Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O2) than under 20% O2 and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our 13C NMR spectroscopic measurements indicate that 13C-lactate is converted to 13C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.
Lactate metabolism; Glycolytic tumor cells; Stromal carcinoma-associated; fibroblasts (CAFs)
The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that β4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.
To correlate proton magnetic resonance spectroscopy (1H-MRS), dynamic contrast-enhanced MRI (DCE-MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in nodal metastases of patients with head and neck squamous cell carcinoma (HNSCC) for assessment of tumor biology. Additionally, pretreatment multimodality imaging (MMI) was evaluated for its efficacy in predicting short-term response to treatment.
Methods and Materials
Metastatic neck nodes were imaged with 1H-MRS, DCE-MRI and 18F-FDG PET in 16 patients with newly diagnosed HNSCC before treatment. Short-term radiological response was evaluated at 3–4 months. The correlations between 1H-MRS (choline concentration, Cho/W), DCE-MRI (volume transfer constant, Ktrans; volume fraction of the extravascular extracellular space, ve; and redistribution rate constant, kep) and 18F-FDG PET (standard uptake value, SUV; and total lesion glycolysis, TLG) were calculated using non-parametric Spearman rank correlation. To predict the short-term response, logistic regression analysis was performed.
A significant positive correlation was found between Cho/W and TLG (ρ = 0.599, p = 0.031). Cho/W correlated negatively with heterogeneity measures std(ve) (ρ = −0.691, p = 0.004) and std(kep) (ρ = −0.704, p = 0.003). SUVmax values correlated strongly with MRI tumor volume (ρ = 0.643, p = 0.007). Logistic regression indicated that std(Ktrans) and SUVmean were significant predictors of short-term response (p < 0.07).
Pretreatment multi-modality imaging using 1H-MRS, DCE-MRI and 18F-FDG PET is feasible in HNSCC patients with nodal metastases. Additionally, combined DCE-MRI and 18F-FDG PET parameters were predictive of short-term response to treatment.
Head and neck squamous cell carcinoma; 1H-MRS; DCE-MRI; 18F-FDG PET; short-term treatment response
In solid tumors, hypoxia contributes significantly to radiation and chemotherapy resistance and to poor outcomes. The “gold standard” pO2 electrode measurements of hypoxia in vivo are unsatisfactory because they are invasive and have limited spatial coverage. Here, we present an approach to identify areas of tumor hypoxia using the signal versus time curves of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data as a surrogate marker of hypoxia. We apply an unsupervised pattern recognition (PR) technique to determine the differential signal versus time curves associated with different tumor microenvironmental characteristics in DCE-MRI data of a preclinical cancer model. Well-perfused tumor areas are identified by rapid contrast uptake followed by rapid washout; hypoxic areas, which are regions of reduced vascularization, are identified by delayed contrast signal buildup and washout; and necrotic areas exhibit slow or no contrast uptake and no discernible washout over the experimental observation. The strength of the PR concept is that it captures the pixel-enhancing behavior in its entirety—during both contrast agent uptake and washout—and thus, subtleties in the temporal behavior of contrast enhancement related to features of the tumor microenvironment (driven by vascular changes) may be detected. The assignment of the tumor compartments/microenvironment to well vascularized, hypoxic, and necrotic is validated by comparison to data previously obtained using complementary imaging modalities. The proposed novel analysis approach has the advantage that it can be readily translated to the clinic, as DCE-MRI is used routinely for the identification of tumors in patients, is widely available, and easily implemented on any clinical magnet.
The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G2/M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G2/M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton (1H)-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83±5% G2/M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5±1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39±10% apoptosis. In vivo 1H-decoupled 31P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies.
irinotecan; flavopiridol; choline kinase; colon cancer; 1H-decoupled 31P MRS; apoptosis
First, to evaluate hepatocyte phospholipid metabolism and energetics during liver regeneration stimulated by portal vein embolization (PVE) using proton-decoupled 31P-magnetic resonance spectroscopic imaging (31P-MRSI). Second, to compare the biophysiologic differences between hepatic regeneration stimulated by PVE and by partial hepatectomy.
