Value Of Positron Emission Tomography Research Articles

Prognostic value of PSMA PET in predicting long-term biochemical control following curative intent treatment for prostate cancer.

The aim of this study is to investigate the prognostic value of 68Ga-labelled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) metrics in predicting long-term biochemical failure-free survival (BFFS) following curative intent treatment for prostate cancer. We completed a prospective study that followed men who had PSMA PET for staging of newly diagnosed prostate cancer between 2015 and 2017 who went on to have curative intent treatment with radiotherapy (RT) or radical prostatectomy (RP). PSMA PET CT imaging was reported and the intraprostatic maximum standardised uptake value (SUVmax) was recorded. The primary outcome was BFFS. Statistical analysis included descriptive statistics, Cox proportional hazards (PH) models, Kaplan-Meier survival analysis and a regression tree structured method. A total of 183 men were included in the analysis with a median age of 66 years and the majority of patients (55.2%) had ISUP grade 1-3 disease. All patients had PSMA PET staging prior to curative intent treatment with RP (66.1%) or external beam radiotherapy (33.9%). PSMA-avid pelvic nodes were present in 26 patients but were not associated with worse biochemical control. A PSMA SUVmax of the prostate primary greater than the median (>5.6) was associated with a lower BFFS (HR: 4.4, 95% CI 1.42-3.72, P = 0.01). A multivariate Cox model incorporating initial biopsy grade, age and PSMA SUVmax showed that PSMA SUVmax was an independent predictor of BFFS. The RT-structured method identified an optimal threshold of 6.8 for PSMA SUVmax, above which patients with ISUP 1-3 disease had a significantly worse BFFS. PSMA SUVmax is a strong predictor of BFFS in patients with non-metastatic prostate cancer who underwent curative intent treatment. Patients with low-risk disease on biopsy (ISUP 1-3) but high PSMA SUVmax may have biochemical failure risk analogous to higher-risk disease (ISUP 4-5). These findings allow for further risk stratification and prognosis of patients with newly diagnosed prostate cancer planned for definitive treatment.

Maximum standardised uptake value of positron emission tomography as a predictor of oesophageal cancer outcomes

ObjectivesThis study aimed to analyse the value of pre-operative 18F-fluorodeoxyglucose positron emission tomography (PET)-computed tomography that can predict tumour pathological complete response, tumour histology grade, overall survival, and recurrence-free survival in patients with locally advanced oesophageal squamous cell carcinoma who underwent neoadjuvant chemoradiotherapy (NCRT) followed by surgery.MethodsWe retrospectively reviewed the cases of patients with locally advanced oesophageal squamous cell carcinoma undergoing NCRT followed by surgery. Patients who did not undergo PET within 3 months of surgery were excluded. We set a pre-operative PET maximum standardised uptake value (SUVmax) of > 5 as the threshold and classified the patients into two groups. We analysed the tumour response and histology grade, and compared the overall survival and recurrence-free survival between the two groups.ResultsThis cohort included 92 patients with oesophageal squamous cell carcinoma who underwent NCRT followed by surgery; 49 patients had a pre-operative PET SUVmax < 5, and 43 patients had a pre-operative PET SUVmax > 5. The patients’ pre-operative PET SUVmax correlated with tumour histology, ypT stage, and tumour response. Patients with a pre-operative SUVmax < 5 had better 2-year-overall survival (78% vs. 62%, P < 0.05) and 2-year recurrence-free survival (62% vs. 34%, P < 0.05) than those with a pre-operative SUV > 5.ConclusionsPre-operative SUVmax may be useful to predict tumour response, survival, and recurrence in patients with locally advanced oesophageal squamous cell carcinoma who undergo NCRT followed by surgery.

Prognostic significance of fludeoxyglucose positron emission tomography delta radiomics following bridging therapy in patients with large B-cell lymphoma undergoing CAR T-cell therapy.

