3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography as an In Vivo Biomarker of inhibition of CDK 4/6-Rb pathway by Palbociclib in a patient derived bladder tumor.

BACKGROUND: Several new generation CDK4/6 inhibitors have been developed and approved for breast cancer therapy in combination with endocrine therapeutics. Application of these inhibitors either alone or in combination in other solid tumors has been proposed, but no imaging biomarkers of response have been reported in non-breast cancer animal models. The purpose of this study was to evaluate 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography (PET) as in vivo biomarker of response to palbociclib in a non-breast cancer model. METHODS: Twenty-four NSG mice bearing patient derived xenografts (PDX) of a well-characterized bladder tumor were randomized into 4 treatment groups: vehicle (n = 6); palbociclib (n = 6); temozolomide (n = 6); and palbociclib plus temozolomide (n = 6) and treated with two cycles of therapy or vehicle. Tumor uptake of [18F]FLT was determined by micro-PET/CT at baseline, 3 days, and 9 days post initiation of therapy. Following the second cycle of therapy, the mice were maintained until their tumors reached a size requiring humane termination. RESULTS: [18F]FLT uptake decreased significantly in the palbociclib and combination arms (p = 0.0423 and 0.0106 respectively at day 3 and 0.0012 and 0.0031 at day 9) with stable tumor volume. In the temozolomide arm [18F]FLT uptake increased with day 9 uptake significantly different than baseline (p = 0.0418) and progressive tumor growth was observed during the treatment phase. All groups exhibited progressive disease after day 22, 10 days following cessation of therapy. CONCLUSION: Significant decreases in [18F]FLT uptake as early as three days post initiation of therapy with palbociclib, alone or in combination with temozolomide, in this bladder cancer model correlates with an absence of tumor growth during therapy that persists until day 18 for the palbociclib group and day 22 for the combination group (6 days and 10 days) following cessation of therapy. These results support early modulation of [18F]FLT as an in vivo biomarker predictive of palbociclib therapy response in a non-breast cancer model.

Design and Implementation of the Pre-Clinical DICOM Standard in Multi-Cohort Murine Studies.

The small animal imaging Digital Imaging and Communications in Medicine (DICOM) acquisition context structured report (SR) was developed to incorporate pre-clinical data in an established DICOM format for rapid queries and comparison of clinical and non-clinical datasets. Established terminologies (i.e., anesthesia, mouse model nomenclature, veterinary definitions, NCI Metathesaurus) were utilized to assist in defining terms implemented in pre-clinical imaging and new codes were added to integrate the specific small animal procedures and handling processes, such as housing, biosafety level, and pre-imaging rodent preparation. In addition to the standard DICOM fields, the small animal SR includes fields specific to small animal imaging such as tumor graft (i.e., melanoma), tissue of origin, mouse strain, and exogenous material, including the date and site of injection. Additionally, the mapping and harmonization developed by the Mouse-Human Anatomy Project were implemented to assist co-clinical research by providing cross-reference human-to-mouse anatomies. Furthermore, since small animal imaging performs multi-mouse imaging for high throughput, and queries for co-clinical research requires a one-to-one relation, an imaging splitting routine was developed, new Unique Identifiers (UID's) were created, and the original patient name and ID were saved for reference to the original dataset. We report the implementation of the small animal SR using MRI datasets (as an example) of patient-derived xenograft mouse models and uploaded to The Cancer Imaging Archive (TCIA) for public dissemination, and also implemented this on PET/CT datasets. The small animal SR enhancement provides researchers the ability to query any DICOM modality pre-clinical and clinical datasets using standard vocabularies and enhances co-clinical studies.

Addition of [18 F]Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography to Cross-Sectional Imaging Improves Staging and Alters Management in Hepatocellular Carcinoma.

