Correlation between imaging and tissue biomarkers of hypoxia in squamous cell cancer of the head and neck (original) (raw)
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Imaging of tumour hypoxia and metabolism in patients with head and neck squamous cell carcinoma
Acta oncologica (Stockholm, Sweden), 2015
Tumour hypoxia and a high tumour metabolism increase radioresistance in patients with head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the correlation between hypoxia ([(18)F]HX4 PET) and glucose metabolism ([(18)F]FDG PET) molecular imaging. [(18)F]HX4 and [(18)F]FDG PET/CT images of 20 HNSCC patients were acquired prior to (chemo)radiotherapy, in an immobilisation mask, with a median time interval of seven days (NCT01347281). Gross tumour volumes of the primary lesions (GTVprim) and pathological lymph nodes (GTVln) were included in the analysis. [(18)F]FDG PET/CT images were rigidly registered to the [(18)F]HX4 PET/CT images. The maximum and mean standardised uptake values (SUVmax, SUVmean) within both GTVs were determined. In addition, the overlap was compared between the [(18)F]HX4 high volume ([(18)F]HX4 HV) with a tumour-to-muscle ratio > 1.4 and the [(18)F]FDG high volume ([(18)F]FDG HV) with an SUV > 50% of the SUVmax. We report the ...
Acta oncologica (Stockholm, Sweden), 2016
Tumor hypoxia is associated with poor prognosis and outcome and can be visualized using 18F-MISO-positron emission tomography (PET) imaging. The goal of this study was to evaluate the correlation between biological markers and biological imaging in a group of patients in whom a correlation between biological imaging and outcome has previously been demonstrated. In a prospective pilot project, 16 patients with locally advanced cancer of the head and neck underwent 18F-MISO-PET scans before and during primary radiochemotherapy in addition to 18F-FDG-PET and computed tomography (CT). Tumor biopsies were stained for three tissue-based markers (Ku80, CAIX, CD44); in addition, human papillomavirus (HPV) status was assessed. H-scores of marker expression were generated and the results were correlated with the biological imaging and clinical outcome. No statistically significant correlation was established between the H-scores for Ku80, CD44 and CAIX or between any of the H-scores and the i...
Journal of Nuclear Medicine, 2013
Hypoxia is a common feature of cancer and a prognostic factor for many types of cancer. 18 F-fluoromisonidazole (18 F-FMISO) PET can detect tumor hypoxia noninvasively. Hypoxia-inducible factor-1 (HIF-1) is a key player in the transcriptional response to low oxygen tension in many types of cancer. Its activity is mainly dependent on the stability and modification of HIF-1a, which is a composition of HIF-1. However, it is unclear whether 18 F-FMISO PET can identify HIF-1a expression in oral squamous cell carcinoma (OSCC). The present study was performed to elucidate the correlation between 18 F-FMISO PET findings and HIF-1a expression in OSCC. Methods: Twenty-three patients (age range, 42-84 y; 15 men, 8 women) with OSCC were enrolled in this study. The T-stages of cancer were T1 in 1 patient, T2 in 9, T3 in 2, and T4a in 11. The N-stages were N0 in 13 patients, N1 in 5, and N2 in 5. Each patient underwent 18 F-FMISO and 18 F-FDG PET before surgery, and the maximum standardized uptake value (SUV max) of both PET studies was measured. HIF-1a expression in the operation materials was evaluated by immunohistochemical staining. The SUV max of both PET studies and HIF-1a findings were compared statistically. Results: 18 F-FMISO PET detected uptake in the primary site in 14 of the 23 patients (61%). The median SUV max of 18 F-FMISO and 18 F-FDG PET in the primary site was 1.83 (range, 0.8-2.7) and 16.5 (range, 1.0-32.3), respectively. There was a weak significant correlation between 18 F-FMISO and 18 F-FDG PET SUV max (P 5 0.02, r 5 0.48). HIF-1a expression was clearly detected in 11 of the 23 patients (48%). The 18 F-FMISO PET SUV max was significantly higher in the HIF-1apositive cases than in the HIF-1a-negative cases (median, 2.1; range, 1.5-2.4, vs. median, 1.6; range, 0.8-2.0, respectively) (P 5 0.002). However, there were no significant correlations between 18 F-FDG PET SUV max and HIF-1a expression (median, 21.8; range, 7.7-29.1 vs. 1.0-32.2) (P 5 0.06). Conclusion: 18 F-FMISO uptake in the primary site of OSCC indicates a hypoxic environment with HIF-1a expression.
Radiotherapy and Oncology, 2011
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 24 h 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 e 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.
International Journal of Radiation Oncology*Biology*Physics, 2007
Purpose: To investigate the expression pattern of hypoxia-induced proteins identified as being involved in malignant progression of head-and-neck squamous cell carcinoma (HNSCC) and to determine their relationship to tumor pO 2 and prognosis. Methods and Materials: We performed immunohistochemical staining of hypoxia-induced proteins (carbonic anhydrase IX [CA IX], BNIP3L, connective tissue growth factor, osteopontin, ephrin A1, hypoxia inducible gene-2, dihydrofolate reductase, galectin-1, IkB kinase b, and lysyl oxidase) on tumor tissue arrays of 101 HNSCC patients with pretreatment pO 2 measurements. Analysis of variance and Fisher's exact tests were used to evaluate the relationship between marker expression, tumor pO 2 , and CA IX staining. Cox proportional hazard model and log-rank tests were used to determine the relationship between markers and prognosis. Results: Osteopontin expression correlated with tumor pO 2 (Eppendorf measurements) (p = 0.04). However, there was a strong correlation between lysyl oxidase, ephrin A1, and galectin-1 and CA IX staining. These markers also predicted for cancer-specific survival and overall survival on univariate analysis. A hypoxia score of 0-5 was assigned to each patient, on the basis of the presence of strong staining for these markers, whereby a higher score signifies increased marker expression. On multivariate analysis, increasing hypoxia score was an independent prognostic factor for cancer-specific survival (p = 0.015) and was borderline significant for overall survival (p = 0.057) when adjusted for other independent predictors of outcomes (hemoglobin and age). Conclusions: We identified a panel of hypoxia-related tissue markers that correlates with treatment outcomes in HNSCC. Validation of these markers will be needed to determine their utility in identifying patients for hypoxiatargeted therapy.
