68Ga-FAP-2286 PET of Solid Tumors: Biodistribution, Dosimetry, and Comparison with 18F-FDG.

Fibroblast activation protein (FAP), expressed in the tumor microenvironment of a variety of cancers, has become a target of novel PET tracers. The purpose of this report is to evaluate the imaging characteristics of 68Ga-FAP-2286, present the first-to our knowledge-dosimetry analysis to date, and compare the agent with 18F-FDG and FAPI compounds. Methods: Patients were administered 219 ± 43 MBq of 68Ga-FAP-2286 and scanned after 60 min. Uptake was measured in up to 5 lesions per patient and within the kidneys, spleen, liver, and mediastinum (blood pool). Absorbed doses were evaluated using MIM Encore and OLINDA/EXM version 1.1 using the International Commission on Radiological Protection publication 103 tissue weighting factor. Results: Forty-six patients were imaged with 68Ga-FAP-2286 PET. The highest average uptake was seen in sarcoma, cholangiocarcinoma, and colon cancer. The lowest uptake was found in lung cancer and testicular cancer. The average SUVmax was significantly higher on 68Ga-FAP-2286 PET than on 18F-FDG PET in cholangiocarcinoma (18.2 ± 6.4 vs. 9.1 ± 5.0, P = 0.007), breast cancer (11.1 ± 6.8 vs. 4.1 ± 2.2, P < 0.001), colon cancer (13.8 ± 2.2 vs. 7.6 ± 1.7, P = 0.001), hepatocellular carcinoma (9.3 ± 3.5 vs. 4.7 ± 1.3, P = 0.01), head and neck cancer (11.3 ± 3.5 vs. 7.6 ± 5.5, P = 0.04), and pancreatic adenocarcinoma (7.4 ± 1.8 vs. 3.7 ± 1.0, P = 0.01). The total-body effective dose was estimated at 1.16E-02 mSv/MBq, with the greatest absorbed organ dose in the urinary bladder wall (9.98E-02 mGy/MBq). Conclusion: 68Ga-FAP-2286 biodistribution, dosimetry, and tumor uptake were similar to those of previously reported FAPI compounds. Additionally,68Ga-FAP-2286 PET had consistently higher uptake than 18F-FDG PET. These results are especially promising in the setting of small-volume disease and differentiating tumor from inflammatory uptake.

Per-patient Negative Predictive Value of the CT and MRI Liver Imaging Reporting and Data System Version 2018 Treatment Response Algorithm for Hepatocellular Carcinoma.

Background The Liver Imaging Reporting and Data System version 2018 (LI-RADS) treatment response algorithm (TRA) is a high-specificity, lower-sensitivity grading system to diagnose hepatocellular carcinoma (HCC) and recurrence after local-regional therapy. However, the emphasis on specificity can result in disease understaging, potentially leading to poorer posttransplant outcomes. Purpose To determine the negative predictive value (NPV) of pretransplant CT and MRI assessment for viable HCC on a per-patient basis using the LI-RADS TRA, considering explant pathology as the reference standard. Materials and Methods Patient records from 218 consecutive adult patients from a single institution with HCC who underwent liver transplant from January 2011 to November 2017 were retrospectively reviewed. Two readers blinded to the original report reviewed immediate (within 90 days) pretransplant imaging and characterized observations according to the LI-RADS TRA. Based on this, patients with LR-4, LR-5, or LR-TR (treatment response) viable tumors were designated as viable tumor; patients with solely LR-3 or LR-TR equivocal tumors were designated as equivocal; and patients with only LR-TR nonviable lesions were designated as no viable disease. Patients were designated as within or outside the Milan criteria. These per-patient designations were compared with the presence of viable disease at explant pathology. Fisher exact test was used to compare the differences between CT and MRI. Weighted κ values were used to calculate interreader reliability. Results Final study sample consisted of 206 patients (median age, 61 years [IQR, 57-65 years]; 157 male patients and 49 female patients). Per-patient LI-RADS TRA assessment of pretransplant imaging had an NPV of 32% (95% CI: 27, 38) and 26% (95% CI: 20, 33) (readers 1 and 2, respectively) for predicting viable disease. Seventy-five percent (reader 1) and 77% (reader 2) of patients deemed equivocal had residual tumors at explant pathology. Weighted interreader reliability was substantial (κ = 0.62). Conclusion Patient-based stratification of viable, equivocal, and nonviable disease at pretransplant CT or MRI, based on LI-RADS TRA, demonstrated low negative predictive value in excluding HCC at explant pathology. © RSNA, 2023 See also the editorial by Tamir and Tau in this issue.

