Christopher C. Riedl

Clinical Cerenkov Luminescence Imaging of 18F-FDG

The aim of this study was to determine the feasibility of Cerenkov luminescence (CL) imaging of patients undergoing diagnostic 18F-FDG scans to detect nodal disease. Methods: Patients undergoing routine 18F-FDG PET/CT for various malignancies consented to being scanned for CL. White-light and Cerenkov images (5-min acquisition) of the surface of the patient contralateral to and at the site of nodal 18F-FDG uptake were acquired using a cooled, intensified charge-coupled-device camera. Results: The camera demonstrated linear correlation between activity and counts into the low nanocurie range using 18F-FDG. Imaging of patients revealed the presence of 18F-FDG uptake in nodes that demonstrated uptake on PET. A correlation between maximum standardized uptake value from PET and counting rate per area on the CL imaging was established. Conclusion: CL imaging with diagnostic doses of 18F-FDG is feasible and can aid in detecting disease in the clinical setting.

18F-FDG PET Scanning Correlates with Tissue Markers of Poor Prognosis and Predicts Mortality for Patients After Liver Resection for Colorectal Metastases

18F-FDG PET has proven invaluable in the staging of patients with metastatic colorectal cancer. The aim of the current study was to determine whether this biologic scan would correlate with other cellular characteristics and the clinical behavior of tumors. Methods: Ninety patients with resectable colorectal cancer metastatic to the liver underwent 18F-FDG PET before hepatectomy. At surgery, tumors were harvested and prepared for assessment by histology and immunohistochemistry. Expression of Ki67 (a marker for cell proliferation), GLUT1 and GLUT3 (markers for glucose transportation), p53 and p27 (markers for cell cycle control), and BCL-2 (a marker for apoptosis) was assessed by a pathologist who was unaware of the PET results and the clinical outcome. Patients were followed to determine outcome. Survival analysis was performed comparing patient outcome in groups segregated according to standardized uptake values (SUVs) greater or less than 5, 7, or 10. Results: Maximum SUV correlated with GLUT1 (P = 0.03), Ki67 (P = 0.026), and p53 (P = 0.024) but did not correlate with p27, BCL-2, or GLUT3. Survival was significantly longer for patients with a low SUV than for patients with a high SUV, with P values of 0.014, 0.025, and 0.0095 for SUV cutoffs of 5, 7, and 10, respectively. Conclusion: 18F-FDG PET is a biologic scan that predicts prognosis in patients with metastatic colorectal cancer. It is uncertain if this ability is due to cellular glucose metabolism or to a correlation with other cellular characteristics of aggressive tumors.

Magnetic resonance imaging of the breast improves detection of invasive cancer, preinvasive cancer, and premalignant lesions during surveillance of women at high risk for breast cancer.

Purpose: To assess the diagnostic accuracy of mammography, ultrasound, and magnetic resonance imaging (MRI) of the breast in the surveillance of women at high risk for breast cancer. Experimental Design: In this prospective comparison study, women at high risk for breast cancer were offered annual surveillance examinations, consisting of mammography, ultrasound, and MRI, at a single tertiary care breast center. The sensitivity and specificity of each modality was based on the histopathologic evaluation of suspicious findings from all modalities plus the detected interval cancers. Results: Three hundred and twenty-seven women underwent 672 complete imaging rounds. Of a total of 28 detected cancers, 14 were detected by mammography, 12 by ultrasound, and 24 by MRI, which resulted in sensitivities of 50%, 42.9%, and 85.7%, respectively (P < 0.01). MRI detected not only significantly more invasive but also significantly more preinvasive cancers (ductal carcinoma in situ). Mammography, ultrasound, and MRI led to 25, 26, and 101 false-positive findings, which resulted in specificities of 98%, 98%, and 92%, respectively (P < 0.05). Thirty-five (35%) of these false-positive findings were atypical ductal hyperplasias, lesions considered to be of premalignant character. Nine (26%) of those were detected by mammography, 2 (6%) with ultrasound, and 32 (91%) with MRI (P < 0.01). Conclusion: Our results show that MRI of the breast improves the detection of invasive cancers, preinvasive cancers, and premalignant lesions in a high-risk population and should therefore become an integral part of breast cancer surveillance in these patients.

