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BACKGROUND: Gene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer. METHODS: The 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels was applied in the analyses. Hypoxic fraction from pimonidazole immunostained whole-mount and biopsy sections was used as reference standard for hypoxia. RESULTS: The gene score was correlated with pimonidazole-defined hypoxic fraction in whole-mount sections, and the two parameters showed almost equal association with clinical markers of tumour aggressiveness. Based on the gene score, incorrect classification according to hypoxic fraction in whole-mount sections was seen in one third of the patients. The incorrect classifications were apparently not due to intra-tumour heterogeneity, since the score had low heterogeneity compared to pimonidazole-defined hypoxic fraction in biopsies. The score showed prognostic significance in uni-and multivariate analysis in independent cohorts. CONCLUSIONS: Our signature from the index lesion reflects tumour hypoxia and predicts prognosis in prostate cancer, independent of intra-tumour heterogeneity in pimonidazole-defined hypoxia.
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Neoplasias de la Próstata , Hipoxia de la Célula/genética , Humanos , Hipoxia/genética , Masculino , Pronóstico , Prostatectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugíaRESUMEN
BACKGROUND: Cancer patients with primary tumors showing extensive hypoxia and highly elevated interstitial fluid pressure (IFP) have poor prognosis. The potential of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing the hypoxic fraction, IFP, and metastatic propensity of tumors was investigated in this study. METHODS: A-07 and R-18 melanoma xenografts were used as general models of human cancer. DW-MRI was performed at 1.5 T, and maps of the apparent diffusion coefficient (ADC) were produced with in-house-made software developed in Matlab. Pimonidazole was used as a hypoxia marker. Tumor cell density and hypoxic fraction were assessed by quantitative analysis of histological sections. IFP was measured with a Millar catheter. Metastatic propensity was determined by examining tumor-bearing mice for pulmonary micrometastases post mortem. RESULTS: ADC decreased with increasing tumor cell density, independent of whether the A-07 and R-18 data were analyzed separately or together. In the A-07 line, ADC decreased with increasing hypoxic fraction and increasing IFP and was lower in metastatic than in nonmetastatic tumors, and in the R-18 line, ADC decreased with increasing hypoxic fraction. There was a strong inverse correlation between ADC and hypoxic fraction as well as between ADC and IFP across the two tumor lines, primarily because low ADC as well as high hypoxic fraction and high IFP were associated with high cell density. CONCLUSION: Low ADC is a potentially useful biomarker of poor prognosis in cancer, since low ADC is mainly a consequence of high cell density, and high cell density may lead to increased hypoxia and interstitial hypertension and, therefore, increased microenvironment-associated metastasis.
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Imagen de Difusión por Resonancia Magnética/métodos , Líquido Extracelular/metabolismo , Melanoma Experimental/patología , Melanoma Experimental/secundario , Animales , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Abstract Background. A high fraction of stroma in malignant tissues is associated with tumor progression, metastasis, and poor prognosis. Possible correlations between the stromal and physiologic microenvironments of tumors and the potential of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in quantification of the stromal microenvironment were investigated in this study. Material and methods. CK-160 cervical carcinoma xenografts were used as preclinical tumor model. A total of 43 tumors were included in the study, and of these tumors, 17 were used to search for correlations between the stromal and physiologic microenvironments, 11 were subjected to DCE-MRI, and 15 were subjected to DW-MRI. DCE-MRI and DW-MRI were carried out at 1.5 T with a clinical MR scanner and a slotted tube resonator transceiver coil constructed for mice. Fraction of connective tissue (CTFCol) and fraction of hypoxic tissue (HFPim) were determined by immunohistochemistry. A Millar SPC 320 catheter was used to measure tumor interstitial fluid pressure (IFP). Results. CTFCol showed a positive correlation to IFP and an inverse correlation to HFPim. The apparent diffusion coefficient assessed by DW-MRI was inversely correlated to CTFCol, whereas no correlation was found between DCE-MRI-derived parameters and CTFCol. Conclusion. DW-MRI is a potentially useful method for characterizing the stromal microenvironment of tumors.