Baseline tumor growth rate highlights the heterogeneity of well differentiated gastroenteropancreatic neuroendocrine tumors and predicts for increases in Ki67 index over time.

Refined risk stratification for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has the potential to improve comparisons of study populations across clinical trials and facilitate drug development. Tumor growth rate (TGR) is a radiological metric with demonstrated prognostic value in well differentiated grade 1 and 2 (G1-2) GEP-NETs, but little is known about TGR in G3 NETs. In this retrospective study of 48 patients with advanced G1-3 GEP-NET, we calculated baseline TGR (TGR0 ) from radiological images of metastases acquired prior to first-line therapy and evaluated its association with disease characteristics and outcomes. The median pretreatment Ki67 proliferation index for G1-3 tumors combined was 5% (range = 0.1%-52%) and median TGR0 was 4.8%/month (m) (range = 0%-45.9%/m). TGR0 correlated with pretreatment Ki67 across G1-3 pooled and within G3 GEP-NET. Patients with higher TGR0 (>11.7%/m) tumors, which were primarily G3 pancreatic NETs, exhibited decreased time to first therapy (median, 2.2 vs. 5.3 months; p = .03) and shorter overall survival (median, 4.1 years vs. not reached; p = .003). Independent of therapies given, higher TGR0 GEP-NETs experienced a greater incidence of Ki67 increase (100 vs. 50%; p = .02) and greater magnitude of Ki67 change (median, 14.0 vs. 0.1%; p = .04) upon serial biopsy. Importantly, TGR0 , but not grade, predicted for future Ki67 increase in this series. Given the heterogeneity of well differentiated GEP-NETs, future clinical trials may benefit from stratification for TGR0 , particularly in G1-2 tumors, in which TGR0 does not correlate with Ki67. TGR0 has the potential to noninvasively identify patients with previously undiagnosed grade progression and those in whom more or less frequent monitoring may be appropriate. Additional research is needed to determine the prognostic and predictive value of TGR0 in larger and more homogeneously treated cohorts, and to ascertain if post-treatment TGR has value in previously treated patients starting a new line of therapy.

Quantitative Assessment of Myocardial Ischemia With Positron Emission Tomography.

Recent advances in positron emission tomography (PET) technology and reconstruction techniques have now made quantitative assessment using cardiac PET readily available in most cardiac PET imaging centers. Multiple PET myocardial perfusion imaging (MPI) radiopharmaceuticals are available for quantitative examination of myocardial ischemia, with each having distinct convenience and accuracy profile. Important properties of these radiopharmaceuticals ( 15 O-water, 13 N-ammonia, 82 Rb, 11 C-acetate, and 18 F-flurpiridaz) including radionuclide half-life, mean positron range in tissue, and the relationship between kinetic parameters and myocardial blood flow (MBF) are presented. Absolute quantification of MBF requires PET MPI to be performed with protocols that allow the generation of dynamic multiframes of reconstructed data. Using a tissue compartment model, the rate constant that governs the rate of PET MPI radiopharmaceutical extraction from the blood plasma to myocardial tissue is calculated. Then, this rate constant ( K1 ) is converted to MBF using an established extraction formula for each radiopharmaceutical. As most of the modern PET scanners acquire the data only in list mode, techniques of processing the list-mode data into dynamic multiframes are also reviewed. Finally, the impact of modern PET technologies such as PET/CT, PET/MR, total-body PET, machine learning/deep learning on comprehensive and quantitative assessment of myocardial ischemia is briefly described in this review.

The role of percutaneous vertebral augmentation in patients with metastatic breast cancer: Literature review including report of two cases.

Patients with metastatic breast cancer are at high risk for developing vertebral compression fractures due to underlying bone metastases and bone density loss. Vertebral augmentation techniques including percutaneous vertebroplasty and percutaneous balloon kyphoplasty are techniques used to stabilize compression fractures and improve pain. However, rare complications from these interventions have been observed, including spinal cord compression, nerve root compression, venous cement embolism, and pulmonary cement embolism. These complications pose unique potential challenges for patients with cancer who may already have decreased lung function and potential for venous thromboembolism. In this review, we first describe the role of percutaneous vertebral augmentations in patients with metastatic cancer, with a particular focus on patients with breast cancer. Then, we describe complications of vertebral augmentation in two patients with metastatic breast cancer including long-term symptomatic and radiographic follow-up.

Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors.

KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.

Positive Versus Neutral Oral Contrast Material for Detection of Malignant Deposits in Intraabdominal Nonsolid Organs on CT.

BACKGROUND. Data are limited regarding utility of positive oral contrast material for peritoneal tumor detection on CT. OBJECTIVE. The purpose of this article is to compare positive versus neutral oral contrast material for detection of malignant deposits in nonsolid intraabdominal organs on CT. METHODS. This retrospective study included 265 patients (133 men, 132 women; median age, 61 years) who underwent an abdominopelvic CT examination in which the report did not suggest presence of malignant deposits and a subsequent CT examination within 6 months in which the report indicated at least one unequivocal malignant deposit. Examinations used positive (iohexol; n = 100) or neutral (water; n = 165) oral agents. A radiologist reviewed images to assess whether the deposits were visible (despite clinical reports indicating no deposits) on unblinded comparison with the follow-up examinations; identified deposits were assigned to one of seven intraabdominal compartments. The radiologist also assessed adequacy of bowel filling with oral contrast material. Two additional radiologists independently reviewed examinations in blinded fashion for malignant deposits. NPV was assessed of clinical CT reports and blinded retrospective readings for detection of malignant deposits visible on unblinded comparison with follow-up examinations. RESULTS. Unblinded review identified malignant deposits in 58.1% (154/265) of examinations. In per-patient analysis of clinical reports, NPV for malignant deposits was higher for examinations with adequate bowel filling with positive oral contrast material (65.8% [25/38]) than for examinations with inadequate bowel filling with positive oral contrast material (45.2% [28/62], p = .07) or with neutral oral contrast material regardless of bowel filling adequacy (35.2% [58/165], p = .002). In per-compartment analysis of blinded interpretations, NPV was higher for examinations with adequate and inadequate bowel filling with positive oral contrast material than for examinations with neutral oral contrast regardless of bowel filling adequacy (reader 1: 94.7% [234/247] and 92.5% [382/413] vs 88.3% [947/1072], both p = .045; reader 2: 93.1% [228/245] and 91.6% [361/394] vs 85.9% [939/1093], both p = .01). CONCLUSION. CT has suboptimal NPV for malignant deposits in intraabdominal nonsolid organs. Compared with neutral material, positive oral contrast material improves detection, particularly with adequate bowel filling. CLINICAL IMPACT. Optimization of bowel preparation for oncologic CT may help avoid potentially severe clinical consequences of missed malignant deposits.

Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. METHODS: We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. RESULTS: Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. CONCLUSIONS: The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.

Müllerian Duct Anomalies: Role in Fertility and Pregnancy.

Müllerian duct anomalies (MDAs) have important implications for the reproductive health of female patients. In patients with both infertility and recurrent pregnancy loss, the incidence of MDAs is as high as 25%. Congenital uterine anomalies are often only part of a complex set of congenital anomalies involving the cervix, vagina, and urinary tract. Multiple classification systems for MDAs exist, each with different criteria that vary most for the diagnosis of septate uterus. Recognizing the features that guide clinical management is essential for interpretation. Identification of an MDA should prompt evaluation for associated urinary tract anomalies. In patients with infertility who seek to use assisted reproductive technologies such as intrauterine insemination, recognition of MDAs may have an affect on reproductive success, particularly in patients who have an incomplete and clinically occult septum that divides the cervix. Two-dimensional US is the first-line modality for evaluating the uterus and adnexa. Three-dimensional (3D) US or MRI may help to visualize the external uterine fundal contour and internal indentation of the endometrial cavity, which are two morphologic characteristics that are keys to the diagnosis of congenital uterine anomalies. Hysterosalpingo contrast-enhanced US may be performed in conjunction with 3D US to evaluate uterine morphologic characteristics, the endometrial cavity, and tubal patency in a single examination. MRI helps to characterize rudimentary uteri in patients with müllerian hypoplasia and allows assessment for ectopic ureters, abnormally positioned ovaries, or associated deep infiltrative endometriosis. Online supplemental material is available for this article. ©RSNA, 2021.

Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection: A Multicenter Prospective Phase 3 Imaging Trial.

IMPORTANCE: The presence of pelvic nodal metastases at radical prostatectomy is associated with biochemical recurrence after prostatectomy. OBJECTIVE: To assess the accuracy of prostate-specific membrane antigen (PSMA) 68Ga-PSMA-11 positron emission tomographic (PET) imaging for the detection of pelvic nodal metastases compared with histopathology at time of radical prostatectomy and pelvic lymph node dissection. DESIGN, SETTING, AND PARTICIPANTS: This investigator-initiated prospective multicenter single-arm open-label phase 3 imaging trial of diagnostic efficacy enrolled 764 patients with intermediate- to high-risk prostate cancer considered for prostatectomy at University of California, San Francisco and University of California, Los Angeles from December 2015 to December 2019. Data analysis took place from October 2018 to July 2021. INTERVENTIONS: Imaging scan with 3 to 7 mCi of 68Ga-PSMA-11 PET. MAIN OUTCOMES AND MEASURES: The primary end point was the sensitivity and specificity for the detection pelvic lymph nodes compared with histopathology on a per-patient basis using nodal region correlation. Each scan was read centrally by 3 blinded independent central readers, and a majority rule was used for analysis. RESULTS: A total of 764 men (median [interquartile range] age, 69 [63-73] years) underwent 1 68Ga-PSMA-11 PET imaging scan for primary staging, and 277 of 764 (36%) subsequently underwent prostatectomy with lymph node dissection (efficacy analysis cohort). Based on pathology reports, 75 of 277 patients (27%) had pelvic nodal metastasis. Results of 68Ga-PSMA-11 PET were positive in 40 of 277 (14%), 2 of 277 (1%), and 7 of 277 (3%) of patients for pelvic nodal, extrapelvic nodal, and bone metastatic disease. Sensitivity, specificity, positive predictive value, and negative predictive value for pelvic nodal metastases were 0.40 (95% CI, 0.34-0.46), 0.95 (95% CI, 0.92-0.97), 0.75 (95% CI, 0.70-0.80), and 0.81 (95% CI, 0.76-0.85), respectively. Of the 764 patients, 487 (64%) did not undergo prostatectomy, of which 108 were lost to follow-up. Patients with follow-up instead underwent radiotherapy (262 of 379 [69%]), systemic therapy (82 of 379 [22%]), surveillance (16 of 379 [4%]), or other treatments (19 of 379 [5%]). CONCLUSIONS AND RELEVANCE: This phase 3 diagnostic efficacy trial found that in men with intermediate- to high-risk prostate cancer who underwent radical prostatectomy and lymph node dissection, the sensitivity and specificity of 68Ga-PSMA-11 PET were 0.40 and 0.95, respectively. This academic collaboration is the largest known to date and formed the foundation of a New Drug Application for 68Ga-PSMA-11. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03368547, NCT02611882, and NCT02919111.

Molecular and Radiological Features of Microsatellite Stable Colorectal Cancer Cases With Dramatic Responses to Immunotherapy.

BACKGROUND/AIM: The majority of colorectal cancer (CRC) cases, which are microsatellite stable (MSS) and do not harbor mismatch repair deficiency/microsatellite instability, are resistant to immunotherapy. Identification of patients with exceptional responses in MSS CRC and predictive biomarkers is an unmet need that needs to be addressed. CASE REPORT: We report three cases of MSS CRC with durable clinical benefit from immunotherapy with anti-PD-1 checkpoint inhibitors. Two cases bear a POLE P286R mutation, which has been associated with lack of immunotherapy response in MSS CRC. Two cases bear alterations in Ataxia-Telangiectasia Mutated (ATM) which may contribute to observed responses, including interaction with a co-administered intratumoral stimulator of interferon genes (STING) pathway agonist in one patient. CONCLUSION: Novel DNA damage repair alterations, including mutations in ATM, can provide insight into additional mechanisms by which genomic alterations can sensitize MSS CRC to diverse immunotherapies.

CT-less Direct Correction of Attenuation and Scatter in the Image Space Using Deep Learning for Whole-Body FDG PET: Potential Benefits and Pitfalls.

