Positive PET Research Articles

50 Effects of Cerebrovascular Risk Factors and Alzheimer’s Disease Pathology on Executive Function and Memory Changes: Analysis of the National Alzheimer’s Coordinating Center Cohort

Objective:A common assumption in clinical neuropsychology is that cerebrovascular risk is adversely associated with executive function, while Alzheimer’s disease (AD) primarily targets episodic memory. The goal of the present study was to determine the cross-sectional and longitudinal validity of these assumptions using validated markers of cerebrovascular and AD burden.Participants and Methods:19271 longitudinally-followed participants from the National Alzheimer Coordinating Center (NACC) database (Mean age= 72.25; SD age= 10.42; 58% women; 51.6% CDR= 0, 33.7% CDR= 0.5, 14.7% CDR> 1) were included. Cognitive outcomes were a composite memory score and an executive function composite score (UDS3-EF; Staffaroni et al., 2020). Baseline presence of cerebrovascular disease was indexed by the presence of moderate to severe white matter hyperintensities or lacunar infarct on brain MRI (yes/no), while baseline AD pathology was indexed by the presence of a positive amyloid PET scan or elevated CSF AD biomarkers (yes/no). We used linear mixed effect models to assess the effects of baseline cerebrovascular disease, baseline AD pathology, and their interactions with time in study (years post baseline) controlling for baseline age, sex, education, and baseline MoCA score.Results:Baseline cerebrovascular disease was significantly associated with a lower intercept on executive functioning (between-person effect) (p < -0.001, 95% CI -0.37, -0.14) but not memory, while presence of AD biomarkers was associated with a lower memory intercept (p < -0.001, 95% CI -0.52, -0.39) but not executive function. However, only presence of AD pathology at baseline was associated with faster longitudinal decline on both memory and executive functioning over time. Baseline cerebrovascular disease did not independently relate to rate of cognitive decline.Conclusions:Consistent with widely held assumptions, our between-person analyses showed that MRI evidence of cerebrovascular disease was associated with worse executive functioning but not memory, while biomarker evidence of AD pathology was associated with worse memory but not executive function. Longitudinally, however, AD is the primary driver of decline in both executive and memory function. These results extend our understanding of how pathology impacts cognition in aging cohorts and highlight the importance of using longitudinal models.

지역사회 노인에서 아밀로이드 PET 양성 예측에 대한 주관적 기억력 저하 설문의 유용성

Objective: This study aimed to assess the usefulness of a memory complaint questionnaire for predicting amyloid PET positivity in community-dwelling older adults.
 Methods: We recruited community-dwelling older adults without history of dementia who wished to participate in the study based on voluntary consent. We performed the Seoul Neuropsychological Screening Battery-Core (SNSB-C), Memory Age-associated Complaint Questionnaire (MACQ), Apolipoprotein E (ApoE) genotyping, and amyloid PET. According to the result of the SNSB-C, participants with objective cognitive impairment were excluded, and finally 124 participants were included in this study. We used receiver operating characteristic (ROC) curve and calculated area under the ROC curve (AUC) to evaluate usefulness of the MACQ compared to the result of ApoE genotyping for predicting amyloid PET positivity in cognitively unimpaired community-dwelling older adults.
 Results: The mean age of the study participants was 73.3 years, and 69.4% were female. ROC curve with MACQ score and with ApoE4 carrier was created and AUC of each model was calculated. AUC value was 0.660 for MACQ score, and 0.695 for ApoE4 carrier. There was no statistically significant difference in AUC value (p=0.494).
 Conclusion: In community-dwelling older adults without objective cognitive decline, the memory complaint questionnaire― MACQ showed no significant difference with ApoE4 carrier for predicting amyloid PET positivity.

