Biomedical subjects

Timothy D Johnson

Publications and source records attributed to Timothy D Johnson.

At least 19 recordsLinked to original sources

PubMed2006

Vascular targeted nanoparticles for imaging and treatment of brain tumors.

PURPOSE: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. EXPERIMENTAL DESIGN: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. RESULTS: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. CONCLUSIONS: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.

Angiography↗

PubMed2006

Child and provider restraints in ambulances: knowledge, opinions, and behaviors of emergency medical services providers.

BACKGROUND: Approximately 16,000 children are transported by ambulances each day, and there are an estimated 4,500 ambulance crashes each year. Information about emergency medical services (EMS) provider knowledge, opinions, and behaviors regarding occupant restraint is lacking. OBJECTIVES: To measure the knowledge, opinions, and behaviors of EMS personnel regarding child and provider restraint use in ambulances. METHODS: A survey was given to all EMS providers in two large ambulance-service organizations and in a hospital-based pediatric ambulance service in a midsized urban area. RESULTS: A total of 302 EMS providers were surveyed, for a return rate of 67.7%. Nearly half were involved in an ambulance crash at least once; of those, 7.6% were injured and 1% had patients in their care injured. The majority (91%) reported some training in child-restraint use in ambulances, and half reported that they know a lot or very much about securing a critically ill child for transport. However, 30% did not identify the correct method of transport for a stable 2-year-old, and 40% did not choose the correct method of securing a child seat to the ambulance cot. Securing a child seat to the cot was viewed by 81% to not take too much time from patient care, and 63% did not view caring for a child in a car seat as difficult. Although 80% of providers regularly transported children in a car seat, 23% transported them on an adult's lap at least sometimes. Specialized pediatric-transport providers were more likely to report safe pediatric and occupant restraint practices than were community EMS providers. Pediatric restraint behaviors were not associated with years of service or history of a crash. Two thirds of respondents reported not wearing their seatbelt on the squad bench while treating patients, and half believe that wearing a seatbelt interferes with patient care. A total of 95% report wearing seatbelts in the front seat of the ambulance. Provider seatbelt use in the patient compartment was not associated with years of service, with number of crashes, or with reporting correct use of pediatric restraints. CONCLUSIONS: This study indicates that the frequency of crashes in ambulances, and therefore the potential for injury, may be underappreciated. Current restraint practices of some of the study group are outside recommendations and may be placing at risk some children who are being transported by ambulances. This problem is complicated by the relative infrequency of pediatric ambulance transports compared with adults. Improved equipment and education may help providers safely transport pediatric patients. In addition, providers are risking their own safety by not wearing seatbelts in the rear ambulance compartment. Improved equipment may help alleviate this risk and allow providers to take care of patients safely.

Accidents, Traffic↗

PubMed2006

A Bayesian hierarchical approach to multirater correlated ROC analysis.

In a common ROC study design, several readers are asked to rate diagnostics of the same cases processed under different modalities. We describe a Bayesian hierarchical model that facilitates the analysis of this study design by explicitly modelling the three sources of variation inherent to it. In so doing, we achieve substantial reductions in the posterior uncertainty associated with estimates of the differences in areas under the estimated ROC curves and corresponding reductions in the mean squared error (MSE) of these estimates. Based on simulation studies, both the widths of coverage intervals and MSE of estimates of differences in the area under the curves appear to be reduced by a factor that often exceeds five. Thus, our methodology has important implications for increasing the power of analyses based on ROC data collected from an available study population.

Bayes Theorem↗

PubMed2006

Dynamic imaging of emerging resistance during cancer therapy.

One of the greatest challenges in developing therapeutic regimens is the inability to rapidly and objectively assess tumor response due to treatment. Moreover, tumor response to therapeutic intervention in many cases is transient, and progressive alterations within the tumor may mask the effectiveness of an initially successful therapy. The ability to detect these changes as they occur would allow timely initiation of alternative approaches, maximizing therapeutic outcome. We investigated the ability of diffusion magnetic resonance imaging (MRI) to provide a sensitive measure of tumor response throughout the course of treatment, possibly identifying changes in sensitivity to the therapy. Orthotopic 9L gliomas were subjected to two separate therapeutic regimens, with one group receiving a single 5-day cycle (1omega) of low-dose 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and a second group receiving two cycles at the same dose, bisected with 2 days of rest (2omega). Apparent diffusion coefficient maps were acquired before and throughout treatment to observe changes in water mobility, and these observations were correlated to standard measures of therapeutic response and outcome. Our results showed that diffusion MRI was indeed able to detect the emergence of a drug-resistant tumor subpopulation subsequent to an initially successful cycle of BCNU therapy, leading to minimal gains from a second cycle. These diffusion MRI findings were highly correlated with tumor growth delay, animal survival, and ex vivo growth inhibition assays showing emerging resistance in excised tumors. Overall, this study highlights the ability of diffusion MRI to provide sensitive dynamic assessment of therapy-induced response, allowing early opportunities for optimization of therapeutic protocols.