Triple-Modality Screening Trial for Familial Breast Cancer Underlines the Importance of Magnetic Resonance Imaging and Questions the Role of Mammography and Ultrasound Regardless of Patient Mutation Status, Age, and Breast Density

PURPOSE To evaluate the breast cancer screening efficacy of mammography, ultrasound, and magnetic resonance imaging (MRI) in a high-risk population and in various population subgroups. PATIENTS AND METHODS In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with a high familial risk (> 20% lifetime risk) for breast cancer were offered screening with mammography, ultrasound, and MRI every 12 months. Diagnostic performance was compared between individual modalities and their combinations. Further comparisons were based on subpopulations dichotomized by screening rounds, mutation status, age, and breast density. RESULTS There were 559 women with 1,365 complete imaging rounds included in this study. The sensitivity of MRI (90.0%) was significantly higher (P < .001) than that of mammography (37.5%) and ultrasound (37.5%). Of 40 cancers, 18 (45.0%) were detected by MRI alone. Two cancers were found by mammography alone (a ductal carcinoma in situ [DCIS] with microinvasion and a DCIS with < 10-mm invasive areas). This did not lead to a significant increase of sensitivity compared with using MRI alone (P = .15). No cancers were detected by ultrasound alone. Similarly, of 14 DCISs, all were detected by MRI, whereas mammography and ultrasound each detected five DCISs (35.7%). Age, mutation status, and breast density had no influence on the sensitivity of MRI and did not affect the superiority of MRI over mammography and ultrasound. CONCLUSION MRI allows early detection of familial breast cancer regardless of patient age, breast density, or risk status. The added value of mammography is limited, and there is no added value of ultrasound in women undergoing MRI for screening.

Characterization of benign and malignant breast lesions with computed tomography laser mammography (CTLM): initial experience.

Objectives:The aim of this study was to characterize benign and malignant breast lesions with computed tomography–laser mammography (CTLM). Materials and Methods:In a prospective study, 100 female patients with 105 breast lesions classified as BIRADS IV to V at mammography underwent mammography, CTLM, and histologic verification at our institution. CTLM images were analyzed by radiologists with knowledge of the lesions position but who were blinded to histology and morphologic findings from mammography. Two radiologists independently evaluated whether there was increased absorption, a sign of malignancy, on CTLM and assessed the appearance (volumes or linear branching) and shape (round or irregular) of the lesions. Results:Histologic analysis revealed 55 benign (52.4%) and 50 malignant (47.6%) breast lesions. Increased absorption was observed significantly more often in malignant than in benign lesions (70.0% vs. 32.7%, P = 0.028). Invasive cancer showed increased absorption in 76.2%, and ductal carcinoma in situ in 37.5%. Common morphologic characteristics of increased absorption were “volumes” (85.7% of malignant and 77.8% of benign lesions) with round shape (78.1% of malignant and 73.3% of benign lesions). Conclusion:Our data indicate that CTLM, when used as an adjunct to mammography, may provide additional information to characterize benign and malignant breast lesions.

