Fluorine-18-Labeled Fluoroestradiol PET/CT: Current Status, Gaps in Knowledge, and Controversies-AJR Expert Panel Narrative Review.

PET/CT using 16α-[18F]-fluoro-17ß-estradiol (FES) noninvasively images tissues expressing estrogen receptors (ERs). FES has undergone extensive clinicopathologic validation for ER+ breast cancer and received FDA approval in 2020 for clinical use as an adjunct to biopsy in patients with recurrent or metastatic ER+ breast cancer. Clinical use of FES PET/CT is increasing, but is not widespread in the United States. This AJR Expert Panel Narrative Review explores the present status and future directions of FES PET/CT, including image interpretation, existing and emerging uses, knowledge gaps, and current controversies. Specific controversies discussed include whether both FES PET/CT and FDG PET/CT are warranted in certain scenarios, whether further workup is required after negative FES PET/CT results, whether FES PET/CT findings should inform endocrine therapy selection, and whether immunohistochemistry should remain the standalone reference standard for determining ER status for all breast cancers. Consensus opinions from the panel include agreement with the appropriate clinical uses of FES PET/CT published by a multidisciplinary expert workgroup in 2023; anticipated expanded clinical use of FES PET/CT for staging ER-positive invasive lobular carcinomas and low-grade invasive ductal carcinomas pending ongoing clinical trial results; and the need for further research regarding use of FES PET/CT for ER-expressing nonbreast malignancies.

Prospective Pilot Study of 18F-Fluoroestradiol PET/CT in Patients With Invasive Lobular Carcinomas.

BACKGROUND. PET/CT with 18F-fluoroestradiol (FES) (FDA-approved in 2020) depicts tissues expressing estrogen receptor (ER). Invasive lobular carcinoma (ILC) is commonly ER positive. OBJECTIVE. The primary aim of this study was to assess the frequency with which sites of histologically proven ILC have abnormal uptake on FES PET/CT. METHODS. This prospective single-center pilot study, conducted from December 2020 to August 2021, enrolled patients with histologically confirmed ILC to undergo FES PET/CT; patients optionally underwent FDG PET/CT. Two nuclear radiologists assessed FES PET/CT and FDG PET/CT studies for abnormal uptake corresponding to known ILC sites at enrollment and for additional sites of abnormal uptake, resolving differences by consensus. The primary endpoint was percentage of known ILC sites showing abnormal FES uptake. The alternative to the null hypothesis was that more than 60% of sites would have abnormal FES uptake, exceeding the percentage of ILC with abnormal FDG uptake described in prior literature. A sample size of 24 biopsied lesions was preselected to provide 81% power for the alternative hypothesis (one-sided α = .10). Findings on FES PET/CT and FDG PET/CT were summarized for additional secondary endpoints. RESULTS. The final analysis included 17 patients (mean age, 59.1 ± 13.2 years) with 25 sites of histologically confirmed ILC at enrollment (22 breast lesions, two axillary lymph nodes, one distant metastasis). FES PET/CT showed abnormal uptake in 22 of 25 (88%) lesions, sufficient to reject the null hypothesis (p = .002). Thirteen patients underwent FDG PET/CT. Four of 23 (17%) sites of histologically confirmed ILC, including additional sites detected and confirmed after enrollment, were identified with FES PET/CT only, and 1 of 23 (4%) was identified only with FDG PET/CT (p = .18). FES PET/CT depicted additional lesions not detected with standard-of-care evaluation in 4 of 17 (24%) patients (two contralateral breast cancers and two metastatic axillary lymph nodes, all with subsequent histologic confirmation). Use of FES PET/CT resulted in changes in clinical stage with respect to standard-of-care evaluation in 3 of 17 (18%) patients. CONCLUSION. The primary endpoint of the trial was met. The frequency of abnormal FES uptake among sites of histologically known ILC was found to be to be significantly greater than 60%. CLINICAL IMPACT. This pilot study shows a potential role of FES PET/CT in evaluation of patients with ILC. TRIAL REGISTRATION. ClinicalTrials.gov NCT04252859.

