Optimization of Q.Clear reconstruction for dynamic 18F PET imaging.

BACKGROUND: Q.Clear, a Bayesian penalized likelihood reconstruction algorithm, has shown high potential in improving quantitation accuracy in PET systems. The Q.Clear algorithm controls noise during the iterative reconstruction through a ß penalization factor. This study aimed to determine the optimal ß-factor for accurate quantitation of dynamic PET scans. METHODS: A Flangeless Esser PET Phantom with eight hollow spheres (4-25 mm) was scanned on a GE Discovery MI PET/CT system. Data were reconstructed into five sets of variable acquisition times using Q.Clear with 18 different ß-factors ranging from 100 to 3500. The recovery coefficient (RC), coefficient of variation (CVRC) and root-mean-square error (RMSERC) were evaluated for the phantom data. Two male patients with recurrent glioblastoma were scanned on the same scanner using 18F-PSMA-1007. Using an irreversible two-tissue compartment model, the area under curve (AUC) and the net influx rate Ki were calculated to assess the impact of different ß-factors on the pharmacokinetic analysis of clinical PET brain data. RESULTS: In general, RC and CVRC decreased with increasing ß-factor in the phantom data. For small spheres (< 10 mm), and in particular for short acquisition times, low ß-factors resulted in high variability and an overestimation of measured activity. Increasing the ß-factor improves the variability, however at a cost of underestimating the measured activity. For the clinical data, AUC decreased and Ki increased with increased ß-factor; a change in ß-factor from 300 to 1000 resulted in a 25.5% increase in the Ki. CONCLUSION: In a complex dynamic dataset with variable acquisition times, the optimal ß-factor provides a balance between accuracy and precision. Based on our results, we suggest a ß-factor of 300-500 for quantitation of small structures with dynamic PET imaging, while large structures may benefit from higher ß-factors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03951142. Registered 5 October 2019, https://clinicaltrials.gov/ct2/show/NCT03951142 . EudraCT no 2018-003229-27. Registered 26 February 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-003229-27/NO .

Optimized SPECT Imaging of 224Ra α-Particle Therapy by 212Pb Photon Emissions.

In preparation for an α-particle therapy trial using 1-7 MBq of 224Ra, the feasibility of tomographic SPECT/CT imaging was of interest. The nuclide decays in 6 steps to stable 208Pb, with 212Pb as the principle photon-emitting nuclide. 212Bi and 208Tl emit high-energy photons up to 2,615 keV. A phantom study was conducted to determine the optimal acquisition and reconstruction protocol. Methods: The spheres of a body phantom were filled with a 224Ra-RaCl2 solution, and the background compartment was filled with water. Images were acquired on a SPECT/CT system. In addition, 30-min scans were acquired for 80- and 240-keV emissions, using triple-energy windows, with both medium-energy and high-energy collimators. Images were acquired at 90-95 and 29-30 kBq/mL, plus an explorative 3-min acquisition at 20 kBq/mL (using only the optimal protocol). Reconstructions were performed with attenuation correction only, attenuation plus scatter correction, 3 levels of postfiltering, and 24 levels of iterative updates. Acquisitions and reconstructions were compared using the maximum value and signal-to-scatter peak ratio for each sphere. Monte Carlo simulations were performed to examine the contributions of key emissions. Results: Secondary photons of the 2,615-keV 208Tl emission produced in the collimators make up most of the acquired energy spectrum, as revealed by Monte Carlo simulations, with only a small fraction (3%-6%) of photons in each window providing useful information for imaging. Still, decent image quality is possible at 30 kBq/mL, and nuclide concentrations are imageable down to approximately 2-5 kBq/mL. The overall best results were obtained with the 240-keV window, medium-energy collimator, attenuation and scatter correction, 30 iterations and 2 subsets, and a 12-mm gaussian postprocessing filter. However, all combinations of the applied collimators and energy windows were capable of producing adequate results, even though some failed to reconstruct the 2 smallest spheres. Conclusion: SPECT/CT imaging of 224Ra in equilibrium with daughters is possible, with sufficient image quality to provide clinical utility for the current trial of intraperitoneally administrated activity. A systematic scheme for optimization was designed to select acquisition and reconstruction settings.

