imaging was performed for 60 min with the Inveon animal PET/CT scanner (Siemens Medical Solutions) on two separate days (randomizing the sequence of the tracers). The dynamic PET images were acquired in list mode. Regions of interest (5 × 5 × 5 mm) were placed in transaxial slices in tumor, muscle (thigh), liver, kidney, and blood. Image analysis was performed calculating tumor to muscle (T/M) ratios based on summed images as well as dynamic data. RESULTS: For [(11)C]SMC, the mean T/M ratio was 2.24 ± 0.56 while the corresponding mean [(11)C]CHO T/M ratio was 1.35 ± 0.28. The T/M ratio for [(11)C]SMC was significant higher compared to [(11)C]CHO (p < 0.001). The time course of T/M ratio (T/Mdyn ratio) of [(11)C]SMC was higher compared to [(11)C]CHO with a statistically significant difference between the magnitudes of the T/M ratios and a significant different change of the T/M ratios over time between [(11)C]CHO and [(11)C]SMC. CONCLUSION: Our results demonstrate that [(11)C]SMC is taken up by the tumor in the PC-3 prostate cancer xenograft model. [(11)C]SMC uptake was significantly higher compared to the clinically utilized [(11)C]CHO tracer with a higher contrast allowing imaging of a prostate cancer xenograft.