Early Assessment Window for Predicting Breast Cancer Neoadjuvant Therapy using Biomarkers, Ultrasound, and Diffuse Optical Tomography.

PURPOSE: The purpose of the study was to assess the utility of tumor biomarkers, ultrasound (US) and US-guided diffuse optical tomography (DOT) in early prediction of breast cancer response to neoadjuvant therapy (NAT). METHODS: This prospective HIPAA compliant study was approved by the institutional review board. Forty one patients were imaged with US and US-guided DOT prior to NAT, at completion of the first three treatment cycles, and prior to definitive surgery from February 2017 to January 2020. Miller-Payne grading was used to assess pathologic response. Receiver operating characteristic curves (ROCs) were derived from logistic regression using independent variables, including: tumor biomarkers, US maximum diameter, percentage reduction of the diameter (%US), pretreatment maximum total hemoglobin concentration (HbT) and percentage reduction in HbT (%HbT) at different treatment time points. Resulting ROCs were compared using area under the curve (AUC). Statistical significance was tested using two-sided two-sample student t-test with P < 0.05 considered statistically significant. Logistic regression was used for ROC analysis. RESULTS: Thirty-eight patients (mean age = 47, range 24-71 years) successfully completed the study, including 15 HER2 + of which 11 were ER + ; 12 ER + or PR + /HER2-, and 11 triple negative. The combination of HER2 and ER biomarkers, %HbT at the end of cycle 1 (EOC1) and %US (EOC1) provided the best early prediction, AUC = 0.941 (95% CI 0.869-1.0). Similarly an AUC of 0.910 (95% CI 0.810-1.0) with %US (EOC1) and %HbT (EOC1) can be achieved independent of HER2 and ER status. The most accurate prediction, AUC = 0.974 (95% CI 0.933-1.0), was achieved with %US at EOC1 and %HbT (EOC3) independent of biomarker status. CONCLUSION: The combined use of tumor HER2 and ER status, US, and US-guided DOT may provide accurate prediction of NAT response as early as the completion of the first treatment cycle. CLINICAL TRIAL REGISTRATION NUMBER: NCT02891681. https://clinicaltrials.gov/ct2/show/NCT02891681 , Registration time: September 7, 2016.

Contrast-Enhanced Spectral Mammography is Comparable to MRI in the Assessment of Residual Breast Cancer Following Neoadjuvant Systemic Therapy.

PURPOSE: To evaluate the performance of contrast-enhanced spectral mammography (CESM) compared to MRI in the assessment of tumor response in breast cancer patients undergoing neoadjuvant systemic therapy (NST). METHODS: The institutional review board approved this study. From September 2014 to June 2017, we identified patients with pathologically confirmed invasive breast cancer who underwent NST. All patients had both CESM and MRI performed pre- and post-NST with pathological assessment after surgical management. Size of residual malignancy on post-NST CESM and MRI was compared with surgical pathology. Lin concordance and Pearson correlation coefficient were used to assess agreement. Bland-Altman plots were used to visualize the differences between tumor size on imaging and pathology. RESULTS: Sixty-five patients were identified. Mean age was 52.7 (range 30-76) years. Type of NST included chemotherapy in 53 (82%) and endocrine therapy in 12 (18%). Mean tumor size after NST was 14.6 (range 0-105) mm for CESM and 14.2 mm (range 0-75 mm) for MRI compared with 19.6 (range 0-100) mm on final surgical pathology. Equivalence tests demonstrated that mean tumor size measured by CESM (p = 0.009) or by MRI (p = 0.01) was equivalent to the mean tumor size measured by pathology within - 1 and 1-cm range. Comparing CESM versus MRI for assessment of complete response, the sensitivity was 95% versus 95%, specificity 66.7% versus 68.9%, positive predictive value 55.9% versus 57.6%, and negative predictive value 96.7% versus 96.9% respectively. CONCLUSIONS: CESM was comparable to MRI in assessing residual malignancy after completion of NST.

The Future of Contrast-Enhanced Mammography.