Bridging radiation therapy (bRT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). It is unknown how the extent of cytoreduction during bRT impacts outcomes. We retrospectively reviewed patients with LBCL treated with bRT followed by CAR T-cell therapy. Metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), SUVmean, and total lesion glycolysis (TLG) were extracted from F18-fluorodeoxyglucose positron emission tomography (PET) scans acquired prior to bRT and between completion of bRT and CAR T-cell infusion. Delta radiomics based on changes of these values were then calculated. The association between delta radiomics and oncologic outcomes [progression-free survival (PFS), freedom from distant progression (FFDP), and local control (LC)] were then examined. Thirty-three sites across 23 patients with LBCL were irradiated. All metabolically active disease was treated in 10 patients. Following bRT, median overall decreases (including unirradiated sites) in MTV, SUVmax, SUVmean, and TLG were 22.2 cc (63.1%), 8.9 (36.8%), 3.4 (31.1%), and 297.9 cc (75.8%), respectively. Median decreases in MTV, SUVmax, SUVmean, and TLG in irradiated sites were 15.6 cc (91.1%), 17.0 (74.6%), 6.8 (55.3%), and 157.0 cc (94.6%), respectively. Median follow-up was 15.2 months. A decrease in SUVmax of at least 54% was associated with improved PFS (24-month PFS: 83.3% vs. 28.1%; p = 0.037) and FFDP (24-month FFDP: 100% vs. 62.4%; p < 0.001). A decrease in MTV of at least 90% was associated with improved FFDP (24-month FFDP: 100% vs. 62.4%; p < 0.001). LC was improved in sites with decreases in SUVmax of at least 71% (24-month LC: 100% vs. 72.7%; p < 0.001). Decreases of MTV by at least 90% (100% vs. 53.3%; p = 0.038) and TLG by at least 95% (100% vs. 56.3%; p = 0.067) were associated with an improved complete response rate. bRT led to substantial reductions in MTV, SUVmax, SUVmean, and TLG. The relative extent of these decreases correlated with improved outcomes after CAR T-cell infusion. Prospective cohorts should validate the value of interim PET following bRT for quantifying changes in disease burden and associated prognosis.

Tau Positron Emission Tomography: Applications in Diagnosis and Prognosis of Various Diseases

Tau positron emission tomography (PET) is a neuroimaging technique that visualizes tau deposition using PET tracers that selectively bind to tau aggregates. Studies have reported the diagnostic and prognostic value of tau PET in Alzheimer's disease and other tauopathies. However, the binding profiles of tau PET drugs vary widely across tauopathies; therefore, an accurate understanding of the disease-specific characteristics is essential for interpretation of tau PET findings. In this review, we discuss the properties of tau-PET agents and their applications in various diseases.

Equine Nuclear Medicine in 2024: Use and Value of Scintigraphy and PET in Equine Lameness Diagnosis.

Scintigraphy and Positron Emission Tomography (PET) are both nuclear medicine imaging techniques, providing functional information of the imaged areas. Scintigraphy is a two-dimensional projected imaging technique that was introduced in equine imaging in the late 1970s. Scintigraphy allows imaging of large body parts and can cover multiple areas, remaining the only technique commonly used in horses for whole body imaging. PET is a cross-sectional imaging technique, first used in horses in 2015, allowing higher resolution three-dimensional functional imaging of the equine distal limb. This manuscript will cover current use and values of these two modalities in equine lameness diagnosis.

18F-FDG PET can effectively rule out conversion to dementia and the presence of CSF biomarker of neurodegeneration: a real-world data analysis

BackgroundPrecisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology.MethodsLongitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer’s Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535–62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer’s Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777–88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels.ResultsAmong the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers.ConclusionA normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term.Trial registrationClinical Trials database (NCT04804722). March 18, 2021. Retrospectively registered.

The impact of PET imaging on triple negative breast cancer: an updated evidence-based perspective.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors. It predominantly affects younger women and is associated with a poor prognosis. This systematic review aims to evaluate the current role of positron emission tomography (PET) in the management of TNBC patients and to identify future research directions. We systematically searched the PubMed, Scopus, and Web of Science databases up to February 2024. A team of five researchers conducted data extraction and analysis. The quality of the selected studies was assessed using a specific evaluation form. Twenty-eight studies involving 2870 TNBC patients were included in the review. Key clinical applications of PET in TNBC included predicting pathological complete response (pCR) in patients undergoing neoadjuvant chemotherapy (NAC), assessing the prognostic value of baseline PET, and initial disease staging. Two studies utilized PSMA-ligand agents, while the majority used [18F]FDG-based PET. Significant associations were found between baseline [18F]FDG uptake and molecular biomarkers such as PDL-1, androgen receptor, and Ki67. Baseline [18F]FDG PET led to the upstaging of patients from stage IIB to stage IV, influencing treatment decisions and survival outcomes. In the NAC setting, serial PET scans measuring changes in [18F]FDG uptake, indicated by maximum standardized uptake value (SUVmax), predicted pCR with varying cut-off values correlated with different response rates. Semiquantitative parameters such as metabolic tumor volume (MTV) and PET lung index were prognostic for metastatic disease. In TNBC patients, [18F]FDG PET is essential for initial disease staging in both localized and metastatic settings. It is also useful for assessing treatment response to NAC. The ability of PET to correlate metabolic activity with molecular markers and predict treatment outcomes highlights its potential in TNBC management. Further prospective studies are needed to refine these clinical indications and establish its definitive role.