Novel oncolytic agent GLV-1h68 is effective against malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a fatal disease with a median survival of less than 14 months. For the first time, a genetically engineered vaccinia virus is shown to produce efficient infection, replication, and oncolytic effect against MPM. GLV-1h68 is a replication-competent engineered vaccinia virus carrying transgenes encoding Renilla luciferase, green fluorescent protein (both inserted at the F14.5L locus), beta-galactosidase (inserted at the J2R locus, which encodes thymidine kinase), and beta-glucuronidase (at the A56R locus, which encodes hemagglutinin). This virus was tested in six human MPM cell lines (MSTO-211H, VAMT, JMN, H-2373, H-2452, and H-2052). GLV-1h68 successfully infected all cell lines. For the most sensitive line, MSTO-211H, expression of green fluorescent protein (GFP) started within 4 hr with increasing intensity over time until nearly 100% of cells expressed GFP at 24 hr. All cell lines were sensitive to killing by GLV-1h68, with the degree of sensitivity predictable by infectivity assay. Even the most resistant cell line exhibited 44 +/- 3.8% cell survival by day 7 when infected at a multiplicity of infection of 1.0. Viral proliferation assays demonstrated 2-to 4-fold logarithmic replication of GLV-1h68 in the cell lines tested. In an orthotopic model, GLV-1h68 effectively prevented development of cachexia and tumor-related morbidity, reduced tumor burden, and cured MPM in both early and late treatment groups. GLV-1h68 was successfully used to treat MPM in vitro and in an orthotopic model (in vivo). These promising results warrant clinical investigation of GLV-1h68 as a novel agent in the treatment of MPM.

Escherichia coli Nissle 1917 Facilitates Tumor Detection by Positron Emission Tomography and Optical Imaging

Purpose: Bacteria-based tumor-targeted therapy is a modality of growing interest in anticancer strategies. Imaging bacteria specifically targeting and replicating within tumors using radiotracer techniques and optical imaging can provide confirmation of successful colonization of malignant tissue. Experimental Design: The uptake of radiolabeled pyrimidine nucleoside analogues and [18F]FDG by Escherichia coli Nissle 1917 (EcN) was assessed both in vitro and in vivo. The targeting of EcN to 4T1 breast tumors was monitored by positron emission tomography (PET) and optical imaging. The accumulation of radiotracer in the tumors was correlated with the number of bacteria. Optical imaging based on bioluminescence was done using EcN bacteria that encode luciferase genes under the control of an l-arabinose–inducible PBAD promoter system. Results: We showed that EcN can be detected using radiolabeled pyrimidine nucleoside analogues, [18F]FDG and PET. Importantly, this imaging paradigm does not require transformation of the bacterium with a reporter gene. Imaging with [18F]FDG provided lower contrast than [18F]FEAU due to high FDG accumulation in control (nontreated) tumors and surrounding tissues. A linear correlation was shown between the number of viable bacteria in tumors and the accumulation of [18F]FEAU, but not [18F]FDG. The presence of EcN was also confirmed by bioluminescence imaging. Conclusion:EcN can be imaged by PET, based on the expression of endogenous E. coli thymidine kinase, and this imaging paradigm could be translated to patient studies for the detection of solid tumors. Bioluminescence imaging provides a low-cost alternative to PET imaging in small animals.

Interactive dedicated training curriculum improves accuracy in the interpretation of MR imaging of prostate cancer

ObjectiveTo assess the effect of interactive dedicated training on radiology fellows’ accuracy in assessing prostate cancer on MRI.MethodsEleven radiology fellows, blinded to clinical and pathological data, independently interpreted preoperative prostate MRI studies, scoring the likelihood of tumour in the peripheral and transition zones and extracapsular extension. Each fellow interpreted 15 studies before dedicated training (to supply baseline interpretation accuracy) and 200 studies (10/week) after attending didactic lectures. Expert radiologists led weekly interactive tutorials comparing fellows’ interpretations to pathological tumour maps. To assess interpretation accuracy, receiver operating characteristic (ROC) analysis was conducted, using pathological findings as the reference standard.ResultsIn identifying peripheral zone tumour, fellows’ average area under the ROC curve (AUC) increased from 0.52 to 0.66 (after didactic lectures; p < 0.0001) and remained at 0.66 (end of training; p < 0.0001); in the transition zone, their average AUC increased from 0.49 to 0.64 (after didactic lectures; p = 0.01) and to 0.68 (end of training; p = 0.001). In detecting extracapsular extension, their average AUC increased from 0.50 to 0.67 (after didactic lectures; p = 0.003) and to 0.81 (end of training; p < 0.0001).ConclusionInteractive dedicated training significantly improved accuracy in tumour localization and especially in detecting extracapsular extension on prostate MRI.