OBJECTIVE: The purpose of this article is to discuss facilitators of and barriers to future implementation of contrast-enhanced mammography (CEM) in the United States. CONCLUSION: CEM provides low-energy 2D mammographic images analogous to digital mammography and contrast-enhanced recombined images that allow assessment of neovascularity similar to that offered by MRI. The utilization of CEM in the United States is currently low but could increase rapidly given the many potential indications for its clinical use.

Initial Experience of Tomosynthesis-Guided Vacuum-Assisted Biopsies of Tomosynthesis-Detected (2D Mammography and Ultrasound Occult) Architectural Distortions.

OBJECTIVE: As experience and aptitude in digital breast tomosynthesis (DBT) have increased, radiologists are seeing more areas of architectural distortion (AD) on DBT images compared with standard 2D mammograms. The purpose of this study is to report our experience using tomosynthesis-guided vacuum-assisted biopsies (VABs) for ADs that were occult at 2D mammography and ultrasound and to analyze the positive predictive value for malignancy. MATERIALS AND METHODS: We performed a retrospective review of 34 DBT-detected ADs that were occult at mammography and ultrasound. RESULTS: We found a positive predictive value of 26% (nine malignancies in 34 lesions). Eight of the malignancies were invasive and one was ductal carcinoma in situ. The invasive cancers were grade 1 (4/8; 50%), grade 2 (2/8; 25%), or grade 3 (1/8; 13%); information about one invasive cancer was not available. The mean size of the invasive cancers at pathologic examination was 7.5 mm (range, 6-30 mm). CONCLUSION: Tomosynthesis-guided VAB is a feasible method to sample ADs that are occult at 2D mammography and ultrasound. Tomosynthesis-guided VAB is a minimally invasive method that detected a significant number of carcinomas, most of which were grade 1 cancers. Further studies are needed.

Signs and Artifacts in Amyloid PET.

Establishing a diagnosis of Alzheimer dementia can be challenging, particularly early in the course of the disease. However, with disease-modifying therapies on the horizon, it is becoming increasingly important to achieve the correct diagnosis as soon as possible. In challenging presentations of dementia, such as patients with clinically atypical features or early-age onset of mild cognitive impairment, amyloid PET is a valuable tool in determining the diagnosis of Alzheimer dementia. Furthermore, preliminary data show that amyloid PET findings alter clinical management in patients who meet the appropriate use criteria. There are currently three U.S. Food and Drug Administration (FDA)-approved fluorine 18 (18F)-labeled radiopharmaceuticals that allow in vivo detection of cerebral amyloid deposition, which is a hallmark pathologic feature of Alzheimer dementia. Knowledge of the common imaging features among these three 18F-labeled radiopharmaceuticals in the normal and abnormal brain will enable the radiologist to more accurately interpret amyloid PET studies. As in other subspecialties of radiology, imaging signs in amyloid PET are helpful to distinguish if a region is normal or abnormal. This article reviews appropriate use criteria for amyloid PET, introduces the properties of the radiopharmaceuticals, explains the algorithmic approach to interpretation with examples of normal and abnormal amyloid PET scans with MRI correlation, and provides an atlas of regional amyloid PET signs and common artifacts. ©RSNA, 2018.

Breast MRI phenotype and background parenchymal enhancement may predict tumor response to neoadjuvant endocrine therapy.

Neoadjuvant endocrine therapy (NET) is increasingly used for the treatment of estrogen receptor positive, HER2 negative breast cancer. We evaluated whether MRI phenotype and background parenchymal enhancement (BPE) can predict response to NET. Patients with localized breast cancer treated with NET and had a pre-treatment breast MRI were identified. Baseline MRI phenotype and BPE was interpreted by a single radiologist blinded to the results of systemic therapy. Response was defined as stable disease or reduction in tumor size on clinical and/or ultrasound examination. Of the 21 patients identified, 17 were responders; all patients with minimal/mild BPE had a response compared to 5/9 (56%) patients with moderate/marked BPE (P = 0.02). All four nonresponders had moderate/marked BPE as compared to 5/17 (29%) responders (P = 0.02). This pilot study suggests that minimal/mild BPE may be predictive of a positive response to NET. A higher degree of background enhancement was significantly predictive of negative response to NET.