Imaging the tumour microenvironment in rectal cancer: Decline in tumour blood flow during radiotherapy predicts good outcome.

Background and purpose: Measuring rectal tumour response to radiation is pivotal to restaging patients and for possibly stratification to a watch-and-wait strategy. Recognizing the importance of the tumour microenvironment, we investigated a less explored quantitative imaging marker assessing tumour blood flow (BF) for its potential to predict overall survival (OS). Materials and methods: 24 rectal cancer patients given curative-intent neoadjuvant radiotherapy underwent a multi-echo dynamic magnetic resonance imaging (MRI) sequence with gadolinium contrast for quantification of tumour BF before either 25x2 Gy (n = 18) with concomitant chemotherapy or 5x5 Gy (n = 6). CD34 staining of excised tumour tissue was performed and baseline blood samples were analysed for lactate dehydrogenase (LDH) and angiopoietin-2 (ANGPT-2). Tumour volumes were measured before and after treatment. After subsequent surgery, ypTN scoring assessed tumour response. Cox regression for 5-year OS analysis and t-test for group comparisons were performed. Results: The change in tumour BF (ΔBF) during neoadjuvant radiotherapy was a significant marker of OS, whereas tumour stage and volume were not related to OS. All patients with >20 % decline in BF were long-term survivors. Separating cases in two groups based on ΔBF revealed that patients with increase or a low decrease had higher baseline LDH (p = 0.032) and ANGPT-2 (p = 0.028) levels. Conclusion: MRI-assessed tumour ΔBF during neoadjuvant treatment is a significant predictor of OS in rectal cancer patients, making ΔBF a potential quantitative imaging biomarker for treatment stratification. Blood LDH and ANGPT-2 indicate that non-responding tumours may have a hypoxic microenvironment resistant to radiotherapy.

Low dose-rate irradiation with [3H]-labelled valine to selectively target hypoxic cells in a human colorectal cancer xenograft model.

BACKGROUND: Earlier in vitro studies show that irradiation with an ultra-low dose-rate of 15 mGy/h delivered with [3H]-valine leads to loss of clonogenicity in hypoxic T-47D cells. Here, the aim was to determine if [3H]-valine could be used to deliver low dose-rate irradiation in a colorectal cancer model. METHODS: Clonogenicity was measured in cultured cancer cell line HT29 irradiated with 15 mGy/h combined with intermittent hypoxia. Mice with HT29 xenografts were irradiated by repeated injections of [3H]-valine intravenously. The activity in the tumor tissue was measured by scintillation counting and tumor growth, hypoxic fraction and tritium distribution within tumors were assessed by pimonidazole staining and autoradiography. RESULTS: Ultra-low dose-rate irradiation decreased clonogenicity in hypoxic colorectal cancer cells. In vivo, the tumor growth, hypoxic fraction and weight of the mice were similar between the treated and untreated group. Autoradiography showed no [3H]-valine uptake in hypoxic tumor regions in contrast to aerobic tissue. CONCLUSION: Continuous low-dose-rate irradiation was well tolerated by aerobic tissue. This indicates a potential use of low dose-rate irradiation to target hypoxic tumor cells in combination with high dose-rate irradiation to eradicate the well oxygenated tumor regions. However, [3H]-valine is not the appropriate method to deliver ultra-low dose-rate irradiation in vivo.

The clinical impact of mean vessel size and solidity in breast carcinoma patients.

