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1.  Serial measurement of hepatic lipids during chemotherapy in colorectal cancer patients: A 1H magnetic resonance spectroscopy study 
NMR in biomedicine  2012;26(2):204-212.
Background and Rationale
Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial 1H magnetic resonance spectroscopy (MRS) measurements of hepatic lipids in patients over the time course of a 24-week chemotherapy regimen to determine whether 1H MRS can be used to monitor the progression of chemotherapy-induced steatosis.
Experimental Procedures
Thirty-four patients with stage III or IV colorectal cancer receiving FOLFOX (n = 21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n=13) were studied prospectively. 1H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A 1H MR spectrum was acquired from the liver during a breath-hold and the ratio of fat to fat+water (FFW) was calculated to give a measure of hepatic triglycerides (HTGC). The methodology was histologically validated in 18 patients and reproducibility was assessed in 16 normal volunteers.
Results
Twenty-seven patients completed baseline, 6-week and 24-week 1H-MRS exams and one was censored. Thirteen of 26 patients (50%) showed an increase in FFW after completion of treatment. Six patients (23%) developed hepatic steatosis and two patients converted from steatosis to non-steatotic liver. Patients whose six-week hepatic lipid levels had increased significantly compared to baseline had a high probability of lipid elevation relative to baseline at the completion of treatment as well.
Conclusion
Serial 1H-MRS is effective for monitoring HTGC changes during chemotherapy and detecting chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks.
doi:10.1002/nbm.2837
PMCID: PMC3519948  PMID: 22961714
fat; liver; FOLFOX; steatosis; imaging
2.  Response of HT29 Colorectal Xenograft Model to Cediranib Assessed with 18F-FMISO PET, Dynamic Contrast-Enhanced and Diffusion-Weighted MRI 
NMR in biomedicine  2012;26(2):151-163.
Cediranib (AZD2171, AstraZeneca, UK) is a small-molecule pan-VEGFR inhibitor. The tumor response to short-term cediranib treatment was studied using dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI at 7 T as well as 18F-fluoromisonidazle (18F-FMISO) PET and histological markers. Rats bearing subcutaneous HT29 human colorectal tumors were imaged at baseline, then received three doses of cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow up imaging performed 2 hours after the final cediranib or vehicle dose. Tumors were excised and evaluated for the perfusion marker Hoechst 33342, endothelial cell marker CD31, smooth muscle actin (SMA), intercapillary distance (ICD) and tumor necrosis. DCE-MRI-derived parameters decreased significantly in cediranib-treated tumors relative to pre-treatment values: the muscle-normalized initial area under the gadolinium concentration curve (nIAUC90) by 48% (p = 0.002), the enhancing fraction (EnF) by 43% (p = 0.003) and Ktrans by 57% (p = 0.003), but remained unchanged in controls. No change between pre- and post-treatment tumor apparent diffusion coefficient (ADC) in either cediranib- or vehicle-treated group was observed over the course of this study. 18F-FMISO SUVmean decreased by 33% (p = 0.008) in the cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31-positive vessels (59 per mm2), the fraction of SMA-positive vessels (80 to 87%) and ICD (0.17 mm) were similar in cediranib- and vehicle-treated groups. The fraction of perfused blood vessels in cediranib-treated tumors (81±7%) was lower than in vehicle controls (91±3%, p = 0.02). The necrotic fraction was slightly higher in cediranib-treated rats (34±12%) than in controls (26±10%, p = 0.23). These findings suggest that short-term treatment with cediranib causes a decrease of tumor perfusion/permeability across the tumor cross-section, but changes in vascular morphology, vessel density or tumor cellularity do not manifest at this early time point.
doi:10.1002/nbm.2830
PMCID: PMC3524412  PMID: 22777834
Cediranib; HT29 Tumors; Dynamic Contrast-Enhanced Magnetic Resonance Imaging; Diffusion Magnetic Resonance Imaging; Histological Analysis
3.  A triple suicide gene strategy that improves therapeutic effects and incorporates multi-modality molecular imaging for monitoring gene-functions 
Cancer gene therapy  2013;20(6):358-365.
Gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, has shown promise in clinical trials. In this preclinical study using stable cell lines and xenograft tumor models, we show that a triple-suicide-gene GDEPT approach produce enhanced therapeutic efficacy over previous methods. Importantly all the three genes (thymidine kinase, cytosine deaminase, and uracil phosphoribosyltransferase) function simultaneously as effectors for GDEPT and markers for multimodality molecular imaging (MMI), using positron-emission-tomography (PET), magnetic resonance-spectroscopy (MRS), and optical (fluorescent and bioluminescent) techniques. It was demonstrated that MMI can evaluate the distribution and function/activity of the triple-suicide-gene. The concomitant expression of these genes significantly enhances prodrug cytotoxicity and radiosensitivity in vitro and in vivo.
doi:10.1038/cgt.2013.28
PMCID: PMC3696018  PMID: 23722591
positron-emission-tomography; magnetic resonance-spectroscopy; optical imaging; Gene-directed enzyme prodrug therapy; radiotherapy
4.  Extension of the Intravoxel Incoherent Motion Model to Non-Gaussian Diffusion in Head and Neck Cancer 
Purpose
To extend the intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) model to restricted diffusion and to simultaneously quantify the perfusion and restricted diffusion parameters in neck nodal metastases.
Materials and Methods
The non-Gaussian (NG)-IVIM model was developed and tested on diffusion-weighted MRI data collected on a 1.5-Tesla MRI scanner from 8 patients with head and neck cancer. Voxel-wise parameter quantification was performed by using a noise-rectified least-square fitting method. The NG-IVIM, IVIM, Kurtosis, and ADC (apparent diffusion coefficient) models were used for comparison. For each voxel, within the metastatic node, the optimal model was determined using the Bayesian Information Criterion. The voxel percentage preferred by each model was calculated and the optimal model map was generated. Monte Carlo simulations were performed to evaluate the accuracy and precision dependency of the new model.
Results
For the 8 neck nodes, the range of voxel percentage preferred by the NG-IVIM model was 2.3% - 79.3%. The optimal modal maps showed heterogeneities within the tumors. The Monte Carlo simulations demonstrated that the accuracy and precision of the NG-IVIM model improved by increasing signal-to-noise ratio and b value.
Conclusion
The NG-IVIM model characterizes perfusion and restricted diffusion simultaneously in neck nodal metastases.
doi:10.1002/jmri.23770
PMCID: PMC3482143  PMID: 22826198
Intravoxel incoherent motion; noise rectification; restricted diffusion; perfusion
5.  Temporal/spatial resolution improvement of in vivo DCE-MRI with compressed sensing-optimized FLASH 
Magnetic resonance imaging  2012;30(6):741-752.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides critical information regarding tumor perfusion and permeability by injecting a T1 contrast agent, such as Gd-DTPA, and making a time-resolved measurement of signal increase. Both temporal and spatial resolutions are required to be high to achieve an accurate and reproducible estimation of tumor perfusion. However, the dynamic nature of the DCE experiment limits simultaneous improvement of temporal and spatial resolution by conventional methods. Compressed sensing (CS) has become an important tool for the acceleration of imaging times in MRI, which is achieved by enabling the reconstruction of subsampled data. Similarly, CS algorithms can be utilized to improve the temporal/spatial resolution of DCE-MRI, and several works describing retrospective simulations have demonstrated the feasibility of such improvements. In this study, the fast low angle shot sequence was modified to implement a Cartesian, CS-optimized, sub-Nyquist phase encoding acquisition/reconstruction with multiple two-dimensional slice selections and was tested on water phantoms and animal tumor models. The mean voxel-level concordance correlation coefficient for Akep values obtained from ×4 and ×8 accelerated and the fully sampled data was 0.87±0.11 and 0.83±0.11, respectively (n=6), with optimized CS parameters. In this case, the reduction of phase encoding steps made possible by CS reconstruction improved effectively the temporal/spatial resolution of DCE-MRI data using an in vivo animal tumor model (n=6) and may be useful for the investigation of accelerated acquisitions in preclinical and clinical DCE-MRI trials.
doi:10.1016/j.mri.2012.02.001
PMCID: PMC3792168  PMID: 22465192
DCE MRI; Compressed sensing; Spatiotemporal resolution; Undersampling
6.  Hypoxia targeted bifunctional suicide gene expression enhances radiotherapy in vitro and in vivo 
Purpose
To investigate whether hypoxia targeted bifunctional suicide gene expression-cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) with 5-FC treatments can enhance radiotherapy.