Materials and Methods
Subjects included 6 patients with hepatic metastases from colorectal cancer who were scheduled to undergo right PVE before definitive resection of right-sided tumor. 31P-MRSI was performed on the left liver lobe prior to PVE and 48 hours following PVE. Normalized quantities of phosphorus-containing hepatic metabolites were analyzed from both visits. In addition, MRSI data at 48 hours following partial hepatectomy were compared with the data from the PVE patients.
At 48 hours after PVE, the ratio of phosphomonoesters to phosphodiesters in the non-embolized lobe was significantly elevated. No significant changes were found in NTP and Pi values. The PME to PDE ratio in regenerating liver 48 hours after partial hepatectomy was significantly greater than PME/PDE 48 hours after PVE.
31P-MRSI is a valid technique to noninvasively evaluate cell membrane metabolism following PVE. The different degree of biochemical change between PH and PVE indicates that hepatic growth following these two procedures does not follow the same course.
spectroscopy; phosphorus; liver; regeneration; portal vein embolization
Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined.
An in vitro co-culture system of dorsal root ganglia (DRG) and pancreatic cancer cells was used as a model of PNI. An in vivo murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer.
Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function.
Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI.
Radical prostatectomy (RP)has significant side effects. Pre-operative information which could predict the long-term outcome of RP would be valuable to both patient and physician. The purpose of this study was to determine whether pre-treatment endorectal MRI/MRSI has the potential to predict biochemical recurrence (BCR) after RP.
Materials and Methods
130 of 202 patients who had endorectal MRI/MRSI from January 2000 to December 2002 followed by RP satisfied all inclusion criteria and were included in the analysis. MRI and MRSI factors with potential predictive capability were compared to BCR data. These included MRI risk score based on local extent of disease, and MRSI index lesion characteristics including the number of voxels and degree of metabolic abnormality (MRSI grade). Associations between MRI and MRSI variables and time-to-BCR were evaluated using Cox Proportional Hazards regression, adjusting for known predictors of BCR such as stage, grade, and PSA.
Within a median followup period of 68 months, there were 26 biochemical failures. MRI risk score, MRSI index lesion volume and presence of high grade voxels each correlated with time-to-BCR. In a model which combined clinical parameters, MRI score, MRSI lesion volume and the presence of at least one high grade voxel, the MRSI variables remained significant whereas the MRI score dropped out.
MRSI index lesion volume and the presence of high grade MRSI voxels correlate with time-to-BCR after radical prostatectomy even when adjusted for clinical data. These results suggest pre-operative predictive utility for endorectal MRI/MRSI in patients considering radical prostatectomy.
MRI; spectroscopy; prostate; cancer; recurrence
Prostate cancer is characterized by its dependence on androgen receptor and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
The two most frequently activated signaling pathways in prostate cancer are driven by AR and PI3K. Inhibitors of the PI3K pathway are in early clinical trials and AR inhibitors confer clinical responses in most patients. However, these inhibitors rarely induce tumor regression in preclinical models. Here we show that these pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Therefore, tumor cells can adapt and survive when either single pathway is inhibited pharmacologically. Our demonstration of profound tumor regressions with combined pathway inhibition in preclinical prostate tumor models provides rationale for combination therapy in patients.
To present a semi-automatic deformable registration algorithm for co-registering T2-weighted (T2w) images of the prostate with whole-mount pathological sections of prostatectomy specimens.
Materials and Methods
Twenty-four patients underwent 1.5-T endorectal MR imaging before radical prostatectomy with whole-mount step-section pathologic analysis of surgical specimens. For each patient, the T2w imaging containing the largest area of tumor was manually matched with the corresponding pathologic slice. The prostate was co-registered using a free form deformation (FFD) algorithm based on B-splines. Registration quality was assessed through differences between prostate diameters measured in right-left (RL) and anteroposterior (AP) directions on T2w images and pathologic slices and calculation of the Dice similarity coefficient, D, for the whole prostate (WP), the peripheral zone (PZ) and the transition zone (TZ).
The mean differences in diameters measured on pathology and MR imaging in the RL direction and the AP direction were 0.49 cm and -0.63 cm, respectively, before registration and 0.10 cm and -0.11 cm, respectively, after registration. The mean D values for the WP, PZ and TZ, were 0.76, 0.65, and 0.77, respectively, before registration and increased to 0.91, 0.76, and 0.85, respectively, after registration. The improvements in D were significant for all three tissues (P < 0.001 for all).