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Tejido Conectivo/patología , Líquido Extracelular/fisiología , Gadolinio DTPA , Hipoxia/patología , Neoplasias del Cuello Uterino/patología , Anciano , Animales , Biomarcadores de Tumor/análisis , Medios de Contraste , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Técnicas para Inmunoenzimas , Metástasis Linfática , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Presión , Células del Estroma/patología , Trasplante Heterólogo , Microambiente Tumoral , Neoplasias del Cuello Uterino/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Improvements in treatment outcome for patients with locally advanced cervical cancer (LACC) require a better classification of patients according to their risk of recurrence. We investigated whether an imaging-based approach, combining pretreatment hypoxia and tumor response during therapy, could improve risk classification. MATERIAL AND METHODS: Ninety-three LACC patients with T2-weigthed (T2W)-, dynamic contrast enhanced (DCE)- and diffusion weighted (DW)-magnetic resonance (MR) images acquired before treatment, and T2W- and, for 64 patients, DW-MR images, acquired at brachytherapy, were collected. Pretreatment hypoxic fraction (HFpre) was determined from DCE- and DW-MR images using the consumption and supply-based hypoxia (CSH)-imaging method. Volume regression at brachytherapy was assessed from T2W-MR images and combined with HFpre. In 17 patients with adequate DW-MR images at brachytherapy, the apparent diffusion coefficient (ADC), reflecting tumor cell density, was calculated. Change in ADC during therapy was combined with volume regression yielding functional regression as explorative response measure. Endpoint was disease free survival (DFS). RESULTS: HFpre was the strongest predictor of DFS, but a significant correlation with outcome was found also for volume regression. The combination of HFpre and volume regression showed a stronger association with DFS than HFpre alone. Patients with disease recurrence were selected to either the intermediate- or high-risk group with a 100 % accuracy. Functional regression showed a stronger correlation to HFpre than volume regression. CONCLUSION: The combination of pretreatment hypoxia and volume regression at brachytherapy improved patient risk classification. Integration of ADC with volume regression showed promise as a new tumor response parameter.
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Braquiterapia , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/diagnóstico por imagen , Braquiterapia/métodos , Braquiterapia/efectos adversos , Persona de Mediana Edad , Medición de Riesgo , Adulto , Anciano , Imagen de Difusión por Resonancia Magnética/métodos , Hipoxia Tumoral , Imagen por Resonancia Magnética/métodos , Anciano de 80 o más AñosRESUMEN
INTRODUCTION: To develop and validate a T2-weighted magnetic resonance imaging (MRI)-based radiomic signature associated with disease-free survival (DFS) in locally advanced cervical cancer. MATERIALS AND METHODS: The study comprised a training dataset of 132 patients (93 Norwegian; 39 The Cancer Imaging Archive (TCIA) and an independent validation Canadian dataset of 199 patients with FIGO stage IB-IVA cervical cancer treated with chemoradiation. Radiomic features were extracted using PyRadiomics. A radiomic signature was developed based on a multivariable radiomic prognostic model for DFS built using the training dataset, with minimal redundancy maximum relevancy feature selection method. Univariate and multivariable Cox regression analyses were then conducted to examine the association of the derived radiomic signature with DFS. RESULTS: A radiomic signature was prognostic for DFS in the training cohort (Norwegian hazard ratio [HR] 5.54, p = 0.002; TCIA HR 3.59, p = 0.04). The radiomic signature remained independently associated with DFS (HR 3.70, p = 0.004) when adjusted for stage and tumor volume. The radiomic signature was also prognostic for DFS in the validation cohort, both on univariate analysis (HR 2.22, p = 0.003), and multivariable analysis adjusted for stage and tumor volume (HR 1.84, p = 0.04). The 4-year DFS rates of patients with radiomic signature score > 0 vs ≤ 0 were 48.2 % vs 87.9 %, and 56.4 % vs 80.8 % for training and validation cohorts respectively. CONCLUSION: An MRI-based radiomic signature can be used as a prognostic biomarker for DFS in patients with locally advanced cervical cancer undergoing chemoradiation.
