18F-DCFPyL PET/CT in advanced high-grade epithelial ovarian cancer: A prospective pilot study.

Objectives: Glutamate carboxypeptidase-II (GCP-II), a zinc metalloenzyme that resides in cell membrane, has been reported as overexpressed in the neovasculature of ovarian cancers. The study objective was to determine whether GCP-II targeted imaging with 18F-DCFPyL PET/CT can detect disease sites in women with advanced high-grade serous ovarian cancer (HGSOC). Materials and methods: Twenty treatment-naïve women with advanced HGSOC were recruited (median age 60 years). Prior to commencing therapy (primary cytoreductive surgery [n=9] or neoadjuvant chemotherapy [n=11]), subjects underwent routine staging with contrast-enhanced abdominopelvic CT (=CT), followed by 18F-DCFPyL PET/CT (=PET). CT and PET were reported independently using a standardized reporting template assessing 25 sites. The performance of PET was compared to CT in all subjects and to surgery and surgical histopathology in 9 patients who underwent primary cytoreductive surgery. Results: Of the 25 sites assessed in 20 patients, CT detected disease in 292/500 (58.4%) locations and PET detected disease in 171/500 (34.2%). Compared to CT the sensitivity (95% CI) of PET to detect disease in the upper abdomen, the gastrointestinal tract or the peritoneum was 0.29 (0.20,0.40), 0.21 (0.11,0.33) and 0.74 (0.64,0.82), respectively. In the surgical cohort, 220 sites in 9 patients were evaluated. The sensitivity and specificity of CT and PET were 0.85 versus 0.54 (p<0.001) and 0.73 versus 0.93 (p<0.001), respectively. Conclusion: Although 18F-DCFPyL has higher specificity than CT in detecting advanced HGSOC tumor sites, it detects less disease sites than CT, especially in the upper abdomen and along the gastrointestinal tract, likely limiting its clinical utility. Clinical trial registration: ClinicalTrials.gov, NCT03811899.

18F-DCFPyL (PSMA) PET in the Management of Men with Biochemical Failure after Primary Therapy: Initial Clinical Experience of an Academic Cancer Center.

PURPOSE: To describe the initial experience of an academic center using 18F-DCFPyL PET in managing men with recurrent prostate cancer. MATERIALS & METHODS: This prospective, single-arm IRB-approved study included men with biochemical failure after primary therapy for prostate cancer and negative/equivocal CT and bone scintigraphy who were candidates for salvage therapy, as determined by a multidisciplinary panel of experts. 18F-DCFPyL PET was assessed for the presence and extent of recurrence: local, oligometastatic (≤4), or extensive. Post-PET management and clinical outcome, including PSA response, was documented. For patients who received PET-directed ablative therapies, response was categorized as "complete" if PSA became undetectable or "favorable" if PSA decreased ≥50%. RESULTS: Forty-seven men with biochemical failure after radical prostatectomy (n = 29), primary radiotherapy (n = 15) or focal tumor ablation (n = 3) were included. PET was positive in (43/47) 91.5%, including local recurrence in (9/47) 19.2%; oligometastatic disease in (16/47) 34%; and extensive metastatic disease in (18/47) 38.3%. PET-directed focal ablative therapies without systemic therapy were given to (13/29) 44.8% of patients without extensive metastases on PET with a mean PSA response of 69% (median, 74.5%; range: 35-100). Favorable biochemical response was observed in (10/13) 76.9% of patients with limited recurrence on PET, and in 23.1% (3/13), there was complete response. CONCLUSION: 18F-DCFPyL PET was positive in >90% of patients with biochemical failure. For those with limited recurrence, PSMA PET-directed local ablative therapies resulted in favorable outcome in more than 3 in 4 patients, and in nearly a quarter of them, there was complete biochemical response.

[18F]DCFPyL PET-MRI/CT for unveiling a molecularly defined oligorecurrent prostate cancer state amenable for curative-intent ablative therapy: study protocol for a phase II trial.