Risk Stratification in Cardiac Sarcoidosis With Cardiac Positron Emission Tomography: A Systematic Review and Meta-Analysis

BackgroundAlthough positron emission tomography (PET) imaging is well established for its diagnostic role in cardiac sarcoidosis, less is known about the prognostic value of PET and its use in risk stratification for major adverse cardiac events (MACE). ObjectivesThe goal of this study was to perform a systematic review and meta-analysis looking at the prognostic value of PET imaging in patients with cardiac sarcoidosis. MethodsStudy investigators systematically searched EMBASE (Excerpta Medica dataBASE), MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ClinicalTrials.gov, and the European Union Clinical Trial Registry for cardiac sarcoidosis and PET imaging. The primary outcome of interest was MACE. ResultsThe search revealed 3,010 records, of which 55 studies were included. This represented 5,250 patients. Factors associated with MACE included the following: the combination of abnormal fluorodeoxyglucose (FDG) uptake and perfusion defect, which had an OR of 2.86 (95% CI: 1.74-4.71; P < 0.0001); abnormal perfusion or FDG uptake, which had an OR of 2.69 (95% CI: 1.67-4.33); abnormal FDG uptake, which had an OR of 2.61 (95% CI: 1.51-4.50); focal abnormal right ventricular uptake, which had an OR of 6.27 (95% CI: 3.19-12.32; P < 0.00001); and a lack of response to immunosuppression on serial PET, which had an OR of 8.43 (95% CI: 3.25-21.85; P < 0.0001). A QUIPS (Quality in Prognostic Studies) tool analysis found a low to moderate risk of bias, particularly given the small sample sizes in the individual studies. ConclusionsMultiple cardiac PET parameters provide risk stratification value in cardiac sarcoidosis. Focal right ventricular uptake and a lack of response to immunosuppressive therapy on serial PET imaging were particularly predictive of MACE.

Predicting continuous amyloid PET values with CSF tau phosphorylation occupancies.

Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non-linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron emission tomography (PET) values. CSF tau phosphorylation occupancies at 10 sites (including pT181/T181, pT217/T217, pT231/T231 and pT205/T205) were measured by mass spectrometry in 346 individuals (57 cognitively impaired, 289 cognitively unimpaired). We generated synthetic amyloid PET scans using biomarkers and evaluated their performance. Concentration of CSF pT217/T217 had low predictive error (average error: 13%), but also a low predictive range (ceiling 63 Centiloids). CSF pT231/T231 has slightly higher error (average error: 19%) but predicted through a greater range (87 Centiloids). Tradeoffs exist in biomarker selection. Some phosphorylation sites offer greater concordance with amyloid PET at lower levels, while others perform better over a greater range. Novel pTau isoforms can predict cortical amyloid burden. pT217/T217 accurately predicts cortical amyloid burden in low-amyloid individuals. Traditional CSF biomarkers correspond with higher levels of amyloid.

UCP2-ACGAN: An adaptive condition GAN guided by U-shaped context perceptual processor for PET/CT images fusion

In order to better highlight the lesion area information and edge detailed information of the fused images, an adaptive condition Generative Adversarial Network (GAN) guided by U-shaped context perceptual processor (UCP2-ACGAN) for Positron Emission Tomography (PET) and Computed Tomography (CT) images fusion is proposed in this paper. Firstly, the network architecture of single generator and dual relative discriminators with weights sharing is used in UCP2-ACGAN. Secondly, a multi-granularity adaptive feature extraction module from coarse to fine (MGAFE) is proposed in generator, it is used to extract the valid information contained in the source images. Thirdly, a dual branch feature interactive fusion module guided by U-shaped context perceptual processor (UCP2-DBFIF) is proposed in generator. The context perceptual feature maps are obtained by U-shaped context perceptual processor (UCP2) and multiply them with the feature extraction results as the guiding conditions in the fusion process. In addition, in order to supplement the effective information lost during the feature fusion process, this paper converges the feature information of different granularity during the feature extraction stage. Finally, compared to the best of the 6 comparison methods, the results of comparison experiments show that UCP2-ACGAN is effective on several evaluation metrics values. For example, on the evaluation metrics of Average Gradient (AG), Edge Intensity (EI), Spatial Frequency (SF), Visual Information Fidelity (VIF) and Mutual Information (MI), the metrics values of CT mediastinal window images and PET fused images average increased by 30.74%, 29.35%, 40.24%, 35.47% and 26.18%.