Angiogenesis quantification, through vessel counting or area estimation in the most vascular part of the tumour, has been found to be of prognostic value across a range of carcinomas, breast cancer included. We have applied computer image analysis to quantify vascular properties pertaining to size, shape and spatial distributions in photographed fields of CD34 stained sections. Aided by a pilot (98 cases), seven parameters were selected and validated on a separate set from 293 breast cancer patients. Two new prognostic markers were identified through continuous cox regression with endpoints breast cancer specific survival and distant disease free survival: The average size of the vessels as measured by their perimeter (p = 0.003 and 0.004, respectively), and the average complexity of the vessel shapes measured by their solidity (p = 0.004 and 0.004). The Hazard ratios for the corresponding median-dichotomized markers were 2.28 (p = 0.005) and 1.89 (p = 0.016) for the mean perimeter and 1.80 (p = 0.041) and 1.55 (p = 0.095) for the shape complexity. The markers were associated with poor histologic type, high grade, necrosis, HR negativity, inflammation, and p53 expression (vessel size only). Both markers were found to strongly influence the prognostic properties of vascular invasion (VI) and disseminated tumour cells in the bone marrow. The latter being prognostic only in cases with large vessels (p = 0.004 and 0.043) or low complexity (p = 0.018 and 0.024), but not in the small or complex vessel groups (p>0.47). VI was significant in all groups, but showed greater hazard ratios for small and low complexity vessels (6.54-11.2) versus large and high complexity vessels (2.64-3.06). We find that not only the overall amount of produced vasculature in angiogenic hot-spots is of prognostic significance, but also the morphological appearance of the generated vessels, i.e. the size and shape of vessels in the studied hot spots.

Quantification of angiogenesis in breast cancer by automated vessel identification in CD34 immunohistochemical sections.

BACKGROUND/AIM: Tumor growth is dependent upon angiogenesis. Tumor vascularity, as measured by microvessel density or Chalkley counts, has been shown to predict treatment outcome. However, many issues related to reproducibility and methodology have prevented its clinical application. We present a method of automatic vessel identification applied to CD34 immunohistochemical sections which facilitates increased reproducibility. MATERIALS AND METHODS: Pixel colour information was used to identify CD34 stain. In order to reduce the effects of noise and background, stained areas smaller than 3.5 µm were ignored. RESULTS: Comparing automatic and manual vessel counts in 50 randomly selected breast cancer cases, the method achieved an intraclass correlation coefficient of r(a)(2)=0.96 and a 95% confidence interval for the percentage difference between the counts from -26.1% to 10.8%. The method was also found to have a sensitivity approaching 100%. CONCLUSION: The method can reliably be used on colour photographs of staining for CD34 to quantify angiogenesis.

Longitudinal magnetic resonance imaging-based assessment of vascular changes and radiation response in androgen-sensitive prostate carcinoma xenografts under androgen-exposed and androgen-deprived conditions.

Prostate cancer (PCa) patients receive androgen-deprivation therapy (ADT) to reduce tumor burden. However, complete eradication of PCa is unusual, and recurrent disease is evident within approximately 2 years in high-risk patients. Clinical evidence suggests that combining ADT with radiotherapy improves local control and disease-free survival in these patients compared with radiotherapy alone. We investigated whether vascularization of androgen-sensitive PCa xenografts changed after ADT and whether such therapy affected radiation response. CWR22 xenografts received combinations of ADT by castration (CWR22-cas) and 15 Gy of single-dose irradiation. At a shortest tumor diameter of 8 mm, vascularization was visualized by dynamic contrast-enhanced magnetic resonance imaging before radiation and 1 and 9 days after radiation. Voxel-wise quantitative modeling of contrast enhancement curves extracted the hemodynamic parameter K(trans), reflecting a combination of permeability, density, and blood flow. Tumor volumes and prostate-specific antigen (PSA) were monitored during the experiment. The results showed that K(trans) of CWR22-cas tumors 36±4 days after ADT was 47.1% higher than K(trans) of CWR22 tumors (P = .01). CWR22-cas tumors showed no significant changes in K(trans) after radiation, whereas K(trans) of CWR22 tumors at day 1 decreased compared with pretreatment values (P = .04) before a continuous increase from day 1 to day 9 followed (P = .01). Total PSA in blood correlated positively to tumor volume (r = 0.59, P < .01). In conclusion, androgen-exposed xenografts demonstrated radiation-induced reductions in vascularization and tumor volumes, whereas androgen-deprived xenografts showed increased vascularization and growth inhibition, but no significant additive effect of radiation.