Sex differences in the physiological response to a demanding military field exercise.

PURPOSE: To investigate sex differences in the effect of a military field exercise on physical performance, body composition, and blood biomarkers. METHODS: Measurements were done in 23 male and 12 female conscripts before, and 0, 1, 3, 7, and 14 days after a 6-day military field exercise. RESULTS: During the field exercise, body mass decreased more in men (-6.5 ± 1.1 kg) than in women (-2.7 ± 0.7 kg), and muscle mass decreased only in men (-2.7 ± 1.0 kg). Body composition recovered within one week. Performance decreased, with no differences between men and women for countermovement jump (CMJ,-19 ± 8 vs. -18 ± 11%), medicine ball throw (MBT, -11 ± 7 vs. -11 ± 7%), and an anaerobic performance test (EVAC, -55 ± 22 vs. -47 ± 31%, men and women, respectively). MBT and EVAC performance recovered within two weeks, whereas CMJ performance was still reduced in men (-17 ± 6%) and women (-9 ± 8%) after two weeks recovery, with a larger reduction in men. Both men and women decreased [IGF-1] (-28 ± 9 vs. -41 ± 8%) and increased [cortisol] (26 ± 26 vs. 66 ± 93%, men and women, respectively) during the exercise. Most biomarkers returned to baseline values within one week. CONCLUSIONS: Men lost more body mass and muscle mass than women during a field exercise, but these differences did not lead to sex differences in changes in explosive strength and anaerobic performance. However, women recovered explosive strength in the legs faster than men.

How to measure CT image quality: variations in CT-numbers, uniformity and low contrast resolution for a CT quality assurance phantom.

PURPOSE: Quality assurance (QA) phantoms for testing different image quality parameters in computed tomography (CT) are commercially available. Such phantoms are also used as reference for acceptance in the specifications of CT-scanners. The aim of this study was to analyze the characteristics of the most commonly used QA phantom in CT: Catphan 500/504/600. METHODS: Nine different phantoms were scanned on the same day, on one CT-scanner with the same parameter settings. Interphantom variations in CT-number values, image uniformity and low contrast resolution were evaluated for the phantoms. Comparisons between manual image analysis and results obtained from the automatic evaluation software QAlite were performed. RESULTS: Some interphantom variations were observed in the low contrast resolution and the CT-number modules of the phantoms. Depending on the chosen regulatory framework, the variations in CT-numbers can be interpreted as substantial. The homogenous modules were found more invariable. However, the automatic image analysis software QAlite measures image uniformity differently than recommended in international standards, and will not necessarily give results in agreement with these standards. CONCLUSIONS: It is important to consider the interphantom variations in relation to ones framework, and to be aware of which phantom is used to study CT-numbers and low contrast resolution for a specific scanner. Comparisons with predicted values from manual and acceptance values should be performed with care and consideration. If automatic software-based evaluations are to be used, users should be aware that large differences can exist for the image uniformity testing.

Assessment of the interstitial fluid pressure of tumors by dynamic contrast-enhanced magnetic resonance imaging with contrast agents of different molecular weights.

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.

Dynamic contrast-enhanced-MRI of tumor hypoxia.

Patients with highly hypoxic primary tumors show increased frequency of locoregional treatment failure and poor survival rates and may benefit from particularly aggressive treatment. The potential of gadolinium diethylene-triamine penta-acetic acid-based dynamic contrast-enhanced-MRI in assessing tumor hypoxia was investigated in this preclinical study. Xenografted tumors of eight human melanoma lines were subjected to dynamic contrast-enhanced-MRI and measurement of the fraction of radiobiologically hypoxic cells and the fraction of pimonidazole-positive hypoxic cells. Tumor images of K(trans) (the volume transfer constant of gadolinium diethylene-triamine penta-acetic acid) and v(e) (the fractional distribution volume of gadolinium diethylene-triamine penta-acetic acid) were produced by pharmacokinetic analysis of the dynamic contrast-enhanced-MRI data, and K(trans) and v(e) frequency distributions of the non-necrotic tumor tissue were established and related to the extent of hypoxia. Tumors showing high K(trans) values and high v(e) values had low fractions of hypoxic cells, whereas tumors showing both low K(trans) values and low v(e) values had high hypoxic fractions. K(trans) differentiated better between tumors with low and high hypoxic fractions than did v(e). This study supports the current attempts to establish dynamic contrast-enhanced-MRI as a method for assessing the extent of hypoxia in human tumors, and it provides guidelines for the clinical development of valid assays.