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BACKGROUND: Cancer patients showing highly elevated interstitial fluid pressure (IFP) in the primary tumor may benefit from particularly aggressive treatment. There is some evidence that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful non-invasive method for providing information on the IFP of tumors. The purpose of this preclinical study was to investigate whether any association between DCE-MRI-derived parametric images and tumor IFP can be strengthened by using MR contrast agents with higher molecular weights than that of Gd-DTPA. MATERIAL AND METHODS: A-07 human melanoma xenografts were used as preclinical models of human cancer. Three contrast agents were compared: Gd-DTPA (0.55 kDa), P846 (3.5 kDa), and gadomelitol (6.5 kDa). A total of 46 tumors were subjected to DCE-MRI and subsequent measurement of IFP. Parametric images of K(trans) (the volume transfer constant of the contrast agent) and v(e) (the fractional distribution volume of the contrast agent) were produced by pharmacokinetic analysis of the DCE-MRI series. RESULTS: Significant inverse correlations were found between median K(trans) and IFP for Gd-DTPA (p = 0.0076; R(2) = 0.46; n = 14) and P846 (p = 0.0042; R(2) = 0.45; n = 16), whereas there was no correlation between median K(trans) and IFP for gadomelitol (p > 0.05; n = 16). Significant correlation between median v(e) and IFP was not found for any of the contrast agents (p > 0.05 for Gd-DTPA, P846, and gadomelitol). CONCLUSION: K(trans) images, but not v(e) images, derived by pharmacokinetic analysis of DCE-MRI data for low-molecular-weight contrast agents may provide information on the IFP of tumors. Any association between K(trans) and IFP cannot be expected to be improved by using contrast agents with higher molecular weights than those of Gd-DTPA and P846.
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Medios de Contraste/farmacocinética , Líquido Extracelular , Imagen por Resonancia Magnética/métodos , Neoplasias/diagnóstico por imagen , Animales , Línea Celular Tumoral , Medios de Contraste/química , Femenino , Gadolinio DTPA/farmacocinética , Humanos , Melanoma/diagnóstico por imagen , Melanoma/metabolismo , Melanoma/patología , Melanoma/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Peso Molecular , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/fisiopatología , Presión , Radiografía , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/fisiopatologíaRESUMEN
BACKGROUND: Gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a useful non-invasive method for providing biomarkers for personalized cancer treatment. In this preclinical study, we investigated whether Gd-DTPA-based DCE-MRI may have the potential to differentiate between poorly and highly metastatic tumors. MATERIAL AND METHODS: CK-160 cervical carcinoma and V-27 melanoma xenografts were used as tumor models. Fifty-six tumors were imaged, and parametric images of K(trans) (the volume transfer constant of Gd-DTPA) and v(e) (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The host mice were examined for lymph node metastases immediately after the DCE-MRI. RESULTS: Highly metastatic tumors showed lower values for median K(trans) than poorly metastatic tumors (p = 0.00033, CK-160; p < 0.00001, V-27). Median v(e) was lower for highly than for poorly metastatic V-27 tumors (p = 0.047), but did not differ significantly between metastatic and non-metastatic CK-160 tumors (p > 0.05). CONCLUSION: This study supports the clinical attempts to establish DCE-MRI as a method for providing biomarkers for tumor aggressiveness and suggests that tumors showing low K(trans) and low ve values may have high probability of lymphogenous metastatic dissemination.