The proposed semi-automatic method enabled successful co-registration of anatomical prostate MR images to pathologic slices.
prostate MR imaging; index tumor; deformable registration; step-section pathologic slides; Dice similarity coefficient
Pretreatment multimodality imaging can provide useful anatomical and functional data about tumors, including perfusion and possibly hypoxia status. The purpose of our study was to assess non-invasively the tumor microenvironment of neck nodal metastases in patients with head and neck (HN) cancer by investigating the relationship between tumor perfusion measured using Dynamic Contrast Enhanced MRI (DCE-MRI) and hypoxia measured by 18F-fluoromisonidazole (18F-FMISO) PET.
Methods and Materials
Thirteen newly diagnosed HN cancer patients with metastatic neck nodes underwent DCE-MRI and 18F-FMISO PET imaging prior to chemotherapy and radiation therapy. The matched regions of interests from both modalities were analyzed. To examine the correlations between DCE-MRI parameters and standard uptake value (SUV) measurements from 18F-FMISO PET, the non-parametric Spearman correlation coefficient was calculated. Furthermore, DCE-MRI parameters were compared between nodes with 18F-FMISO uptake and nodes with no 18F-FMISO uptake using Mann-Whitney U tests.
For the 13 patients, a total of 18 nodes were analyzed. The nodal size strongly correlated with the 18F-FMISO SUV (ρ=0.74, p<0.001). There was a strong negative correlation between the median kep (ρ=−0.58, p=0.042) and the 18F-FMISO SUV. Hypoxic nodes (moderate to severe 18F-FMISO uptake) had significantly lower median Ktrans (p=0.049) and median kep (p=0.027) values than did non-hypoxic nodes (no 18F-FMISO uptake).
This initial evaluation of the preliminary results support the hypothesis that in metastatic neck lymph nodes, hypoxic nodes are poorly perfused (i.e., have significantly lower kep and Ktrans values) compared to non-hypoxic nodes.
Dynamic Contrast Enhanced-MRI (DCE-MRI); 18F-fluoromisonidazole (FMISO) PET; 18F-fluorodeoxyglucose (FDG); head and neck (HN) cancer
The purpose of this study was to develop a paradigm for quantitative molecular imaging of bone cell activity. We hypothesized the feasibility of non-invasive imaging of the osteoblast enzyme alkaline phosphatase (ALP) using a small imaging molecule in combination with 19Flourine magnetic resonance spectroscopic imaging (19FMRSI). 6, 8-difluoro-4-methylumbelliferyl phosphate (DiFMUP), a fluorinated ALP substrate that is activatable to a fluorescent hydrolysis product was utilized as a prototype small imaging molecule. The molecular structure of DiFMUP includes two Fluorine atoms adjacent to a phosphate group allowing it and its hydrolysis product to be distinguished using 19Fluorine magnetic resonance spectroscopy (19FMRS) and 19FMRSI. ALP-mediated hydrolysis of DiFMUP was tested on osteoblastic cells and bone tissue, using serial measurements of fluorescence activity. Extracellular activation of DiFMUP on ALP-positive mouse bone precursor cells was observed. Concurringly, DiFMUP was also activated on bone derived from rat tibia. Marked inhibition of the cell and tissue activation of DiFMUP was detected after the addition of the ALP inhibitor levamisole. 19FMRS and 19FMRSI were applied for the non-invasive measurement of DiFMUP hydrolysis. 19FMRS revealed a two-peak spectrum representing DiFMUP with an associated chemical shift for the hydrolysis product. Activation of DiFMUP by ALP yielded a characteristic pharmacokinetic profile, which was quantifiable using non-localized 19FMRS and enabled the development of a pharmacokinetic model of ALP activity. Application of 19FMRSI facilitated anatomically accurate, non-invasive imaging of ALP concentration and activity in rat bone. Thus, 19FMRSI represents a promising approach for the quantitative imaging of bone cell activity during bone formation with potential for both preclinical and clinical applications.