Accuracy of Unenhanced MR Imaging in the Detection of Acute Appendicitis: Single-Institution Clinical Performance Review.

PURPOSE: To determine the accuracy of unenhanced magnetic resonance (MR) imaging in the detection of acute appendicitis in patients younger than 50 years who present to the emergency department with right lower quadrant (RLQ) pain. MATERIALS AND METHODS: The institutional review board approved this retrospective study of 403 patients from August 1, 2012, to July 30, 2014, and waived the informed consent requirement. A cross-department strategy was instituted to use MR imaging as the primary diagnostic modality in patients aged 3-49 years who presented to the emergency department with RLQ pain. All MR examinations were performed with a 1.5- or 3.0-T system. Images were acquired without breath holding by using multiplanar half-Fourier single-shot T2-weighted imaging without and with spectral adiabatic inversion recovery fat suppression without oral or intravenous contrast material. MR imaging room time was measured for each patient. Prospective image interpretations from clinical records were reviewed to document acute appendicitis or other causes of abdominal pain. Final clinical outcomes were determined by using (a) surgical results (n = 77), (b) telephone follow-up combined with review of the patient's medical records (n = 291), or (c) consensus expert panel assessment if no follow-up data were available (n = 35). Logistic regression analysis was performed to evaluate the sensitivity and specificity of MR imaging in the detection of acute appendicitis, and corresponding 95% confidence intervals were determined. RESULTS: Of the 403 patients, 67 had MR imaging findings that were positive for acute appendicitis, and 336 had negative findings. MR imaging had a sensitivity of 97.0% (65 of 67) and a specificity of 99.4% (334 of 336). The mean total room time was 14 minutes (range, 8-62 minutes). An alternate diagnosis was offered in 173 (51.5%) of 336 patients. CONCLUSION: MR imaging is a highly sensitive and specific test in the evaluation of patients younger than 50 years with acute RLQ pain that uses a rapid imaging protocol performed without intravenous or oral contrast material.

Meta-analysis: Radial Scar and Breast MRI.

BACKGROUND: The implementation of digital breast tomosynthesis has increased the detection of radial scar (RS). Managing this finding may be experienced as a clinical dilemma in daily practice. Breast Contrast-Enhanced MRI (CE-BMR) is a known modality in case of problem-solving tool for mammographic abnormalities. However, the data about AD and CE-BMR are scant. OBJECTIVE: The purpose was to estimate the benefit of CE-BMR in the setting of RS detected mammographically through a systematic review and meta-analysis of the literature. METHODS: A search of MEDLINE and EMBASE databases were conducted in 2022. Based on the PRISMA guidelines, an analysis was performed. The primary endpoint was the correlation between CE-BMR findings and definite outcome for RS (pure RS versus RS associated with atypia or malignancy). RESULTS: Three studies were available. The negative predictive value (NPV) was 100% for each. CONCLUSION: The high NPV could allow for deferral of a biopsy in favor of a short-interval imaging follow-up in the setting of a negative CE-BMR.

State-of-the-art for contrast-enhanced mammography.

Contrast-enhanced mammography (CEM) is an emerging breast imaging technology with promise for breast cancer screening, diagnosis, and procedural guidance. However, best uses of CEM in comparison with other breast imaging modalities such as tomosynthesis, ultrasound, and MRI remain inconclusive in many clinical settings. This review article summarizes recent peer-reviewed literature, emphasizing retrospective reviews, prospective clinical trials, and meta-analyses published from 2020 to 2023. The intent of this article is to supplement prior comprehensive reviews and summarize the current state-of-the-art of CEM.

At Which Mean Glandular Dose Does the Benefit of Breast Cancer Deaths Averted Equal the Risk of Lives Lost to Screening From Radiation-induced Malignancy for Mammography With and Without Tomosynthesis?

