Background Parenchymal Uptake on Molecular Breast Imaging and Breast Cancer Risk: A Cohort Study.

BACKGROUND. Background parenchymal uptake (BPU) on molecular breast imaging (MBI) was identified in a case-control study as a breast cancer risk factor beyond mammographic density. To our knowledge, this finding has not yet been confirmed in a cohort study. OBJECTIVE. The objectives of this study were to examine the association of BPU with breast cancer and to estimate the absolute risk and discriminatory accuracy of BPU in a cohort study. METHODS. A retrospective cohort was established that included women without a history of breast cancer who underwent MBI from 2004 to 2015. Radiologists who were blinded to future breast cancer diagnoses assessed BPU on baseline MBI examinations as low (photopenic or minimal) or elevated (mild, moderate, or marked). Associations of BPU with breast cancer were estimated using multivariable Cox proportional hazards models of the time to diagnosis. The 5-year absolute risk was calculated for study subgroups. The discriminatory accuracy of BPU was also assessed. RESULTS. Among 2992 women (mean age, 56.3 years; SD, 10.6 years) who underwent MBI, breast cancer events occurred in 144 women (median follow-up, 7.3 years). Median time to diagnosis after MBI was 4.2 years (range, 0.5-11.6 years). Elevated BPU was associated with a greater breast cancer risk (hazard ratio [HR], 2.39; 95% CI, 1.68-3.41; p ≤ .001). This association remained in postmenopausal women (HR, 3.50; 95% CI, 2.31-5.31; p < .001) but was not significant in premenopausal women (HR, 1.29; 95% CI, 0.72-2.32; p = .39). The 5-year absolute risk of breast cancer was 4.3% (95% CI, 2.9-5.7%) for women with elevated BPU versus 2.5% (95% CI, 1.8-3.1%) for those with low BPU. Postmenopausal women with dense breasts and elevated BPU had a 5-year absolute risk of 8.1% (95% CI, 4.3-11.8%) versus 2.8% (1.8-3.8%) for those with low BPU. Among postmenopausal women, discriminatory accuracy for invasive cancer was improved with the addition of BPU versus use of the Gail risk score alone (C statistic, 65.1 vs 59.1; p = .04) or use of the Breast Cancer Surveillance Consortium risk score alone (C statistic, 66.4 vs 60.4; p = .04). CONCLUSION. BPU on MBI is an independent risk factor for breast cancer, with the strongest association observed among postmenopausal women with dense breasts. In postmenopausal women, BPU provides incremental discrimination in predicting breast cancer when combined with either the Gail model or the Breast Cancer Surveillance Consortium model. CLINICAL IMPACT. Observation of elevated BPU on MBI may identify a subset of women with dense breasts who would benefit most from supplemental screening or preventive options.

Molecular Breast Imaging in Clinical Practice.

OBJECTIVE. The purpose of this article is to review clinical uses and image interpretation of molecular breast imaging (MBI) and clarify radiation risks. CONCLUSION. MBI detects additional cancers compared with conventional imaging in women with dense breasts and those with elevated risk of breast cancer. Its role as an imaging biomarker of cancer risk and in assessing neoadjuvant chemotherapy response is growing. Radiation risk is minimal; benefit-to-risk ratio is similar to that of mammography. MBI is low cost, well tolerated, and easily adapted into clinical practice.

Dose Reduction in Molecular Breast Imaging With a New Image-Processing Algorithm.

OBJECTIVE. The purpose of this study was to determine whether application of a proprietary image-processing algorithm would allow a reduction in the necessary administered activity for molecular breast imaging (MBI) examinations. MATERIALS AND METHODS. Images from standard-dose MBI examinations (300 MBq 99mTc-sestamibi) of 50 subjects were analyzed. The images were acquired in dynamic mode and showed at least one breast lesion. Half-dose MBI examinations were simulated by summing one-half of the dynamic frames and were processed with the algorithm under study in both a default and a preferred filter mode. Two breast radiologists independently completed a set of two-alternative forced-choice tasks to compare lesion conspicuity on standard-dose images, half-dose images, and the algorithm-processed half-dose images in both modes. RESULTS. Relative to the standard-dose images, the half-dose images were preferred in 4, the default-filtered half-dose images in 50, and preferred-filtered half-dose images in 76 of 100 readings. Compared with standard-dose images, in terms of lesion conspicuity, the half-dose images were rated better in 2, equivalent in 6, and poorer in 92 of 100 readings. The default-filtered half-dose images were rated better, equivalent, or poorer in 13, 73, and 14 of 100 readings. The preferred-filtered half-dose images were rated as better, equivalent, or poorer in 55, 34, and 11 of 100 readings. CONCLUSION. Compared with that on standard-dose images, lesion conspicuity on images obtained with the algorithm and acquired at one-half the standard dose was equivalent or better without compromise of image quality. The algorithm can also be used to decrease imaging time with a resulting increase in patient comfort and throughput.