INTRODUCTION: The oligometastatic (OM) disease hypothesis of an intermediate metastatic state with limited distant disease deposits amenable for curative therapies remains debatable. Over a third of prostate cancer (PCa) patients treated with radical prostatectomy and postoperative radiotherapy experience disease recurrence; these patients are considered incurable by current standards. Often the recurrence cannot be localised by conventional imaging (CT and bone scan). Combined anatomical imaging with CT and/or MR with positron emission tomography (PET) using a novel second-generation prostate-specific membrane antigen (PSMA) probe, [18F]DCFPyL, is a promising imaging modality to unveil disease deposits in these patients. A new and earlier molecularly defined oligorecurrent (OR) state may be amenable to focal-targeted ablative curative-intent therapies, such as stereotactic ablative radiotherapy (SABR) or surgery, thereby significantly delaying or completely avoiding the need for palliative therapies in men with recurrent PCa after maximal local treatments. METHODS AND ANALYSIS: This ongoing single-institution phase II study will enrol up to 75 patients total, to include up to 37 patients with response-evaluable disease, who have rising prostate-specific antigen (range 0.4-3.0 ng/mL) following maximal local therapies with no evidence of disease on conventional imaging. These patients will undergo [18F]DCFPyL PET-MR/CT imaging to detect disease deposits, which will then be treated with SABR or surgery. The primary endpoints are performance of [18F]DCFPyL PET-MR/CT, and treatment response rates following SABR or surgery. Demographics and disease characteristics will be summarised and analysed descriptively. Response rates will be described with waterfall plots and proportions. ETHICS AND DISSEMINATION: Ethics approval was obtained from the institutional Research Ethics Board. All patients will provide written informed consent. [18F]DCFPyL has approval from Health Canada. The results of the study will be disseminated by the principal investigator. Patients will not be identifiable as individuals in any publication or presentation of this study. TRIAL REGISTRATION NUMBERS: NCT03160794.

Convolutional Neural Networks in Predicting Nodal and Distant Metastatic Potential of Newly Diagnosed Non-Small Cell Lung Cancer on FDG PET Images.

OBJECTIVE. The purpose of this study was to assess, by analyzing features of the primary tumor with 18F-FDG PET, the utility of deep machine learning with a convolutional neural network (CNN) in predicting the potential of newly diagnosed non-small cell lung cancer (NSCLC) to metastasize to lymph nodes or distant sites. MATERIALS AND METHODS. Consecutively registered patients with newly diagnosed, untreated NSCLC were retrospectively included in a single-center study. PET images were segmented with local image features extraction software, and data were used for CNN training and validation after data augmentation strategies were used. The standard of reference for designation of N category was invasive lymph node sampling or 6-month follow-up imaging. Distant metastases developing during the study follow-up period were assessed by imaging (CT or PET/CT), in tissue obtained from new suspected sites of disease, and according to the treating oncologist's designation. RESULTS. A total of 264 patients with NSCLC participated in follow-up for a median of 25.2 months (range, 6-43 months). N category designations were available for 223 of 264 (84.5%) patients, and M category for all 264. The sensitivity, specificity, and accuracy of CNN for predicting node positivity were 0.74 ± 0.32, 0.84 ± 0.16, and 0.80 ± 0.17. The corresponding values for predicting distant metastases were 0.45 ± 0.08, 0.79 ± 0.06, and 0.63 ± 0.05. CONCLUSION. This study showed that using a CNN to analyze segmented PET images of patients with previously untreated NSCLC can yield moderately high accuracy for designation of N category, although this may be insufficient to preclude invasive lymph node sampling. The sensitivity of the CNN in predicting distant metastases is fairly poor, although specificity is moderately high.

Publisher Correction to: 18F-FDG PET/CT metabolic tumor parameters and radiomics features in aggressive non-Hodgkin's lymphoma as predictors of treatment outcome and survival.

In the original publication of the article, the title was incorrectly.

18F-FDG PET/CT metabolic tumor parameters and radiomics features in aggressive non-Hodgkin's lymphoma as predictors of treatment outcome and survival.