The successful translation of gene therapy for clinical application will require the assessment of transgene activity as a measure of the biological function of a therapeutic transgene. While current imaging permits the non-invasive detection of transgene expression, the critical need for quantitative imaging of the action of the expressed transgene has not been met. Magnetic resonance spectroscopic imaging (MRSI) was applied to quantitatively delineate both the concentration and activity of a cytosine deaminase-uracil phosphoribosyltransferase (CD-UPRT) fusion enzyme expressed from a transgene. MRSI enabled the generation of anatomically accurate maps of the intratumoral heterogeneity in fusion enzyme activity. We observed an excellent association between the CD-UPRT concentration and activity and the percentage of CD-UPRT+ cells. Moreover, the regional levels of UPRT activity, as measured by imaging, correlated well with the biological affect of this enzyme. This study presents a translational imaging strategy for precise, in vivo measurements of transgene activity with potential applications in both pre-clinical and clinical settings.
Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks.
Patients and Methods
Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability.
The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) –defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses ≥ 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker.
IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
One reported function of the tumor suppressor p19Arf is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19Arf, p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19Arf in prostate epithelium does not accelerate—but rather partially inhibits—the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19Arf double-mutant mice. In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19Arf. However, in contrast to that in the prostate epithelium, p19Arf deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance. Consistent with the effect of p19Arf loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14ARF (the human equivalent of mouse p19Arf). Collectively, these data reveal differential consequences of p19Arf inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway.
17-Allylamino, 17-Demethoxygeldanamycin (17-AAG), an effective inhibitor of the heat shock protein hsp90, preferentially inhibiting tumor hsp90 compared to hsp90 from normal cells (1), has shown promising results against several cancers, including hormone resistant prostate cancer. Levels of several oncogenic proteins critical to tumor growth and progression, such as AR (androgen receptor) and HER2/neu, were reduced 4 hours post 17-AAG treatment. Post treatment metabolic changes have also been observed in several tumor cell lines. In this study total choline (t-cho) distributions in hormone sensitive CWR22 and hormone resistant CWR22r prostate cancer xenograft tumors in mice were measured before, 4 hours and 48 hours after a single bolus 17-AAG treatment at 100 mg/kg using proton MRS. Our results show that tumor t-cho levels declined 4 hours after the treatment for CWR22 (P = 0.001) and 48 hours post treatment for CWR22r (P=0.003). Metabolic changes, in particular of t-cho intensity detected by 1H MRSI, are consistent with the observed immunohistochemistry changes, tumor growth inhibition for CWR22r (P=0.01 at 14 days post treatment) and a constant PSA level versus increasing PSA for control CWR22 (P=0.01). Metabolic changes in t-cho by proton MRSI can be used as an early biomarker of response for advanced stage prostate cancer in targeted therapy such as 17-AAG.
Squamous cell carcinoma of the head and neck (HNSCC) is the seventh most common cancer in the United States. Angiogenesis, the process by which new blood vessels are formed, is an essential element at the basis of both tumor growth and metastases. This review discusses pertinent aspects of the role of imaging modalities in assessing angiogenesis and anti-angiogenic therapy in advanced HNSCC.
Head and neck squamous cell carcinoma; Angiogenesis; Anti-angiogenic treatment; Imaging techniques; Magnetic resonance imaging; Computed tomography; Positron emission tomography; Ultrasound; Molecular imaging
Bladder cancer is one of the most common causes of death in industrialized countries. New tumor markers and therapeutic approaches are still needed to improve management of bladder cancer patients. Choline Kinase alpha (ChoKα) is a metabolic enzyme that has a role in cell proliferation and transformation. Inhibitors of ChoKα display antitumoral activity and are expected to be soon in clinical trials. This study is aimed to asses whether ChoKα plays a role in the aggressiveness of bladder tumors and constitute a new approach for bladder cancer treatment. We demonstrate here that ChoKα is constitutively altered in human bladder tumor cells. Furthermore, in vivo murine models including an orthotopic model to mimic as much as possible the physiological conditions, revealed that increased levels of ChoKα potentiates both tumor formation (p≤0.0001) and aggressiveness of the disease over different endpoints (p=0.011). Accordingly, increased levels of ChoKα significantly reduces survival of mice with bladder cancer (p=0.05). Finally, treatment with ChoKα specific inhibitor resulted in a significant inhibition of tumor growth (p=0.02) and in a relevant increase in survival (p=0.03).