Assessment of tumor radioresponsiveness and metastatic potential by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: It has been suggested that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide clinically useful biomarkers for personalized cancer treatment. In this preclinical study, we investigated the potential of DCE-MRI as a noninvasive method for assessing the radioresponsiveness and metastatic potential of tumors. METHODS AND MATERIALS: R-18 melanoma xenografts growing in BALB/c nu/nu mice were used as experimental tumor models. Fifty tumors were subjected to DCE-MRI, 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 tumors were irradiated after the DCE-MRI, either with a single dose of 10 Gy for detection of radiobiological hypoxia (30 tumors) or with five fractions of 4 Gy in 48 h for assessment of radioresponsiveness (20 tumors). The host mice were then euthanized and examined for lymph node metastases, and the primary tumors were resected for measurement of cell survival in vitro. RESULTS: Tumors with hypoxic cells showed significantly lower Ktrans values than tumors without significant hypoxia (p<0.0001, n=30), and Ktrans decreased with increasing cell surviving fraction for tumors given fractionated radiation treatment (p<0.0001, n=20). Tumors in metastasis-positive mice had significantly lower Ktrans values than tumors in metastasis-negative mice (p<0.0001, n=50). Significant correlations between ve and tumor hypoxia, radioresponsiveness, or metastatic potential could not be detected. CONCLUSIONS: R-18 tumors with low Ktrans values are likely to be resistant to radiation treatment and have a high probability of developing lymph node metastases. The general validity of these observations should be investigated further by studying preclinical tumor models with biological properties different from those of the R-18 tumors.

Assessment of tumor hypoxia and interstitial fluid pressure by gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging.

BACKGROUND AND PURPOSE: Extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor may cause resistance to radiation treatment and promote metastatic spread. The potential of gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the extent of hypoxia and the level of interstitial hypertension in tumors was investigated in this preclinical study. MATERIALS AND METHODS: Twenty-three A-07 tumors were subjected to DCE-MRI and subsequent measurement of IFP and fraction of pimonidazole-positive hypoxic tissue (HF(Pim)). Parametric tumor images of K(trans), v(e), and V(b)(Tofts) (Tofts model) and of K(i) and V(b)(Patlak) (Patlak model) were produced by pharmacokinetic analyses of the DCE-MRI series. RESULTS: There was no correlation between IFP and HF(Pim) in the tumors. K(trans) and K(i) decreased significantly with increasing HF(Pim), whereas V(b)(Tofts) and V(b)(Patlak) increased significantly with increasing IFP. CONCLUSION: Information on both the extent of hypoxia and the level of interstitial hypertension in A-07 tumors can be derived from a single DCE-MRI series by using gadomelitol as contrast agent.

Interstitial fluid pressure and vascularity of intradermal and intramuscular human tumor xenografts.

PURPOSE: High interstitial fluid pressure (IFP) in tumors has been shown to be associated with poor prognosis. Mechanisms underlying the intertumor heterogeneity in IFP were investigated in this study. METHODS AND MATERIALS: A-07 melanoma xenografts were transplanted intradermally or intramuscularly in BALB/c nu/nu mice. IFP was measured in the center of the tumors with a Millar catheter. Tumor blood perfusion and extracellular volume fraction were assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The necrotic fraction, vascular density, and vessel diameters of the tumors were determined by image analysis of histological preparations. RESULTS: Significant intertumor heterogeneity in IFP, blood perfusion, and microvascular morphology was observed whether the tumors were transplanted intradermally or intramuscularly. High IFP was mainly a consequence of high resistance to blood flow caused by low vessel diameters in either transplantation site. IFP decreased with increasing blood perfusion in intradermal tumors and increased with increasing blood perfusion in intramuscular tumors, mainly because the morphology of the tumor microvasculature differed systematically between the two tumor models. CONCLUSION: The potential of DCE-MRI as a noninvasive method for assessing the IFP of tumors may be limited because any relationship between IFP and blood perfusion may differ with the tumor growth site.