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Medios de Contraste , Gadolinio DTPA , Imagen por Resonancia Magnética/métodos , Melanoma/patología , Neoplasias Cutáneas/patología , Neoplasias del Cuello Uterino/patología , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Trasplante de Neoplasias , Planificación de la Radioterapia Asistida por Computador/métodosRESUMEN
BACKGROUND/AIM: Radiomics involves high throughput extraction of mineable precise quantitative imaging features that serve as non-invasive prognostic or predictive biomarkers. High levels of hypoxia are associated with a poorer prognosis in prostate cancer and limit radiation therapy efficacy. Most patients with prostate cancer undergo magnetic resonance imaging (MRI) as a part of their diagnostics, and T2 imaging is the most utilised imaging method. The aim of this study was to determine whether hypoxia in prostate tumors could be identified using a radiomics model extracted from T2-weighted MR images. MATERIALS AND METHODS: Eighty eight intermediate or high-risk prostate cancer patients were evaluated. Prior to radical prostatectomy, all patients received pimonidazole (PIMO). PIMO hypoxic scores were assigned in whole-mount sections from prostatectomy specimens by an experienced pathologist who was blinded to MRI. The region of interest used for radiomics analysis included the prostatic index tumor. Radiomics extraction yielded 165 features using a special evaluation version of RadiomiX [RadiomiX Research Toolbox version 20180831 (OncoRadiomics SA, Liège, Belgium)] for non-clinical use. Multivariable logistic regression with Elastic Net regularization was utilised using 10 times repeated 10-fold cross-validation to select the best model hyperparameters, optimizing for area under the receiver operating characteristic curve (AUC). RESULTS: The average (out of sample) performance based on the repeated cross validation using the ONESE model yielded an AUC of 0.60±0.2. Shape-based features were the most prominent in the model. CONCLUSION: The development of a radiomics hypoxia model using T2 weighted MR images, standard in the staging of prostate cancer, is possible.
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Nitroimidazoles , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodos , Próstata/patología , Estudios RetrospectivosRESUMEN
Anti-VEGF (vascular endothelial growth factor) treatment improves response rates, but not progression-free or overall survival in advanced breast cancer. It has been suggested that subgroups of patients may benefit from this treatment; however, the effects of adding anti-VEGF treatment to a standard chemotherapy regimen in breast cancer patients are not well studied. Understanding the effects of the anti-vascular treatment on tumor vasculature may provide a selection of patients that can benefit. The aim of this study was to study the vascular effect of bevacizumab using clinical dynamic contrast-enhanced MRI (DCE-MRI). A total of 70 women were randomized to receive either chemotherapy alone or chemotherapy with bevacizumab for 25 weeks. DCE-MRI was performed at baseline and at 12 and 25 weeks, and in addition 25 of 70 patients agreed to participate in an early MRI after one week. Voxel-wise pharmacokinetic analysis was performed using semi-quantitative methods and the extended Tofts model. Vascular architecture was assessed by calculating the fractal dimension of the contrast-enhanced images. Changes during treatment were compared with baseline and between the treatment groups. There was no significant difference in tumor volume at any point; however, DCE-MRI parameters revealed differences in vascular function and vessel architecture. Adding bevacizumab to chemotherapy led to a pronounced reduction in vascular DCE-MRI parameters, indicating decreased vascularity. At 12 and 25 weeks, the difference between the treatment groups is severely reduced.
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BACKGROUND AND PURPOSE: The biology behind individual hypoxia levels in patient tumors is poorly understood. Here, we used radiogenomics to identify associations between magnetic resonance imaging (MRI)-based hypoxia levels and biological processes derived from gene expression data in prostate cancer. MATERIALS AND METHODS: For 85 prostate cancer patients, MRI-based hypoxia images were constructed by combining diffusion-weighted images reflecting oxygen consumption and supply. The ability to differentiate hypoxia levels in these images was verified by comparison with matched biopsy sections stained for the hypoxia marker pimonidazole. For MRI-defined hypoxia levels, corresponding hypoxic fractions were calculated and correlated with biopsy gene expression profiles. Biological processes were predicted by gene set enrichment analysis (GSEA) and validated by immunohistochemistry (Ki67 proliferation marker, reactive stroma grade) and RT-PCR (MYC). RESULTS: Genes with correlation between expression level and hypoxic fraction were identified for 56 MRI-based hypoxia levels. At all levels, GSEA identified proliferation as the predominant biological process enriched among the correlating genes. Two independent proliferative gene signatures were developed. The Peak1 signature, upregulated at moderate/severe hypoxia, reflected MYC upregulation and high Ki67-proliferation index of cancer cells in pimonidazole-positive regions. The Peak2 signature, upregulated at mild to non-hypoxic levels, was associated with fibroblast gene signature and reactive stroma grade. High scores of both Peak1 and Peak2 indicated elevated risk of biochemical recurrence in multiple cohorts. CONCLUSION: Radiogenomics identified two gene expression programs activated at different hypoxia levels, reflecting proliferation of cancer cells and stroma cells. Genes involved in these programs could be candidate targets for intervention.