In this work, we characterize the value of positron emission tomography (PET) with computed tomography (CT) in combination with cross-sectional imaging for staging and prognostication of hepatocellular carcinoma (HCC) patients. In this retrospective cohort study, HCC patients underwent PET-CT after initial staging with contrast-enhanced CT or magnetic resonance imaging (MRI). The benefit of PET-CT was measured by the identification of new HCC lesions, and potential harm was quantified by the number of false positives and subsequent diagnostic evaluation. We used multivariate Cox regression analysis to evaluate the association between the highest grade on PET-CT with the risk of extrahepatic metastasis, progression-free, and overall survival. Among 148 patients, PET-CT detected additional extrahepatic metastasis in 11.9% of treatment-naïve and 13.8% of treatment-experienced patients. PET-CT changed the Barcelona Clinic Liver Cancer (BCLC) staging in 5.9% of treatment-naïve and 18.8% of treatment-experienced patients compared with CT/MRI alone, changing HCC management in 9.9% and 21.3% of patients, respectively. Of the patients, 5% (n = 8) experienced severe physical harm requiring additional procedures to evaluate extrahepatic findings. High tumor grade on PET-CT was independently associated with a higher likelihood of extrahepatic metastasis (hazard ratio [HR], 17.1; 95% confidence interval [CI], 3.6-81.5) and worse overall survival (HR, 2.4; 95% CI, 1.4-4.3). Treatment-experienced patients (versus treatment-naïve patients; HR, 9.7; 95% CI, 1.9-49.4) and BCLC stage A (HR, 8.2; 95% CI, 1.5-45.9; P < 0.01) and BCLC stage B (HR, 20.6; 95% CI, 1.5-282.2; P < 0.05) were more likely to have an upstaging with PET-CT compared with BCLC stage C (reference). PET-CT provides prognostic information and improves tumor staging beyond CT/MRI alone, with subsequent changes in management for patients with HCC.

A spontaneously metastatic model of bladder cancer: imaging characterization.

BACKGROUND: Spontaneously metastatic xenograft models of cancer are infrequent and the few that exist are resource intensive. In xenografts, caliper measurements can be used to determine primary tumor burden and response to therapy but in metastatic disease models determination of the presence of metastatic disease, metastatic burden, and response to therapy are difficult, often requiring serial necropsy. In this study we characterized the development of visceral metastases in a patient derived xenograft model (PDXM) using in vivo imaging. RESULTS: We identified and characterized the previously unreported development of spontaneous liver and bone metastasis in a known patient derived xenograft, bladder xenograft BL0293F, developed by Jackson Laboratories and the University of California at Davis and available from the National Cancer Institute Patient-Derived Models Repository [1]. Among FDG-PET/CT, contrast-enhanced MRI and non-contrast MRI, non-contrast T2w MRI was the most effective and efficient imaging technique. On non-contrast T2 weighted MRI, hepatic metastases were observed in over 70% of animals at 52 days post tumor implantation without resection of the xenograft and in 100% of animals at day 52 following resection of the xenograft. In a group of animals receiving one cycle of effective chemotherapy, no animals demonstrated metastasis by imaging, confirming the utility of this model for therapy evaluation. There was good agreement between pathologic grade and extent of involvement observed on MRI T2w imaging. CONCLUSION: PDX BL0293F is a reliable visceral organ (liver) metastatic model with high penetrance in both non-aggravated and post excisional situations, providing a reliable window for therapy intervention prior to required excision of the xenograft. The imaging characteristics of this model are highly favorable for non-clinical research studies of metastatic disease when used in conjunction with non-contrast T2 weighted MRI.

In vivo MRI virtual colonography in a mouse model of colon cancer.

