Textural Parameters of Tumor Heterogeneity in ¹8F-FDG PET/CT for Therapy Response Assessment and Prognosis in Patients with Locally Advanced Rectal Cancer.

UNLABELLED: (18)F-FDG PET/CT is effective in the assessment of therapy response. Changes in glucose uptake or tumor size are used as a measure. Tumor heterogeneity was found to be a promising predictive and prognostic factor. We investigated textural parameters for their predictive and prognostic capability in patients with rectal cancer using histopathology as the gold standard. In addition, a comparison to clinical outcome was performed. METHODS: Twenty-seven patients with rectal cancer underwent (18)F-FDG PET/CT before, 2 wk after the start, and 4 wk after the completion of neoadjuvant chemoradiotherapy. In all PET/CT scans, conventional parameters (tumor volume, diameter, maximum and mean standardized uptake values, and total lesion glycolysis [TLG]) and textural parameters (coefficient of variation [COV], skewness, and kurtosis) were determined to assess tumor heterogeneity. Values on pretherapeutic PET/CT as well as changes early in the course of therapy and after therapy were compared with histopathologic response. In addition, the prognostic value was assessed by correlation with time to progression and survival time. RESULTS: The COV showed a statistically significant capability to assess histopathologic response early in therapy (sensitivity, 68%; specificity, 88%) and after therapy (79% and 88%, respectively). Thereby, the COV had a higher area under the curve in receiver-operating-characteristic analysis than did any analyzed conventional parameter for early and late response assessment. The COV showed a statistically significant capability to evaluate disease progression and to predict survival, although the latter was not statistically significant. CONCLUSION: Tumor heterogeneity assessed by the COV, being superior to the investigated conventional parameters, is an important predictive factor in patients with rectal cancer. Furthermore, it can provide prognostic information. Therefore, its application is an important step for personalized treatment of rectal cancer.

Comparison of (immuno-)fluorescence data with serial [¹8F]Fmiso PET/CT imaging for assessment of chronic and acute hypoxia in head and neck cancers.

PURPOSE: Both, acute and chronic hypoxia can have unfavorable impacts on tumor progression and therapy response. The aim of this study was to optimize a macroscopic technique for the quantification of acute and chronic hypoxia (Wang model assessment of serial [(18)F]Fmiso PET/CT imaging) by comparing with a microscopic technique [(immuno-)fluorescence staining in tumor cryosections]. MATERIALS AND METHODS: Tumor pieces from the human squamous cell carcinoma lines from the head and neck FaDu and CAL33 were xenografted into the hind leg of NMRI nu/nu mice. Tumor-bearing mice were placed on an in-house developed multi-point fixation system and subjected to two consecutive dynamic [(18)F]Fmiso PET/CTs within a 24h interval. The Wang model was applied to SUV (standard uptake values) to quantify the fractions of acute and chronic hypoxia. Hypoxia subtypes were also assessed in vital tumor tissue of cryosections from the same tumors for (immuno-)fluorescence distributions of Hoechst 33342 (perfusion), pimonidazole (hypoxia), and CD31 (endothelium) using pattern recognition in microcirculatory supply units (defined as vital tumor tissue area supplied by a single microvessel). RESULTS: Using our multi-point fixation system, acceptable co-registration (registration errors ε ranged from 0.34 to 1.37) between serial PET/CT images within individual voxels was achieved. The Wang model consistently yielded higher fractions of acute hypoxia than the MCSU method. Through specific modification of the Wang model (Wang(mod)), it was possible to reduce the fraction of acute hypoxia. However, there was no significant correlation between the fractions of acute hypoxia in individual tumors assessed by the Wang(mod) model and the MCSU method for either tumor line (FaDu: r=0.68, p=0.21 and CAL33: r=0.71, p=0.18). This lack of correlation is most-likely due to the difference between the non-linear uptake of [(18)F]Fmiso and the spatial assessment of MCSUs. CONCLUSIONS: Whether the Wang model can be used to predict radiation response after serial [(18)F]Fmiso PET imaging, needs to be confirmed in experimental and clinical studies.

Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques.