Enhancing the Diagnostic Utility of ASL Imaging in Temporal Lobe Epilepsy through FlowGAN: An ASL to PET Image Translation Framework.

Positron Emission Tomography (PET) using fluorodeoxyglucose (FDG-PET) is a standard imaging modality for detecting areas of hypometabolism associated with the seizure onset zone (SOZ) in temporal lobe epilepsy (TLE). However, FDG-PET is costly and involves the use of a radioactive tracer. Arterial Spin Labeling (ASL) offers an MRI-based quantification of cerebral blood flow (CBF) that could also help localize the SOZ, but its performance in doing so, relative to FDG-PET, is limited. In this study, we seek to improve ASL's diagnostic performance by developing a deep learning framework for synthesizing FDG-PET-like images from ASL and structural MRI inputs. We included 68 epilepsy patients, out of which 36 had well lateralized TLE. We compared the coupling between FDG-PET and ASL CBF values in different brain regions, as well as the asymmetry of these values across the brain. We additionally assessed each modality's ability to lateralize the SOZ across brain regions. Using our paired PET-ASL data, we developed FlowGAN, a generative adversarial neural network (GAN) that synthesizes PET-like images from ASL and T1-weighted MRI inputs. We tested our synthetic PET images against the actual PET images of subjects to assess their ability to reproduce clinically meaningful hypometabolism and asymmetries in TLE. We found variable coupling between PET and ASL CBF values across brain regions. PET and ASL had high coupling in neocortical temporal and frontal brain regions (Spearman's r > 0.30, p < 0.05) but low coupling in mesial temporal structures (Spearman's r < 0.30, p > 0.05). Both whole brain PET and ASL CBF asymmetry values provided good separability between left and right TLE subjects, but PET (AUC = 0.96, 95% CI: [0.88, 1.00]) outperformed ASL (AUC = 0.81; 95% CI: [0.65, 0.96]). FlowGAN-generated images demonstrated high structural similarity to actual PET images (SSIM = 0.85). Globally, asymmetry values were better correlated between synthetic PET and original PET than between ASL CBF and original PET, with a mean correlation increase of 0.15 (95% CI: [0.07, 0.24], p<0.001, Cohen's d = 0.91). Furthermore, regions that had poor ASL-PET correlation (e.g. mesial temporal structures) showed the greatest improvement with synthetic PET images. FlowGAN improves ASL's diagnostic performance, generating synthetic PET images that closely mimic actual FDG-PET in depicting hypometabolism associated with TLE. This approach could improve non-invasive SOZ localization, offering a promising tool for epilepsy presurgical assessment. It potentially broadens the applicability of ASL in clinical practice and could reduce reliance on FDG-PET for epilepsy and other neurological disorders.

Added Value of [18F]PSMA-1007 PET/CT and PET/MRI in Patients With Biochemically Recurrent Prostate Cancer: Impact on Detection Rates and Clinical Management.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) can change management in a large fraction of patients with biochemically recurrent prostate cancer (BCR). To investigate the added value of PET to MRI and CT for this patient group, and to explore whether the choice of the PET paired modality (PET/MRI vs. PET/CT) impacts detection rates and clinical management. Retrospective. 41 patients with BCR (median age [range]: 68 [55-78]). 3T, including T1-weighted gradient echo (GRE), T2-weighted turbo spin echo (TSE) and dynamic contrast-enhanced GRE sequences, diffusion-weighted echo-planar imaging, and a T1-weighted TSE spine sequence. In addition to MRI, [18F]PSMA-1007 PET and low-dose CT were acquired on the same day. Images were reported using a five-point Likert scale by two teams each consisting of a radiologist and a nuclear medicine physician. The radiologist performed a reading using CT and MRI data and a joint reading between radiologist and nuclear medicine physician was performed using MRI, CT, and PET from either PET/MRI or PET/CT. Findings were presented to an oncologist to create intended treatment plans. Intrareader and interreader agreement analysis was performed. McNemar test, Cohen's κ, and intraclass correlation coefficients. A P-value <0.05 was considered significant. 7 patients had positive findings on MRI and CT, 22 patients on joint reading with PET/CT, and 18 patients joint reading with PET/MRI. For overall positivity, interreader agreement was poor for MR and CT (κ = 0.36) and almost perfect with addition of PET (PET/CT κ = 0.85, PET/MRI κ = 0.85). The addition of PET from PET/CT and PET/MRI changed intended treatment in 20 and 18 patients, respectively. Between joint readings, intended treatment was different for eight patients. The addition of [18F]PSMA-1007 PET/MRI or PET/CT to MRI and CT may increase detection rates, could reduce interreader variability, and may change intended treatment in half of patients with BCR. 3 TECHNICAL EFFICACY: Stage 3.