We have developed a reliable noninvasive method for monitoring colonic tumors and mucosal inflammation in a mouse model of colon cancer using magnetic resonance colonography (MRC). After a mild cleansing enema, the colon is filled with Fluorinert, a perfluorinated liquid that does not produce a proton MR signal. The mouse is placed in a dedicated volume MR receiver coil, and high-resolution images are acquired in three planes. The Fluorinert enema distends the mouse colon, creating an artifact-free black homogeneous background, allowing clear delineation of the inflamed colonic wall and visualization of luminal tumors in various stages of development. A gadolinium-based contrast agent can be administered i.v. to the animal to detect mural inflammation or tumor vascularity. This technique is useful for serial monitoring of the effects of preventive or therapeutic strategies on tumor development without killing the animal or requiring invasive endoscopies. The animal preparation and imaging can be completed in ∼1.5 h.

Zirconium-89 labeled panitumumab: a potential immuno-PET probe for HER1-expressing carcinomas.

INTRODUCTION: Anti-HER1 monoclonal antibody (mAb), panitumumab (Vectibix) is a fully human mAb approved by the FDA for the treatment of epidermal growth factor receptor (EGFR, HER1)-expressing colorectal cancers. By combining the targeted specificity of panitumumab with the quantitative in vivo imaging capabilities of PET, we evaluated the potential of (89)Zr-DFO-panitumumab PET/CT imaging and performed non-invasive, in vivo imaging of HER1 expression and estimated human dosimetry. METHODS: Panitumumab was radiolabeled with (89)Zr using a derivative of desferrioxamine (DFO-Bz-NCS) and with (111)In using CHX-A" DTPA as bifunctional chelators. Comparative biodistribution/dosimetry of both radiotracers was performed in non-tumor bearing athymic nude mice (n=2 females and n=2 males) over 1-week following i.v. injection of either using (89)Zr-DFO-panitumumab or (111)In-CHX-A"-DTPA-panitumumab. Micro-PET/CT imaging of female athymic nude mice bearing human breast cancer tumors (n=5 per tumor group) with variable HER1-expression very low (BT-474), moderate (MDA-MB-231), and very high (MDA-MB-468) was performed at over 1 week following i.v. injection of (89)Zr-DFO-panitumumab. RESULTS: Radiochemical yield and purity of (89)Zr-Panitumumab was >70% and >98% respectively with specific activity 150 ± 10 MBq/mg of panitumumab in a ~4 hr synthesis time. Biodistribution of (111)In-CHX-A" DTPA -panitumumab and (89)Zr-DFO-panitumumab in athymic non-tumor bearing nude mice displayed similar percent injected dose per gram of tissue with prominent accumulation of both tracers in the lymph nodes, a known clearance mechanism of panitumumab. Also exhibited was prolonged blood pool with no evidence of targeted accumulation in any organ. Human radiation dose estimates showed similar biodistributions with estimated human effective doses of 0.578 and 0.183 mSv/MBq for (89)Zr-DFO-panitumumab and (111)In-CHX-A"-DTPA-panitumumab, respectively. Given the potential quantitative and image quality advantages of PET, imaging of tumor bearing mice was only performed using (89)Zr-DFO-panitumumab. Immuno-PET imaging of (89)Zr-DFO-panitumumab in mice bearing breast cancer xenograft tumors with variable HER1 expression showed high tumor uptake (SUV >7) in the MDA-MB-468 high HER1-expressing mice and a strong correlation between HER1-expression level and tumor uptake (R(2)= 0.857, P < .001). CONCLUSIONS: (89)Zr-DFO-panitumumab can prepared with high radiochemical purity and specific activity. (89)Zr-DFO-panitumumab microPET/CT showed uptake corresponding to HER-1 expression. Due to poor clearance, initial dosimetry estimates suggest that only a low dose (89)Zr-DFO-panitumumab shows favorable human dosimetry; however due to high tumor uptake, the use of (89)Zr-DFO-panitumumab is expected to be clinically feasible.

Early FDG/PET scanning as a pharmacodynamic marker of anti-EGFR antibody activity in colorectal cancer.