Bladder cancer; Choline Kinase; Therapeutic target; Tumor promoter
Retrospective analyses of clinical dynamic contrast-enhanced (DCE) MRI studies may be limited by failure to measure the longitudinal relaxation rate constant (R1) initially, which is necessary for quantitative analysis. In addition, errors in R1 estimation in each individual experiment can cause inconsistent results in derivations of pharmacokinetic parameters, Ktrans and ve, by kinetic modeling of the DCE-MRI time course data. A total of 18 patients with lower extremity osteosarcomas underwent multislice DCE-MRI prior to surgery. For the individual R1 measurement approach, the R1 time course was obtained using the two-point R1 determination method. For the average R10 (pre-contrast R1) approach, the R1 time course was derived using the DCE-MRI pulse sequence signal intensity equation and the average R10 value of this population. The whole tumor and histogram median Ktrans (0.57 ± 0.37 and 0.45 ± 0.32 min−1) and ve (0.59 ± 0.20 and 0.56 ± 0.17) obtained with the individual R1 measurement approach are not significantly different (paired t test) from those (Ktrans: 0.61 ± 0.46 and 0.44 ± 0.33 min−1; ve: 0.61 ± 0.19 and 0.55 ± 0.14) obtained with the average R10 approach. The results suggest that it is feasible, as well as practical, to use a limited-population-based average R10 for pharmacokinetic modeling of osteosarcoma DCE-MRI data.
dynamic contrast-enhanced MRI; osteosarcoma; R1; pharmacokinetic modeling; Ktrans; ve
The endothelin-1 antagonist, Atrasentan (ABT-627) was used to modify perfusion in the human tumor xenograft model, HT29, growing in nude mice. Atrasentan produced a significant increase in perfusion, as measured in vivo by Gd-DTPA DCE-MRI. Changes in tumor hypoxia were assessed by comparing the binding of two hypoxia tracers, pimonidazole and EF5 given before and after Atrasentan administration. In vehicle-treated controls, the distribution of EF5 and pimonidazole was very similar. However, Atrasentan treatment was associated with decreased uptake of the second hypoxia tracer (EF5), relative to the first (pimonidazole). Although Atrasentan had no independent effect on the growth of HT29 tumors, Atrasentan combined with 20 Gy radiation led to a modest but significant increase in tumor growth delay compared to radiation alone.
Atrasentan; tumor hypoxia; tumor perfusion; HT29; pimonidazole; EF5
The question of whether magnetic resonance spectroscopic imaging (MRSI) can be used to predict the Gleason score has been recently examined at our institution (1) and higher Gleason grade was associated with higher R=(choline+creatine)/citrate values. We wish to quantify this correlation by calculating as a function of R the probability that a particular voxel has a pathologic Gleason score ≥4+3, with sextant biopsy BxG and lesion volume V as cofactors.
Methods and Materials
The data consist of MRSI ratios R stratified by patient, lesion (contiguous abnormal voxels), voxels, biopsy and pathologic Gleason, and lesion volume. The data were analyzed using a logistic model.
For both low- and high-Gleason biopsy lesions, the probability of pathologic Gleason score ≥4+3 increases with lesion volume. At low values of R a lesion volume of at least 15–20 voxels is needed to reach a probability of success of 80%; the biopsy result helps reduce the prediction uncertainty. At larger MRS ratios (R>6) the biopsy result becomes essentially uninformative, once the lesion volume is >12 voxels. With the exception of low values of R, for lesions with low-Gleason score at biopsy, the MRS ratios serve primarily as a selection tool for assessing lesion volumes.