PURPOSE: To determine whether metabolic tumor parameters and radiomic features extracted from 18F-FDG PET/CT (PET) can predict response to therapy and outcome in patients with aggressive B-cell lymphoma. METHODS: This institutional ethics board-approved retrospective study included 82 patients undergoing PET for aggressive B-cell lymphoma staging. Whole-body metabolic tumor volume (MTV) using various thresholds and tumor radiomic features were assessed on representative tumor sites. The extracted features were correlated with treatment response, disease-free survival (DFS) and overall survival (OS). RESULTS: At the end of therapy, 66 patients (80.5%) had shown complete response to therapy. The parameters correlating with response to therapy were bulky disease > 6 cm at baseline (p = 0.026), absence of a residual mass > 1.5 cm at the end of therapy CT (p = 0.028) and whole-body MTV with best performance using an SUV threshold of 3 and 6 (p = 0.015 and 0.009, respectively). None of the tumor texture features were predictive of first-line therapy response, while a few of them including GLNU correlated with disease-free survival (p = 0.013) and kurtosis correlated with overall survival (p = 0.035). CONCLUSIONS: Whole-body MTV correlates with response to therapy in patient with aggressive B-cell lymphoma. Tumor texture features could not predict therapy response, although several features correlated with the presence of a residual mass at the end of therapy CT and others correlated with disease-free and overall survival. These parameters should be prospectively validated in a larger cohort to confirm clinical prognostication.

18F-FDG PET/CT in the management of patients with malignant pleural mesothelioma being considered for multimodality therapy: experience of a tertiary referral center.

OBJECTIVE: To compare the N- and M-staging accuracy of PET vs CT, as per the American Joint Committee on Cancer (AJCC) eighth edition in patients with malignant pleural mesothelioma (MPM) being considered for multimodality therapy in a tertiary referral center. A secondary aim was to assess survival outcome of patients chosen for surgical management after PET. METHODS: A retrospective, single institution comparison of PET and CT was performed in patients with histologically proven MPM being considered for multimodality therapy. Performance of each modality in identifying nodal category and presence or absence of distant metastases was abstracted from electronic patient records. The standard of reference was surgical histopathology for nodal stage and histopathology or clinical and imaging follow-up of >3 months for distant metastases. RESULTS: There were 101 eligible patients with complete data sets; 82 males, 19 females with a mean age of 66.6 years (range: 39-85). Most patients (n = 68) had epithelioid histology. Surgery was performed in 61/101 patients (60.4%), most of whom had multimodality therapy. Nodal category was concordant to surgical histopathology in 38/60 patients (63.3%) on PET, compared to 27/60 (45%) on CT (p = 0.001). For detection of ≥N1 disease only, PET and CT correctly staged 15/37 patients (40.5%) and 8/37 (21.6%), respectively (p = 0.023). Distant metastases were identified uniquely on PET in eight patients and on CT only in one patient. Overall, PET and CT correctly identified 11/12 (91.6%) and 4/12 (33.3%) patients with distant metastases, respectively (p = 0.0391). CONCLUSION: PET identifies significantly more patients with nodal or distant metastatic disease than CT and may contribute to more appropriate selection of patients with MPM for surgery or multimodality therapy. Advances in knowledge: In patients with MPM, fludeoxyglucose-PET/CT detects significantly more patients with distant metastases than CT. PET/CT can help in the selection of patients with MPM who would benefit from surgery or multimodality therapy.

Effect of chemotherapy on the impact of FDG-PET/CT in selection of patients for surgical resection of colorectal liver metastases: single center analysis of PET-CAM randomized trial.

