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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 β- or α-particle emitters are under study in clinical trials. In particular, the β-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)., Competing Interests: Conflicts of interest and sources of funding: none declared. M.C. is a consultant for Invicro, LLC for medical imaging review, outside of the scope of this project. P.H.K. is an employee of Invicro. He is a consultant and/or speaker for Amgen, Eisai, General Electric Healthcare, Novartis, Invicro, Bayer, Chimerix, Fusion Pharma, and UroToday. He is a recipient of research grants from Blue Earth Diagnostics and General Electric Healthcare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: A 54-year-old man with hepatocellular carcinoma from alcohol-induced cirrhosis presented with hepatic encephalopathy and refractory ascites related to decompensated liver disease. MRI confirmed disease progression adjacent the site of prior radiofrequency ablation, performed 2 years prior, with associated right hepatic vein tumor thrombus. 99mTc-labeled macroaggregated albumin lung shunt imaging performed before 90Y radioembolization identified a left lower lobe wedge-shaped defect, confirmed as pulmonary embolism on CT pulmonary angiography and MRI., Competing Interests: Conflicts of interest and sources of funding: P.H.K. is a speaker, consultant, and recipient of grants from GE Healthcare. M.D.K. and P.H.K. are consultants for Invicro. P.H.K. is an employee of Invicro. He is a consultant and/or speaker for Amgen, Eisai, General Electric Healthcare, Novartis, Invicro, Bayer, Chimerix, Fusion Pharma, and UroToday. He is a recipient of research grants from Blue Earth Diagnostics and General Electric Healthcare. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: We evaluated K-means clustering to classify amyloid brain PETs as positive or negative., Patients and Methods: Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data., Results: Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%., Conclusions: K-means clustering may be a powerful algorithm for classifying amyloid brain PET., Competing Interests: Conflicts of interest and sources of funding: This is a multisite project of the Toronto Dementia Research Alliance partly funded by Brain Canada, The Edward Foundation, the Canadian Institutes of Health Research, the LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, and the Dr Sandra Black Centre for Brain Resilience and Recovery. Phillip H. Kuo is a consultant for Novartis, Konica Minolta, and Bayer; is a consultant and speaker for Esai and General Electric Healthcare; and received a grant from Blue Earth Diagnostics. The other authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: A 74-year-old woman with primary hyperparathyroidism diagnosed from routine laboratory tests described symptoms of fatigue and difficulty with concentration. During surgical consultation, the cervical and thoracic spine MRI scans from the preceding 10-year period, performed for relapsing-remitting multiple sclerosis, were reviewed. In this clinical context, the slowly enlarging left upper paraesophageal lesion, reported as a lateral proximal esophageal (Killian-Jamieson) diverticulum, was reevaluated for a potential parathyroid adenoma. 99mTc-sestamibi SPECT/CT demonstrated focal uptake in the paraesophageal lesion with surgical resection, confirming it to be a large parathyroid adenoma., Competing Interests: Conflicts of interest and sources of funding: P.H.K. and M.D.K. are consultants to Invicro. P.H.K. is also a speaker for, consultant to, and recipient of grants from GE Healthcare. The remaining authors have none declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Dopamine transporter SPECT with I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (I-ioflupane) aids in the diagnosis of parkinsonian syndrome by demonstrating loss of striatal dopamine transporters, proportional to nigrostriatal dopaminergic neuronal loss. Quantitative software analysis (QSA) is a helpful adjunct to visual interpretation. An atlas of pearls and pitfalls of QSA is presented. Examples include correction for head tilt/orientation, scaling artifacts, and detection of balanced loss of activity. Additional examples are provided where QSA can potentially fail such as patient variation and vascular disease.

Purpose: The aim of this study was to evaluate random forests (RFs) to identify ROIs on F-florbetapir and F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score., Materials and Methods: Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial, had MoCA and F-florbetapir PET; 55 had F-FDG PET. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter (F-florbetapir PET), or pons (F-FDG PET). SUV ratio data and MoCA score were used for supervised training of RFs programmed in MATLAB., Results: F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid increased with decreasing MoCA score. F-FDG PETs were randomly divided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. F-FDG decreased with decreasing MoCA score., Conclusions: Random forests help pinpoint clinically relevant ROIs associated with MoCA score; amyloid increased and F-FDG decreased with decreasing MoCA score, most significantly in the posterior cingulate gyrus.

A 17-year-old girl with World Health Organization grade IV glioblastoma with primitive neuronal components (histone H3 G34-mutant and IDH1 wild type) underwent whole-body FDG PET/CT staging due to vertebral metastases on initial MRI. PET/CT revealed extracranial metastatic disease with spinal leptomeningeal dissemination, osseous metastases, and peritoneal seeding via a ventriculoperitoneal shunt. Glioblastoma is uncommon in pediatric patients and particularly those with primitive neuronal components. Extracranial metastases from glioblastoma are more common in those with primitive neuronal components. This case demonstrates the utility of FDG PET/CT for revealing distant metastases from glioblastoma.