Differentiation between hypoxic and non-hypoxic experimental tumors by dynamic contrast-enhanced magnetic resonance imaging.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a useful method for detecting tumor hypoxia. In this study, we investigated whether DCE-MRI can differentiate between hypoxic and non-hypoxic experimental tumors. MATERIALS AND METHODS: Three tumor models with hypoxic tissue and three tumor models without hypoxic tissue were subjected to DCE-MRI. 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. Tumor oxygenation status was assessed by using a radiobiological assay and a pimonidazole-based immunohistochemical assay. Tumor response to fractionated irradiation (six fractions of 2Gy in 60h) was measured in vitro by using a clonogenic assay. RESULTS: Tumors with hypoxic regions were more resistant to radiation treatment than were tumors without hypoxia. K(trans) was significantly higher for radiation sensitive tumors without hypoxia than for radiation resistant tumors with hypoxic regions, whereas v(e) did not differ significantly between non-hypoxic and hypoxic tumors. CONCLUSION: This study supports the clinical attempts to establish DCE-MRI as a noninvasive method for providing useful biomarkers for personalized radiation therapy.

Quantitative assessment of hypoxia in melanoma xenografts by dynamic contrast-enhanced magnetic resonance imaging: intradermal versus intramuscular tumors.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a useful method for assessing the extent of hypoxia in tumors. In this study, we investigated whether differences in hypoxic fraction between tumors caused by the site of growth can be detected by DCE-MRI. MATERIALS AND METHODS: Intradermal and intramuscular A-07 tumors were subjected to DCE-MRI, histological analysis of microvascular characteristics, and measurement of hypoxic cell fractions using a radiobiological assay and a pimonidazole-based immunohistochemical assay. Parametric images of E·F (blood perfusion) and v(e) (extracellular volume fraction) were produced by pharmacokinetic analysis of the DCE-MRI series. RESULTS: The intramuscular tumors had 3-4-fold higher hypoxic fractions than the intradermal tumors, owing to a lower microvascular density. This difference in extent of hypoxia was not detectable in the parametric MR images. Most likely, larger vessel diameters compensated for the lower vessel density in the intramuscular tumors, resulting in E·F images that were similar to those of the intradermal tumors. CONCLUSION: Quantitative assessment of hypoxic fractions from parametric MR images may require tumor site-specific translational criteria.

Dynamic contrast-enhanced magnetic resonance imaging of tumors: preclinical validation of parametric images.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a valuable method for characterizing the physiological microenvironment of tumors and thus a promising method for individualizing cancer treatment. The aim of this study was to test the hypothesis that valid parametric images of the tumor microenvironment can be obtained by pharmacokinetic analysis of DCE-MRI series. Cells of four human melanoma xenograft lines (A-07, D-12, R-18 and T-22) were used as preclinical models of human cancer. DCE-MRI was performed at 1.5 T at a spatial resolution of 0.23 x 0.47 x 2.0 mm(3) and a time resolution of 14 s. Gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) was used as contrast agent. The DCE-MRI data were analyzed on a voxel-by-voxel basis by using a pharmacokinetic model recommended for analysis of clinical DCE-MRI series. Parametric DCE-MR images were compared with tumor blood perfusion measured by the (86)Rb uptake method, and fractional volume of the extravascular extracellular space assessed by analysis of histological preparations. Parametric images reflecting tumor blood perfusion and fractional volume of the extravascular extracellular space were obtained. The numerical values of the DCE-MRI-derived parameters were not significantly different from the absolute values of tumor blood perfusion or fractional volume of the extravascular extracellular space in any of the tumor lines. This study shows that DCE-MRI can provide valid quantitative parametric images of the tumor microenvironment in preclinical cancer models and thus supports the suggestion that DCE-MRI may be developed to be a clinically useful method for individualization of microenvironment-based cancer treatment, a possibility that merits increased clinical interest.

Human cervical carcinoma xenograft models for studies of the physiological microenvironment of tumors.

OBJECTIVE: To establish and characterize experimental tumor models of advanced squamous cell carcinoma of the uterine cervix. METHODS: Permanent cell lines (CK-160 and TS-415) were established from pelvic lymph node metastases of two cervical carcinoma patients. Xenografted tumors were initiated by inoculating 5 x 10(5) cells into the gastrocnemius muscle of BALB/c nu/nu mice. The tumors were characterized with respect to histological appearance, fraction of necrotic tissue (NF), pimonidazole hypoxic fraction (HF(Pim)), interstitial fluid pressure (IFP), extracellular pH (pH(e)), metastatic propensity, and radiation sensitivity. RESULTS: The xenografted tumors reflected the donor patients' tumors in histological appearance, metastatic propensity, and radiation sensitivity and showed significant intertumor heterogeneity in growth rate, NF, HF(Pim), IFP, and pH(e). CONCLUSIONS: CK-160 and TS-415 xenografts possess properties making them relevant models for studies of the physiological microenvironment of cervical carcinoma and its influence on metastatic dissemination and response to treatment.