The largest randomized controlled trial (RCT) on the effect of FDG-PET on surgical management for metastatic colorectal adenocarcinoma to liver ("PET-CAM") reported only a modest change in surgical management (8%). PURPOSE: To explore the relationship between prior chemotherapy and detection of metastatic disease on PET in patients from PET-CAM. Secondary aim: to determine whether centralized imaging interpretation could have impacted trial results. METHODS: The study included 120 patients from a single institution. Local PET interpretation (PET-L) was recorded from the original database. Retrospective PET interpretation was performed independently by at least one additional reader (PET-C). The presence of extrahepatic disease (EHD) and significant additional liver metastases (=SALM), defined as metastases not originally planned for resection, was recorded. Patients were stratified to responders to recent chemotherapy (Group R) versus all others (Group O) according to surgical pathology and RECIST criteria. RESULTS: Thirty-seven of 50 patients who received recent chemotherapy (<90 days) were responders (Group R). EHD was present in 30/120 (25%) patients. There was no difference in detection of EHD on PET-L (7/37;18.9%), PET-C (7/37;18.9%), and CT (4/37;10.8%) for Group R (p = 0.375), but in Group O more EHD was detected on both PET-L (15/83;18.1%) and PET-C (22/83;26.5%) than CT (8/83;9.6%); p = 0.039 and p < 0.001, respectively. For the entire cohort, PET-L and PET-C detected EHD and/or SALM not reported on CT in 14 (11.7%) and 22 (18.3%) patients. CONCLUSION: The impact of recent chemotherapy on detection of colorectal metastases with PET suggests that the utility of PET in patient selection for liver resection in the prior PET-CAM-RCT may have been underestimated.

Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study.

BACKGROUND: The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated L(A) and L(G). Only L(A) is associated with high levels of in vitro 5-HTT expression, whereas L(G) is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([(11)C]DASB) positron emission tomography. METHODS: The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. RESULTS: The L(A)/L(A) was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. CONCLUSIONS: The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy L(A)/L(A) carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the L(A)/L(A) genotype into in vivo brains of healthy human subjects.

An automated method for the extraction of regional data from PET images.

Manual drawing of regions of interest (ROIs) on brain positron emission tomography (PET) images is labour intensive and subject to intra- and inter-individual variations. To standardize analysis and improve the reproducibility of PET measures, we have developed image analysis software for automated quantification of PET data. The method is based on the individualization of a set of standard ROIs using a magnetic resonance (MR) image co-registered with the PET image. To evaluate the performance of this automated method, the software-based quantification has been compared with conventional manual quantification of PET images obtained using three different PET radiotracers: [(11)C]-WAY 100635, [(11)C]-raclopride and [(11)C]-DASB. Our results show that binding potential estimates obtained using the automated method correlate highly with those obtained by trained raters using manual delineation of ROIs for frontal and temporal cortex, thalamus, and striatum (global intraclass correlation coefficient >0.8). For the three radioligands, the software yields time-activity data that are similar (within 8%) to those obtained by manual quantification, eliminates investigator-dependent variability, considerably shortens the time required for analysis and thus provides an alternative method for accurate quantification of PET data.

Effects of tryptophan depletion on the serotonin transporter in healthy humans.

BACKGROUND: Lowering of brain serotonin by acute tryptophan depletion (TD) frequently leads to transient symptoms of depression in vulnerable individuals but not in euthymic healthy subjects with a negative family history of depression. The effects of TD on regional serotonin transporter binding potential (5-HTT BP), an index of 5-HTT density and affinity, were studied in healthy individuals using 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ([11C]DASB) positron emission tomography (PET). Adaptive decreases in 5-HTT density and/or affinity during TD would be a possible compensatory mechanism to maintain sufficient extracellular serotonin levels during TD, thereby preventing a depressive relapse. METHODS: Regional noninvasive 5-HTT BP was found in 25 healthy subjects using [11C]DASB PET. Fourteen subjects were scanned twice, once after TD and once after sham depletion, and 11 other healthy subjects were scanned twice to measure test-retest reliability of the method. RESULTS: None of the healthy subjects experienced depressive symptoms during TD and there was no difference in regional 5-HTT BP during TD as compared with sham depletion. CONCLUSIONS: Acute changes in 5-HTT density or affinity are unlikely to play a role in protecting healthy subjects against mood symptoms during TD. Other mechanisms that may be associated with greater resilience against acute lowering of extracellular serotonin should be explored to gain further insight into the neurochemical basis of different vulnerabilities to short-term depressive relapse.

Tryptophan depletion and serotonin loss in selective serotonin reuptake inhibitor-treated depression: an [(18)F] MPPF positron emission tomography study.