Comparison of 99mTc-Sestamibi Molecular Breast Imaging and Breast MRI in Patients With Invasive Breast Cancer Receiving Neoadjuvant Chemotherapy.

OBJECTIVE. The purpose of this study is to prospectively compare the size of invasive breast cancer before and after neoadjuvant chemotherapy (NAC) at breast MRI and molecular breast imaging (MBI) and to assess the accuracy of post-NAC MBI and MRI relative to pathologic analysis. SUBJECTS AND METHODS. Women with invasive breast cancer greater than or equal to 1.5 cm were enrolled to compare the longest dimension before and after NAC at MRI and MBI. MBI was performed on a dual-detector cadmium zinc telluride system after administration of 6.5 mCi (240 MBq) 99mTc-sestamibi. The accuracy of MRI and MBI in assessing residual disease (invasive disease or ductal carcinoma in situ) was determined relative to pathologic examination. RESULTS. The longest dimension at MRI was within 1.0 cm of that at MBI in 72.3% of cases before NAC and 70.1% of cases after NAC. The difference between the longest dimension at imaging after NAC and pathologic tumor size was within 1 cm for 58.7% of breast MRI cases and 59.6% of MBI cases. Ninety patients underwent both MRI and MBI after NAC. In the 56 patients with invasive residual disease, 10 (17.9%) cases were negative at MRI and 23 (41.1%) cases were negative at MBI. In the 34 patients with breast pathologic complete response, there was enhancement in 10 cases (29.4%) at MRI and uptake in six cases (17.6%) at MBI. Sensitivity, specificity, positive predictive value, and negative predictive value after NAC were 82.8%, 69.4%, 81.4%, and 71.4%, respectively, for MRI and 58.9%, 82.4%, 84.6%, and 54.9%, respectively, for MBI. CONCLUSION. Breast MRI and MBI showed similar disease extent before NAC. MBI may be an alternative to breast MRI in patients with a contraindication to breast MRI. Neither modality showed sufficient accuracy after NAC in predicting breast pathologic complete response to obviate tissue diagnosis to assess for residual invasive disease. Defining the extent of residual disease compared with pathologic evaluation was also limited after NAC for both breast MRI and MBI.

Impact of short-term low-dose tamoxifen on molecular breast imaging background parenchymal uptake: a pilot study.

BACKGROUND: High background parenchymal uptake (BPU) on molecular breast imaging (MBI) has been identified as a breast cancer risk factor. We explored the feasibility of offering a short-term intervention of low-dose oral tamoxifen to women with high BPU and examined whether this intervention would reduce BPU. METHODS: Women with a history of high BPU and no breast cancer history were invited to the study. Participants had an MBI exam, followed by 30 days of low-dose oral tamoxifen at either 5 mg or 10 mg/day, and a post-tamoxifen MBI exam. BPU on pre- and post-tamoxifen MBI exams was quantitatively assessed as the ratio of average counts in breast fibroglandular tissue vs. average counts in subcutaneous fat. Pre-tamoxifen and post-tamoxifen BPU were compared with paired t tests. RESULTS: Of 47 women invited, 22 enrolled and 21 completed the study (10 taking 5 mg tamoxifen, 11 taking 10 mg tamoxifen). Mean age was 47.7 years (range 41-56 years). After 30 days low-dose tamoxifen, 8 of 21 women (38%) showed a decline in BPU, defined as a decrease from the pre-tamoxifen MBI of at least 15%; 11 of 21 (52%) had no change in BPU (within ± 15%); 2 of 21 (10%) had an increase in BPU of greater than 15%. Overall, the average post-tamoxifen BPU was not significantly different from pre-tamoxifen BPU (1.34 post vs. 1.43 pre, p = 0.11). However, among women taking 10 mg tamoxifen, 5 of 11 (45%) showed a decline in BPU; average BPU was 1.19 post-tamoxifen vs. 1.34 pre-tamoxifen (p = 0.005). In women taking 5 mg tamoxifen, 2 of 10 (20%) showed a decline in BPU; average BPU was 1.51 post-tamoxifen vs.1.53 pre-tamoxifen (p = 0.99). CONCLUSIONS: Short-term intervention with low-dose tamoxifen may reduce high BPU on MBI for some patients. Our preliminary findings suggest that 10 mg tamoxifen per day may be more effective than 5 mg for inducing declines in BPU within 30 days. Given the variability in BPU response to tamoxifen observed among study participants, future study is warranted to determine if BPU response could predict the effectiveness of tamoxifen for breast cancer risk reduction within an individual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02979301 . Registered 01 December 2016.

