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Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI.

ABSTRACT: Purpose: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients.Experimental Design: Quantitation of the transverse relaxation rate, R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin in human CALR xenografts and patients with HNSCC at 3T. Autocovariance and power spectrum analysis of variations in R2* was performed for each imaged voxel, to assess statistical significance and frequencies of cycling changes in tumor blood oxygenation. Pathologic correlates with tumor perfusion (Hoechst 33342), hypoxia (pimonidazole), and vascular density (CD31) were sought in the xenografts, and dynamic contrast-enhanced (DCE) MRI was used to assess patient tumor vascularization. The prevalence of fluctuations within patient tumors, DCE parameters, and treatment outcome were reported.Results: Spontaneous R2* fluctuations with a median periodicity of 15 minutes were detected in both xenografts and patient tumors. Spatially, these fluctuations were predominantly associated with regions of heterogeneous perfusion and hypoxia in the CALR xenografts. In patients, R2* fluctuations spatially correlated with regions of lymph nodes with low Ktrans values, typically in the vicinity of necrotic cores.Conclusions: IS-MRI can be used to monitor variations in levels of paramagnetic deoxyhemoglobin, associated with cycling hypoxia. The presence of such fluctuations may be linked with impaired tumor vasculature, the presence of which may impact treatment outcome. Clin Cancer Res; 23(15); 4233-41. ©2017 AACR.

SUBMITTER: Panek R

PROVIDER: S-EPMC5516915 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI.

Panek Rafal R Welsh Liam L Baker Lauren C J LCJ Schmidt Maria A MA Wong Kee H KH Riddell Angela M AM Koh Dow-Mu DM Dunlop Alex A Mcquaid Dualta D d'Arcy James A JA Bhide Shreerang A SA Harrington Kevin J KJ Nutting Christopher M CM Hopkinson Georgina G Richardson Cheryl C Box Carol C Eccles Suzanne A SA Leach Martin O MO Robinson Simon P SP Newbold Kate L KL

Clinical cancer research : an official journal of the American Association for Cancer Research 20170317 15

Purpose: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients.Experimental Design: Quantitation of the transverse relaxation rate, R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin i ...[more]

PMID: 28314789

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Project description:BackgroundHypoxia and large tumor volumes are negative prognostic factors for patients with head and neck squamous cell carcinoma (HNSCC) treated with radiation therapy (RT). PET-scanning with specific hypoxia-tracers (hypoxia-PET) can be used to non-invasively assess hypoxic tumor volume. Primary tumor volume is readily available for patients undergoing RT. However, the relationship between hypoxic volume and primary tumor volume is yet an open question. The current study investigates the hypotheses that larger tumors contain both a larger hypoxic volume and a higher hypoxic fraction.MethodsPubMed and Embase were systematically searched to identify articles fulfilling the predefined criteria. Individual tumor data (primary tumor volume and hypoxic volume/fraction) was extracted. Relationship between hypoxic volume and primary tumor volume was investigated by linear regression. The correlation between hypoxic fraction and log2(primary tumor volume) was determined for each cohort and in a pooled analysis individual regression slopes and coefficients of determination (R2) were weighted according to cohort size.Results21 relevant articles were identified and individual data from 367 patients was extracted, out of which 323 patients from 17 studies had quantifiable volumes of interest. A correlation between primary tumor volume and PET-determined hypoxic volume was found (P <.001, R2 = 0.46). Larger tumors had a significantly higher fraction of hypoxia compared with smaller tumors (P<.01). The weighted analysis of all studies revealed that for each doubling of the tumor volume, the hypoxic fraction increased by four percentage points.ConclusionThis study shows correlations between primary tumor volume and hypoxic volume as well as primary tumor volume and the hypoxic fraction in patients with HNSCC. The findings suggest that not only do large tumors contain more cancer cells, they also have a higher proportion of potentially radioresistant hypoxic cells. This knowledge can be important when individualizing RT.