Assessment of hypoxia in human cervical carcinoma xenografts by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: Patients with advanced cervical cancer and highly hypoxic primary tumors show increased frequency of locoregional treatment failure and poor disease-free and overall survival rates. The potential usefulness of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing tumor hypoxia noninvasively was investigated in the present preclinical study. METHODS AND MATERIALS: CK-160 and TS-415 human cervical carcinoma xenografts transplanted intramuscularly (i.m.) or subcutaneously (s.c.) in BALB/c nu/nu mice were subjected to DCE-MRI and measurement of fraction of radiobiologically hypoxic cells. Tumor images of K(trans) (the volume transfer constant of Gd-DTPA) and v(e) (the extracellular volume fraction of the imaged tissue) were produced by pharmacokinetic analysis of the DCE-MRI data. Fraction of radiobiologically hypoxic cells was measured by using the paired survival curve method. RESULTS: Fraction of radiobiologically hypoxic cells differed significantly among the four tumor groups. The mean values +/- SE were determined to be 44% +/- 7% (i.m. CK-160), 77% +/- 10% (s.c. CK-160), 23% +/- 5% (i.m. TS-415), and 52% +/- 6% (s.c. TS-415). The four tumor groups differed significantly also in K(trans), and there was an unambiguous inverse relationship between K(trans) and fraction of radiobiologically hypoxic cells. On the other hand, significant differences among the groups in v(e) could not be detected. CONCLUSIONS: The study supports the clinical development of DCE-MRI as a method for assessing the extent of hypoxia in carcinoma of the cervix.

Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure.

BACKGROUND AND PURPOSE: High interstitial fluid pressure (IFP) in the primary tumor has been shown to promote metastasis in melanoma xenografts and to predict for poor survival in cervical cancer patients. The potential usefulness of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessing tumor IFP noninvasively was investigated in the present study. MATERIALS AND METHODS: A-07 and R-18 melanoma xenografts with and without necrotic regions were subjected to DCE-MRI and subsequent measurement of IFP. Tumor images of E.F (E is the initial extraction fraction of Gd-DTPA and F is blood perfusion) and lambda (lambda is proportional to extracellular volume fraction) were produced by Kety analysis of DCE-MRI series. RESULTS: In tumors without necrosis, significant inverse correlations were found between E.F and IFP, both for A-07 and R-18 tumors, and between lambda and IFP for A-07 tumors. Significant correlations between E.F and IFP or between lambda and IFP could not be detected for tumors with necrotic regions. CONCLUSIONS: DCE-MRI may be developed to be a useful noninvasive method for assessing IFP in tumors without necrosis. This possibility warrants further studies involving several physiologically different experimental tumor lines, as well as human tumors.

Detection of different hypoxic cell subpopulations in human melanoma xenografts by pimonidazole immunohistochemistry.

This study aimed at developing immunohistochemical assays for different subpopulations of hypoxic cells in tumors. BALB/c-nu/nu mice bearing A-07 or R-18 tumors were given a single dose of 90 mg/kg body weight or three doses (3 h apart) of 30 mg/kg body weight of pimonidazole hydrochloride intravenously. The fraction of pimonidazole-labeled cells was assessed in paraffin-embedded and frozen tumor sections and compared with the fraction of radiobiologically hypoxic cells. The staining pattern in paraffin-embedded sections indicated selective staining of chronically hypoxic cells. Frozen sections showed a staining pattern consistent with staining of both chronically and acutely/repetitively hypoxic cells. Fraction of pimonidazole-labeled cells in paraffin-embedded sections was lower than the fraction of radiobiologically hypoxic cells (single-dose and triple-dose experiment). In frozen sections, fraction of pimonidazole-labeled cells was similar to (single-dose experiment) or higher than (triple-dose experiment) fraction of radiobiologically hypoxic cells. Three different subpopulations of hypoxic cells could be quantified by pimonidazole immunohistochemistry: the fraction of cells that are hypoxic because of limitations in oxygen diffusion, the fraction of cells that are hypoxic simultaneously because of fluctuations in blood perfusion, and the fraction of cells that are exposed to one or more periods of hypoxia during their lifetime because of fluctuations in blood perfusion.