Classification of Background Parenchymal Uptake on Molecular Breast Imaging Using a Convolutional Neural Network.

PURPOSE: Background parenchymal uptake (BPU), which describes the level of radiotracer uptake in normal fibroglandular tissue on molecular breast imaging (MBI), has been identified as a breast cancer risk factor. Our objective was to develop and validate a deep learning model using image convolution to automatically categorize BPU on MBI. METHODS: MBI examinations obtained for clinical and research purposes from 2004 to 2015 were reviewed to classify the BPU pattern using a standardized five-category scale. Two expert radiologists provided interpretations that were used as the reference standard for modeling. The modeling consisted of training and validating a convolutional neural network to predict BPU. Model performance was summarized in data reserved to test the performance of the algorithm at the per-image and per-breast levels. RESULTS: Training was performed on 24,639 images from 3,133 unique patients. The model performance on the withheld testing data (6,172 images; 786 patients) was evaluated. Using direct matching on the predicted classification resulted in an accuracy of 69.4% (95% CI, 67.4% to 71.3%), and if prediction within one category was considered, accuracy increased to 96.0% (95% CI, 95.2% to 96.7%). When considering the breast-level prediction of BPU, the accuracy remained strong, with 70.3% (95% CI, 68.0% to 72.6%) and 96.2% (95% CI, 95.3% to 97.2%) for the direct match and allowance for one category, respectively. CONCLUSION: BPU provided a robust target for training a convolutional neural network. A validated computer algorithm will allow for objective, reproducible encoding of BPU to foster its integration into risk-stratification algorithms.

Molecular Breast Imaging in Patients with Suspicious Calcifications.

OBJECTIVE: We evaluated the accuracy of molecular breast imaging (MBI)-a nuclear medicine technique that employs dedicated dual-detector, cadmium zinc telluride gamma cameras to image the functional uptake of a radiopharmaceutical (typically Tc-99m sestamibi) in the breast-in patients with suspicious calcifications on mammography. METHODS: Women scheduled for stereotactic biopsy of calcifications detected on 2D digital mammography were prospectively enrolled to undergo MBI before biopsy. Molecular breast imaging was performed with injection of Tc-99m sestamibi and a dual-detector, cadmium zinc telluride gamma camera. Positive findings on either modality were biopsied. High-risk and malignant biopsy findings were excised. RESULTS: In 71 participants, 76 areas of calcifications were recommended for biopsy after mammography, and 24 (32%) were malignant, including 20 cases of ductal carcinoma in situ (DCIS) and 4 cases of invasive ductal cancer. Prebiopsy MBI was positive in 17 of the 76 (22%) calcifications, including 10 of 20 (50%) DCISs and 2 of 4 (50%) invasive cancers. The median pathologic size for MBI-positive cancers was 1.5 cm (range 0.5-3.2 cm) compared with 0.9 cm (range 0.1-2.0 cm) for MBI-negative cancers (P = 0.09).Non-mass uptake on MBI led to additional biopsies of 6 sites in 6 patients, and 2 of 6 (33%) MBI-detected incidental lesions showed malignancy; both DCIS contralateral to the mammographically detected calcifications. The overall per-lesion positive and negative predictive values of MBI in this prebiopsy setting were 61% (14 of 23) and 80% (47 of 59), respectively. CONCLUSION: Molecular breast imaging has insufficient negative predictive value to identify calcifications in which biopsy could be avoided. However, among women presenting for biopsy of suspicious calcifications, MBI revealed additional sites of mammographically occult breast cancer.To avoid biopsy of suspicious calcifications on mammography, negative findings on MBI should not be used.