Material and Methods
Stable transfectant of R3327-AT cells were established which express a triple-fusion-gene: CD, UPRT and monomoric DsRed (mDsRed) controlled by a hypoxia inducible promoter. Hypoxia-induced expression/function of CDUPRTmDsRed was varified by western blot, flow cytometry, fluorescent microscopy, and cytotoxicity assay of 5-FU and 5-FC. Tumor-bearing mice were treated with 5-FC and locally radiation. Tumor volume were monitored and compared with those treated with 5-FC or radiation alone. In addition, the CDUPRTmDsRed distribution in hypoxic regions of tumor sections was visualized with fluorescent microscopy.
Results
Hypoxic induction of CDUPRTmDsRed protein correlated with increased sensitivity to 5-FC and 5-FU. Significant radiosensitization effects were detected after 5-FC treatments under hypoxic conditions. In the tumor xenografts, the distribution of CDUPRTmDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC to mice in combined with local irradiation resulted in significant tumor regression, as comparison with 5-FC or radiation treatments alone.
Conclusions
Our data suggest that the hypoxia-inducible CDUPRT/5-FC gene therapy strategy has the ability to specifically target hypoxic cancer cells and significantly improves the tumor control in combination with radiotherapy.
doi:10.1016/j.radonc.2012.07.011
PMCID: PMC3747309  PMID: 22938726
hypoxia; radiosensitization; cytosine deaminase; uracil phosphoribosyltransferase; 5-flurocytosine
7.  Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Predictor of Outcome in Head and Neck Squamous Cell Carcinoma Patients with Nodal Metastases 
Purpose
Dynamic contrast-enhanced-MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of the present study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery.
Methods and Materials
Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using Tofts model. DCE-MRI parameters were related to treatment outcome (progression free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD) or dead of other causes (DOC). Prognostic significance was assessed using the log rank test for single variables and Cox proportional hazards regression for combinations of variables.
Results
At last clinical follow-up, for stage III, all 12 pts were NED, for stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. Ktrans is volume transfer constant. In a stepwise Cox regression skewness of Ktrans was the strongest predictor for stage IV patients (PFS and OS: p<0.001).
Conclusion
Our study shows that skewness of Ktrans was the strongest predictor of PFS and OS in stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter Ktrans as a predictor of outcome in these patients.
doi:10.1016/j.ijrobp.2011.03.006
PMCID: PMC3177034  PMID: 21601373
Dynamic Contrast Enhanced-MRI (DCE-MRI); head and neck squamous cell carcinoma (HNSCC); volume transfer constant (Ktrans)
8.  Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment* 
Experimental Cell Research  2011;318(4):326-335.
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.
doi:10.1016/j.yexcr.2011.11.014
PMCID: PMC3402174  PMID: 22178238
Lactate metabolism; Glycolytic tumor cells; Stromal carcinoma-associated; fibroblasts (CAFs)
9.  β4 Integrin signaling induces expansion of prostate tumor progenitors 
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.
doi:10.1172/JCI60720
PMCID: PMC3561800  PMID: 23348745
10.  Tumor Metabolism and Perfusion in Head and Neck Squamous Cell Carcinoma: Pretreatment Multimodality Imaging with 1H-Magnetic Resonance Spectroscopy, Dynamic Contrast-Enhanced MRI and 18F-FDG PET 
Purpose
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ijrobp.2010.11.022
PMCID: PMC3137671  PMID: 21236594
Head and neck squamous cell carcinoma; 1H-MRS; DCE-MRI; 18F-FDG PET; short-term treatment response
11.  Mapping Tumor Hypoxia In Vivo Using Pattern Recognition of Dynamic Contrast-enhanced MRI Data12 
Translational Oncology  2012;5(6):437-447.
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.
PMCID: PMC3546126  PMID: 23326621
12.  Preclinical Study of Treatment Response in HCT-116 Cells and Xenografts with 1H-decoupled 31P MRS 
NMR in biomedicine  2011;24(9):1159-1168.