Purpose: To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification., Methods: The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB., Results: A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees)., Conclusions: Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

Dementia is an important cause of morbidity and mortality worldwide and encompasses a very heterogenous group of disease processes. Positron emission tomography (PET) of the brain using fluorodeoxyglucose (FDG) is a useful modality for differentiating types of dementia. Because FDG does not bind to pathologic proteins, FDG-PET requires that the reader recognize characteristic patterns of glucose hypometabolism to identify pathology. These patterns have been documented in the literature for both primary neurodegenerative disorders and secondary causes of dementia. This article presents an algorithm for organizing these findings and systematically applying them to interpret FDG-PET brain imaging for dementia.

An 85-year-old man with stage IIIA Merkel cell carcinoma of the left arm was initially treated with local excision and axillary node dissection followed by radiation therapy. Eight months after surgery, whole-body FDG PET/CT demonstrated intensely hypermetabolic hepatic metastases and abdominal lymphadenopathy. Given his age and comorbidities, he was considered a poor candidate for chemotherapy, and therefore the novel programmed cell death ligand 1 inhibitor avelumab was initiated. FDG PET/CT after 4 cycles showed complete resolution of hepatic and nodal metastases. Whole-body FDG PET/CT can be used for monitoring response of multisystem metastases from Merkel cell carcinoma to active immunotherapy.

A 65-year-old woman with metastatic lung cancer was referred for CT-guided cryoablation of a right adrenal metastasis. For cryoablation, probes were placed into the adrenal region. FDG PET/CT 3 months later showed new activity in hepatic segment 6 initially suspected to be metastasis. Proximity of the hepatic lesion to the adrenal metastasis was a strange coincidence and prompted review of imaging from the cryoablation. CT showed the probe entered the liver, and postablation image demonstrated injury to the liver adjacent to the adrenal metastasis. Careful review of treatment history and imaging from ablation procedures are important to avoid this pitfall.

PET using FDG is a critical tool for evaluation of dementias, with characteristic patterns of hypometabolism suggesting specific diagnoses. Hypometabolism in the occipital region is recognized as an important finding associated with dementia with Lewy bodies and posterior cortical atrophy. We describe here the novel "occipital tunnel" sign, which results from relative sparing of FDG uptake in the medial occipital (primary visual) cortex compared with more severe loss in the surrounding lateral occipital (visual association) cortex. This sign is useful for recognizing the occipital findings of dementia with Lewy bodies and posterior cortical atrophy, especially when viewing sagittal projections.

A 61-year-old woman with lung adenocarcinoma failed first-line treatment and was placed on immunotherapy with nivolumab. FDG-PET/CT before immunotherapy showed metastases to thoracic nodes, liver, adrenal gland, and skeleton. Seven weeks after starting nivolumab, FDG-PET/CT showed mild residual activity in thoracic nodes and otherwise complete response. After 15 weeks, enlarged and FDG-avid axillary lymphadenopathy and worsening supraclavicular lymphadenopathy developed. After 20 weeks, FDG-PET/CT demonstrated marked improvement of axillary and supraclavicular lymphadenopathy. This case demonstrates that later progression of disease can still respond to continuing immunotherapy, hypothetically because of dynamic adaptations in the tug-of-war between the immunotherapy-augmented immune system and tumor.

Purpose: Dopamine transporter (DaT) imaging is an adjunct diagnostic tool in parkinsonian disorders. Interpretation of DaT scans is based on visual reads. SBRquant is an automated method that measures the striatal binding ratio (SBR) in DaT scans, but has yet to be optimized. We aimed to (1) optimize SBRquant parameters to distinguish between patients with Parkinson disease (PD) and healthy controls using the Parkinson's Progression Markers Initiative (PPMI) database and (2) test the validity of these parameters in an outpatient cohort., Methods: For optimization, 336 DaT scans (215 PD patients and 121 healthy controls) from the PPMI database were used. Striatal binding ratio was calculated varying the number of summed transverse slices (N) and positions of the striatal regions of interest (d). The resulting SBRs were evaluated using area under the receiver operating characteristic curve. The optimized parameters were then applied to 77 test patients (35 PD and 42 non-PD patients). Striatal binding ratios were also correlated with clinical measures in the PPMI-PD group., Results: The optimal parameters discriminated the training groups in the PPMI cohort with 95.8% sensitivity and 98.3% specificity (lowest putamen SBR threshold, 1.037). The same parameters discriminated the groups in the test cohort with 97.1% sensitivity and 100% specificity (lowest putamen SBR threshold, 0.875). A significant negative correlation (r = -0.24, P = 0.0004) was found between putamen SBRs and motor severity in the PPMI-PD group., Conclusions: SBRquant discriminates DaT scans with high sensitivity and specificity. It has a high potential for use as a quantitative diagnostic aid in clinical and research settings.

F-NaF PET/CT is an evolving technique that provides high sensitivity for detection of osseous metastases. In addition to detecting pathological osseous lesions, F uptake is occasionally detected in extraosseous lesions. However, reporting of extraosseous uptake in the literature is limited, and the increasing use of F-NaF PET/CT dictates that interpreting physicians learn to recognize extraosseous findings. An atlas of extraosseous findings detected by F-NaF PET/CT is presented, which includes cases under 2 broad categories: nonneoplastic and neoplastic.