Patient Acceptance of Half-dose Vs. Half-time Molecular Breast Imaging.

OBJECTIVE: A number of strategies have been implemented at our institution to allow reductions in the administered dose or imaging time for molecular breast imaging (MBI). In this work, we examine patient opinions of whether dose reduction or time reduction is preferred. METHODS: Sixty female volunteers were randomized to undergo MBI at either half-dose (150 MBq Tc-99m sestamibi; images acquired for 10 minutes per view) or half-time (300 MBq Tc-99m sestamibi; images acquired for 5 minutes per view). A survey was then performed to assess patient comfort and examination preferences. Survey responses were compared between groups using Fisher's exact test. RESULTS: No differences were observed between groups regarding opinions of radiation dose, duration of examination, examination comfort, and willingness to undergo MBI in the future. Of those who responded, most women (39/55 [70%]) indicated a preference for the examination type they underwent, either half-dose or half-time MBI, rather than the other protocol. CONCLUSIONS: Survey findings support that MBI, whether performed at half-time or half-dose, is well accepted by patients.

Quantitative background parenchymal uptake on molecular breast imaging and breast cancer risk: a case-control study.

BACKGROUND: Background parenchymal uptake (BPU), which refers to the level of Tc-99m sestamibi uptake within normal fibroglandular tissue on molecular breast imaging (MBI), has been identified as a breast cancer risk factor, independent of mammographic density. Prior analyses have used subjective categories to describe BPU. We evaluate a new quantitative method for assessing BPU by testing its reproducibility, comparing quantitative results with previously established subjective BPU categories, and determining the association of quantitative BPU with breast cancer risk. METHODS: Two nonradiologist operators independently performed region-of-interest analysis on MBI images viewed in conjunction with corresponding digital mammograms. Quantitative BPU was defined as a unitless ratio of the average pixel intensity (counts/pixel) within the fibroglandular tissue versus the average pixel intensity in fat. Operator agreement and the correlation of quantitative BPU measures with subjective BPU categories assessed by expert radiologists were determined. Percent density on mammograms was estimated using Cumulus. The association of quantitative BPU with breast cancer (per one unit BPU) was examined within an established case-control study of 62 incident breast cancer cases and 177 matched controls. RESULTS: Quantitative BPU ranged from 0.4 to 3.2 across all subjects and was on average higher in cases compared to controls (1.4 versus 1.2, p < 0.007 for both operators). Quantitative BPU was strongly correlated with subjective BPU categories (Spearman's r = 0.59 to 0.69, p < 0.0001, for each paired combination of two operators and two radiologists). Interoperator and intraoperator agreement in the quantitative BPU measure, assessed by intraclass correlation, was 0.92 and 0.98, respectively. Quantitative BPU measures showed either no correlation or weak negative correlation with mammographic percent density. In a model adjusted for body mass index and percent density, higher quantitative BPU was associated with increased risk of breast cancer for both operators (OR = 4.0, 95% confidence interval (CI) 1.6-10.1, and 2.4, 95% CI 1.2-4.7). CONCLUSION: Quantitative measurement of BPU, defined as the ratio of average counts in fibroglandular tissue relative to that in fat, can be reliably performed by nonradiologist operators with a simple region-of-interest analysis tool. Similar to results obtained with subjective BPU categories, quantitative BPU is a functional imaging biomarker of breast cancer risk, independent of mammographic density and hormonal factors.

Molecular Breast Imaging: Administered Activity Does Not Require Adjustment Based on Patient Size.