PURPOSE: To demonstrate the feasibility of CT-less attenuation and scatter correction (ASC) in the image space using deep learning for whole-body PET, with a focus on the potential benefits and pitfalls. MATERIALS AND METHODS: In this retrospective study, 110 whole-body fluorodeoxyglucose (FDG) PET/CT studies acquired in 107 patients (mean age ± standard deviation, 58 years ± 18; age range, 11-92 years; 72 females) from February 2016 through January 2018 were randomly collected. A total of 37.3% (41 of 110) of the studies showed metastases, with diverse FDG PET findings throughout the whole body. A U-Net-based network was developed for directly transforming noncorrected PET (PETNC) into attenuation- and scatter-corrected PET (PETASC). Deep learning-corrected PET (PETDL) images were quantitatively evaluated by using the standardized uptake value (SUV) of the normalized root mean square error, the peak signal-to-noise ratio, and the structural similarity index, in addition to a joint histogram for statistical analysis. Qualitative reviews by radiologists revealed the potential benefits and pitfalls of this correction method. RESULTS: The normalized root mean square error (0.21 ± 0.05 [mean SUV ± standard deviation]), mean peak signal-to-noise ratio (36.3 ± 3.0), mean structural similarity index (0.98 ± 0.01), and voxelwise correlation (97.62%) of PETDL demonstrated quantitatively high similarity with PETASC. Radiologist reviews revealed the overall quality of PETDL. The potential benefits of PETDL include a radiation dose reduction on follow-up scans and artifact removal in the regions with attenuation correction- and scatter correction-based artifacts. The pitfalls involve potential false-negative results due to blurring or missing lesions or false-positive results due to pseudo-low-uptake patterns. CONCLUSION: Deep learning-based direct ASC at whole-body PET is feasible and potentially can be used to overcome the current limitations of CT-based approaches, benefiting patients who are sensitive to radiation from CT.Supplemental material is available for this article.© RSNA, 2020.

Mask-Guided Convolutional Neural Network for Breast Tumor Prognostic Outcome Prediction on 3D DCE-MR Images.

In this proof-of-concept work, we have developed a 3D-CNN architecture that is guided by the tumor mask for classifying several patient-outcomes in breast cancer from the respective 3D dynamic contrast-enhanced MRI (DCE-MRI) images. The tumor masks on DCE-MRI images were generated using pre- and post-contrast images and validated by experienced radiologists. We show that our proposed mask-guided classification has a higher accuracy than that from either the full image without tumor masks (including background) or the masked voxels only. We have used two patient outcomes for this study: (1) recurrence of cancer after 5 years of imaging and (2) HER2 status, for comparing accuracies of different models. By looking at the activation maps, we conclude that an image-based prediction model using 3D-CNN could be improved by even a conservatively generated mask, rather than overly trusting an unguided, blind 3D-CNN. A blind CNN may classify accurately enough, while its attention may really be focused on a remote region within 3D images. On the other hand, only using a conservatively segmented region may not be as good for classification as using full images but forcing the model's attention toward the known regions of interest.

MR-based Attenuation Correction for Brain PET Using 3D Cycle-Consistent Adversarial Network.

Attenuation correction (AC) is important for the quantitative merits of positron emission tomography (PET). However, attenuation coefficients cannot be derived from magnetic resonance (MR) images directly for PET/MR systems. In this work, we aimed to derive continuous AC maps from Dixon MR images without the requirement of MR and computed tomography (CT) image registration. To achieve this, a 3D generative adversarial network with both discriminative and cycle-consistency loss (Cycle-GAN) was developed. The modified 3D U-net was employed as the structure of the generative networks to generate the pseudo CT/MR images. The 3D patch-based discriminative networks were used to distinguish the generated pseudo CT/MR images from the true CT/MR images. To evaluate its performance, datasets from 32 patients were used in the experiment. The Dixon segmentation and atlas methods provided by the vendor and the convolutional neural network (CNN) method which utilized registered MR and CT images were employed as the reference methods. Dice coefficients of the pseudo-CT image and the regional quantification in the reconstructed PET images were compared. Results show that the Cycle-GAN framework can generate better AC compared to the Dixon segmentation and atlas methods, and shows comparable performance compared to the CNN method.

