Andrij Abramyuk

Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer

PURPOSE To explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer. PATIENTS AND METHODS Twenty-five patients with stage III/IV head and neck cancer were investigated with [(18)F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8-10 Gy, 18-20 Gy,50-60 Gy). FMISO PET/CT image parameters were extracted including maximum-tumour-to-background (TBR(max)) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests. RESULTS FMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023-0.048 and 0.042-0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS. CONCLUSION This prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going.

Comment on "Developing DCE-CT to Quantify Intra-Tumor Heterogeneity in Breast Tumors With Differing Angiogenic Phenotype

The objective of this study is to evaluate the ability of dynamic contrast enhanced computed tomography (DCE-CT) to assess intratumor physiological heterogeneity in tumors with different angiogenic phenotypes. DCE-CT imaging was performed on athymic nude mice bearing xenograft wild type (MCF-7neo) and VEGF-transfected (MCF-7VEGF) tumors by using a clinical multislice CT, and compared to skeletal muscle. Parametrical maps of tumor physiology-perfusion (F), permeability-surface area (PS), fractional intravascular plasma (fp), and interstitial space ( fis)-were obtained by fitting the time-dependent contrast-enhanced curves to a two-compartmental kinetic model for each voxel (0.3 x 0.3 x 0.75 mm3). Mean physiological measurements were compared with positron emission tomography (PET) imaging, and the spatial distribution of tumor vasculature was compared with histology. No statistically significant difference was found in mean physiological values of F, PS, and fp in MCF-7neo and muscle, while fis of MCF-7neo was a factor of two higher (p<0.04). MCF-7neo tumors also showed a radial heterogeneity with significant higher physiological values in periphery than those in middle and core regions (p<0.01 for all physiological parameters). MCF-7VEGF tumors demonstrated significant increases in all physiological parameters compared with MCF-7neo tumors, and a distinct saccular heterogeneous pattern compared with MCF-7neo and muscle. Both PET imaging and histological results showed good correlation with the above results for this same mouse model. No statistically significant difference was found in the mean perfusion and intravascular volume measured by PET imaging and DCE-CT. Increases in cross-sectional area of blood vessels (p<0.002) were observed in MCF-7VEGF tumors than MCF-7neo, and their spatial distribution correlated well with the spatial distribution of fp obtained by DCE-CT. The results of this study demonstrated the feasibility of DCE-CT in quantification of spatial heterogeneity in tumor physiology in small animal models. Monitoring variations in the tumor environment using DCE-CT offers an in vivo tool for the evaluation and optimization of new therapeutic strategies.The objective of this study is to evaluate the ability of dynamic contrast enhanced computed tomography (DCE-CT) to assess intratumor physiological heterogeneity in tumors with different angiogenic phenotypes. DCE-CT imaging was performed on athymic nude mice bearing xenograft wild type (MCF-7neo) and VEGF-transfected (MCF-7VEGF) tumors by using a clinical multislice CT, and compared to skeletal muscle. Parametrical maps of tumor physiology-perfusion (F), permeability-surface area (PS), fractional intravascular plasma (fp), and interstitial space ( fis)-were obtained by fitting the time-dependent contrast-enhanced curves to a two-compartmental kinetic model for each voxel (0.3 x 0.3 x 0.75 mm3). Mean physiological measurements were compared with positron emission tomography (PET) imaging, and the spatial distribution of tumor vasculature was compared with histology. No statistically significant difference was found in mean physiological values of F, PS, and fp in MCF-7neo and muscle, while fis of MCF-7neo was a factor of two higher (p<0.04). MCF-7neo tumors also showed a radial heterogeneity with significant higher physiological values in periphery than those in middle and core regions (p<0.01 for all physiological parameters). MCF-7VEGF tumors demonstrated significant increases in all physiological parameters compared with MCF-7neo tumors, and a distinct saccular heterogeneous pattern compared with MCF-7neo and muscle. Both PET imaging and histological results showed good correlation with the above results for this same mouse model. No statistically significant difference was found in the mean perfusion and intravascular volume measured by PET imaging and DCE-CT. Increases in cross-sectional area of blood vessels (p<0.002) were observed in MCF-7VEGF tumors than MCF-7neo, and their spatial distribution correlated well with the spatial distribution of fp obtained by DCE-CT. The results of this study demonstrated the feasibility of DCE-CT in quantification of spatial heterogeneity in tumor physiology in small animal models. Monitoring variations in the tumor environment using DCE-CT offers an in vivo tool for the evaluation and optimization of new therapeutic strategies.