A 41-year-old man with gastric adenocarcinoma presented with hepatic metastases. The metastases were refractory to systemic chemotherapy, so radioembolization with Y microspheres was performed. Because of stasis or saturation of the tumor with embolic particles, 79% of the microspheres were injected. At follow-up, the patient complained of "red bumps" that had developed on his right foot/ankle the day after the radioembolization. Because a portion of the dose was still in the catheter when withdrawn from the right femoral artery, the interventional radiologist used a Geiger counter to confirm radioactivity in the cutaneous lesions and thus the distal embolization of the microspheres.

61-year-old woman with stage IIIa (T3a N1a M0) left lower leg melanoma with lesions suggestive of in-transit metastases 8 months following wide local excision and femoral nodal dissection. FDG-PET/CT demonstrated 5 FDG-avid in-transit nodal metastases in the distal left leg, confirmed on biopsy. Talimogene laherparepvec (T-VEC) oncolytic immunotherapy consisting of intralesional injections of modified herpes simplex virus-expressing granulocyte-macrophage colony-stimulating factor was completed over 6 months. Subsequent FDG-PET/CT demonstrated reduced or resolved FDG activity in the treated in-transit metastases and a new FDG-avid left thigh in-transit metastasis. FDG-PET/CT can monitor response to T-VEC and potentially other novel viral immunotherapies.

Ascites can cause pleural effusions when the peritoneal fluid crosses the diaphragm through a pleuroperitoneal shunt in the setting of hepatic cirrhosis (hepatic hydrothorax) or malignant ascites. Scintigraphic imaging for pleuroperitoneal shunt requires intraperitoneal injection of Tc-SC or Tc-macroaggregated albumin followed by planar imaging of the chest and abdomen. Pleuroperitoneal shunt is confirmed by identifying radiotracer crossing the diaphragm from the peritoneal to pleural space. An atlas of pleuroperitoneal shunt imaging pitfalls is presented to facilitate optimal performance and interpretation of nuclear pleuroperitoneal shunt examinations. Examples include cases of nondiagnostic radiotracer injections, processing errors, and nontarget uptake.

Objective: Nuclear imaging can confirm pleuroperitoneal shunt as the cause of pleural effusion. No society guidelines exist for scintigraphic pleuroperitoneal shunt detection. Our institutional protocol was evaluated to determine optimal imaging time points for shunt detection., Methods: Pleuroperitoneal shunt studies over 4 years were blindly reviewed by 2 nuclear radiologists. Data from blinded review included presence or absence of pleuroperitoneal shunt, laterality of shunt and time points for shunt detection., Results: Chart review yielded 30 studies. Three cases were excluded because of improper injection. Imaging was positive for pleuroperitoneal shunt in 81% (22/27) of cases. In positive cases, activity was identified in the right hemithorax in 82% (18/22), left hemithorax in 9% (2/22), and bilaterally in 9% (2/22). One-hour imaging demonstrated 91% (20/22) of positive cases. The remaining 2 positive cases were negative at 1 hour but positive after 4 hours. No study was negative at 1 and 4 hours and positive at 24 hours. All negative cases (5/27) were confirmed on 24-hour imaging., Conclusions: The majority of positive pleuroperitoneal shunt examinations will demonstrate activity in the right hemithorax on 1-hour imaging. Although no case was negative at 1 and 4 hours and positive at 24 hours, imaging at 24 hours may still be necessary to confirm absence of shunt. Therefore, optimal imaging time points consist of early 1-hour and delayed 24-hour images if the 1-hour time point was negative. The 4-hour time point may be considered optional, thereby potentially optimizing patient safety and resource utilization.

Intense FDG uptake by bone marrow following recent chemotherapy limits evaluation for osseous metastases. The impact of marrow rebound on accuracy of (18)F-fluoride PET/CT is unclear. A 73-year-old woman with breast cancer presented for restaging FDG PET/CT, which showed intense activity throughout almost the entire axial skeleton and no osseous metastases. An (18)F-fluoride PET/CT performed 7 days later identified multiple osseous metastases in the spine, ribs, and pelvis. This case demonstrates that (18)F-fluoride PET/CT should be considered for the evaluation of osseous metastases in patients with rebound marrow uptake on FDG PET/CT.

Cerebellar hypometabolism on FDG PET has been described in several conditions, for example, chronic alcohol abuse, antiepileptic medication use, multiple system atrophy, and cerebellar infarction. Corresponding cross-sectional examination is paramount in distinguishing possible etiologies because each condition has a relatively characteristic appearance. We present a case of an asymptomatic patient with diffuse cerebellar hypometabolism found incidentally on FDG PET/CT performed for suspected recurrence of gastric carcinoma. Accompanying CT images demonstrated calcification of the cerebellum and therefore confirmed the etiology of diffuse idiopathic cerebellar calcification. Identifying this diagnosis is critical for using the cerebellum as a standard to evaluate other brain structures.