OBJECTIVE: To estimate benefit-to-radiation-risk mean glandular dose (MGD) equivalence values for screening mammography, defined as the yearly MGD (over a 10-year period) at which the estimated benefit of mammography in terms of deaths averted equals the estimated risk of lives lost to screening due to radiation exposure (a benefit-to-risk ratio of 1). METHODS: Benefit-to-risk ratios were calculated as the ratio of breast cancer deaths averted and lives lost to screening over 10-year intervals starting at age 40 for mammography and tomosynthesis using previously published methodology. The MGD values at which estimated benefit equals risk were tabulated. RESULTS: The MGD values at which benefit-to-risk equivalence points were met for digital screening mammography are 63 milligray (mGy) (ages 40-49), 88 mGy (ages 50-59), 176 mGy (ages 60-69), and 336 mGy (ages 70-79). The MGD values that met benefit-to-risk equivalence for screening tomosynthesis plus digital mammography or synthetic mammography are 80 mGy (ages 40-49), 111 mGy (ages 50-59), 224 mGy (ages 60-69), and 427 mGy (ages 70-79). CONCLUSION: Cutoff MGD values at which the estimated benefit from screening equals the estimated risk are well above standard screening MGD exposures. Care is necessary to ensure that threshold values are not exceeded during a screening exam, particularly for women ages 40-49 years old when using digital mammography plus tomosynthesis (due to an approximate doubling of dose per exam that will more readily exceed cutoff MGD values) and when many additional views are obtained.

Utility of PET to Appropriately Select Patients for PSMA-Targeted Theranostics.

ABSTRACT: The majority of aggressive prostate cancers overexpress the transmembrane protein prostate-specific membrane antigen (PSMA). PSMA is, therefore, an attractive target for drug development. Over the last decade, numerous PSMA-targeted radiopharmaceuticals for imaging and therapy have been developed and investigated in theranostic combination. PSMA-targeted radiopharmaceuticals for imaging have been primarily developed for PET. PSMA PET provides whole-body evaluation of the degree of PSMA expression on tumors and potentially provides a method to better select patients for PSMA-targeted therapy. Numerous PSMA-targeted therapeutic agents using ß- or α-particle emitters are under study in clinical trials. In particular, the ß-particle-emitting radioisotope 177Lu bound to PSMA-targeted small molecules have ongoing and completed late-stage clinical trials in metastatic castration-resistant prostate cancer. To define the most appropriate patient group for PSMA-targeted therapeutics, multiple studies have investigated PSMA and FDG PET/CT to establish PET parameters as predictive and prognostic biomarkers. This article discusses recent clinical trials that examine the optimal use of PET for the selection of patients for PSMA-targeted therapeutics and provides an integrative overview of choice of PET tracer(s), targeting molecule, therapeutic radioisotope, nonradioactive therapy, and cancer type (prostate or nonprostate).

Advances and Future Directions in Molecular Breast Imaging.

Molecular breast imaging (MBI) using 99mTc-sestamibi has advanced rapidly over the past decade. Technical advances allow lower-dose, higher-resolution imaging and biopsy capability. MBI can be used for supplemental breast cancer screening with mammography for women with dense breasts, as well as to assess neoadjuvant therapy response, evaluate disease extent, and predict breast cancer risk. This article highlights the current state of the art and future directions in MBI.

PET-CT in Clinical Adult Oncology-VI. Primary Cutaneous Cancer, Sarcomas and Neuroendocrine Tumors.

PET-CT is an advanced imaging modality with many oncologic applications, including staging, therapeutic assessment, restaging and surveillance for recurrence. The goal of this series of six review articles is to provide practical information to providers and imaging professionals regarding the best use of PET-CT for specific oncologic indications, the potential pitfalls and nuances that characterize these applications, and guidelines for image interpretation. Tumor-specific clinical information and representative PET-CT images are provided. The current, sixth article in this series addresses PET-CT in an evaluation of aggressive cutaneous malignancies, sarcomas and neuroendocrine tumors. A discussion of the role of FDG PET for all types of tumors in these categories is beyond the scope of this review. Rather, this article focuses on the most common malignancies in adult patients encountered in clinical practice. It also focuses on Food and Drug Agency (FDA)-approved and clinically available radiopharmaceuticals rather than research tracers or those requiring a local cyclotron. This information will serve as a guide to primary providers for the appropriate role of PET-CT in managing patients with cutaneous malignancies, sarcomas and neuroendocrine tumors. The nuances of PET-CT interpretation as a practical guide for imaging providers, including radiologists, nuclear medicine physicians and their trainees, are also addressed.