Cognitive impact of multidomain intervention and omega 3 according to blood Aβ42/40 ratio: a subgroup analysis from the randomized MAPT trial

BackgroundIn MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET. However, screening eligible patients for multidomain intervention by PET is difficult to generalize in real-world settings.MethodsMAPT study was a 3-year, randomized, placebo-controlled trial followed by a 2-year observational and optional extension. All participants were non-demented and randomly assigned (1:1:1:1) to the MI plus omega 3, MI plus placebo, omega 3 alone, or placebo alone group. The objectives were to assess the cognitive effect of MAPT interventions (omega 3 supplementation, MI, combined intervention) in non-demented subjects according to amyloid blood status at 12, 36, and 60 months. In this subgroup analysis (n = 483), amyloid status was defined by plasma Aβ42/40 ratio (cutoff ≤ 0.0107). The primary outcome measure was the change in cognitive composite score after a 1, 3, and 5-year clinical follow-up.ResultsThe intention-to-treat (ITT) population included 483 subjects (161 positive and 322 negative amyloid participants based on plasma Aβ42/40 ratio). In the positive amyloid ITT population, we showed a positive effect of MI plus omega 3 on the change in composite cognitive score in 12 (raw p = .0350, 0.01917, 95% CI = [0.0136 to 0.3699]) and 36 months (raw p = .0357, 0.2818, 95% CI = [0.0190 to 0.5446]). After correction of multiple comparisons and adjustments, these differences were not significant (adjusted p = .1144 and .0690). In the per-protocol positive amyloid group (n = 154), we observed a significant difference between the combined intervention and placebo groups at 12 (p = .0313, 0.2424, 0.0571 to 0.4276) and 36 months (p = .0195, 0.3747, 0.1055 to 0.6439) persisting after adjustment. In the ITT and per-protocol analyses, no cognitive effect was observed in the positive and negative amyloid group at 60-month visit.ConclusionsThese findings suggest a benefit of MI plus omega 3 in positive blood amyloid subjects. This promising trend needs to be confirmed before using blood biomarkers for screening in preventive trials.Trial registrationClinicalTrials.gov Identifier: NCT01513252.

A - 36 Neuroprotective and Resilience Factors in an Individual with Positive ad Biomarkers.

There is conflicting research on risk indicators relating to the diagnosis of early-onset Alzheimer's disease (EOAD). We assessed an individual with numerous factors that are associated with EOAD including the presence of two APOE e4 alleles, family history of EOAD, and positive biomarkers (i.e., Amyloid PET Scan; CSF). Longitudinal neuropsychological data reflect minimal cognitive decline through age 73, suggesting substantial mediating effects of cognitive reserve and neuroprotective measures: aerobic exercise, cognitive stimulation, and psychological health. A 73-year-old man was seen for repeat neuropsychological evaluation in 2022 at an academic medical center following his baseline evaluation in 2019, which did not reveal cognitive deficits. Testing was conducted and interpreted by a clinical neuropsychologist in the context of available neuroimaging and neurodiagnostic information. Results of the neuropsychological assessment were interpreted in the context of High Average to Superior premorbid functioning, a significant family history of EOAD, a positive Amyloid PET scan and two ApoE4 alleles (4/4). Results of his 2022 evaluation remain consistent or improved from 2019 and do not suggest mild cognitive impairment (MCI). Functionally, this individual is fully independent in IADLs and does not report significant subjective cognitive concerns. Phenotypic expression of ad symptoms are delayed in this individual despite his genetic risk and pathologic biomarkers; the reason is likely multifactorial but includes several resilience factors, including good cardiovascular health (i.e., aerobic exercise 5x/week), continued cognitive stimulation, and psychological health. These are areas worthy of further research.

Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project

BackgroundExposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer’s disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected.MethodsWe examined 237 men ages 45–74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates.ResultsThere were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [− 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [− 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning.ConclusionsCognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications.Trial registrationNCT02798185.

Somatostatin Receptor Expression in Lung Neuroendocrine Tumors: An Analysis of DOTATATE PET Scans.

Somatostatin receptor (SSTR) expression in metastatic lung neuroendocrine tumors (NETs) has not been well characterized using PET imaging. Understanding the degree and uniformity of SSTR expression is important to establish the role of SSTR-targeted treatments in lung NETs. Methods: A retrospective institutional review of patients with metastatic lung NETs who underwent DOTATATE PET imaging from March 2017 to February 2023 was performed. Results: In total, 48 patients with metastatic lung NETs who underwent 68Ga- or 64Cu-DOTATATE PET imaging were identified. Four had completely negative SSTR expression, and 10 had very weak expression (less than in a normal liver). Among the remaining 34 patients, 21 had uniformly positive DOTATATE PET scans, and 13 had heterogeneous expression. Only 44% had uniformly positive receptor expression, identifying them as candidates for peptide receptor radionuclide therapy. Conclusion: Most metastatic lung NETs lack uniform SSTR expression and are thus suboptimal candidates for SSTR-targeted therapy. SSTR imaging in lung NETs should be evaluated carefully for uniformity of expression.