Prostate-specific Membrane Antigen PET in Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals are playing a large role at the time of initial staging and biochemical recurrence for localizing prostate cancer, as well as in other emerging clinical settings. PSMA PET has demonstrated increased detection rate compared with conventional imaging and has been shown to change management plans in a substantial percentage of cases. The aims of this narrative review are to highlight the development and clinical impact of PSMA PET radiopharmaceuticals, to compare PSMA to other agents such as fluorine 18 fluciclovine and carbon 11 choline, and to highlight some of the individual PSMA PET agents that have contributed to the advancement of prostate cancer imaging.

The Synthesis and Structural Requirements for Measuring Glucocorticoid Receptor Expression In Vivo with (±)-11C-YJH08 PET.

Noninvasive methods to study glucocorticoid receptor (GR) signaling are urgently needed to elaborate the complexity of GR signaling in normal physiology and human disorders, as well as to identify selective GR modulators to treat diseases. Here, we report evidence supporting translational studies with (±)-11C-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]-quinoline ((±)-11C-YJH08), a radioligand for PET that engages the ligand binding domain on GR. Methods: (±)-11C-YJH08 was synthesized by reacting the phenol precursor with 11C-methyl iodide. The biodistribution was studied in vivo. Specific binding was tested in vivo with adrenalectomy and ligand competition. A library of analogs was synthesized and studied in vitro and in vivo to understand the (±)-11C-YJH08 structure-activity relationship. Rodent dosimetry studies were performed to estimate the human-equivalent doses of (±)-11C-YJH08. Results: (±)-11C-YJH08 was synthesized by reaction of the phenolic precursor with 11C-methyl iodide, giving a radiochemical yield of 51.7% ± 4.7% (decay-corrected to starting 11C-methyl iodide). Specific binding was observed in many tissues, including the brain. An analysis of the (±)-YJH08 structure-activity relationship showed that (R)- and (S)-enantiomers are equally avid for GR by occupying discrete binding modes. A focused chemical screen revealed that the aryl fluoride motif on YJH08 is essential for high-affinity GR binding in vitro, high tissue uptake in vivo, and efficient passage across the blood-brain barrier. Lastly, we performed dosimetry studies on rodents, from which we estimated the human-equivalent doses of (±)-11C-YJH08 to be commensurate with the widely used 11C and 18F tracers. Conclusion: These studies reveal the molecular determinants of a high-affinity and high-selectivity ligand-receptor interaction and support the use of (±)-11C-YJH08 PET to make the first measurements of GR expression in human subjects.

Gastrointestinal Stromal Tumor Incidentally Detected on 18F-Fluciclovine PET/CT.

ABSTRACT: We present a case of metastatic gastrointestinal stromal tumor incidentally detected on 18F-fluciclovine PET/CT. A 68-year-old man with history of intermediate-risk prostate cancer (Gleason score 4 + 3 = 7; pT2cN0M0) previously treated with retropubic radical prostatectomy, adjuvant whole pelvis radiation, and androgen deprivation therapy (leuprolide) presented with slowly rising serum prostate-specific antigen over 3 years, concerning for recurrent prostate cancer. To identify potential sites of recurrent disease, an 18F-fluciclovine PET/CT was obtained. Multiple tracer-avid mesenteric masses and enlarged lymph nodes were found throughout the abdomen and pelvis, later biopsy-proven to reflect metastatic gastrointestinal stromal tumor.

Molecular Insights in Transmission of Cancer From an Organ Donor to Four Transplant Recipients.

Organ donors are systematically screened for infection, whereas screening for malignancy is less rigorous. The true incidence of donor-transmitted malignancies is unknown due to a lack of universal tumor testing in the posttransplant setting. Donor-transmitted malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. We describe the detection of a gastrointestinal adenocarcinoma transmitted from a young donor to 4 transplant recipients. Multidimensional histopathologic and genomic profiling showed a CDH1 mutation and MET amplification, consistent with gastric origin. At the time of writing, one patient in this series remains alive and without evidence of cancer after prompt organ explant after cancer was reported in other recipients. Because identification of a donor-derived malignancy changes management, our recommendation is to routinely perform short tandem repeat testing (or a comparable assay) immediately upon diagnosis of cancer in any organ transplant recipient. Routine testing for a donor-origin cancer and centralized reporting of outcomes are necessary to establish a robust evidence base for the future development of clinical practice guidelines.