Animals↗

PubMed2006

Inhibition of vascular endothelial growth factor (VEGF)-A causes a paradoxical increase in tumor blood flow and up-regulation of VEGF-D.

PURPOSE: Vascular endothelial growth factor (VEGF)-A is an important mediator of angiogenesis in almost all solid tumors. The aim of this study was to evaluate the effect of VEGF-A expression on tumor growth, perfusion, and chemotherapeutic efficacy in orthotopic 9L gliosarcomas. EXPERIMENTAL DESIGN: Stable 9L cell lines underexpressing and overexpressing VEGF-A were generated. Anatomic, susceptibility contrast, and continuous arterial spin-labeling magnetic resonance imaging were used to quantify the volume, blood volume, and blood flow of tumors orthotopically grown from these and wild-type 9L cells. Histologic, immunohistochemical, and quantitative reverse transcription-PCR analyses were also done on excised tumors. Finally, the effects of carmustine chemotherapy were also evaluated. RESULTS: Orthotopic tumors underexpressing VEGF-A had slower growth rates (increased median survival), greater blood flow, vessel density, and VEGF-D expression, but no statistical difference in blood volume and chemotherapeutic sensitivity, compared with tumors with wild-type levels of VEGF-A. Tumors overexpressing VEGF-A had faster growth rates, greater blood volume, vessel density, and blood flow but no statistical difference in VEGF-D expression and chemotherapeutic sensitivity compared with wild-type VEGF-A-expressing tumors. CONCLUSION: Blood volume and blood flow are independent and different biomarkers of tumor perfusion. Therefore, both should be measured when characterizing the efficacy of antiangiogenic therapies. Underexpression of VEGF-A does not result in complete inhibition of angiogenesis. Moreover, these tumors have a different perfusion phenotype, suggesting that angiogenesis is mediated by an alternative pathway. The results indicate that VEGF-D is a plausible alternative mediator of this angiogenesis.

Animals↗

PubMed2006

Sodium and proton diffusion MRI as biomarkers for early therapeutic response in subcutaneous tumors.

The ability to quantitate early effects of tumor therapeutic response using noninvasive imaging would have a major impact in clinical oncology. One area of active research interest is the ability to use MR techniques to detect subtle changes in tumor cellular density. In this study, sodium and proton diffusion MRI were compared for their ability to detect early cellular changes in tumors treated with a cytotoxic chemotherapy. Subcutaneous 9L gliosarcomas were treated with a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea. Both sodium and diffusion imaging modalities were able to detect changes in tumor cellularity as early as 2 days after treatment, which continued to evolve as increased signal intensities reached a maximum approximately 8 days posttreatment. Early changes in tumor sodium and apparent diffusion coefficient values were predictive of subsequent tumor shrinkage, which occurred approximately 10 days later. Overall, therapeutical induced changes in sodium and diffusion values were found to have similar dynamic and spatial changes. These findings suggest that these imaging modalities detected similar early cellular changes after treatment. The results of this study support the continued clinical testing of diffusion MRI for evaluation of early tumor treatment response and demonstrate the complementary insights of sodium MRI for oncology applications.

Animals↗

PubMed2006

Proton and sodium MRI assessment of emerging tumor chemotherapeutic resistance.