Serial FDG-PET on patients with head and neck cancer: Implications for radiation therapy

Purpose: To assess possible consequences for radiotherapy (RT) planning, e.g., reduction of treatment volume by a decreased tumour volume in Fluor-18-fluoro-deoxy-glucose-Positron emission tomography (FDG-PET) based on a close-meshed evaluation of FDG uptake in primary head and neck cancer (HNC) during RT. Materials and method: PET data were analysed using a source-to-background based algorithm. The following parameters were obtained: max. standardised uptake value (SUVmax), PET-based gross tumour volume (GTV-PET) and metabolic volume (MV). Results: While the median SUVmax decreased (initial: 15.2, 1st/2nd week: 10.2, 3rd/4th week: 6.5, 5th/6th week: 6.4), the median values of GTV-PET (9.3 cm3, 12.4 cm3, 14.0 cm3, 17.9 cm3) and MV (92.2 cm3, 61.7 cm3, 60.0 cm3, 71.3 cm3) seemed to increase during radiotherapy. The intra-individual development of SUVmax could be divided into two groups: group A having continuously decreasing values of SUVmax (n = 10 patients), and group B having a temporary increase of SUVmax (n = 13). Conclusions: Data suggest that a reduction of treatment volume is not possible by an adaptive re-planning based on FDG-PET, e.g., at 50 Gy. This may be caused by a consecutive therapy associated inflammation. This limitation is probably related to the use of a source-to-background based algorithm.

Quantitative modifications of TNM staging, clinical staging and therapeutic intent by FDG-PET/CT in patients with non small cell lung cancer scheduled for radiotherapy — A retrospective study

It is obvious that FDG-PET has added value to CT, but there is still insufficient data to define the role of FDG-PET/CT in clinical practice. Usually data are gathered from multiple sources and in consequence the information obtained is heterogeneous and not always comparable between patients. To alleviate this lack of data, we attempted to investigate the differences in staging and therapeutic intent as compared with conventional staging in non small cell lung cancer (NSCLC) patients scheduled for RT after adding FDG-PET/CT to conventional staging in 104 included subjects. In contrary to the multicentric studies relying on patients medical records from outside institutions, these data were generated entirely with the institutions PET/CT unit. Significant modifications of both, M-stage and clinical stage were detected after inclusion of FDG-PET/CT data (p<0.001), while there was no statistically significant T- and N-stage modification. Overall implenting FDG-PET/CT revised RT intention decision in 34% of patients. FDG-PET/CT provides enhanced staging capabilities compared to conventional CT in staging of non small cell lung carcinoma and allows improved selection of patients suitable for curative intention, while avoiding unnecessary irradiation and costs in patients eligible to palliative intention.

Preliminary assessment of dynamic contrast-enhanced CT implementation in pretreatment FDG-PET/CT for outcome prediction in head and neck tumors.

Background: Recently published data show some controversy concerning the impact of [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in predicting head and neck tumors (HNT) outcome. Assessment of tumor blood supply parameters using dynamic contrast-enhanced CT (DCE-CT) may deliver additional information concerning this important question. Purpose: To evaluate the contribution of DCE-CT implemented in pretherapeutic FDG-PET/CT protocol for prognosis prediction in patients with HNT. Material and Methods: Ten consecutive patients (median age 50 years, range 47–74 years) with histologically proven HNT underwent FDG-PET/CT with DCE-CT before treatment. FDG uptake was measured by maximum standardized uptake value (SUVmax). Relative tumor blood volume (rTBV) was determined from DCE-CT using Patlak analysis. Intratumoral heterogeneity was assessed by means of lacunarity analysis. Obtained values were compared with time-to-progression and overall survival. PET and DCE-CT images were compared on a pixel-by-pixel basis using Pearson coefficient of correlation. Results: Three patients with lower FDG uptake (SUVmax: 8±1) and five patients with higher FDG uptake (SUVmax: 15±4, P=0.004) were free of local recurrence for 24 months. Two groups of patients with significantly differing lower (group A: 0.37±0.02, n=6) and higher (group B: 0.52±0.01, n=4; P<0.01), tumor heterogeneity (lacunarity) were identified. Corresponding mean rTBV was higher in group A (9.6±1.8 ml/100 ml) than in group B (6.2±0.6 ml/100 ml). All six patients with homogeneous tumor blood supply (lower lacunarity) and higher rTBV were free of local recurrence during 24 months, while two of four patients with heterogeneous tumor blood supply (higher lacunarity) and lower rTBV died during follow-up due to tumor relapse. A weak correlation between FDG-PET and DCE-CT rTBV was observed (R2=0.1). Conclusion: FDG-PET/CT and DCT-CT are complementary methods for surveillance assessment in patients with HNT. Implementation of DCE-CT in the pretreatment FDG-PET/CT protocol may improve tumor outcome prediction.