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.
doi:10.1002/nbm.1674
PMCID: PMC3201722  PMID: 21994185
irinotecan; flavopiridol; choline kinase; colon cancer; 1H-decoupled 31P MRS; apoptosis
13.  31P-Magnetic Resonance Spectroscopic Imaging Detects Regenerative Changes in Human Liver Stimulated by Portal Vein Embolization 
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1002/jmri.22616
PMCID: PMC3146030  PMID: 21780228
spectroscopy; phosphorus; liver; regeneration; portal vein embolization
14.  Radiation Impairs Perineural Invasion by Modulating the Nerve Microenvironment 
PLoS ONE  2012;7(6):e39925.
Purpose
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.
Experimental Design
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0039925
PMCID: PMC3386941  PMID: 22768171
15.  An exploratory study of endorectal MRI and spectroscopy of the prostate as pre-operative predictive biomarkers of biochemical relapse after radical prostatectomy 
The Journal of urology  2010;184(6):2320-2327.
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.juro.2010.07.037
PMCID: PMC3074584  PMID: 20952035
MRI; spectroscopy; prostate; cancer; recurrence
16.  Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer 
Cancer cell  2011;19(5):575-586.
Summary
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.
Significance
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.
doi:10.1016/j.ccr.2011.04.008
PMCID: PMC3142785  PMID: 21575859
17.  Semi-automatic Deformable Registration of Prostate MR Images to Pathological Slices 
Purpose
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).
Results
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).
Conclusion
The proposed semi-automatic method enabled successful co-registration of anatomical prostate MR images to pathologic slices.
doi:10.1002/jmri.22347
PMCID: PMC2975408  PMID: 21031521
prostate MR imaging; index tumor; deformable registration; step-section pathologic slides; Dice similarity coefficient
18.  Noninvasive assessment of tumor microenvironment using dynamic contrast enhanced MRI and 18F- fluoromisonidazole PET imaging in neck nodal metastases 
Purpose
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ijrobp.2009.07.009
PMCID: PMC2888682  PMID: 19906496
Dynamic Contrast Enhanced-MRI (DCE-MRI); 18F-fluoromisonidazole (FMISO) PET; 18F-fluorodeoxyglucose (FDG); head and neck (HN) cancer
19.  Imaging of Alkaline Phosphatase Activity in Bone Tissue 
PLoS ONE  2011;6(7):e22608.
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.
doi:10.1371/journal.pone.0022608
PMCID: PMC3143164  PMID: 21799916
20.  Imaging Transgene Activity 
Cancer research  2008;68(8):2878-2884.
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.
doi:10.1158/0008-5472.CAN-07-6028
PMCID: PMC3043616  PMID: 18413756
21.  Phase I Study of Intravenous Vascular Endothelial Growth Factor Trap, Aflibercept, in Patients With Advanced Solid Tumors 
Journal of Clinical Oncology  2009;28(2):207-214.
Purpose
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.
Results
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.
Conclusion
IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
doi:10.1200/JCO.2009.22.9237
PMCID: PMC2815710  PMID: 19949018
22.  Differential p53-independent Outcomes of p19Arf Loss in Oncogenesis 
Science signaling  2009;2(84):ra44.
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.
doi:10.1126/scisignal.2000053
PMCID: PMC2928478  PMID: 19690330
23.  Proton MRS detects Metabolic Changes in Hormone Sensitive and Resistant Human Prostate Cancer Model CWR22 and CWR22r 
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.
doi:10.1002/mrm.22137
PMCID: PMC2859036  PMID: 19780165
24.  Non-invasive imaging of angiogenesis in head and neck squamous cell carcinoma 
Angiogenesis  2010;13(2):149-160.
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.
doi:10.1007/s10456-010-9167-z
PMCID: PMC2912423  PMID: 20383743
Head and neck squamous cell carcinoma; Angiogenesis; Anti-angiogenic treatment; Imaging techniques; Magnetic resonance imaging; Computed tomography; Positron emission tomography; Ultrasound; Molecular imaging
25.  A critical role for Choline Kinase alpha in the aggressiveness of bladder carcinomas 
Oncogene  2009;28(26):2425-2435.
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).
doi:10.1038/onc.2009.91
PMCID: PMC2908237  PMID: 19448670
Bladder cancer; Choline Kinase; Therapeutic target; Tumor promoter

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