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BACKGROUND: High interstitial fluid pressure (IFP) in the primary tumor is associated with poor disease-free survival in locally advanced cervical carcinoma. A noninvasive assay is needed to identify cervical cancer patients with highly elevated tumor IFP because these patients may benefit from particularly aggressive treatment. It has been suggested that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as contrast agent may provide useful information on the IFP of cervical carcinomas. In this preclinical study, we investigated whether DCE-MRI with contrast agents with higher molecular weights (MW) than Gd-DTPA would be superior to Gd-DTPA-based DCE-MRI. METHODS: CK-160 human cervical carcinoma xenografts were subjected to DCE-MRI with Gd-DTPA (MW of 0.55 kDa) or gadomelitol (MW of 6.5 kDa) as contrast agent before tumor IFP was measured invasively with a Millar SPC 320 catheter. The DCE-MRI was carried out at a spatial resolution of 0.23 × 0.23 × 2.0 mm³ and a time resolution of 14 s by using a 1.5-T whole-body scanner and a slotted tube resonator transceiver coil constructed for mice. Parametric images were derived from the DCE-MRI recordings by using the Tofts iso-directional transport model and the Patlak uni-directional transport model. RESULTS: When gadomelitol was used as contrast agent, significant positive correlations were found between the parameters of both pharmacokinetic models and tumor IFP. On the other hand, significant correlations between DCE-MRI-derived parameters and IFP could not be detected with Gd-DTPA as contrast agent. CONCLUSION: Gadomelitol is a superior contrast agent to Gd-DTPA in DCE-MRI of the IFP of CK-160 cervical carcinoma xenografts. Clinical studies attempting to develop DCE-MRI-based assays of the IFP of cervical carcinomas should involve contrast agents with higher MW than Gd-DTPA.
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Carcinoma/diagnóstico , Medios de Contraste , Líquido Extracelular/fisiología , Gadolinio DTPA , Compuestos Heterocíclicos , Imagen por Resonancia Magnética/métodos , Compuestos Organometálicos , Neoplasias del Cuello Uterino/diagnóstico , Animales , Carcinoma/patología , Carcinoma/fisiopatología , Medios de Contraste/farmacocinética , Evaluación Preclínica de Medicamentos , Femenino , Gadolinio DTPA/farmacocinética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Presión , Trasplante Heterólogo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/fisiopatologíaRESUMEN
BACKGROUND: The prognosis is particularly poor for patients with advanced squamous cell carcinoma of the uterine cervix when the primary tumor has developed severe physiological abnormalities. The impact of the physiological microenvironment of the primary tumor on lymph node metastasis was investigated in this preclinical study. MATERIAL AND METHODS: Xenografted tumors of two human cervical carcinoma lines (CK-160 and TS-415) transplanted into BALB/c nu/nu mice were included in the study. The fraction of radiobiologically hypoxic cells (HF(Rad)), interstitial fluid pressure (IFP), and extracellular pH (pH(e)) were measured in 22 CK-160 tumors and 16 TS-415 tumors and related to the metastatic status of the host mice. RESULTS: In CK-160, HF(Rad) was significantly higher in the metastatic than in the nonmetastatic tumors, whereas the metastatic and nonmetastatic tumors did not differ significantly in IFP or pH(e). In TS-415, IFP was significantly higher in the tumors that metastasized than in those that did not metastasize, whereas the tumors of the metastasis-positive and metastasis-negative mice did not differ significantly in HF(Rad) or pH(e). CONCLUSION: Lymph node metastasis is associated with abnormalities in the physiological microenvironment of the primary tumor in cervical carcinoma xenografts, and tumor line-specific mechanisms are probably involved.