Panitumumab is an anti-EGF receptor (EGFR) antibody approved for use in treatment of chemotherapy-refractory colorectal cancers lacking K-RAS mutations. Despite overall response rates approximating 10%, no marker predictive of clinical benefit has been identified. We describe a chemotherapy-refractory patient whose clinical condition necessitated rapid identification of an effective agent in whom we used (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomographic scanning 48 hours after an initial dose of panitumumab to document a pharmacodynamic response to the antibody. The initial 46% ± 2.7% drop in SUV(max) of four target lesions correlated with a partial response by Response Evaluation Criteria in Solid Tumors and a >90% drop in serum carcinoembryonic antigen at 8 weeks, indicating that an early decrease in FDG uptake may predict subsequent clinical benefit in response to anti-EGFR antibody therapy in colorectal cancer.

Mortality based on the presenting electrocardiogram in patients with myocardial infarction in the troponin era.

BACKGROUND: Studies reporting short-term mortality in patients with myocardial infarction (MI) based on the initial electrocardiogram (ECG) are often limited by requiring an ischemic ECG for inclusion. Because few patients with normal or nonspecific findings were included, outcomes in these patients are less clear, especially in the troponin era. METHODS: Consecutive patients diagnosed as having MI using troponin I (TnI) over a 6-year period were included and classified into 8 mutually exclusive groups based on the initial ECG using standard criteria. Patients were included in only 1 group. The MI size was estimated using multiples of peak creatine kinase-MB (CK-MB), and 30-day mortality rate was assessed. RESULTS: Among 1641 patients with MI, patients with ST elevation represented only 22% of all MIs. Patients with ST elevation had the largest MI size, with 2 of 3 having a peak CK-MB greater than 10 times normal. In contrast, most of the patients representing all the other ECG groups had a peak CK-MB less than 5 times normal, with approximately 1 of 3 having no CK-MB elevation and were diagnosed by TnI elevation alone. Patients could be separated into a high-risk group (ST elevation, ischemia, other, or left bundle-branch block), in which mortality rate exceeded 9% (mean, 14%), and a lower-risk group (prior MI, left ventricular hypertrophy, nonspecific changes, and normal), in which the 30-day mortality rate averaged 6% (P < .001; range, 5.23%-7.1%). CONCLUSIONS: Specific ECG findings other than ischemia portend poor outcomes in patients with MI. Once MI is diagnosed, patients are no longer low risk.

Value of simultaneous functional assessment in association with acute rest perfusion imaging for predicting short- and long-term outcomes in emergency department patients with chest pain.

BACKGROUND: Rest tomographic myocardial perfusion imaging (MPI) has significant utility for clinical decision making in emergency department chest pain patients. The role of functional data, commonly acquired with perfusion, has not been systematically evaluated. METHODS AND RESULTS: Low- to moderate-risk patients undergoing rest MPI for risk stratification were included. The patients' MPI findings were classified as normal (normal perfusion or function), abnormal (perfusion defect with abnormal regional function), or discordant (perfusion defect with normal regional function). Ejection fraction was determined from the gated MPI studies. Events based on perfusion classifications and ejection fraction were evaluated. A total of 2,826 consecutive patients (abnormal MPI results in 40%, normal in 32%, and discordant in 27%) were studied. Outcomes were similar for those with normal MPI results versus those with discordant MPI results (myocardial infarction [MI] based on troponin I [TnI], 3.5% vs 4.0%; MI based on creatine kinase-MB, 1.5% vs 1.7%; revascularization, 5.2% vs 5.5%; and MI/revascularization based on TnI, 7.9% vs 8.1%) (P = not significant for all). Both groups had significantly fewer events (P < .001 for all) when compared with patients with abnormal MPI studies (MI based on TnI, 15%; MI based on creatine kinase-MB, 10%; revascularization, 17%; MI based on TnI or revascularization, 24%). The mortality rate was not different among the 3 groups. Multivariate analysis showed that mild/moderate and severe systolic dysfunction were independent predictors of 30-day and 1-year mortality rates (P = .001). CONCLUSIONS: The concurrent evaluation of perfusion and function (regional and global) with MPI provides significant risk/outcome predictive power.