At our institution, molecular breast imaging (MBI) is performed with 300 MBq of 99mTc-sestamibi for all patients. For some nuclear medicine procedures, administered activity or imaging time is increased for patients of larger size to obtain adequate counts. Our objective was to assess whether uptake of 99mTc-sestamibi in the breast is influenced by patient size. Methods: Records from patients who underwent a clinical MBI examination between July and November 2016 were reviewed. Those in whom our standard injection and preparation techniques were followed were included in the analysis. Patients were injected with approximately 300 MBq of 99mTc-sestamibi. Residual activity was measured to allow calculation of exact administered activity for each patient. Breast images were acquired at 10 min/view using a dual-head cadmium zinc telluride-based γ-camera. Breast thickness was measured as the distance between the 2 detectors. Patient height, weight, body surface area, and body mass index were obtained from records. Lean body mass with the James equation (LBMJames) and Janmahasatian correction (LBMJanma) was calculated. Count density in the breast tissue was measured by drawing a region of interest around the central breast tissue of the right breast mediolateral-oblique view of the lower detector. Count density was expressed as cts/cm2/MBq of administered activity. Spearman correlation coefficient (rs) was calculated. Results: A total of 200 patients were analyzed. No dose infiltration was suspected at any injection. Average administered activity was 292 MBq (SD, 13.8 MBq; range, 247-326 MBq). Average count density was 7.2 cts/cm2/MBq (SD, 2.7 cts/cm2/MBq; range, 3.1-17.8 cts/cm2/MBq). MBI count density was weakly negatively correlated with height (rs = -0.18; P = 0.01), weight (rs = -0.23; p = <0.001), body mass index (rs = -0.16; P = 0.02), body surface area (rs = -0.22; P = 0.002), LBMJames (rs = -0.23; P = 0.001), and LBMJanma (rs = -0.23; P = 0.001). No correlation was observed between count density and breast thickness (rs = 0.06; P = 0.37). Conclusion: Our results suggest a lack of relationship between uptake of 99mTc-sestamibi in breast tissue and body size or compressed breast thickness. Altering from the standard 300 MBq of administered activity for larger patients is likely unnecessary.

BEST PRACTICES IN MOLECULAR BREAST IMAGING: A GUIDE FOR TECHNOLOGISTS.

Molecular breast imaging (MBI) technologists are required to possess a combination of nuclear medicine skills and mammographic positioning techniques. Currently, no formal programs offer this type of hybrid technologist training. The purpose of this perspective is to provide a best practices guide for technologists performing MBI. Familiarity with best practices may aid in obtaining high-quality MBI examinations by decreasing the likelihood of image artifacts, positioning problems and other factors that contribute to false negative or false positive findings.

Analysis of Brain SPECT Images Coregistered with MRI in Patients with Epilepsy: Comparison of Three Methods.

BACKGROUND AND PURPOSE: SISCOM and STATISCOM were clinically proved to be effective for ictal/inter-ictal single-photon emission computed tomography (SPECT) analysis coregistered with magnetic resonance imaging (MRI) for seizure localization. Recently, a software package also became available for this analysis. This study aimed to investigate and compare the performance of these analysis methods for seizure localization. METHODS: A total of 378 patients who underwent 99m Tc-ethyl cysteinate dimer (ECD) SPECT scans were retrospectively reviewed and 28 remained after applying exclusion criteria. Their SPECT and MRI images were analyzed with SISCOM (with z-score of 1.5 and 2), STATISCOM, and MIMneuro, resulting in a total of 112 image data sets. Two experienced radiologists participated in the blind review process using a custom tool and they can mark up to two hyper- and/or hypoperfusion regions. Their review results were analyzed using the Jackknife Free Response Receiver-Operating Characteristics (JAFROC) test and the JAFROC figure-of-merit (FoM) was reported for each method. The interobserver agreement was also assessed using Cohen's kappa test. RESULTS: Based on the readers' two choices, averaged FoM was 85.7%, 83.9%, 66.1%, and 51.8% for STATISCOM, MIMneuro, SISCOM (z-score = 2), and SISCOM (z-score = 1.5), respectively. The average confidence rating was 2.5, 2.3, 1.6, and 1.1 for STATISCOM, MIMneuro, SISCOM (z-score = 2), and SISCOM (z-score = 1.5), respectively. For interobserver agreement, kappa was .742 for STATISCOM, .816 for MIMneuro, .517 for SISCOM (z-score = 2), and .441 for SISCOM (z-score = 1.5; all P < .001). CONCLUSION: Our study demonstrated that STATISCOM showed the best performance for seizure localization, which was closely followed by MIMneuro. In addition, MIMneuro was not inferior to SISCOM with either z-score.

Improved visualization of breast tissue on a dedicated breast PET system through ergonomic redesign of the imaging table.