Diagnosis of giant cell arteritis by 18F-FDG PET/CT in patients on glucocorticoid therapy: importance of delayed imaging.

The aim of this study is to analyse the diagnostic value of positron emission tomography (PET) in patients with giant cell arteritis (GCA) despite glucocorticoid (GC) therapy before PET acquisition. Consecutive patients with strongly suspected GCA according to 2022 EULAR/ACR criteria were included. The physician diagnosis of GCA after 6 months of follow-up was the gold standard. PET was performed at baseline and 6 months later. In patients with negative results at 60 min, delayed imaging was performed at 180 min. Twenty-six patients were included with a median (IQR) age of 70.5 (57-88) years. Baseline PET was positive in all but one: 18 patients at 60 min and 7 patients after delayed imaging at 180 min. The median (IQR) GC dose at the time of baseline PET was 45 mg/d (26.2-45) of prednisone equivalent with a median exposure of 14 days (7-76.2). At 6 months of follow-up, PET was performed in 22 patients, with positive results in 16. Delayed imaging was performed in 6 patients due to negative PET at 60 min, with positive results in all cases, despite treatment with GC and/or biological therapy. In patients on GC therapy, delayed imaging protocols applying procedural recommendations for vascular quantification could improve diagnostic accuracy. Therefore, we suggest performing imaging only at 180 min in patients who have been on GCs for more than 3 days as well as in those with highly suspected GCA but negative findings in baseline PET at 60 min.

Feasibility of noise-reduction reconstruction technology based on non-local-mean principle in SiPM-PET/CT

Quantitative values of positron emission tomography (PET) images using non-local-mean in a silicon photomultiplier (SiPM)-PET/computed tomography (CT) system with phantom and clinical images.The evaluation was conducted on a National Electrical Manufacturers Association body phantom with micro-spheres (4, 5, 6, 8, 10, 13 mm) and clinical images using the SiPM-PET/CT system.The signal-to-background ratio of the phantom was set to 4, and all PET image data was obtained and reconstructed using three-dimensional ordered subset expectation maximization, time-of-flight, point-spread function, and a 4-mm Gaussian filter (GF) and clear adaptive low-noise method (CaLM) in mild, standard, and strong intensities.The evaluation included the standardized uptake value (SUV), percent contrast (QH), coefficient of variation of the background area (CVbackground) clinical imaging for SUV of lung nodules, liver signal-to-noise ratio (SNR), and visual evaluation.SUVmax for 8-mm sphere in phantom images at 2 min for GF and CaLM (mild, standard, strong) were 2.11, 2.32, 2.02, and 1.72; the QH, 8 mm was 27.33 %, 27.47 %, 21.81 %, and 16.09 %; and CVbackground was 12.78, 11.35, 7.86, and 4.71, respectively.CaLM demonstrated higher SUVmax in clinical images than GF for all lung nodule sizes. The average SUVmax for nodules with a diameter of ≤ 1 cm were 5.9 ± 2.4, 9.9 ± 4.9, 9.9 ± 5.0, and 9.9 ± 5.0 for GF and CaLM-mild, standard, and strong intensities, respectively.Liver SNRs were higher for CaLM (mild, standard, strong) compared to GF, with increasing CaLM intensity causing higher liver SNR. CaLM-mild and standard demonstrated suitability for diagnosis in visual evaluation.

Treatment Response to Neoadjuvant Therapy in Squamous Esophageal Cancer-Correlation Between Metabolic Response and Histopathology.