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Carcinoma de Células Escamosas/patología , Hipoxia de la Célula , Líquido Extracelular , Neoplasias Pélvicas/secundario , Microambiente Tumoral , Neoplasias del Cuello Uterino/patología , Animales , Femenino , Humanos , Concentración de Iones de Hidrógeno , Metástasis Linfática , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , PronósticoRESUMEN
A phase II trial, investigating whether the antidiabetic drug metformin could reduce hypoxia in cervical cancer, used imaging to preselect patients and test the biological hypothesis behind the drug effect. This trial design would be of importance for the implementation of targeted treatment in the clinic. See related article by Han et al., p. 5263.
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Metformina , Neoplasias del Cuello Uterino , Femenino , Humanos , Metformina/uso terapéutico , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Hipoglucemiantes/uso terapéuticoRESUMEN
Tumours exhibit abnormal interstitial structures and vasculature function often leading to impaired and heterogeneous drug delivery. The disproportionate spatial accumulation of a drug in the interstitium is determined by several microenvironmental properties (blood vessel distribution and permeability, gradients in the interstitial fluid pressure). Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the quantification of tracer perfusion based on contrast enhancement measured with non-invasive imaging techniques. An advanced cross-voxel exchange model (CVXM) was recently developed to provide a comprehensive description of tracer extravasation as well as advection and diffusion based on cross-voxel tracer kinetics (Sinnoet al2021). Transport parameters were derived from DCE-MRI of twenty TS-415 human cervical carcinoma xenografts by using CVXM. Tracer velocity flows were measured at the tumour periphery (mean 1.78-5.82µm.s-1) pushing the contrast outward towards normal tissue. These elevated velocity measures and extravasation rates explain the heterogeneous distribution of tracer across the tumour and its accumulation at the periphery. Significant values for diffusivity were deduced across the tumours (mean 152-499µm2.s-1). CVXM resulted in generally smaller values for the extravasation parameterKext(mean 0.01-0.04 min-1) and extravascular extracellular volume fractionve(mean 0.05-0.17) compared to the standard Tofts parameters, suggesting that Toft model underestimates the effects of inter-voxel exchange. The ratio of Tofts' extravasation parameters over CVXM's was significantly positively correlated to the cross-voxel diffusivity (P< 0.0001) and velocity (P= 0.0005). Tofts' increasedvemeasurements were explained using Sinnoet al(2021)'s theoretical work. Finally, a scan time of 15 min renders informative estimations of the transport parameters. However, a duration as low as 7.5 min is acceptable to recognize the spatial variation of transport parameters. The results demonstrate the potential of utilizing CVXM for determining metrics characterizing the exchange of tracer between the vasculature and the tumour tissue. Like for many earlier models, additional work is strongly recommended, in terms of validation, to develop more confidence in the results, motivating future laboratory work in this regard.