Project description:Purpose To cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility MRI measurements and to demonstrate the feasibility of translation of the technique for patients. Materials and Methods Preclinical studies in nine 786-0-R renal cell carcinoma (RCC) xenografts and prospective clinical studies in eight patients with RCC were performed. Longitudinal relaxation rate changes (?R1) after 100% oxygen inhalation were quantified, reflecting the paramagnetic effect on tissue protons because of the presence of molecular oxygen. Native transverse relaxation rate (R2*) and oxygen-induced R2* change (?R2*) were measured, reflecting presence of deoxygenated hemoglobin molecules. Median and voxel-wise values of ?R1 were compared with values of R2* and ?R2*. Tumor regions with dynamic contrast agent-enhanced MRI perfusion, refractory to signal change at OE MRI (referred to as perfused Oxy-R), were distinguished from perfused oxygen-enhancing (perfused Oxy-E) and nonperfused regions. R2* and ?R2* values in each tumor subregion were compared by using one-way analysis of variance. Results Tumor-wise and voxel-wise ?R1 and ?R2* comparisons did not show correlative relationships. In xenografts, parcellation analysis revealed that perfused Oxy-R regions had faster native R2* (102.4 sec-1 vs 81.7 sec-1) and greater negative ?R2* (-22.9 sec-1 vs -5.4 sec-1), compared with perfused Oxy-E and nonperfused subregions (all P < .001), respectively. Similar findings were present in human tumors (P < .001). Further, perfused Oxy-R helped identify tumor hypoxia, measured at pathologic analysis, in both xenografts (P = .002) and human tumors (P = .003). Conclusion Intrinsic susceptibility biomarkers provide cross validation of the OE MRI biomarker perfused Oxy-R. Consistent relationship to pathologic analyses was found in xenografts and human tumors, demonstrating biomarker translation. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Project description:Tumor hypoxia plays a major role in radio- and chemotherapy resistance in solid tumors. Carbonic Anhydrase IX (CAIX) is an endogenous hypoxia-related protein, which is associated with poor patient outcome. The quantitative assessment of CAIX expression of tumors may steer cancer treatment by predicting therapy response or patient selection for antihypoxia or CAIX-targeted treatment. Recently, the single-photon emission computerized tomography (SPECT) tracer [111In]In-DTPA-girentuximab-F(ab')2 was developed and validated for targeting CAIX. The aim of this study was to optimize quantitative microSPECT/CT of CAIX expression in vivo in head and neck tumor models. Athymic mice with subcutaneous SCCNij153 and SCCNij202 head and neck squamous cell carcinoma xenografts were injected with [111In]In-DTPA-girentuximab-F(ab')2. First, the protein dose, timing, and image acquisition settings were optimized. Tracer uptake was determined by quantitative SPECT, ex vivo radioactivity counting, and by autoradiography of tumor sections. The same tumor sections were immunohistochemically stained for CAIX expression and hypoxia. Highest tumor-normal-tissue contrast was obtained at 24 h after injection of the tracer. A protein dose of 10 μg resulted in the highest tumor-to-muscle ratio at 24 h p.i. Ex vivo biodistribution studies showed a tumor uptake of 3.0 ± 0.6%ID/g and a tumor-to-muscle ratio of 8.7 ± 1.4 (SCCNij153). Quantitative analysis of the SPECT images enabled us to distinguish CAIX antigen blocked from nonblocked tumors, fractions positive for CAIX expression: 0.22 ± 0.02 versus 0.08 ± 0.01 ( p < 0.01). Immunohistochemical, autoradiographic, and microSPECT/CT analyses showed a distinct intratumoral spatial correlation between localization of the radiotracer and CAIX expression. Here, we demonstrate that [111In]In-DTPA-girentuximab-F(ab')2 specifically targets CAIX-expressing cells in head and neck cancer xenografts. SPECT imaging with indium-labeled girentuximab-F(ab')2 allows quantitative assessment of the fraction of CAIX positive tissue in head and neck cancer xenografts. These results indicate that [111In]In-DTPA-girentuximab-F(ab')2 is a promising tracer to image hypoxia-related CAIX expression.

Dataset Information

Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI.

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Noninvasive Imaging of Cycling Hypoxia in Head and Neck Cancer Using Intrinsic Susceptibility MRI.

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