Post-treatment PET/CT for p16-positive oropharynx cancer treated with definitive proton therapy.

Given emerging data suggesting that uncertainty in the relative biologic effectiveness at the distal end of the Bragg peak results in increased mucosal injury in patients with oropharynx cancer receiving adjuvant proton therapy, we evaluated the results of post-treatment positron emission tomography-computed tomography (PET/CT) in patients with p16-positive oropharynx cancer (p16+OPC) treated with definitive intensity-modulated proton therapy (IMPT). A retrospective cohort study of patients with p16+OPC treated with definitive IMPT between 2016 and 2022 was performed at a single institution. Patients with PET/CT scans within 6 months following completion of IMPT were included in the study. Positive post-treatment scans were defined by a maximum standard uptake values (SUVmax) >4.0 or a <65% reduction in SUVmax in either the primary tumor or lymph node. The Fisher's exact test was used to evaluate factors associated with positive post-treatment PET/ CT values. Sixty-two patients were included for analysis. Median follow-up was 21 months (range: 3-71 months) with a median time to post-treatment PET/CT of 3 months (range: 2-6 months). Median post-treatment SUVmax of the primary disease and nodal disease was 0 (mean: 0.8, range: 0-7.7) and 0 (mean: 0.7, range: 0-9.5), respectively. Median post-treatment percent reduction in SUVmax for the primary site and lymph node was 100% (mean: 94%, range: 31.3-100%) and 100% (mean: 89%, range: 23-100%), respectively. Eleven patients had a positive post-treatment PET/CT with one biopsy-proven recurrence. Negative and positive predictive values (NPV and PPV) were 98% and 9.1%, respectively. There were no factors associated with positive post-treatment PET/CT. Similar to patients treated with photon-based radiation therapy, post-treatment PET/CT has a high NPV for patients with p16+OPC treated with definitive proton therapy and should be used to guide patient management. Additional patients and more events are needed to confirm the PPV of a post-treatment PET/CT in this favorable patient cohort.

Positive Predictive Value of PET CT in HPV Associated Oropharyngeal Cancers Treated with Definitive Proton Therapy

Proton therapy (PT) offers attractive dosimetric advantages but there is emerging literature suggesting relative biological effectiveness (RBE) differences at the distal end of the Bragg peak may result in increased posttreatment FDG avidity. While the utility of PET CT is well established, lingering posttreatment inflammation from PT may affect the interpretation of posttreatment scans (PTS). We seek to characterize the positive predictive value (PPV) and negative predictive value (NPV) for residual disease/locoregional recurrence in patients undergoing definitive PT with HPV associated oropharyngeal cancer. We performed a single institution retrospective analysis of patients with HPV associated oropharyngeal cancer treated with PT between 2016-2022. Patients were included if they had both pretreatment and initial posttreatment restaging PET/CT available for analysis. SUVmax was recorded in both the primary tumor and involved lymph nodes. Patients were considered to have a positive PET CT if there was an SUV decrease of less than 65% from the baseline exam or if there was SUV > 4.0 based on thresholds defined by previous studies. Chi-square analysis was used to compare patients who had a positive PTS to those who did not. Sixty-two patients were included for analysis with a median age of 62. The entire cohort had a median follow up of 21 months (Range 2-71 months) of whom 86% received chemotherapy. Eleven patients (17%) had PTS defined as positive, of whom only one (PPV 9%) was found to have residual/locoregionally recurrent disease within an area of FDG avidity on PTS. Another patient developed a new primary tumor 9 months later in an area outside of FDG avidity on PTS. The remainder were followed with serial clinical exam with or without the compliment of repeat imaging. They remained without evidence of residual/locoregionally recurrent disease at the time of last follow up. Fifty-one patients had negative posttreatment scans, with only one patient having residual/locoregionally recurrent disease (NPV 98%). On Chi-square analysis T1-2 vs T3-4 tumor, use of CTV margin vs no margin, chemotherapy vs no chemotherapy, smoking history, and tonsil vs base of tongue subsite were not statistically significant in association with positive PTS. PET/CT for post-treatment evaluation of patients treated with PT had an expectedly high NPV of 98% for residual/locoregionally recurrent disease; however, the PPV was 9% (1/11) which is much lower than would be expected with photon-based treatment. These findings may be the result of lingering acute inflammation caused by RBE differences at the distal end of the Bragg peak. Our findings are hypothesis generating and require validation with larger well-matched patient cohorts.