BACKGROUND: Breast lesions closer than 2 cm to the chest wall are difficult to position in the field of view of dedicated breast PET (db-PET) systems. This inability to detect such lesions is a significant limitation of these systems. The primary objective of this study was to determine if modifications to the design of the imaging table and detector used for a db-PET system would enable improved visualization of breast tissue close to the chest wall. All studies were performed on a commercially available db-PET system (Mammi-PET). A central square section of the imaging table, containing the standard 180-mm circular aperture, was modified such that it could be removed and replaced by thinner sections with a larger aperture. Additional changes were made to the cover plate of the detector array and the patient mattress. A total of 60 patients were studied. After administration of F-18 FDG, 30 patients were imaged with a 220-mm-diameter aperture and the standard aperture, and 30 patients with a 200-mm aperture and the standard aperture. On all scans, the length of breast tissue in the field of view was measured as the greatest extent of tissue from the nipple back to the posterior edge of the breast. Image quality and patient comfort were recorded. RESULTS: Averaged over both breasts, relative to the standard aperture, the increase in breast length was 12.5 + 7.7 mm with the 220-mm aperture, and 12.3 + 6.5 mm with the 200-mm aperture (p < 0.05 for both apertures). In ~ 5% of cases, the larger apertures resulted in some degradation in image quality due to closer proximity to cardiac/hepatic activity. In 10-20% of cases, movement of the breast tissue was observed as the detector ring was moved to scan the anterior region of the breast. The patient survey indicated no significant difference in the comfort level between the standard aperture and either of the prototype apertures. CONCLUSIONS: Modifications to the image table and system resulted in a significant gain in the volume of breast tissue that could be imaged on the db-PET system and should allow better visualization of lesions close to the chest wall.

Risk of low-dose radiation and the BEIR VII report: A critical review of what it does and doesn't say.

This article briefly reviews the history behind the BEIR VII report and the use of the linear no-threshold hypothesis. The BEIR VII committee considered four primary sources of data on the stochastic effects of ionizing radiation. These were environmental studies, occupational studies, medical studies and studies on the atomic bomb survivors. These sources are briefly reviewed along with key studies that run counter to the LNT hypothesis. We review many of the assumptions, hypotheses and subjective decisions used to generate risk estimates in the BEIR VII report. Position statement by the Health Physics Society, American Association of Physicists in Medicine, and UNSCEAR support the conclusion that the risk estimates in the BEIR VII report should not be used for estimating cancer risks from low doses of ionizing radiation.

Technical Note: Development of a combined molecular breast imaging/ultrasound system for diagnostic evaluation of MBI-detected lesions.

PURPOSE: The purpose of this study was to perform a pilot evaluation of an integrated molecular breast imaging/ultrasound (MBI/US) system designed to enable, in real-time, the registration of US to MBI and diagnostic evaluation of breast lesions detected on MBI. METHODS: The MBI/US system was constructed by modifying an existing dual-head cadmium zinc telluride (CZT)-based MBI gamma camera. The upper MBI detector head was replaced with a mesh panel, which allowed an ultrasound probe to access the breast. An optical tracking system was used to monitor the location of the ultrasound transducer, referenced to the MBI detector. The lesion depth at which ultrasound was targeted was estimated from analysis of previously acquired dual-head MBI datasets. A software tool was developed to project the US field of view onto the current MBI image. Correlation of lesion location between both modalities with real-time MBI/US scanning was confirmed in a breast phantom model and assessed in 12 patients with a breast lesion detected on MBI. RESULTS: Combined MBI/US scanning allowed for registration of lesions detected on US and MBI as validated in phantom experiments. In patient studies, successful registration was achieved in 8 of 12 (67%) patients, with complete registration achieved in seven and partial registration achieved in one patient. In 4 of 12 (37%) patients, lesion registration was not achieved, partially attributed to uncertainty in lesion depth estimates from MBI. CONCLUSION: The MBI/US system enabled successful registration of US to MBI in over half of patients studied in this pilot evaluation. Future studies are needed to determine if real-time, registered US imaging of MBI-detected lesions may obviate the need to proceed to more expensive procedures such as contrast-enhanced breast MRI for diagnostic workup or biopsy of MBI findings.

Comparison of Tc-99m maraciclatide and Tc-99m sestamibi molecular breast imaging in patients with suspected breast cancer.