Esophageal cancer is among the leading causes of cancer-related mortality worldwide. Patients presenting with localized and loco-regionally advanced cancer without distant metastases have reasonable survival with multimodality management. Adequate and comprehensive staging is the backbone for proper selection of patients fit for curative treatment. Positron emission tomography (PET) in combination with contrast-enhanced computed tomography (CECT) is utilized as the standard staging modality. Multimodality treatment has been able to achieve evaluable tumor responses including pathological complete response (pCR). It is, therefore, necessary to understand whether the impact of neoadjuvant therapy can be evaluated on imaging, i.e., standardized uptake value (SUV) on PET scan done for response assessment and if this can be correlated with histopathological response and later, with survival. Squamous cell carcinoma (SCC) is more common globally and in the Indian subcontinent; hence, we chose this subgroup to evaluate our hypothesis. This is a single institution, retrospective study. Out of the 1967 patients who were treated between 2009 and 2019, 1369 (78.54%) patients had SCC. Out of these, 44 received NACTRT, whereas 1325 received NACT followed by curative surgery. The standardized uptake value (SUV) of 18-fluorodeoxyglucose was recorded during pre- and post-neoadjuvant treatment (NAT) using positron emission tomography (PET). The histopathology of the final resection specimen was evaluated using the Mandard tumor regression grade (TRG) criteria with response being graded from 0 to 5 as no residual tumor (NRT), scanty residual tumor (SRT), and residual tumor We attempted to find a cut-off value of the post neoadjuvant SUV of the primary tumor site which correlated with achievement of better histopathological response. Out of 1325 patients of SCC esophagus who underwent surgery, 943 patients had available data of TRG, and it was categorized into the 0-2 category which had 325 patients (34.5%) and 3-5 category, 618 patients (65.5%). The SUV was taken only from the PET scans done at our institution, so as to achieve a more homogenous cohort, and this was available for 186 patients, 151 from the NACT group and 35 from the NACTRT group. The ROC method was used to find the cut-off for SUV (5.05) in the NACT cohort, which depicted significant difference in the outcome. Out of these, 93 patients who underwent NACT had SUV > 5.05 and 58 had SUV < 5.05. It was found that the subjective and objective histopathological scores correlated at a p value of < 0.0001. Specifically, the majority of cases with SRT tended to be in the 3-5 category of TRG, whereas cases with NRT are predominantly in the 0-2 category. In the ≥ 5.05 category of SUV, there were 76 cases with SRT. In the NACT cohort, the < 5.05 category of SUV, there are 26 cases with SRT and 32 cases with NRT. Among cases with SRT, 74.5% had SUV ≥ 5.05, while 25.5% had SUV < 5.05. Among cases with NRT, 34.7% had SUV ≥ 5.05, while 65.3% had SUV < 5.05 (p value 0.007). No significant association was found in the radio-pathological correlation in the NACTRT group. Our study confirms the correlation of post neoadjuvant chemotherapy PET SUV with histopathological response, the cut-off of SUV being 5.05 in our cohort. This confirms the predictive value of FDG PET as demonstrated in other studies. Furthermore, its prognostic value with respect to survival has been verified in multiple other studies. With larger scale randomized studies, we may be able to identify the group of patients who have borderline operability anatomically as well as physiologically, where alternative treatment regimens may be indicated to improve outcomes.

Theranostics with somatostatin receptor antagonists in SCLC: Correlation of 68Ga-SSO120 PET with immunohistochemistry and survival.

Rationale: Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan (68Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of 68Ga-SSO120 PET at initial staging of patients with SCLC. Methods: We analyzed patients who underwent 68Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUVmax and TLRpeak) in 68Ga-SSO120 PET on a lesion level. Highest lesion SUVmax/TLRpeak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression. Results: We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUVmax/TLRpeak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p < 0.001; ANOVA p < 0.001). High SSTR2 expression in IHC, 68Ga-SSO120 SUVmax and TLRpeak of the hottest lesion per patient, whole-body TLRmean, MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLRpeak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (< 1), 21 (38.9%) intermediate (≥ 1 but < 2), 14 (25.9%) high (≥ 2 but < 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLRmean. Conclusion: In patients with SCLC, SSTR2 expression assessed by 68Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.