The ultimate goal of any cancer therapy is to target the elimination of neoplastic cells. Although newer therapeutic strategies are in constant development, therapeutic assessment has been hampered by the inability to assess, rapidly and quantitatively, efficacy in vivo. Diffusion imaging and, more recently, sodium MRI have demonstrated their distinct abilities to detect therapy-induced alterations in tumor cellularity, which has been demonstrated to be indicative of therapeutic efficacy. More importantly, both imaging modalities detect tumor response much earlier than traditional methodologies that rely on macroscopic volumetric changes. In this study, the correlation between tumor sodium and diffusion was further tested to demonstrate the sensitivity of sodium imaging to gauge tumor response to therapy by using a 9L rat gliosarcoma treated with varying doses of BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea]. This orthotopic model has been demonstrated to display variability in response to BCNU therapy where initial insult has been shown to lead to drug-resistance. In brief, a single 26.6 mg/kg BCNU dose yielded dramatic responses in both diffusion and sodium MRI. However, a second equivalent BCNU dose yielded a much smaller change in diffusion and sodium, suggesting a drop in tumor sensitivity to BCNU. The MRI responses of animals treated with 13.3 mg/kg BCNU were much lower and similar responses were observed after the initial and secondary applications of BCNU. Furthermore, these results were further validated using volumetric measurements of the tumor and also ex vivo determination of tumor sensitivity to BCNU. Overall, these experiments demonstrate the sensitivity and applicability of sodium and diffusion MRI as tools for dynamic assessment of tumor response to therapy.

Animals↗

PubMed2006

Evaluation of lung MDCT nodule annotation across radiologists and methods.

RATIONALE AND OBJECTIVES: Integral to the mission of the National Institutes of Health-sponsored Lung Imaging Database Consortium is the accurate definition of the spatial location of pulmonary nodules. Because the majority of small lung nodules are not resected, a reference standard from histopathology is generally unavailable. Thus assessing the source of variability in defining the spatial location of lung nodules by expert radiologists using different software tools as an alternative form of truth is necessary. MATERIALS AND METHODS: The relative differences in performance of six radiologists each applying three annotation methods to the task of defining the spatial extent of 23 different lung nodules were evaluated. The variability of radiologists' spatial definitions for a nodule was measured using both volumes and probability maps (p-map). Results were analyzed using a linear mixed-effects model that included nested random effects. RESULTS: Across the combination of all nodules, volume and p-map model parameters were found to be significant at P < .05 for all methods, all radiologists, and all second-order interactions except one. The radiologist and methods variables accounted for 15% and 3.5% of the total p-map variance, respectively, and 40.4% and 31.1% of the total volume variance, respectively. CONCLUSION: Radiologists represent the major source of variance as compared with drawing tools independent of drawing metric used. Although the random noise component is larger for the p-map analysis than for volume estimation, the p-map analysis appears to have more power to detect differences in radiologist-method combinations. The standard deviation of the volume measurement task appears to be proportional to nodule volume.

Artificial Intelligence↗

PubMed2006

The functional diffusion map: an imaging biomarker for the early prediction of cancer treatment outcome.

Functional diffusion map (fDM) has been recently reported as an early and quantitative biomarker of clinical brain tumor treatment outcome. This approach spatially maps and quantifies treatment-induced changes in tumor water diffusion values resulting from alterations in cell density/cell membrane function and microenvironment. This current study was designed to evaluate the capability of fDM for preclinical evaluation of dose escalation studies and to determine if these changes were correlated with outcome measures (cell kill and overall survival). Serial T2-weighted were carried out on rodents with orthotopically implanted 9L brain tumors receiving three doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (6.65, 13.3, and 26.6 mg/kg, i.p.). All images were coregistered to baseline T2-weighted images for fDM analysis. Analysis of tumor fDM data on day 4 posttreatment detected dose-dependent changes in tumor diffusion values, which were also found to be spatially dependent. Histologic analysis of treated tumors confirmed spatial changes in cellularity as observed by fDM. Early changes in tumor diffusion values were found to be highly correlative with drug dose and independent biologic outcome measures (cell kill and survival). Therefore, The fDM imaging biomarker for early prediction of treatment efficacy can be used in the drug development process.

Animals↗

PubMed2006

MRI of sonographically indeterminate adnexal masses.