BACKGROUND: Molecular breast imaging (MBI) performed with 99mTc sestamibi has been shown to be a valuable technique for the detection of breast cancer. Alternative radiotracers such as 99mTc maraciclatide may offer improved uptake in breast lesions. The purpose of this study was to compare relative performance of 99mTc sestamibi and 99mTc maraciclatide in patients with suspected breast cancer, using a high-resolution dedicated gamma camera for MBI. Women with breast lesions suspicious for malignancy were recruited to undergo two MBI examinations-one with 99mTc sestamibi and one with 99mTc maraciclatide. A radiologist interpreted MBI studies in a randomized, blinded fashion to assign an assessment score (1-5) and measured lesion size. Lesion-to-background (L/B) ratio was measured with region-of-interest analysis. RESULTS: Among 39 analyzable patients, 21 malignant tumors were identified in 21 patients. Eighteen of 21 tumors (86%) were seen on 99mTc sestamibi MBI and 19 of 21 (90%) were seen on 99mTc maraciclatide MBI (p = 1). Tumor extent measured with both radiopharmaceuticals correlated strongly with pathologic size (99mTc sestamibi, r = 0.84; 99mTc maraciclatide, r = 0.81). The L/B ratio in detected breast cancers was similar for the two radiopharmaceuticals: 1.55 ± 0.36 (mean ± S.D.) for 99mTc sestamibi and 1.62 ± 0.37 (mean ± S.D.) for 99mTc maraciclatide (p = 0.53). No correlation was found between the L/B ratio and molecular subtype for 99mTc sestamibi (r s = 0.12, p = 0.63) or 99mTc maraciclatide (r s = -0.12, p = 0.64). Of 20 benign lesions, 10 (50%) were seen on 99mTc sestamibi and 9 of 20 (45%) were seen on 99mTc maraciclatide images (p = 0.1). The average L/B ratio for benign lesions was 1.34 ±0.40 (mean ±S.D.) for 99mTc sestamibi and 1.41 ±0.52 (mean ±S.D.) for 99mTc maraciclatide (p = 0.75). Overall diagnostic performance was similar for both radiopharmaceuticals. AUC from ROC analysis was 0.83 for 99mTc sestamibi and 0.87 for 99mTc maraciclatide (p = 0.64). CONCLUSIONS: 99mTc maraciclatide offered comparable lesion uptake to 99mTc sestamibi, in both malignant and benign lesions. There was good correlation between lesion extent and uptake measured from both radiopharmaceuticals. 99mTc maraciclatide offered a marginal (but not significant) improvement in sensitivity over 99mTc sestamibi. Our findings did not support an association between the uptake of either radiopharmaceutical and tumor molecular subtype. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00888589.

Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1.

We tested the hypothesis that ex vivo hepatocyte gene therapy can correct the metabolic disorder in fumarylacetoacetate hydrolase-deficient (Fah(-/-)) pigs, a large animal model of hereditary tyrosinemia type 1 (HT1). Recipient Fah(-/-) pigs underwent partial liver resection and hepatocyte isolation by collagenase digestion. Hepatocytes were transduced with one or both of the lentiviral vectors expressing the therapeutic Fah and the reporter sodium-iodide symporter (Nis) genes under control of the thyroxine-binding globulin promoter. Pigs received autologous transplants of hepatocytes by portal vein infusion. After transplantation, the protective drug 2-(2-nitro-4-trifluoromethylbenzyol)-1,3 cyclohexanedione (NTBC) was withheld from recipient pigs to provide a selective advantage for expansion of corrected FAH(+) cells. Proliferation of transplanted cells, assessed by both immunohistochemistry and noninvasive positron emission tomography imaging of NIS-labeled cells, demonstrated near-complete liver repopulation by gene-corrected cells. Tyrosine and succinylacetone levels improved to within normal range, demonstrating complete correction of tyrosine metabolism. In addition, repopulation of the Fah(-/-) liver with transplanted cells inhibited the onset of severe fibrosis, a characteristic of nontransplanted Fah(-/-) pigs. This study demonstrates correction of disease in a pig model of metabolic liver disease by ex vivo gene therapy. To date, ex vivo gene therapy has only been successful in small animal models. We conclude that further exploration of ex vivo hepatocyte genetic correction is warranted for clinical use.