Comparison of the modification of diet in renal disease and the Cockcroft-Gault equations for predicting mortality in patients admitted for exclusion of myocardial ischemia.

Renal dysfunction is an important predictor of mortality in patients with acute coronary syndrome. Until recently, the Cockcroft-Gault (C-G) equation has been most commonly used to estimate renal function, although the Modification of Diet in Renal Disease (MDRD) equation is now recommended. Which equation better predicts mortality is unclear. Consecutive patients without ST elevation on the initial electrocardiogram admitted for exclusion of myocardial ischemia were included. Admission creatinine was used to estimate renal function, and 30-day and 1-year mortality were compared after classifying patients as having no (estimated glomerular filtration rate [eGFR] > or =60 ml/min/m(2)), moderate (eGFR 30 to 59 ml/min/ m(2)), or severe (eGFR <30 ml/min/m(2)) renal dysfunction using the 2 equations. Of the 4,343 patients (49% women, 64% African-American) included, 16% had troponin I elevations consistent with myocardial infarction, and 1-year mortality was 10%. Agreement between the 2 equations was high (r = 0.87 p <0.001, concordance 86%). Mortality was similar in the 2 renal function classifications, with no significant differences based on race or troponin I status at 30 days or 1 year. However, the area of the receiver operator characteristic curve was significantly larger for predicting 1-year mortality with the C-G equation (0.75 [0.72 to 0.77] vs 0.71 [0.68 to 0.73]; p <0.01); both were superior to creatinine alone (0.68 [0.66 to 0.71]; p <0.01 for both C-G and MDRD). Results for 30-day mortality were similar. In conclusion, the C-G equation appears to be superior to the MDRD equation for predicting short- and long-term mortality in patients admitted for exclusion of ischemia, although differences are minor.

Predictive power of systolic function and congestive heart failure in patients with patients admitted for chest pain without ST elevation in the troponin era.

BACKGROUND: Impaired systolic function and congestive heart failure (CHF) are powerful predictors of adverse outcomes in patients with myocardial infarction (MI). However, there are little data in which both of these variables were assessed in heterogenous patients admitted from the emergency department for exclusion of ischemia. METHODS: Consecutive patients admitted for MI exclusion who had ejection fraction (EF) measured were included. Systolic dysfunction was defined as EF <40%. Congestive heart failure was diagnosed based on clinical or x-ray evidence in the first 24 hours. Multivariate analysis was used to determine predictors of 30-day and 1-year mortality. RESULTS: Of the 4,343 consecutive patients admitted, 3,682 (85%) had EF assessed (including 97% of the troponin I [TnI]-positive patients) and were included. One-year unadjusted mortality was 9.5%, but in the presence of systolic dysfunction or CHF, it increased to 22% and 26%, respectively. The most important multivariate predictors of 30-day and 1-year mortality were similar and included CHF (OR for 1-year mortality 2.5, 95% CI 1.9-3.4), TnI elevations (OR 2.0, 95% CI 1.5-2.6), and severe renal failure (OR 5.2, 95% CI 3.7-7.2). Systolic dysfunction was predictive of 1 year (OR 1.9, 95% CI 1.4-2.5) but not 30-day mortality. Results were similar in the 3,018 patients who were troponin-negative. CONCLUSIONS: Congestive heart failure is an independent predictor of both short- and long-term mortality in patients admitted for MI exclusion. In contrast, systolic dysfunction predicts long-term but not short-term mortality. One cannot be used as a surrogate for the other.

Ability of myoglobin to predict mortality in patients admitted for exclusion of myocardial infarction.