OBJECTIVE: The purpose of this study was to assess the ability of MRI to characterize sonographically indeterminate adnexal masses and to define the sonographic features contributing to indeterminate diagnoses. MATERIALS AND METHODS: Two blinded radiologists retrospectively reviewed the MRI examinations of 87 patients with 95 sonographically indeterminate adnexal masses. Reviewers determined the origin of a mass, its tissue content (cystic, solid, complex cystic, or cystic and solid), tissue characteristics (fat, blood, fibrous, or leiomyomatous), and benignity versus malignancy. Sonograms were reviewed by three reviewers to determine the origin of a mass, its tissue content, and reasons for an indeterminate diagnosis. Sensitivity and specificity of MRI were calculated, and agreement of sonography and MRI with the final diagnosis was determined using kappa statistics. The final diagnosis was determined by histopathology, surgical findings, or imaging or clinical follow-up. RESULTS: The sensitivity of MRI for identifying malignancy (n = 5) was 100% and its specificity for benignity (n = 90) was 94%. Excellent agreement was seen between MRI and the final diagnosis for determining the origin (kappa = 0.93), tissue content (kappa = 0.98), and tissue characteristics (kappa = 0.91) of a mass. Sonography had poor agreement with the final diagnosis for the origin (kappa = 0.19) and tissue content (kappa = 0.33) of a mass. The main reasons for indeterminate sonographic diagnoses were the inability to determine origin because of location and large mass size and the appearances of purely solid or complex cystic masses. CONCLUSION: Sonographically indeterminate adnexal masses of uncertain origin and solid or complex cystic content benefit from further evaluation with MRI, which is highly accurate for identifying the origin of a mass and characterizing its tissue content, obviating surgery.

Adnexa Uteri↗

PubMed2005

Evaluation of the functional diffusion map as an early biomarker of time-to-progression and overall survival in high-grade glioma.

Diffuse malignant gliomas, the most common type of brain tumor, carry a dire prognosis and are poorly responsive to initial treatment. The response to treatment is typically evaluated by measurements obtained from radiographic images several months after the start of treatment; therefore, an early biomarker of tumor response would be useful for making early treatment decisions and for prognostic information. Thirty-four patients with malignant glioma were examined by diffusion MRI before treatment and 3 weeks later. These images were coregistered, and differences in tumor-water diffusion values were calculated as functional diffusion maps (fDM), which were correlated with the radiographic response, time-to-progression (TTP), and overall survival (OS). Changes in fDM at 3 weeks were closely associated with the radiographic response at 10 weeks. The percentage of the tumor undergoing a significant change in the diffusion of water (V(T)) was different between patients with progressive disease (PD) vs. stable disease (SD) (P < 0.001). Patients classified as PD by fDM analysis at 3 weeks were found to have a shorter TTP compared with SD (median TTP, 4.3 vs. 7.3 months; P < 0.04). By using fDM, early patient stratification also was correlated with shorter OS in the PD group compared with SD patients (median survival, 8.0 vs. 18.2 months; P < 0.01). On the basis of fDM, tumor assessment provided an early biomarker for response, TTP, and OS in patients with malignant glioma. Further evaluation of this technique is warranted to determine whether it may be useful in the individualization of treatment or evaluation of the response in clinical protocols.

Adult↗

PubMed2005

A Bayesian mixture model relating dose to critical organs and functional complication in 3D conformal radiation therapy.

A goal of cancer radiation therapy is to deliver maximum dose to the target tumor while minimizing complications due to irradiation of critical organs. Technological advances in 3D conformal radiation therapy has allowed great strides in realizing this goal; however, complications may still arise. Critical organs may be adjacent to tumors or in the path of the radiation beam. Several mathematical models have been proposed that describe the relationship between dose and observed functional complication; however, only a few published studies have successfully fit these models to data using modern statistical methods which make efficient use of the data. One complication following radiation therapy of head and neck cancers is the patient's inability to produce saliva. Xerostomia (dry mouth) leads to high susceptibility to oral infection and dental caries and is, in general, unpleasant and an annoyance. We present a dose-damage-injury model that subsumes any of the various mathematical models relating dose to damage. The model is a nonlinear, longitudinal mixed effects model where the outcome (saliva flow rate) is modeled as a mixture of a Dirac measure at zero and a gamma distribution whose mean is a function of time and dose. Bayesian methods are used to estimate the relationship between dose delivered to the parotid glands and the observational outcome-saliva flow rate. A summary measure of the dose-damage relationship is modeled and assessed by a Bayesian chi(2) test for goodness-of-fit.

Bayes Theorem↗

PubMed2005

Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response.