Microglial Activation Contributes to Neuropsychiatric Dysfunction in Alzheimer’s Disease

AbstractBackgroundPrevious studies have shown that microglial activation (MA) plays a key role in the pathophysiological and clinical progressions of Alzheimer’s disease (AD). However, little is known whether MA is also associated with the development of neuropsychiatric symptoms typically found in patients with AD. Thus, we aim to investigate here the association of MA with neuropsychiatric symptoms (NPS) of individuals across the AD continuum.MethodWe assessed 132 individuals (86 cognitively unimpaired (CU), 28 MCI, and 18 AD dementia) from the TRIAD cohort who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q), and had positron emission tomography (PET) for amyloid‐ß (Aß) ([18F]AZD4694), tau tangles ([18F]MK6240) and MA ([11C]PBR28) at the same visit. Regions were tailored using Desikan‐Killiany (DK) atlas. SUVRs were calculated using the cerebellum gray matter as a reference. Linear regression tested the association between biomarkers accounting for age, sex, and cognitive status.ResultNPI‐Q total score was significantly associated with [11C]PBR28 in the cingulate, inferior temporal, and precuneus accounting for age, sex, and after false discovery rate (FDR) correction for multiple comparisons (Figures 1A, 1B, 1C). This association was independent of Aß and tau levels (Table 1). Notably, MA predicted neuropsychiatric dysfunction with higher magnitude than Aß or tau using PET values from overlap region (regional SUVR) and if we use a global measure for all tracers (global SUVR) (Figure 2A). When we stratify NPI‐Q domains (agitation, irritability, motor disturbance, disinhibition, elation, delusion, hallucinations, nighttime disturbance, depression, anxiety, apathy, and appetite disturbance) severity score, we found that the hyperactivity subdomain (agitation, irritability, motor disturbance, disinhibition, and elation) showed the larger contribution to the results (Figure 2B).ConclusionOur results suggest MA as a key element associated with neuropsychiatric dysfunction in AD independent of Aß and tau pathologies. These findings provide additional rationale for the therapeutics targeting glial cells activation in AD patients.

Microglial Activation Contributes to Neuropsychiatric Dysfunction in Alzheimer’s Disease

AbstractBackgroundPrevious studies have shown that microglial activation (MA) plays a key role in the pathophysiological and clinical progressions of Alzheimer’s disease (AD). However, little is known whether MA is also associated with the development of neuropsychiatric symptoms typically found in patients with AD. Thus, we aim to investigate here the association of MA with neuropsychiatric symptoms (NPS) of individuals across the AD continuum.MethodWe assessed 132 individuals (86 cognitively unimpaired (CU), 28 MCI, and 18 AD dementia) from the TRIAD cohort who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q), and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694), tau tangles ([18F]MK6240) and MA ([11C]PBR28) at the same visit. Regions were tailored using Desikan‐Killiany (DK) atlas. SUVRs were calculated using the cerebellum gray matter as a reference. Linear regression tested the association between biomarkers accounting for age, sex, and cognitive status.ResultNPI‐Q total score was significantly associated with [11C]PBR28 in the cingulate, inferior temporal, and precuneus accounting for age, sex, and after false discovery rate (FDR) correction for multiple comparisons (Figures 1A, 1B, 1C). This association was independent of Aβ and tau levels (Table 1). Notably, MA predicted neuropsychiatric dysfunction with higher magnitude than Aß or tau using PET values from overlap region (regional SUVR) and if we use a global measure for all tracers (global SUVR) (Figure 2A). When we stratify NPI‐Q domains (agitation, irritability, motor disturbance, disinhibition, elation, delusion, hallucinations, nighttime disturbance, depression, anxiety, apathy, and appetite disturbance) severity score, we found that the hyperactivity subdomain (agitation, irritability, motor disturbance, disinhibition, and elation) showed the larger contribution to the results (Figure 2B).ConclusionOur results suggest MA as a key element associated with neuropsychiatric dysfunction in AD independent of Aβ and tau pathologies. These findings provide additional rationale for the therapeutics targeting glial cells activation in AD patients.

