Noninvasive assessment and quantification of tumor vascularization using [18F]FDG-PET/CT and CE-CT in a tumor model with modifiable angiogenesis-an animal experimental prospective cohort study.

BACKGROUND: This study investigated the noninvasive assessment of tumor vascularization with clinical F-18-fluorodeoxyglucose positron emission tomography/computed tomography and contrast-enhanced computed tomography ([18F]FDG-PET/CT and CE-CT) in experimental human xenograft tumors with modifiable vascularization and compared results to histology. Tumor xenografts with modifiable vascularization were established in 71 athymic nude rats by subcutaneous transplantation of human non-small-cell lung cancer (NSCLC) cells. Four different groups were transplanted with two different tumor cell lines (either A549 or H1299) alone or tumors co-transplanted with rat glomerular endothelial (RGE) cells, the latter to increase vascularization. Tumors were assessed noninvasively by [18F]FDG PET/CT and contrast-enhanced CT (CE-CT) using clinical scanners. This was followed by histological examinations evaluating tumor vasculature (CD-31 and intravascular fluorescent beads). RESULTS: In both tumor lines (A549 and H1299), co-transplantation of RGE cells resulted in faster growth rates [maximal tumor diameter of 20 mm after 22 (± 1.2) as compared to 45 (± 1.8) days, p < 0.001], higher microvessel density (MVD) determined histologically after CD-31 staining [171.4 (± 18.9) as compared to 110.8 (± 11) vessels per mm2, p = 0.002], and higher perfusion as indicated by the number of beads [1.3 (± 0.1) as compared to 1.1 (± 0.04) beads per field of view, p = 0.001]. In [18F]FDG-PET/CT, co-transplanted tumors revealed significantly higher standardized uptake values [SUVmax, 2.8 (± 0.2) as compared to 1.1 (± 0.1), p < 0.001] and larger metabolic active volumes [2.4 (± 0.2) as compared to 0.4 (± 0.2) cm3, p < 0.001] than non-co-transplanted tumors. There were significant correlations for vascularization parameters derived from histology and [18F]FDG PET/CT [beads and SUVmax, r = 0.353, p = 0.005; CD-31 and SUVmax, r = 0.294, p = 0.036] as well as between CE-CT and [18F]FDG PET/CT [contrast enhancement and SUVmax, r = 0.63, p < 0.001; vital CT tumor volume and metabolic PET tumor volume, r = 0.919, p < 0.001]. CONCLUSIONS: In this study, a human xenograft tumor model with modifiable vascularization implementable for imaging, pharmacological, and radiation therapy studies was successfully established. Both [18F]FDG-PET/CT and CE-CT are capable to detect parameters closely connected to the degree of tumor vascularization, thus they can help to evaluate vascularization in tumors noninvasively. [18F]FDG-PET may be considered for characterization of tumors beyond pure glucose metabolism and have much greater contribution to diagnostics in oncology.

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.

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 institution's 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.

Early FDG PET at 10 or 20 Gy under chemoradiotherapy is prognostic for locoregional control and overall survival in patients with head and neck cancer.

PURPOSE: Our study aimed to explore the optimal timing as well as the most appropriate prognostic parameter of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) during chemoradiotherapy (CRT) for an early prediction of outcome for patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Serial PET data (before and three times during CRT) of 37 patients with advanced stage HNSCC, receiving combined CRT between 2005 and 2009, were evaluated. The maximum standardized uptake value (SUV(max)), the average SUV (SUV(mean)) and the gross tumour volume determined by FDG PET (GTV PET), based on a source to background algorithm, were analysed. Stratified actuarial analysis was performed for overall survival (OS), disease-free survival (DFS) and locoregional control (LRC). The median follow-up time was 26 months (range 8-50). RESULTS: For all patients, OS was 51%, DFS 44% and LRC 55% after 2 years. The 2-year OS (88%) and 2-year LRC (88%) were higher for patients whose SUV(max) of the primary tumour decreased 50% or more from the beginning (0 Gy) to week 1 or 2 (10 or 20 Gy) of CRT (ΔSUV(max10/20) ≥ 50%) than for patients with ΔSUV(max20) < 50% (2-year OS = 38%; p = 0.02; 2-year LRC 40%; p = 0.06). A pretreatment GTV PET below the median of 10.2 ml predicted a better 2-year OS (34% for GTV PET ≥ 10.2 ml vs 83% for GTV PET < 10.2 ml; p = 0.02). CONCLUSION: The decrease of SUV(max) from before (0 Gy) to week 1 or 2 (10 or 20 Gy) of CRT is a potential prognostic marker for patients with HNSCC. Because GTV PET depends on the applied method of analysis, we suggest the use of SUV(max), especially ΔSUV(max10/20), for an early estimation of therapy outcome. Confirmatory studies are warranted.