Assessment of radiation and chemotherapy efficacy for brain cancer patients is traditionally accomplished by measuring changes in tumor size several months after therapy has been administered. The ability to use noninvasive imaging during the early stages of fractionated therapy to determine whether a particular treatment will be effective would provide an opportunity to optimize individual patient management and avoid unnecessary systemic toxicity, expense, and treatment delays. We investigated whether changes in the Brownian motion of water within tumor tissue as quantified by using diffusion MRI could be used as a biomarker for early prediction of treatment response in brain cancer patients. Twenty brain tumor patients were examined by standard and diffusion MRI before initiation of treatment. Additional images were acquired 3 weeks after initiation of chemo- and/or radiotherapy. Images were coregistered to pretreatment scans, and changes in tumor water diffusion values were calculated and displayed as a functional diffusion map (fDM) for correlation with clinical response. Of the 20 patients imaged during the course of therapy, 6 were classified as having a partial response, 6 as stable disease, and 8 as progressive disease. The fDMs were found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator of subsequent volumetric tumor response. Overall, fDM analysis provided an early biomarker for predicting treatment response in brain tumor patients.

Adolescent↗

PubMed2005

Sonographic evaluation of early-stage breast cancers that undergo neoadjuvant chemotherapy.

OBJECTIVE: We prospectively evaluated low-stage breast cancers treated with neoadjuvant chemotherapy using whole-volume sonography and color Doppler imaging. METHODS: Thirty-four women with breast cancer (mean maximum size, 2.4 cm) received neoadjuvant chemotherapy with doxorubicin and docetaxel. Targeted whole-volume sonography of tumor sites was performed before and after chemotherapy to assess mass size, color pixel speed-weighted density, and American College of Radiology Breast Imaging Reporting and Data System sonographic characteristics. After chemotherapy, tumor sites were excised by lumpectomy or mastectomy. RESULTS: Three (11.3%) of 34 patients had a complete histologic response. After chemotherapy, correlation was r = 0.716 between final histologic and sonographic sizes. Compared with histologic residual tumors, sonography had 4 false-negative results, 3 false-positive results, and 27 true-positive results (sensitivity, 87%), with no false-negative results among a subgroup of tumors of 7 mm and larger (sensitivity, 100%). The 3 cases with false-positive results were histologic fibrosis or biopsy changes. Mean speed-weighted density was 0.015 before and 0.0082 after chemotherapy (P = .03). After chemotherapy, vascularity was less common within (P = .06) or adjacent to (P = .009) masses or in tumor sites (P = .05). Prechemotherapy variables of gray scale characteristics and vascularity were compared with final histologic size, and all had P > .20. CONCLUSIONS: Postchemotherapy sensitivity of sonography was high for residual tumors of 7 mm or larger. Correlation was moderate between histologic and sonographic final tumor sizes. False-positive results were caused by fibrosis or biopsy-related changes. False-negative results occurred with residual tumor size of 6 mm or smaller. After chemotherapy, vascularity usually decreased, and this was not specific for complete response. Before chemotherapy, no vascular or gray scale feature at initial imaging predicted complete responders.

Adult↗

PubMed2004

Therapeutic efficacy of DTI-015 using diffusion magnetic resonance imaging as an early surrogate marker.

To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model, tumors were treated with direct intratumoral administration of DTI-015, a solution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats, and three treatment groups were established: DTI-015, EtOH, and sham. Two groups of rats received intratumoral injection of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 mul under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1, 24, 48, and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast, rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours, which further increased over time, followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage, development of a cystic region, and enhanced animal survival. Finally, not only were ADC measurements predictive of differences between treatment groups, but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy.

Animals↗

PubMed2004

T2-weighted MR imaging in the assessment of cirrhotic liver.