Retrospective Analysis of 18F-FDG PET/CT for Staging Asymptomatic Breast Cancer Patients Younger Than 40 Years

National Comprehensive Cancer Network guidelines consider 18F-FDG PET/CT for only clinical stage III breast cancer patients. However, there is debate whether TNM staging should be the only factor in considering if PET/CT is warranted. Patient age may be an additional consideration, because young breast cancer patients often have more aggressive tumors with potential for earlier metastases. This study assessed PET/CT for staging of asymptomatic breast cancer patients younger than 40 y. Methods: In this Institutional Review Board–approved retrospective study, our hospital information system was screened for breast cancer patients younger than 40 y who underwent staging PET/CT before any treatment. Patients with symptoms or conventional imaging findings suggestive of distant metastases or with prior malignancy were excluded. Initial stage was based on physical examination, mammography, ultrasound, and breast MR imaging. PET/CT was then evaluated to identify unsuspected extraaxillary regional nodal and distant metastases. Results: One hundred thirty-four patients with initial breast cancer stage I to IIIC met inclusion criteria. PET/CT findings led to upstaging to stage III or IV in 28 patients (21%). Unsuspected extraaxillary regional nodes were found in 15 of 134 patients (11%) and distant metastases in 20 of 134 (15%), with 7 of 134 (5%) demonstrating both. PET/CT revealed stage IV disease in 1 of 20 (5%) patients with initial clinical stage I, 2 of 44 (5%) stage IIA, 8 of 47 (17%) stage IIB, 4 of 13 (31%) stage IIIA, 4 of 8 (50%) stage IIIB, and 1 of 2 (50%) stage IIIC. All 20 patients upstaged to stage IV were histologically confirmed. Four synchronous thyroid and 1 rectal malignancies were identified. Conclusion: PET/CT revealed distant metastases in 17% of asymptomatic stage IIB breast cancer patients younger than 40 y. Although guidelines of the National Comprehensive Cancer Network recommend against systemic staging in patients with stage II disease, our data suggest that PET/CT might be valuable in younger patients with stage IIB and III disease. Use of PET/CT in younger patients has the potential to reduce the morbidity and cost of unnecessary therapies in young breast cancer patients.

Magnetic Resonance Imaging Improves Breast Screening Sensitivity in BRCA Mutation Carriers Age ≥ 50 Years: Evidence From an Individual Patient Data Meta-Analysis

PURPOSE There is no consensus on whether magnetic resonance imaging (MRI) should be included in breast screening protocols for women with BRCA1/2 mutations age ≥ 50 years. Therefore, we investigated the evidence on age-related screening accuracy in women with BRCA1/2 mutations using individual patient data (IPD) meta-analysis. PATIENTS AND METHODS IPD were pooled from six high-risk screening trials including women with BRCA1/2 mutations who had completed at least one screening round with both MRI and mammography. A generalized linear mixed model with repeated measurements and a random effect of studies estimated sensitivity and specificity of MRI, mammography, and the combination in all women and specifically in those age ≥ 50 years. RESULTS Pooled analysis showed that in women age ≥ 50 years, screening sensitivity was not different from that in women age < 50 years, whereas screening specificity was. In women age ≥ 50 years, combining MRI and mammography significantly increased screening sensitivity compared with mammography alone (94.1%; 95% CI, 77.7% to 98.7% v 38.1%; 95% CI, 22.4% to 56.7%; P < .001). The combination was not significantly more sensitive than MRI alone (94.1%; 95% CI, 77.7% to 98.7% v 84.4%; 95% CI, 61.8% to 94.8%; P = .28). Combining MRI and mammography in women age ≥ 50 years resulted in sensitivity similar to that in women age < 50 years (94.1%; 95% CI, 77.7% to 98.7% v 93.2%; 95% CI, 79.3% to 98%; P = .79). CONCLUSION Addition of MRI to mammography for screening BRCA1/2 mutation carriers age ≥ 50 years improves screening sensitivity by a magnitude similar to that observed in younger women. Limiting screening MRI in BRCA1/2 carriers age ≥ 50 years should be reconsidered.