In patients with biopsy Gleason score ≥4+3, high MRSI tumor volume and (Cho+Cr)/Cit may justify the initiation of voxel-specific dose escalation. This is an example of biologically-motivated focal treatment for which IMRT and especially brachytherapy are ideally suited.
prostate cancer; focal treatment; magnetic resonance spectroscopic imaging; Gleason grade
An MRI technique is proposed for complete fat signal elimination. This approach exploits the fact that water rapidly exchanges magnetization with protons in protein and membrane phospholipid of tissue and cells but does not exchange magnetization with triglyceride or fat protons in the tissue. Saturation of the proton signal from protein and membrane phospholipid thus results in partial saturation of the water proton signal, allowing acquisition of an image including a portion of the water signal and the full fat signal. Subtraction of this image from the standard image, containing both water and fat signals, results in an image in which all fat signal is cancelled. This fat-free image is sensitive to magnetization transfer and to water density and relaxation time, providing the possibility of additional contrast. Unlike most fat suppression techniques, this method is not compromised by the static or radiofrequency field heterogeneity and is equally efficient for all fat resonances independent of their chemical shift frequency.
To test a hypothesis that, with 5-fluorocytosine (5-FC) treatment, the co-expression of cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) can lead to greater radiosensitization and bystander effect than CD-expression alone.
Methods and Materials
R3327-AT cell lines stably expressing CD or CDUPRT were generated. The 5-FC and 5-FU cytotoxicity, and the radiosensitivity with/without 5-FC treatment, of these cells were evaluated under both aerobic and hypoxic conditions. The bystander effect was assessed by apoptosis staining and clonogenic survival. The pharmacokinetics of 5-FU and 5-FC metabolism was followed in mice bearing CD- or CDUPRT-expressing tumors using 19F MR spectroscopy (MRS).
CDUPRT-expressing cells were more sensitive to 5-FC and 5-FU than CD-expressing cells. CDUPRT-expression more effectively enhanced the radiosensitizing effect of 5-FC than CD-expression. A 25-fold-lower dose of 5-FC resulted in the same magnitude of radiosensitization in CDUPRT-expressing cells, relative to that in CD-expressing cells. The 5-FC cytotoxicity in co-cultures of parental cells mixed with 10–20% CDUPRT cells was similar as that in 100% CDUPRT cells. 19F MRS measurements showed that expression of CDUPRT leads to enhanced accumulation of fluorine nucleotide (FNuc) in vivo.
Our study indicates that CDUPRT/5-FC strategy may be more effective than CD/5-FC when used as an adjuvant to radiotherapy.
cytosine deaminase; uracil phosphoribosyltransferase; 5-fluorocytosine; radiosensitization; bystander effect
To implement in vivo detection of lactate in the presence of lipids by proton magnetic resonance spectroscopy at a 3 Tesla (T) field strength for potential applications in human tumors outside of the brain.
Materials and Methods
The BASING J-difference sequence was implemented in the presence of high lipid concentrations in phantoms and in vivo at 3 Tesla.
The effectiveness of the lactate editing scheme is demonstrated in phantoms containing both lactate and lipids and in vivo in ischemic induced human muscle.
The ability of the BASING J-difference technique to detect lactate in the presence of strong lipid signals outside the brain at 3T is feasible. This robust technique should permit noninvasive lactate measurements in human tumors to investigate its potential as a prognostic indicator.
lactate; magnetic resonance spectroscopy; BASING; PRESS; 3 Tesla; lipid
For clinical dynamic contrast-enhanced (DCE) MRI studies, it is often not possible to obtain reliable arterial input function (AIF) in each measurement. Thus, it is important to find a representative AIF for pharmacokinetic modeling of DCE-MRI data when individual AIF (Ind-AIF) measurements are not available. A total of 16 patients with osteosarcomas in the lower extremity (knee region) underwent multislice DCE-MRI. Reliable Ind-AIFs were obtained in five patients with a contrast injection rate of 2 cc/s and another five patients with a 1 cc/s injection rate. Average AIF (Avg-AIF) for each injection rate was constructed from the corresponding five Ind-AIFs. For each injection rate there are no statistically significant differences between pharmacokinetic parameters of the five patients derived with Ind-AIFs and Avg-AIF. There are no statistically significant changes in pharmacokinetic parameters of the 16 patients when the two Avg-AIFs were applied in kinetic modeling. The results suggest that it is feasible, as well as practical, to use a limited-population-based Avg-AIF for pharmacokinetic modeling of osteosarcoma DCE-MRI data. Further validation with a larger population and multiple regions is desirable.
dynamic contrast-enhanced MRI; arterial input function; osteosarcoma; Ktrans; pharmakinetic modeling