BACKGROUND: Myoglobin can be used as an early marker to diagnose myocardial infarction (MI); and although nonspecific for myocardial necrosis, it seems to be a strong mortality predictor. Because myoglobin elevations are often present in patients with renal insufficiency, it is possible that the predictive value of myoglobin is secondary to identifying patients with renal insufficiency. METHODS: Consecutive patients admitted for MI exclusion without ST elevation on the initial electrocardiogram underwent serial assessment of cardiac markers (creatine kinase [CK], CK-myocardial band [MB], and troponin I [TnI]). Myoglobin was assessed at the time of admission and/or 3 hours later. Renal insufficiency was defined as a creatinine clearance <60 mL/min. Multivariate analysis was performed to identify predictors of 30-day and 1-year all-cause mortality. RESULTS: A total of 3461 patients were included in the analysis. Overall 30-day and 1-year mortality was 2.4% and 9.7%. Myoglobin was elevated in 675 (20%), CK-MB in 421 (12%), and TnI in 517 (15%). Among the 993 patients with renal insufficiency, myoglobin was elevated in 43%, CK-MB in 17%, and TnI in 21%. Independent predictors of 30-day and 1-year mortality were similar and included age > or =65 years, prior MI, and an ischemic electrocardiogram, whereas myoglobin was the strongest multivariate predictor (odds ratio [OR] 2.8, 95% confidence interval [CI] 2.1-3.7), including those with renal insufficiency (OR 2.3, 95% CI 1.6-3.4). Troponin I had borderline predictive value (P = .08, OR 1.4, 95% CI 0.96-2.0), whereas CK-MB was not predictive in either group. CONCLUSIONS: Despite the absence of cardiac specificity, an elevated myoglobin strongly predicts mortality, even in patients with renal insufficiency.

Workshop on imaging science development for cancer prevention and preemption.

The concept of intraepithelial neoplasm (IEN) as a near-obligate precursor of cancers has generated opportunities to examine drug or device intervention strategies that may reverse or retard the sometimes lengthy process of carcinogenesis. Chemopreventive agents with high therapeutic indices, well-monitored for efficacy and safety, are greatly needed, as is development of less invasive or minimally disruptive visualization and assessment methods to safely screen nominally healthy but at-risk patients, often for extended periods of time and at repeated intervals. Imaging devices, alone or in combination with anticancer drugs, may also provide novel interventions to treat or prevent precancer.

Implication of the new low-density lipoprotein goals in dyslipidemia management of patients with acute coronary syndrome.

OBJECTIVE: To assess the ability of patients with an acute coronary syndrome (ACS) to meet the recommended low-density lipoprotein cholesterol (LDL-C) goal of 100 mg/dL and optional aggressive lowering to 70 mg/dL. PATIENTS AND METHODS: Patients diagnosed as having ACS who had lipid levels measured within 24 hours of admission from January 1, 1998, through December 31, 2002, were assessed for the ability to meet the 2 target LDL-C levels. Patients were considered to have ACS if they were diagnosed as having myocardial infarction, had significant disease on angiography, or had a history of coronary artery disease. Patients were classified into 1 of 4 groups on the basis of the degree of LDL-C lowering required to meet the 2 different goals: less than 33%, 33% to 39%, 40% to 49%, and 50% or more. Patients with myocardial infarction who had lipid sampling performed more than 24 hours after admission were excluded. RESULTS: The mean plus-or-minus SD LDL-C level was 111 plus-or-minus 43 mg/dL in the 1322 patients who met criteria for ACS and had LDL-C levels assessed. On the basis of a target LDL-C value of less than 100 mg/dL, 43% of patients were at goal and did not require treatment, and only 2.5% had an LDL-C level that required a 50% or greater reduction to meet goal. In contrast, using the newer LDL-C target of 70 mg/dL, 85% patients required treatment, and 23% of patients required a 50% or greater decrease in LDL-C level and therefore were likely to require more than 1 lipid-lowering agent. CONCLUSION: Decreasing the LDL-C target to less than 70 mg/dL substantially increases the number of patients with ACS who would require treatment. A significant proportion of patients will require a reduction in LDL-C level of 50% or more, which is not easily achievable with current lipid-lowering monotherapy.

Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy.

PURPOSE: The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable. RESULTS: Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. CONCLUSIONS: This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.

In vitro and in vivo imaging studies of a new endohedral metallofullerene nanoparticle.

PURPOSE: To evaluate the effectiveness of a functionalized trimetallic nitride endohedral metallofullerene nanoparticle as a magnetic resonance (MR) imaging proton relaxation agent and to follow its distribution for in vitro agarose gel infusions and in vivo infusions in rat brain. MATERIALS AND METHODS: The animal study was approved by the animal care and use committee. Gd(3)N@C(80) was functionalized with poly(ethylene glycol) units, and the carbon cage was hydroxylated to provide improved water solubility and biodistribution. Relaxation rate measurements (R1 = 1/T1 and R2 = 1/T2) of water solutions of this contrast agent were conducted at 0.35-, 2.4-, and 9.4-T MR imaging. Images of contrast agent distributions were produced following infusions in six agarose gel samples at 2.4 T and from direct brain infusions into normal and tumor-bearing rat brain at 2.4 T. The relaxivity of a control functionalized lutetium agent, Lu(3)N@C(80), was also determined. RESULTS: Water hydrogen MR imaging relaxivity (r1) for this metallofullerene nanoparticle was markedly higher than that for commercial agents (eg, gadodiamide); r1 values of 102, 143, and 32 L . mmol(-1) . sec(-1) were measured at 0.35, 2.4, and 9.4 T, respectively. In studies of in vitro agarose gel infusion, the use of functionalized Gd(3)N@C(80) at concentrations an order of magnitude lower resulted in equivalent visualization in comparison with commercial agents. Comparable contrast enhancement was obtained with direct infusions of 0.013 mmol/L of Gd(3)N@C(80) and 0.50 mmol/L of gadodiamide in live normal rat brain. Elapsed-time studies demonstrated lower diffusion rates for Gd(3)N@C(80) relative to gadodiamide in live normal rat brain tissue. Functionalized metallofullerenes directly infused into a tumor-bearing brain provided an improved tumor delineation in comparison with the intravenously injected conventional Gd(3+) chelate. A control lutetium functionalized Lu(3)N@C(80) nanoparticle exhibited very low MR imaging relaxivity. CONCLUSION: The new functionalized trimetallic nitride endohedral metallofullerene species Gd(3)N@C(80)[DiPEG5000(OH)(x)] is an effective proton relaxation agent, as demonstrated with in vitro relaxivity and MR imaging studies, in infusion experiments with agarose gel and in vivo rat brain studies simulating clinical conditions of direct intraparenchymal drug delivery for the treatment of brain tumors.

The progress and promise of molecular imaging probes in oncologic drug development.

As addressed by the recent Food and Drug Administration Critical Path Initiative, tools are urgently needed to increase the speed, efficiency, and cost-effectiveness of drug development for cancer and other diseases. Molecular imaging probes developed based on recent scientific advances have great potential as oncologic drug development tools. Basic science studies using molecular imaging probes can help to identify and characterize disease-specific targets for oncologic drug therapy. Imaging end points, based on these disease-specific biomarkers, hold great promise to better define, stratify, and enrich study groups and to provide direct biological measures of response. Imaging-based biomarkers also have promise for speeding drug evaluation by supplementing or replacing preclinical and clinical pharmacokinetic and pharmacodynamic evaluations, including target interaction and modulation. Such analyses may be particularly valuable in early comparative studies among candidates designed to interact with the same molecular target. Finally, as response biomarkers, imaging end points that characterize tumor vitality, growth, or apoptosis can also serve as early surrogates of therapy success. This article outlines the scientific basis of oncology imaging probes and presents examples of probes that could facilitate progress. The current regulatory opportunities for new and existing probe development and testing are also reviewed, with a focus on recent Food and Drug Administration guidance to facilitate early clinical development of promising probes.