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.

Comment on "Developing DCE-CT to quantify intra-tumor heterogeneity in breast tumors with differing angiogenic phenotype".

In our comment some essential issues concerning determination of arterial input function (AIF), cardiac and respiratory related motion artifacts, contrast agent application and compartmental model fitting done by Cao et al., 2009 are discussed.

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 (SUV(max)). 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 (SUV(max): 8+/-1) and five patients with higher FDG uptake (SUV(max): 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 (R(2)=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.

Visualization of somatostatin receptors in prostate cancer and its bone metastases with Ga-68-DOTATOC PET/CT.

PURPOSE: To assess DOTATOC-affine somatostatin receptor expression in advanced prostate cancer and its bone metastases with regard to DOTATOC-mediated receptor therapies, using a Ga-68-DOTATOC PET/CT. PROCEDURES: Twenty consecutive patients with advanced prostate cancer underwent bone scintigraphy, followed by Ga-68-DOTATOC PET/CT within 3 weeks. Through side-by-side comparison with bone scintigraphy, the number of visible bone metastases on PET was determined. In addition, in cases of visible metastases, the maximum standard uptake value (SUV(max)) of Ga-68-DOTATOC was measured in the metastases and in normal bone. In patients who did not undergo a prostatectomy (n = 12), the SUV(max) was additionally measured in the prostate and in adjacent tissue. For focal lesions, the difference in SUV(max) (Delta SUV(max)) between the metastases and normal bone was calculated. For patients still having their prostate, a Delta SUV(max) between the prostate and its adjacent tissue was calculated. RESULTS: Sixty four of 216 metastases (30%) were visible in 13 patients with focal metastases. Of six patients with diffuse metastases (superscan), one showed diffuse metastases, three showed a total of ten focal metastases, and two showed no correlate on PET. One patient with a neuroendocrine prostate cancer showed no correlate on PET. The maximum Delta SUV(max) between metastases and normal bone was 4.9 (mean = 1.6 +/- 0.9) and between the prostate and adjacent tissue 5.9 (mean = 2.8 +/- 1.6). CONCLUSIONS: In prostate cancer and its bone metastases, DOTATOC-affine somatostatin receptors (subtype 2 and 5) can be visualized with Ga-68-DOTATOC PET/CT. But their expression is so weak that other conjugates should be tested for receptor-mediated therapies which are better at addressing the prostate cancer-specific somatostatin receptor subtypes 1 and 4-or even other receptors.

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 cm(3), 12.4 cm(3), 14.0 cm(3), 17.9 cm(3)) and MV (92.2 cm(3), 61.7 cm(3), 60.0 cm(3), 71.3 cm(3)) 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.

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.

Is pre-therapeutical FDG-PET/CT capable to detect high risk tumor subvolumes responsible for local failure in non-small cell lung cancer?

BACKGROUND AND PURPOSE: Local failure is a significant issue following radiotherapy (RT) for patients with non-small cell lung cancer (NSCLC). The aim of this study was to find out whether FDG-PET/CT is capable to predict tumor relapse location in patients with NSCLC, in particular to determine high risk tumors' subvolumes responsible for local failure. MATERIAL AND METHODS: Ten patients with locoregional relapse of NSCLC underwent FDG-PET/CT before, during, and in the 4-12 months following curative chemoradiotherapy (ChRT, 66 Gy) using a combined PET/CT scanner. Morphologic and metabolic tumor volumetry and an evaluation of FDG-uptake dynamics were performed. RESULTS: CT showed partial reduction of tumor volume after RT in all patients. PET-revealed partial in eight patients and complete metabolic response in two patients during RT. Six to nine months after RT, local failure was diagnosed in all patients with both methods. Tumor recurrences were localized mostly in the most active ones of pre-therapeutically metabolic regions of the primary tumor. CONCLUSIONS: Local failure in NSCLC appears most common at the primary site and within the irradiated target volume with the highest FDG uptake. This observation may be useful for further optimization of radiotherapy of NSCLC, for example, by the application of additional radiation dose to subvolumes of primary tumors with higher FDG uptake.