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Medios de Contraste , Neoplasias del Cuello Uterino , Femenino , Humanos , Medios de Contraste/química , Imagen por Resonancia Magnética/métodos , Imagen de Difusión por Resonancia Magnética , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/patología , DifusiónRESUMEN
BACKGROUND AND PURPOSE: MRI, applying dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) sequences, and 18F-fluorodeoxyglucose (18F-FDG) PET/CT provide information about tumor aggressiveness that is unexploited in treatment of locally advanced cervical cancer (LACC). We investigated the potential of a multimodal combination of imaging parameters for classifying patients according to their risk of recurrence. MATERIALS AND METHODS: Eighty-two LACC patients with diagnostic MRI and FDG-PET/CT, treated with chemoradiotherapy, were collected. Thirty-eight patients with MRI only were included for validation of MRI results. Endpoints were survival (disease-free, cancer-specific, overall) and tumor control (local, locoregional, distant). Ktrans, reflecting vascular function, apparent diffusion coefficient (ADC), reflecting cellularity, and standardized uptake value (SUV), reflecting glucose uptake, were extracted from DCE-MR, DW-MR and FDG-PET images, respectively. By applying an oxygen consumption and supply-based method, ADC and Ktrans parametric maps were voxel-wise combined into hypoxia images that were used to determine hypoxic fraction (HF). RESULTS: HF showed a stronger association with outcome than the single modality parameters. This association was confirmed in the validation cohort. Low HF identified low-risk patients with 95% precision. Based on the 50th SUV-percentile (SUV50), patients with high HF were divided into an intermediate- and high-risk group with high and low SUV50, respectively. This defined a multimodality biomarker, HF/SUV50. HF/SUV50 increased the precision of detecting high-risk patients from 41% (HF alone) to 57% and showed prognostic significance in multivariable analysis for all endpoints. CONCLUSION: Multimodal combination of MR- and FDG-PET/CT-images improves classification of LACC patients compared to single modality images and clinical factors.
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Fluorodesoxiglucosa F18 , Neoplasias del Cuello Uterino , Femenino , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/terapia , Radiofármacos , Tomografía Computarizada por Rayos X/métodos , Tomografía de Emisión de Positrones/métodos , Quimioradioterapia , Imagen por Resonancia Magnética/métodos , Imagen de Difusión por Resonancia MagnéticaRESUMEN
The purpose of the present study is to investigate if consumption and supply hypoxia (CSH) MR-imaging can depict breast cancer hypoxia, using the CSH-method initially developed for prostate cancer. Furthermore, to develop a generalized pan-cancer application of the CSH-method that doesn't require a hypoxia reference standard for training the CSH-parameters. In a cohort of 69 breast cancer patients, we generated, based on the principles of intravoxel incoherent motion modelling, images reflecting cellular density (apparent diffusion coefficient; ADC) and vascular density (perfusion fraction; fp). Combinations of the information in these images were compared to a molecular hypoxia score made from gene expression data, aiming to identify a way to apply the CSH-methodology in breast cancer. Attempts to adapt previously proposed models for prostate cancer included direct transfers and model parameter rescaling. A novel approach, based on rescaling ADC and fp data to give more nuanced response in the relevant physiologic range, was also introduced. The new CSH-method was validated in a prostate cancer cohort with known hypoxia status. The proposed CSH-method gave estimates of hypoxia that was strongly correlated to the molecular hypoxia score in breast cancer, and hypoxia as measured in pathology slices stained with pimonidazole in prostate cancer. The generalized approach to CSH-imaging depicted hypoxia in both breast and prostate cancers and requires no model training. It is easy to implement using readily available technology and encourages further investigation of CSH-imaging in other cancer entities and in other settings, with the goal being to overcome hypoxia-induced resistance to treatment.
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Many patients with locally advanced cervical cancer experience recurrence within the radiation field after chemoradiotherapy. Biomarkers of tumor radioresistance are required to identify patients in need of intensified treatment. Here, the biomarker potential of miR-200 family members was investigated in this disease. Also, involvement of tumor hypoxia in the radioresistance mechanism was determined, using a previously defined 6-gene hypoxia classifier. miR-200 expression was measured in pretreatment tumor biopsies of an explorative cohort (n = 90) and validation cohort 1 (n = 110) by RNA sequencing. Publicly available miR-200 data of 79 patients were included for the validation of prognostic significance. A score based on expression of the miR-200a/b/-429 (miR-200a, miR-200b, and miR-429) cluster showed prognostic significance in all cohorts. The score was significant in multivariate analysis of central pelvic recurrence. No association with distant recurrence or hypoxia status was found. Potential miRNA target genes were identified from gene expression profiles and showed enrichment of genes in extracellular matrix organization and cell adhesion. miR-200a/b/-429 overexpression had a pronounced radiosensitizing effect in tumor xenografts, whereas the effect was minor in vitro. In conclusion, miR-200a/b/-429 downregulation is a candidate biomarker of central pelvic recurrence and seems to predict cell adhesion-mediated tumor radioresistance independent of clinical markers and hypoxia.
