Tord Hompland

Magnetic resonance imaging identifies early effects of sunitinib treatment in human melanoma xenografts.

BackgroundAntiangiogenic treatment may change the tumor microenvironment and hence influence the effect of conventional therapies. The potential of diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced MRI (DCE-MRI) in assessing microenvironmental effects of sunitinib treatment was investigated in this preclinical study.MethodsSunitinib-treated and untreated A-07 tumors were subjected to DW-MRI and DCE-MRI, and parametric images of ADC and Ktrans were produced. Microvascular density, hypoxic fraction, and necrotic fraction were assessed from immunohistochemical preparations, and tumor interstitial fluid pressure (IFP) was assessed with probe measurement.ResultsSunitinib-treated tumors showed reduced microvascular density, increased hypoxic fraction, increased necrotic fraction, increased ADC, and reduced Ktrans, but did not differ from untreated tumors in growth rate and IFP.ConclusionsSunitinib treatment affected the tumor microenvironment without affecting tumor size. DW-MRI and DCE-MRI were sensitive to the sunitinib-induced changes in the tumor microenvironment.

DCE-MRI of the hypoxic fraction, radioresponsiveness, and metastatic propensity of cervical carcinoma xenografts

BACKGROUND AND PURPOSE Locoregional treatment failure and poor survival rates are associated with extensive hypoxia in the primary tumor in advanced cervical carcinoma. The potential of gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the hypoxic fraction, radioresponsiveness, and metastatic propensity of cervical carcinomas was investigated in this preclinical study. MATERIALS AND METHODS CK-160 and TS-415 cervical carcinoma xenografts were used as tumor models. DCE-MRI was carried out at 1.5 T, and parametric images of K(trans) and v(e) were produced by pharmacokinetic analysis of the DCE-MRI series. Pimonidazole was used as a hypoxia marker. Tumor radioresponsiveness was determined by irradiating tumors with five fractions of 4 Gy in 48 h and measuring cell survival in vitro. Metastatic propensity was determined by examining host mice for tumor growth in lymph nodes. RESULTS Low values of K(trans) were associated with extensive hypoxia and radiation resistance in tumors of both lines and with high incidence of metastases in CK-160 tumors. Associations between ve and hypoxia, radioresponsiveness, or metastatic propensity were not found in any of the tumor lines. CONCLUSION K(trans) is a potentially useful biomarker of tumor hypoxia, radiation resistance, and metastatic growth in advanced cervical carcinoma.

Microenvironment-associated lymph node metastasis of human cervical carcinoma xenografts

Abstract 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 (HFRad), interstitial fluid pressure (IFP), and extracellular pH (pHe) 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, HFRad was significantly higher in the metastatic than in the nonmetastatic tumors, whereas the metastatic and nonmetastatic tumors did not differ significantly in IFP or pHe. 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 HFRad or pHe. 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.

Connective tissue of cervical carcinoma xenografts: Associations with tumor hypoxia and interstitial fluid pressure and its assessment by DCE-MRI and DW-MRI

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.

Peritumoral interstitial fluid flow velocity predicts survival in cervical carcinoma

BACKGROUND AND PURPOSE High tumor interstitial fluid pressure (IFP) is associated with poor outcome in locally advanced carcinoma of the uterine cervix. We have recently developed a noninvasive assay of the IFP of tumors, and in this assay, the outward interstitial fluid flow velocity at the tumor surface (v0) is measured by Gd-DTPA-based DCE-MRI and used as a parameter for IFP. Here, we investigated the independent prognostic significance of v0 in cervical cancer patients given cisplatin-based concurrent chemoradiotherapy with curative intent. PATIENTS The study involved 62 evaluable patients from a cohort of 74 consecutive patients (Stage IB through IIIB) with a median follow-up of 5.5 years. RESULTS The actuarial disease-free survival (DFS) and overall survival (OS) at 5 years were 67% and 76%, respectively. Significant associations were found between v0 dichotomized about the median value and DFS and OS, both in the total patient cohort and a subcohort of 40 Stage IIB patients. Multivariate analysis involving stage, tumor volume, lymph node status, and v0 revealed that only v0 provided independent prognostic information about DFS and OS. CONCLUSION This investigation demonstrates a strong, independent prognostic impact of the pretreatment peritumoral fluid flow velocity in cervical cancer.

Short-term pretreatment DCE-MRI in prediction of outcome in locally advanced cervical cancer.