PET-CT in Clinical Adult Oncology-IV. Gynecologic and Genitourinary Malignancies.

Concurrently acquired positron emission tomography and computed tomography (PET-CT) is an advanced imaging modality with diverse oncologic applications, including staging, therapeutic assessment, restaging and longitudinal surveillance. This series of six review articles focuses on providing practical information to providers and imaging professionals regarding the best use and interpretative strategies of PET-CT for oncologic indications in adult patients. In this fourth article of the series, the more common gynecological and adult genitourinary malignancies encountered in clinical practice are addressed, with an emphasis on Food and Drug Administration (FDA)-approved and clinically available radiopharmaceuticals. The advent of new FDA-approved radiopharmaceuticals for prostate cancer imaging has revolutionized PET-CT imaging in this important disease, and these are addressed in this report. However, [18F]F-fluoro-2-deoxy-d-glucose (FDG) remains the mainstay for PET-CT imaging of gynecologic and many other genitourinary malignancies. This information will serve as a guide for the appropriate role of PET-CT in the clinical management of gynecologic and genitourinary cancer patients for health care professionals caring for adult cancer patients. It also addresses the nuances and provides guidance in the accurate interpretation of FDG PET-CT in gynecological and genitourinary malignancies for imaging providers, including radiologists, nuclear medicine physicians and their trainees.

PET-CT in Clinical Adult Oncology: III. Gastrointestinal Malignancies.

PET-CT is an advanced imaging modality with many oncologic applications, including staging, assessment of response to therapy, restaging and longitudinal surveillance for recurrence. The goal of this series of six review articles is to provide practical information to providers and imaging professionals regarding the best use of PET-CT for specific oncologic indications, and the potential pitfalls and nuances that characterize these applications. In the third of these review articles, key tumor-specific clinical information and representative PET-CT images are provided to outline the role that PET-CT plays in the management of patients with gastrointestinal malignancies. The focus is on the use of 18F fluorodeoxyglucose (FDG), rather than on research radiopharmaceuticals under development. Many different types of gastrointestinal tumors exist, both pediatric and adult. A discussion of the role of FDG PET-CT for all of these is beyond the scope of this review. Rather, this article focuses on the most common adult gastrointestinal malignancies that may be encountered in clinical practice. The information provided here will provide information outlining the appropriate role of PET-CT in the clinical management of patients with gastrointestinal malignancies for healthcare professionals caring for adult cancer patients. It also addresses the nuances and provides interpretive guidance related to PET-CT for imaging providers, including radiologists, nuclear medicine physicians and their trainees.

PET-CT in Clinical Adult Oncology: II. Primary Thoracic and Breast Malignancies.

Positron emission tomography combined with x-ray computed tomography (PET-CT) is an advanced imaging modality with oncologic applications that include staging, therapy assessment, restaging, and surveillance. This six-part series of review articles provides practical information to providers and imaging professionals regarding the best use of PET-CT for the more common adult malignancies. The second article of this series addresses primary thoracic malignancy and breast cancer. For primary thoracic malignancy, the focus will be on lung cancer, malignant pleural mesothelioma, thymoma, and thymic carcinoma, with an emphasis on the use of FDG PET-CT. For breast cancer, the various histologic subtypes will be addressed, and will include 18F fluorodeoxyglucose (FDG), recently Food and Drug Administration (FDA)-approved 18F-fluoroestradiol (FES), and 18F sodium fluoride (NaF). The pitfalls and nuances of PET-CT in breast and primary thoracic malignancies and the imaging features that distinguish between subcategories of these tumors are addressed. This review will serve as a resource for the appropriate roles and limitations of PET-CT in the clinical management of patients with breast and primary thoracic malignancies for healthcare professionals caring for adult patients with these cancers. It also serves as a practical guide for imaging providers, including radiologists, nuclear medicine physicians, and their trainees.