BACKGROUND: Recurrence of depressive symptoms after tryptophan depletion (TD) in selective serotonin reuptake inhibitor (SSRI)-treated depression is an important, unexplained phenomenon. With [(18)F] MPPF positron emission tomography (PET), serotonin (5-hydroxytryptamine, 5-HT) 1A receptor binding potential (5-HT(1A)BP) was measured after TD in various brain regions in citalopram-treated depression. This 5-HT(1A)BP measurement is sensitive to changes in extracellular 5-HT in animal models. METHODS: Eight remitted patients with major depressive disorder received [(18)F] MPPF PET scans twice: once after TD and once after sham depletion. Behavioral measures were evaluated with the Hamilton Depression Rating Scale and visual analog scales. RESULTS: No effect on regional 5-HT(1A)BP was observed after TD, despite an 86% decrease in total plasma tryptophan and transient depressive relapse in six of eight patients. CONCLUSIONS: Large-magnitude changes in extracellular 5-HT are not crucial for the mood effects observed in SSRI-treated subjects after TD. Therefore, greater consideration must be given to other mechanisms that involve vulnerability to small perturbations in extracellular 5-HT, such as impairment of signal transduction.

Imaging cAMP-specific phosphodiesterase-4 in human brain with R-[11C]rolipram and positron emission tomography.

Evidence of disruptions in cAMP-mediated signaling in several neuropsychiatric disorders has led to the development of R-[(11)C]rolipram for imaging phosphodiesterase-4 (PDE4) enzymes with positron emission tomography (PET). The high-affinity PDE4 inhibitor rolipram was previously reported to have an antidepressant effect in humans. PDE4 is abundant in the brain, and it hydrolyzes cAMP produced following stimulation of various neurotransmitter systems. PDE4 is regulated by intracellular cAMP levels. This paper presents the first PET study of R-[(11)C]rolipram in living human brain. Consistent with the wide distribution of PDE4, high radioactivity retention was observed in all regions representing the gray matter. Rapid metabolism was observed, and kinetic analysis demonstrated that the data fit in a two-tissue compartment model. R-[(11)C]Rolipram is thus suitable for imaging PDE4 and possibly cAMP signal transduction in the living human brain with PET.

Brain serotonin 5-HT(1A) receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635.

BACKGROUND: Results of postmortem studies show an elevation in serotonin-1A (5-hydroxytryptamine-1A [5-HT(1A)]) receptor density in the prefrontal and temporal cortices of patients with schizophrenia. This study examined 5-HT(1A) receptors in vivo in patients with schizophrenia using positron emission tomography and [carbonyl-(11)C]-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide ([(11)C]WAY-100635). METHODS: The 5-HT(1A) binding potential of 14 antipsychotic drug-naïve patients with a DSM-IV diagnosis of schizophrenia was compared with that of 14 age-matched healthy controls. Positron emission tomography data were analyzed using 9 cortical regions of interest, which were delineated on a coregistered magnetic resonance image and transferred to the positron emission tomographic image, with the cerebellum as the reference region for a simplified reference tissue model. We also performed a voxel-wise comparison using statistical parametric mapping. RESULTS: The region of interest-based analysis revealed a significant mean +/- SD cortical 5-HT(1A) receptor binding potential increase of 7.1% +/- 6.4% in patients with schizophrenia (F = 2.975; P =.02); local differences were +20% in the left medial temporal cortex (F = 9.339;P =.005) and +13% in the right medio temporal cortex (F = 4.453; P =.045). There were no significant differences in regional tracer delivery or cerebellar [(11)C]WAY-100635 uptake. The voxel-based analysis also confirmed a group difference in the left medial temporal cortex. CONCLUSIONS: The biological significance of elevated 5-HT(1A) receptor density in schizophrenia remains unclear. Given the location of 5-HT(1A) receptors on pyramidal cells, this elevation may reflect an abnormal glutamatergic network. Our finding needs to be viewed in light of preclinical evidence supporting a role for 5-HT(1A) receptors in mediating antipsychotic action and extrapyramidal adverse effects of drugs.