Imaging in the evaluation of the patient with suspected acute coronary syndrome.

Over the last decade, major advances have been made in the treatment of acute coronary syndromes (ACSs). However, effective implementation of these treatments requires timely and accurate identification of the high-risk patient among all those presenting to the emergency department (ED) with symptoms suggestive of ACS. The opportunity for improving outcomes is time-dependent, so that early identification of the patient who has true ACS is essential. This necessity further increases the need for rapid triage tools, especially in the current setting of ED and hospital overcrowding that has become the norm in large urban centers.

Predictive power of ejection fraction and renal failure in patients admitted for chest pain without ST elevation in the troponin era.

BACKGROUND: Ejection fraction (EF) and renal failure (RF) are powerful predictors of mortality in patients with myocardial infarction (MI). There are limited data assessing the predictive value of EF and RF compared with clinical variables in patients without ST elevation using troponin as the diagnostic MI criteria. METHODS: Consecutive patients admitted from the emergency department underwent serial assessment of cardiac markers, including troponin I. Abnormal EF was defined as < 50%; RF, as creatinine clearance (CrCl) < 60 mL/min. Multivariate analysis was used to compare clinical variables, CrCl, and EF for predicting short- and long-term outcomes. RESULTS: A total of 3074 patients had EF assessed. Mild to moderately reduced EF and CrCl were present in 639 (21%) and 582 (19%) patients, with 403 (13%) and 233 (7.6%) having severe systolic dysfunction and severe RF, respectively. Abnormal EF and RF were both present in 13% of patients (1-year mortality 26%), whereas 52% had both normal EF and CrCl (1-year mortality 3.2%). The presence of either systolic dysfunction or RF increased mortality 3- to 4-fold compared with patients without either. The most important multivariate predictors of 1-year mortality were EF (OR 2.6 [95% CI 1.7-3.8, P < .0001]) and CrCl (OR 2.8 [95% CI 1.8-4.2, P < .0001]). CONCLUSIONS: Both RF and EF are strong predictors of cardiac mortality in patients admitted for exclusion of MI. Prediction models that do not include these 2 variables will underestimate risk.

Outcomes in patients admitted for chest pain with renal failure and troponin I elevations.

BACKGROUND: The significance of troponin I (TnI) elevations in patients with renal failure (RF) admitted for possible myocardial ischemia is unclear. We therefore compared outcomes in patients with and without TnI elevations based on renal function. METHODS: Consecutive patients without ST elevation admitted for exclusion of ischemia underwent serial assessment of cardiac markers including TnI. Coronary angiography, significant disease, and revascularization were determined, and 1-year cardiac mortality and all-cause mortality were assessed. Mortality was assessed based on TnI elevations in patients with no (creatinine clearance [CrCl] > or = 60 mL/min), moderate (CrCl 30-59 mL/min), and severe (CrCl < 30 mL/min) RF. RESULTS: Troponin I elevations were present in 17% of the 3774 consecutive patients and were significantly more frequent in patients with RF (CrCl < 30 mL/min: 26%; CrCl 30-59 mL/min: 19%; CrCl > 60 mL/min: 13%, all P < or = .01). Coronary angiography was performed significantly less frequently in patients with RF, whether TnI elevations were present. One-year all-cause mortality increased with both RF and TnI positivity (TnI [+] vs TnI [-], CrCl < 30 mL/min: 52% vs 26%; CrCl 30-59 mL/min: 21% vs 14%; CrCl > 60 mL/min: 8.9% vs 4.9%, all P < .001) . Troponin I was the most important independent predictor of mortality in the 3 RF groups (odds ratio 3.3 for CrCl < 30 mL/min, 2.2 for CrCl 30-59 mL/min, and 3.3 for CrCl > 60 mL/min). CONCLUSIONS: Troponin I elevations identified a high-risk cohort, and its prognostic value was not diminished in patients with RF.