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MicroARNs , Neoplasias del Cuello Uterino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Hipoxia de la Célula , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier.
RESUMEN
BACKGROUND: Emerging biomarkers from medical imaging or molecular characterization of tumour biopsies open up for combining the two and exploiting their synergy in treatment planning of cancer patients. We generated a paired data set of imaging- and gene-based hypoxia biomarkers in cervical cancer, appraised the influence of intratumour heterogeneity in patient classification, and investigated the benefit of combining the methodologies in prediction of chemoradiotherapy failure. METHODS: Hypoxic fraction from dynamic contrast enhanced (DCE)-MR images and an expression signature of six hypoxia-responsive genes were assessed as imaging- and gene-based biomarker, respectively in 118 patients. FINDINGS: Dichotomous biomarker cutoff to yield similar hypoxia status by imaging and genes was defined in 41 patients, and the association was validated in the remaining 77 patients. The two biomarkers classified 75% of 118 patients with the same hypoxia status, and inconsistent classification was not related to imaging-defined intratumour heterogeneity in hypoxia. Gene-based hypoxia was independent on tumour cell fraction in the biopsies and showed minor heterogeneity across multiple samples in 9 tumours. Combining imaging- and gene-based classification gave a significantly better prediction of PFS than one biomarker alone. A combined dichotomous biomarker optimized in 77 patients showed a large separation in PFS between more and less hypoxic tumours, and separated the remaining 41 patients with different PFS. The combined biomarker showed prognostic value together with tumour stage in multivariate analysis. INTERPRETATION: Combining imaging- and gene-based biomarkers may enable more precise and informative assessment of hypoxia-related chemoradiotherapy resistance in cervical cancer. FUNDING: Norwegian Cancer Society, South-Eastern Norway Regional Health Authority, and Norwegian Research Council.
Asunto(s)
Biomarcadores de Tumor/genética , Proteínas de Neoplasias/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia/efectos adversos , Diagnóstico por Imagen , Femenino , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Noruega/epidemiología , Pronóstico , Supervivencia sin Progresión , Resultado del Tratamiento , Hipoxia Tumoral/efectos de los fármacos , Hipoxia Tumoral/efectos de la radiación , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/genéticaRESUMEN
Tumor hypoxia levels range from mild to severe and have different biological and therapeutical consequences but are not easily assessable in patients. Here we present a method based on diagnostic dynamic contrast enhanced (DCE) MRI that reflects a continuous range of hypoxia levels in patients with tumors of cervical cancer. Hypoxia images were generated using an established approach based on pixel-wise combination of DCE-MRI parameters ν e and K trans, representing oxygen consumption and supply, respectively. Using two tumor models, an algorithm to retrieve surrogate measures of hypoxia levels from the images was developed and validated by comparing the MRI-defined levels with hypoxia levels reflected in pimonidazole-stained histologic sections. An additional indicator of hypoxia levels in patient tumors was established on the basis of expression of nine hypoxia-responsive genes; a strong correlation was found between these indicator values and MRI-defined hypoxia levels in 63 patients. Chemoradiotherapy outcome of 74 patients was most strongly predicted by moderate hypoxia levels, whereas more severe or milder levels were less predictive. By combining gene expression profiles and MRI-defined hypoxia levels in cancer hallmark analysis, we identified a distribution of levels associated with each hallmark; oxidative phosphorylation and G2-M checkpoint were associated with moderate hypoxia, epithelial-to-mesenchymal transition, and inflammatory responses with significantly more severe levels. At the mildest levels, IFN response hallmarks together with HIF1A protein expression by IHC appeared significant. Thus, our method visualizes the distribution of hypoxia levels within patient tumors and has potential to distinguish levels of different prognostic and biological significance. SIGNIFICANCE: These findings present an approach to image a continuous range of hypoxia levels in tumors and demonstrate the combination of imaging with molecular data to better understand the biology behind these different levels.