Usefulness of dynamic contrast enhanced computed tomography in patients with non-small-cell lung cancer scheduled for radiation therapy

OBJECTIVE The goal of this study was to investigate the local tumor blood supply parameters relative tumor blood volume (rTBV) and transfer coefficient (K(trans)) measurable with dynamic contrast enhanced computed tomography (DCE-CT) in patients with non-small-cell lung cancer (NSCLC) scheduled for radiation therapy (RT). MATERIALS AND METHODS rTBV and K(trans) were measured before RT in 31 patients with clinically inoperable NSCLC (Stages I-III), which received (n=19) or did not receive (n=12) induction chemotherapy (IChT). Possible links between rTBV and K(trans) and time-to-progression (TTP), overall survival (OS) and maximum standardized uptake value (SUV(max)) from fluorodeoxyglucose positron emission tomography as well as histology were analyzed. RESULTS NSCLC showed a wide range of rTBV and K(trans) values as estimated by DCE-CT (6.4±0.6ml/100ml and 18.2±1.5ml/100ml/min correspondingly). A significant difference in rTBV values in patients with IChT (4.6±0.6ml/100ml) and without IChT (7.5±0.9ml/100ml; p=0.023), depending on the number of cycles of the IChT and the clinical stage was found. A negative correlation between rTBV and TTP was revealed only in RT patients up-staged by FDG-PET/CT from stage III to stage IV (n=7, r=-0.96, p=0.0006). An inverse correlation between K(trans) and TTP (n=24, r=-0.53, p=0.008) was observed in all RT patients. No relevant correlation was detected between rTBV, K(trans) and SUV(max) or histologic subtypes and grading. CONCLUSIONS Tumor blood supply parameters derived from DCE-CT are useful to characterize tumor vascularization before radiotherapy in patients with NSCLC and data on outcome prediction are supplemented.

Protection of p53 Wild Type Cells From Taxol by Genistein in the Combined Treatment of Lung Cancer

This study specifies the basic principles to selectively kill p53-deficient cells (H1299, FaDu) by taxol and to protect p53 wild type cells (A549) by the prior administration of structurally related flavonoids (apigenin, genistein, and quercetin). Cytotoxic and cytostatic properties of flavonoids were investigated in vitro by flow cytometry and were compared to known anticancer drugs (cisplatin, doxorubicin, etoposide). It was confirmed that doxorubicin induced growth arrest and protected A549 cells from taxol while simultaneously killing or blocking H1299 and FaDu cancer cells. It was found that doxorubicin could be successfully substituted in this way by the isoflavone genistein used at physiologically relevant concentrations. The other compounds analyzed revealed less selectivity (apigenin, cisplatin) or demonstrated higher toxicity (cisplatin, etoposide, and quercetin). We concluded that genistein-based therapy may have antagonistic effects when combined with mitotic poisons. The proposed therapeutic strategy allows protection of p53 wild type cells from taxol and selectively increases apoptosis in p53-deficient cells. This strategy exploits the naturally occurring compound that can be used without significant toxicity in rather high concentrations as present in common diets.

Distribution of fluorescent microspheres in vascular space and parenchymal organs of intact nude rats.

Purpose: To assess kinetics of elimination of different sized microspheres (MS) from the blood pool and tendency of their distribution in parenchymal organs of intact nude rats. Materials and methods: A mixture of 1 μm and 3 μm MS in phosphate-buffered saline was injected intravenously into eight rats under intraperitoneal anaesthesia. Blood samples were collected before, just after and in 2, 5 and 10 min after MS injection. Dynamics of MS elimination from blood pool was evaluated with flow cytometry. After euthanasia, histological sections were prepared and distributions of MS through the liver, spleen, kidney and lung were analysed with fluorescence microscopy and flow cytometry. Results: The number of microspheres registered in the intravascular space showed a marked exponential decrease over time independent of MS size. Different amounts and proportions of 1 μm and 3 μm MS were revealed in lung, liver, spleen and kidneys of the rats. Most of 1 μm MS were localised in liver and spleen. In contrast, 3 μm MS were detected predominantly in lung. Conclusion: 1 μm and 3 μm MS may be assumed as free circulating particles only for a short period of time after injection. Their elimination kinetics seems to be tightly linked to specific tissue properties such a pulmonary vasoconstriction and phagocytosis.

Retrospective analysis of radiation load during examination of cancer patients by 68Ga-DOTATOC and 18F-FDG positron emission tomography

We present retrospective analysis of the results of examinations of 1338 cancer patients by 68Ga-DOTATOC and 18F-FDG positron emission and computer-aided tomography. It was shown that complex devices for positron emission and computer-aided tomography provide more informative data than individual methods. The protocol for examination by methods of positron emission and computer-aided tomography in each case is determined by clinical requirements and risk of extra exposure of the patient.

Fusion of images in multistep analysis of neovascularisation.

Purpose: The aim of our study was to develop a method for the fusion of images received after repeated staining of the same sample taking into account spatial differences between the images. Material and methods: A method of objective fusion performance was investigated on the images receiving during multistep staining of the xenograft tumour cross-sections. Results: It was shown that several images receiving from different steps of staining procedures may be successfully fused by fluorescent marking of slide position with Trout red blood cells before analysis. Conclusions: Proposed technique provides an accurate rigid fusion of light and fluorescent images receiving during multistep image analysis under microscope and may be applied for study of neovascularisation.