BACKGROUND AND PURPOSE: Hypoxia is a characteristic of tumors, is known to increase aggressiveness, and causes treatment resistance. Traditional classification suggests two types of hypoxia: chronic and acute. Acute hypoxia is mostly caused by transient disruptions in perfusion, while chronic hypoxia is caused by diffusion limitations. This classification may be insufficient in terms of pathogenetic and pathophysiological mechanisms. Therefore, we quantified hypoxia subtypes in tumors based on (immuno-)fluorescent marker distribution patterns in microcirculatory supply units (MCSUs). MATERIAL AND METHODS: Cryosections from hSCC lines (SAS, FaDu, UT-SCC-5, UT-SCC-14, UT-SCC-15) were analyzed. Hypoxia was identified by pimonidazole, perfusion by Hoechst 33342, and endothelial cells by CD31. The following patterns were identified in vital tumor tissue: (1) normoxia: Hoechst 33342 fluorescence around microvessels, no pimonidazole, (2) chronic hypoxia: Hoechst 33342 fluorescence around microvessels, pimonidazole distant from microvessels, (3) acute hypoxia: no Hoechst 33342 fluorescence around microvessels, pimonidazole in immediate vicinity of microvessels, and (4) hypoxemic hypoxia: Hoechst 33342 fluorescence and pimonidazole directly around microvessels. RESULTS: Quantitative assessment of MCSUs show predominance for normoxia in 4 out of 5 tumor lines (50.1-72.8%). Total hypoxia slightly prevails in UT-SCC-15 (56.9%). Chronic hypoxia is the dominant subtype (65.4-85.9% of total hypoxia). Acute hypoxia only accounts for 12.9-29.8% and hypoxemic hypoxia for 1.2-6.4% of total hypoxia. The fraction of perfused microvessels ranged from 82.5-96.6%. CONCLUSION: Chronic hypoxia is the prevailing subtype in MCSUs. Acute hypoxia and hypoxemic hypoxia account for only a small fraction. This approach enables assessment and recognition of different hypoxia subtypes including hypoxemic hypoxia and may facilitate methods to (clinically) identify and eliminate hypoxia.

Quantitative assessment of hypoxia kinetic models by a cross-study of dynamic 18F-FAZA and 15O-H2O in patients with head and neck tumors.

UNLABELLED: Several kinetic models have been proposed to assess the underlying oxygenation status behind hypoxia tracer uptake and have shown advantages, compared with static analysis, in discriminating hypoxic regions. However, the quantitative assessment of mathematic models that take into consideration clinical applications and their biologic nature is still challenging. We performed a feasibility study to assess hypoxia kinetic models using voxelwise cross-analysis between the uptake of the perfusion tracer (15)O-H(2)O and the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA). METHODS: Five patients with advanced head and neck cancer were included. For each patient, dynamic sequences of (15)O-H(2)O for 5 min and (18)F-FAZA for 60 min were acquired consecutively after injections of approximately 1 GBq and 300 MBq of each tracer, respectively. The compartment model, Thorwarth model, Patlak plot, Logan plot, and Cho model were applied to model the process of tracer transport and accumulation under hypoxic conditions. The standard 1-tissue-compartment model was used to compute a perfusion map for each patient. The hypoxia kinetic models were based on the assumption of a positive correlation between tracer delivery and perfusion and a negative (inverse) correlation between tracer accumulation (hypoxia) and perfusion. RESULTS: Positive correlations between tracer delivery and perfusion were observed for the Thorwarth and Cho models in all patients and for the reversible and irreversible 2-compartment models in 4 patients. Negative correlations between tracer accumulation and perfusion were observed for the reversible 2-compartment model in all patients and for the irreversible 2-compartment model and Cho model in 4 patients. When applied to normal skeletal muscle, the smallest correlation variance over all 5 patients was observed for the reversible 2-compartment model. CONCLUSION: Hypoxia kinetic modeling delivers different information from static measurements. Different models generate different results for the same patient, and they even can lead to opposite physiologic interpretations. On the basis of our assessment of physiologic precision and robustness, the reversible 2-compartment model corresponds better to the expectations of our assumptions than the other investigated models.

Assessment of tumor volumes in skull base glomus tumors using Gluc-Lys[(18)F]-TOCA positron emission tomography.

PURPOSE: To assess a threshold for Gluc-Lys[(18)F]-TOCA positron emission tomography (PET) in target volume delineation of glomus tumors in the skull base and to compare with MRI-based target volume delineation. METHODS AND MATERIALS: The threshold for volume segmentation in the PET images was determined by a phantom study. Nine patients with a total of 11 glomus tumors underwent PET either with Gluc-Lys[(18)F]-TOCA or with (68)Ga-DOTATOC (in 1 case). All patients were additionally scanned by MRI. Positron emission tomography and MR images were transferred to a treatment-planning system; MR images were analyzed for lesion volume by two observers, and PET images were analyzed by a semiautomated thresholding algorithm. RESULTS: Our phantom study revealed that 32% of the maximum standardized uptake value is an appropriate threshold for tumor segmentation in PET-based target volume delineation of gross tumors. Target volume delineation by MRI was characterized by high interobserver variability. In contrast, interobserver variability was minimal if fused PET/MRI images were used. The gross tumor volumes (GTVs) determined by PET (GTV-PET) showed a statistically significant correlation with the GTVs determined by MRI (GTV-MRI) in primary tumors; in recurrent tumors higher differences were found. The mean GTV-MRI was significantly higher than mean GTV-PET. The increase added by MRI to the common volume was due to scar tissue with strong signal enhancement on MRI. CONCLUSIONS: In patients with glomus tumors, Gluc-Lys[(18)F]-TOCA PET helps to reduce interobserver variability if an appropriate threshold for tumor segmentation has been determined for institutional conditions. Especially in patients with recurrent tumors after surgery, Gluc-Lys[(18)F]-TOCA PET improves the accuracy of GTV delineation.