PURPOSE: To assess if T2-weighted magnetic resonance (MR) imaging provides added diagnostic value in combination with dynamic gadolinium-enhanced MR imaging in the detection and characterization of nodular lesions in cirrhotic liver. MATERIALS AND METHODS: Two readers retrospectively and independently analyzed 54 MR imaging studies in 52 patients with cirrhosis. In session 1, readers reviewed T1-weighted and dynamic gadolinium-enhanced images. In session 2, readers reviewed T1-weighted, dynamic gadolinium-enhanced, and respiratory-triggered T2-weighted fast spin-echo images. Readers identified and characterized all focal lesions by using a scale of 1-4 (1, definitely benign; 4, definitely malignant). Multireader correlated receiver operating characteristic (ROC) analysis was employed to assess radiologist performance in session 2 compared with session 1. The difference in the areas under the ROC curves for the two sessions was tested. In a third session, readers assessed conspicuity of biopsy-proved lesions on T2-weighted MR images by using a scale of 1-3 (1, not seen; 3, well seen) and identified causes of reduced conspicuity. RESULTS: Two additional benign lesions were detected by each reader in session 2. Fifty-five lesions had pathologic verification, including 32 malignant, three high-grade dysplastic, and 20 benign nodules. There was no significant difference in the area under the ROC curves between the two sessions (P =.48). Thirty-two lesions were inconspicuous on T2-weighted MR images because of parenchymal heterogeneity, breathing artifacts (particularly in patients with ascites), and lesion isointensity with liver parenchyma. T2-weighted MR imaging was useful in the evaluation of cysts and lymph nodes. CONCLUSION: T2-weighted MR imaging does not provide added diagnostic value in the detection and characterization of focal lesions in cirrhotic liver.

Adult↗

PubMed2004

MRI for preoperative staging of renal cell carcinoma using the 1997 TNM classification: comparison with surgical and pathologic staging.

OBJECTIVE: The purpose of our study was to determine the accuracy of MRI for preoperative staging of renal cell carcinoma using the 1997 TNM classification. MATERIALS AND METHODS: We conducted a retrospective review of MRI performed in 40 consecutive patients with 42 renal cell carcinomas before radical (n = 35) or partial (n = 4) nephrectomy or exploratory laparotomy (n = 3). The interval between imaging and surgery ranged from 1 to 59 days (mean, 17.9 days). Imaging was performed with T1- and T2-weighted, dynamic gadolinium-enhanced, and time-of-flight sequences. MRI and surgical-pathologic staging was performed using the 1997 TNM staging system. MRI staging was compared with surgical-pathologic staging as the gold standard. Agreement between the two staging methods was assessed using the kappa statistic. RESULTS: Agreement between MRI and surgical-pathologic staging was good for T staging (kappa = 0.72 and 0.78 for reviewers 1 and 2 respectively), poor for N staging (kappa = 0.13, both reviewers), good for M staging (kappa = 0.66, both reviewers), and excellent for the assessment of venous involvement (kappa = 0.93, both reviewers). MRI overestimated the T stage in five patients and the N stage in five and underestimated the T stage in three, the N stage in four, the M stage in one, and the extent of venous thrombosis in two patients. CONCLUSION: MRI is a reliable method for preoperative staging of renal cell carcinoma using the 1997 TNM classification, in particular for assessing venous involvement.

Adolescent↗

PubMed2003

Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma.

PURPOSE: Osteosarcoma, the most common pediatric primary bone tumor, is an aggressive malignancy with a tendency for early pulmonary metastasis. A reliable biomarker to predict clinical outcome at diagnosis has not yet been identified. To date, pathological review of neoadjuvant chemotherapy-induced necrosis is the most useful determinant of which patients are likely to develop metastatic disease. There is a clinical need to identify patients who will benefit from more aggressive preoperative therapy or perhaps require less aggressive chemotherapy. More than 30 human P450 isoenzymes have been characterized, with at least nine possessing some clinical relevance. One of these, CYP3A4/5 is involved in metabolic activation and detoxification of a wide number of carcinogens and chemotherapeutic agents, including many drugs that are useful in the treatment of osteosarcomas. MATERIALS AND METHODS: Osteosarcoma tissue microarray blocks containing biopsies from 18 primary tumors were used to analyze the expression of P450s 1A1/2, 1B1, 2B6, 2D6, and 3A4/5 by enzyme-linked avidin-biotin complexed immunohistochemistry. The frequencies of expression were 83%, 67%, and 83% for P450s 1A1/2, 1B1, and 3A4/5, respectively. P450s 2B6 and 2D6 were not detectable. RESULTS: These results were extended by developing a fluorescent-based quantitative immunocytochemistry technique to assess the levels of CYP3A4/5 in 18 paraffin-embedded primary biopsy sections. Expression of CYP3A4/5 was found to be significantly higher in primary biopsies of patients who developed distant metastatic disease compared with biopsies from patients with nonmetastatic disease (P = 0.0004). CONCLUSION: High cytochrome P450 CYP3A4/5 expression may predict metastasis and poor prognosis in osteosarcomas. Its use as a biomarker of therapeutic response will have implications for the treatment of these tumors.

Adolescent↗