BACKGROUND AND PURPOSE Several investigators have indicated that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has the potential to provide biomarkers for personalized treatment of cervical carcinoma. However, some clinical studies have suggested that treatment failure is associated with low tumor signal enhancement, whereas others have reported associations between high signal enhancement and poor outcome. The purpose of this investigation was to clear up these conflicting reports and to provide a method for identifying biomarkers that easily can be implemented in routine DCE-MRI diagnostics. METHODS The study involved 85 patients (FIGO stage IB through IVA) treated with concurrent chemoradiotherapy. Low-enhancing tumor volume (LETV) and low-enhancing tumor fraction (LETF), defined as the volume and fractional volume of low-enhancing voxels, respectively, were calculated from signal intensities recorded within 1 min after contrast administration by using two methods reported to give conflicting conclusions. RESULTS Multivariate analysis involving tumor volume, lymph node status, FIGO stage, and LETV or LETF revealed that LETV and LETF provided independent prognostic information on treatment outcome, independent of the method of calculation. CONCLUSION Low signal enhancement is associated with poor prognosis in cervical carcinoma, and biomarkers predicting poor outcome can be provided by short-term DCE-MRI without advanced image analysis.

Dynamic contrast-enhanced magnetic resonance imaging of the metastatic potential of tumors: A preclinical study of cervical carcinoma and melanoma xenografts

Abstract 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 Ktrans (the volume transfer constant of Gd-DTPA) and ve (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 Ktrans than poorly metastatic tumors (p = 0.00033, CK-160; p < 0.00001, V-27). Median ve 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 Ktrans and low ve values may have high probability of lymphogenous metastatic dissemination.

Preclinical evaluation of Gd-DTPA and gadomelitol as contrast agents in DCE-MRI of cervical carcinoma interstitial fluid pressure

BackgroundHigh 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.MethodsCK-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.ResultsWhen 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.ConclusionGadomelitol 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.

Combined MR Imaging of Oxygen Consumption and Supply Reveals Tumor Hypoxia and Aggressiveness in Prostate Cancer Patients

The established role of hypoxia-induced signaling in prostate cancer growth, metastasis, and response to treatment suggests that a method to image hypoxia in tumors could aid treatment decisions. Here, we present consumption and supply-based hypoxia (CSH) imaging, an approach that integrates images related to oxygen consumption and supply into a single image. This integration algorithm was developed in patients with prostate cancer receiving hypoxia marker pimonidazole prior to prostatectomy. We exploited the intravoxel incoherent motion (IVIM) signal in diagnostic diffusion-weighted (DW) magnetic resonance (MR) images to generate separate images of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV). ADC and fBV correlated with cell density (CD) and blood vessel density (BVD) in histology and whole-mount sections from 35 patients, thus linking ADC to oxygen consumption and fBV to oxygen supply. Pixel-wise plots of ADC versus fBV were utilized to predict the hypoxia status of each pixel in a tumor and to visualize the predicted value in a single image. The hypoxic fraction (HFDWI) of CSH images correlated strongly (R2 = 0.66; n = 41) with pimonidazole immunoscore (HSPimo); this relationship was validated in a second pimonidazole cohort (R2 = 0.54; n = 54). We observed good agreement between CSH images and pimonidazole staining in whole-mount sections. HFDWI correlated with tumor stage and lymph node status, consistent with findings for HSPimo Moreover, CSH imaging could be applied on histologic CD and BVD images, demonstrating transferability to a histopathology assay. Thus, CSH represents a robust approach for hypoxia imaging in prostate cancer that could easily be translated into clinical practice.Significance: These findings present a novel imaging strategy that indirectly measures tumor hypoxia and has potential application in a wide variety of solid tumors and other imaging modalities.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4774/F1.large.jpg Cancer Res; 78(16); 4774-85. ©2018 AACR.

DCE-MRI–Derived Measures of Tumor Hypoxia and Interstitial Fluid Pressure Predict Outcomes in Cervical Carcinoma

PURPOSE The poor outcome of locally advanced cervical cancer has been associated with extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor. In the present study, measures of tumor hypoxia and IFP were provided using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) and related to the treatment outcomes. METHODS AND MATERIALS The data from 54 cervical cancer patients treated with concurrent cisplatin-based chemoradiotherapy were studied. A low-enhancing tumor volume (LETV) and peritumoral fluid flow velocity (v0) were used as measures of tumor hypoxia and IFP, respectively. RESULTS Poor disease-free survival and overall survival were associated with large LETV and high v0. The multivariate analysis results suggested that the prognostic power of v0 and LETV is independent of established clinical prognostic factors and that the prognostic power of v0 is strong compared with that of LETV. The outcomes was especially poor for patients with a high v0 combined with a large LETV and especially good for those with a low v0 combined with a small LETV, with 5-year disease-free survival and overall survival of 13% versus 100%, respectively. CONCLUSIONS The outcome of locally advanced cervical carcinoma seems to be influenced strongly by the tumor IFP and to a lesser extent by tumor hypoxia. DCE-MRI might have the power to provide important biomarkers for the outcome of cervical cancer.