Gallium-68 prostate-specific membrane antigen ([68Ga]Ga-PSMA-11) PET for imaging of thyroid cancer: a feasibility study.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is expressed in the microvasculature of thyroid cancer. This suggests the potential use of PSMA as a diagnostic agent in patients with aggressive forms of thyroid cancer. The purpose of the current study was to determine the feasibility and utility of [68Ga]Ga-PSMA-11 PET/MRI in thyroid cancer patients. METHODS: Eligible patients for this prospective pilot study were adults with a history of pathology-proven thyroid cancer who had abnormal radiotracer uptake on an 2-[18F]FDG PET and/or 131I scintigraphy performed in the 12 months prior to study enrollment. Patients underwent a [68Ga]Ga-PSMA-11 PET/MRI, and comparison was made to the prior qualifying 2-[18F]FDG PET CT/MRI for lesion location and relative intensity. RESULTS: Twelve patients underwent [68Ga]Ga-PSMA-11 PET/MRI, one of which was excluded from analysis due to debulking surgery prior to the PSMA PET. Of the remaining patients, 7/11 had differentiated disease (3 papillary, 2 follicular, 2 Hurthle cell) and 4/11 had dedifferentiated disease (2 poorly differentiated papillary, 2 anaplastic). Out of 43 lesions, 41 were visually 2-[18F]FDG positive (uptake greater than background, detection rate 95.3%) and 28 were PSMA positive (uptake greater than background, detection rate 65.1%). Uptake was heterogeneous between patients, and in some cases within patients. 3/11 patients (1 poorly differentiated papillary, 2 follicular) had PSMA uptake which was greater than FDG uptake. For the remaining 8 patients, 2-[18F]FDG uptake was greater than PSMA. Using one eligibility guideline in the prostate cancer literature for PSMA radioligand therapy (RLT), 8/11 could be considered eligible for possible future PSMA RLT. This was not predictable based on thyroid cancer subtype. CONCLUSIONS: [68Ga]Ga-PSMA-11 PET demonstrated lower detection rate when compared to 2-[18F]FDG PET for thyroid cancer lesion visualization. Thyroid cancer subtype alone may not be sufficient to predict PSMA uptake, and radiotracer uptake may vary between patients and even within patients.

Impact of 68Ga-PSMA-11 PET on the Management of Recurrent Prostate Cancer in a Prospective Single-Arm Clinical Trial.

Prostate-specific membrane antigen (PSMA) ligand PET induces management changes in patients with prostate cancer. We aim to better characterize the impact of 68Ga-PSMA-11 PET (68Ga-PSMA PET) on management of recurrent prostate cancer in a large prospective cohort. Methods: We report management changes after 68Ga-PSMA PET, a secondary endpoint of a prospective multicenter trial in men with biochemical recurrence of prostate cancer. Pre-PET (Q1), post-PET (Q2), and posttreatment (Q3) questionnaires were sent to referring physicians recording site of recurrence and intended (Q1 to Q2 change) and implemented (Q3) therapeutic and diagnostic management. Results: Q1 and Q2 response was collected for 382 of 635 patients (60%, intended cohort), and Q1, Q2, and Q3 response was collected for 206 patients (32%, implemented cohort). An intended management change occurred in 260 of 382 (68%) patients. The intended change was considered major in 176 of 382 (46%) patients. Major changes occurred most often for patients with prostate-specific antigen of 0.5 to less than 2.0 ng/mL (81/147, 55%). By analysis of stage groups, management change was consistent with PET disease location, that is, a majority of major changes toward active surveillance (47%) for unknown disease site (103/382, 27%), toward local or focal therapy (56%) for locoregional disease (126/382, 33%), and toward systemic therapy (69% M1a; 43% M1b/c) for metastatic disease (153/382, 40%). According to Q3 responses, the intended management was implemented in 160 of 206 (78%) patients. In total, 150 intended diagnostic tests, mostly CT (n = 43, 29%) and bone scans or 18F-NaF PET (n = 52, 35%), were prevented by 68Ga-PSMA PET; 73 tests, mostly biopsies (n = 44, 60%) as requested by the study protocol, were triggered. Conclusion: According to referring physicians, sites of recurrence were clarified by 68Ga-PSMA PET, and disease localization translated into management changes in more than half of patients with biochemical recurrence of prostate cancer.