European Journal of Nuclear Medicine and Molecular Imaging, 2014
Purpose Hypoxia in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis and outcome. 18 F-Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within tumor. The aim of this study was to evaluate the use of 18 F-FAZA-PET for assessment of hypoxia before and during radiation therapy. Methods Twelve patients with locally advanced HNSCC underwent 18 F-FAZA-PET scans before and at fraction 7 and 17 of concomitant chemo-radiotherapy. A hypoxic voxel was defined as a voxel expressing a standardized uptake value (SUV) equal or above the SUV mean of the posterior contralateral neck muscles plus three standard deviations. The fractional hypoxic volume fraction (FHV) and the spatial move of hypoxic volumes during treatment were analyzed. Results A hypoxic volume could be identified in ten patients before treatment. FAZA-PET FHV varied from 0 to 54.3 % and from 0 to 41.4 % in the primary tumor and in the involved node, respectively. Six out of these ten patients completed all the FAZA-PET-computed tomography (CT) during the radiotherapy. In all patients, FHV and SUV max values decreased. All patient presented a spatial move of hypoxic volume, but only three patients had newborn hypoxic voxels after 17 fractions. Conclusion This study indicated that 18 F-FAZA-PET could be used to identify and quantify tumor hypoxia before and during concomitant radio-chemotherapy in patients with locally advanced HNSCC. In addition to the information on prognostic value, the use of 18 F-FAZA-PET allowed the delineation of hypoxic volumes for dose escalation protocols. However, due to fluctuation of hypoxia during treatment, repeated scan will have to be performed (i.e. adaptive radiotherapy).
18F-EF5: A New PET Tracer for Imaging Hypoxia in Head and Neck Cancer
Journal of Nuclear Medicine, 2008
The aim of this study was to evaluate 2-(2-nitro-1 H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) labeled with 18 F-fluorine to image hypoxia in patients with squamous cell carcinoma of the head and neck (HNSCC). Methods: Fifteen patients with HNSCC were studied. Measurement of tumor blood flow was followed by an 18 F-EF5 PET/CT scan. On a separate day, 18 F-FDG PET/CT was performed to determine the metabolically active tumor volume. In 6 patients, dynamic 18 F-EF5 images of the head and neck area were acquired, followed by static images acquired at 1, 2, and 3 h after injection. In the remaining 9 patients, only static images were obtained. 18 F-EF5 uptake in tumors was compared with that in neck muscle, and the 18 F-EF5 findings were correlated with the 18 F-FDG PET/CT studies. Results: A total of 13 primary tumors and 5 lymph node metastases were evaluated for their uptake of 18 F-EF5. The median tumor-to-muscle 18 F-EF5 uptake ratio (T/M) increased over time and was 1.38 (range, 1.1-3.2) 3 h after tracer injection. The median blood flow in tumors was 36.7 mL/100 g/min (range, 23.3-78.6 mL/100 g/min). Voxel-by-voxel analysis of coregistered blood flow and 18 F-EF5 images revealed a distinct pattern, resulting in a T/M of 1.5 at 3 h to be chosen as a cutoff for clinically significant hypoxia. Fourteen of 18 tumors (78%) had subvolumes within the metabolically active tumor volumes with T/M greater than or equal to 1.5. Conclusion: On the basis of these data, the potential of 18 F-EF5 to detect hypoxia in HNSCC is encouraging. Further development of 18 F-EF5 for eventual targeting of antihypoxia therapies is warranted.
2002
Hypoxia within head and neck squamous cell carcinoma (HNSCC) predicts a poor response to radiotherapy and poor prognosis. Hypoxiainducible factor (HIF)-1 and HIF-2 are nuclear transcription factors that regulate the cellular response to hypoxia and are important for solid tumor growth and survival. Overexpression of HIF-1␣ and HIF-2␣ was demonstrated in three HNSCC cell lines under hypoxia and tumor tissue versus normal tissue (n ؍ 20, HIF-1␣, P ؍ 0.023; HIF-2␣, P ؍ 0.013). On immunostaining, HIF-1␣ and HIF-2␣ expression were localized to tumor nuclei; HIF-2␣ expression was also seen in tumor-associated macrophages. Expression of HIF-1␣ in surgically treated patients with HNSCC (n ؍ 79) was associated with improved disease-free survival (P ؍ 0.016) and overall survival (P ؍ 0.027). . The abbreviations used are: HNSCC, head and neck squamous cell carcinoma; Glut 1, glucose transporter 1; HIF, hypoxia-inducible factor; LDH, lactate dehydrogenase; MoAb, monoclonal antibody; NS, not significant; MVD, microvessel density; TAM, tumor-associated macrophage.