Prediction of continuous amyloid PET values by CSF tau measures

AbstractBackgroundAlzheimer disease (AD) is a slowly progressive neurodegenerative disorder characterized by the presence of amyloid plaques that can be measured in vivo with positron emission tomography (PET). PET quantifies the lifetime accumulation of amyloid plaques, while cerebrospinal fluid (CSF) biomarkers reflect the production and clearance of Aβ and tau peptides at time of CSF collection. Previous work has demonstrated a relative plateau of CSF values at higher levels of amyloid burden. Our objective was to identify the range of amyloid PET values predicted by CSF measures of tau phosphorylation, which have been found to be strongly associated with amyloid PET burden.MethodCSF was collected within two years of an amyloid PET scan from 417 (63 cognitively impaired) participants enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (mean age 69.8 years, standard deviation 8.9 years). PET imaging was performed with Pittsburgh Compound B (PiB). CSF Aβ42, p‐tau181 and Aβ40 were measured with Lumipulse automated immunoassays. The CSF tau phosphorylation occupancies (percent of tau phosphorylated) at T111, T153, T175, T181, S199, S202, T205, S208, T217, and T231 were evaluated with an immunoprecipitation‐mass spectrometry (IPMS) assay. We applied a neural network to generate a simulated PET‐PiB scan and cortical summary estimates using the fluid biomarkers as modeled inputs. We used asymptotic regression to evaluate the range of amyloid PET values predicted by each CSF measure (Figure 1).ResultCombining fluid biomarkers generated a cortical amyloid burden estimate within 12.6% mean average percent error (MAPE). Four of the assessed fluid biomarkers individually generated estimates within 20% MAPE (Figure 2). Of these, CSF Lumipulse p‐tau181/Aβ42, pS208/S208 (%), and pT231/T231 (%) predicted amyloid PET burden up until a high level (3.08 SUVR/91.1 Centiloids; 3.01 SUVR/88.0 Centiloids; 2.79 SUVR/78.1 Centiloids, respectively) (Figure 3). CSF pT217/217 (%) also had high accuracy but a slightly lower prediction threshold (2.65 SUVR/71.8 Centiloids).ConclusionCSF measures including phosphorylated tau predict amyloid PET over different ranges. Combining different measures of CSF tau phosphorylation can generate estimates of cortical amyloid burden. Future work will evaluate the prediction of tau PET by CSF measures.

Towards the Integrative Theory of Alzheimer's Disease: Linking Molecular Mechanisms of Neurotoxicity, Beta-amyloid Biomarkers, and the Diagnosis.

A major gap in amyloid-centric theories of Alzheimer's disease (AD) is that even though amyloid fibrils per se are not toxic in vitro, the diagnosis of AD clearly correlates with the density of beta-amyloid (Aβ) deposits. Based on our proposed amyloid degradation toxicity hypothesis, we developed a mathematical model explaining this discrepancy. It suggests that cytotoxicity depends on the cellular uptake of soluble Aβ rather than on the presence of amyloid aggregates. The dynamics of soluble beta-amyloid in the cerebrospinal fluid (CSF) and the density of Aβ deposits is described using a system of differential equations. In the model, cytotoxic damage is proportional to the cellular uptake of Aβ, while the probability of an AD diagnosis is defined by the Aβ cytotoxicity accumulated over the duration of the disease. After uptake, Aβ is concentrated intralysosomally, promoting the formation of fibrillation seeds inside cells. These seeds cannot be digested and are either accumulated intracellularly or exocytosed. Aβ starts aggregating on the extracellular seeds and, therefore, decreases in concentration in the interstitial fluid. The dependence of both Aβ toxicity and aggregation on the same process-cellular uptake of Aβ-explains the correlation between AD diagnosis and the density of amyloid aggregates in the brain. We tested the model using clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), which included records of beta-amyloid concentration in the cerebrospinal fluid (CSF-Aβ42) and the density of beta-amyloid deposits measured using positron emission tomography (PET). The model predicts the probability of AD diagnosis as a function of CSF-Aβ42 and PET and fits the experimental data at the 95% confidence level. Our study shows that existing clinical data allows for the inference of kinetic parameters describing beta-amyloid turnover and disease progression. Each combination of CSF-Aβ42 and PET values can be used to calculate the individual's cellular uptake rate, the effective disease duration, and the accumulated toxicity. We show that natural limitations on these parameters explain the characteristic distribution of the clinical dataset for these two biomarkers in the population. The resulting mathematical model interprets the positive correlation between the density of Aβ deposits and the probability of an AD diagnosis without assuming any cytotoxicity of the aggregated beta-amyloid. To the best of our knowledge, this model is the first to mechanistically explain the negative correlation between the concentration of Aβ42 in the CSF and the probability of an AD diagnosis. Finally, based on the amyloid degradation toxicity hypothesis and the insights provided by mathematical modeling, we propose new pathophysiology-relevant biomarkers to diagnose and predict AD.