Predictors of PSMA PET Positivity: Analysis in a Selected Cohort of Biochemical Recurrence Prostate Cancer Patients after Radical Prostatectomy.

Localized prostate cancer (PCa) can be treated with radical prostatectomy (RP). Up to 30% of patients undergoing this procedure experience biochemical recurrence (BCR), namely the rise in serum prostate-specific antigen (PSA) levels during the post-surgical follow-up, requiring further treatments and with the risk of severe disease progression. Currently, the most accurate imaging technique to confirm, detect, and locate disease relapses in BCR patients is prostate-specific membrane antigen (PSMA)-targeted PET, as recommended by international clinical guidelines. The aim of the study was to investigate potential clinical and pathological predictors of PSMA PET positivity, validated by clinical and instrumental follow-up or histopathological data. In this study, a selected cohort of BCR patients after RP and no other PCa-related therapy who underwent either PSMA PET/CT or PSMA PET/MRI has been analysed. Among the considered predictors, both pathological staging after RP equal or higher than pT3a and higher PSA levels at the time of the scan were significantly correlated with PSMA PET positivity on multivariate logistic regression analysis. As expected, PSMA PET confirmed its role as an accurate imaging technique in the setting of BCR in PCa. These findings may inform appropriate and tailored patient selection and scan timing to optimize and fully exploit this powerful diagnostic tool.

P15.11.B POSTOPERATIVE68GA-DOTATATE/PET-CT IMAGING IS PROGNOSTIC FOR PROGRESSION-FREE SURVIVAL IN MENINGIOMA WHO GRADE 1: A PROSPECTIVE SINGLE-CENTER STUDY

Abstract BACKGROUND Microsurgical tumor resection represents the first-line treatment for symptomatic meningiomas, and extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. However, prognostic relevance of postoperative PET for progression-free survival in meningiomas remains unclear. METHODS We conducted a prospective study including patients with surgically removed meningioma WHO grade 1 and collected clinical and imaging data. All patients received postoperative MRI and 68Gallium-DOTATATE/PET, and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression. RESULTS We included 46 patients with 49 tumors. Mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029) whereas MRI was not. 20/20 patients (100%) with negative PET findings remained recurrence-free. Location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032). CONCLUSION Our data show that 68Ga-DOTATATE/PET is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas.

Performance of plasma Aβ42/40, measured using a fully automated immunoassay, across a broad patient population in identifying amyloid status

BackgroundPlasma biomarkers have emerged as promising screening tools for Alzheimer’s disease (AD) because of their potential to detect amyloid β (Aβ) accumulation in the brain. One such candidate is the plasma Aβ42/40 ratio (Aβ42/40). Unlike previous research that used traditional immunoassay, recent studies that measured plasma Aβ42/40 using fully automated platforms reported promising results. However, its utility should be confirmed using a broader patient population, focusing on the potential for early detection.MethodsWe recruited 174 participants, including healthy controls (HC) and patients with clinical diagnoses of AD, frontotemporal lobar degeneration, dementia with Lewy bodies/Parkinson’s disease, mild cognitive impairment (MCI), and others, from a university memory clinic. We examined the performance of plasma Aβ42/40, measured using the fully automated high-sensitivity chemiluminescence enzyme (HISCL) immunoassay, in detecting amyloid-positron emission tomography (PET)-derived Aβ pathology. We also compared its performance with that of Simoa-based plasma phosphorylated tau at residue 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL).ResultsUsing the best cut-off derived from the Youden Index, plasma Aβ42/40 yielded an area under the receiver operating characteristic curve (AUC) of 0.949 in distinguishing visually assessed 18F-Florbetaben amyloid PET positivity. The plasma Aβ42/40 had a significantly superior AUC than p-tau181, GFAP, and NfL in the 167 participants with measurements for all four biomarkers. Next, we analyzed 99 participants, including only the HC and those with MCI, and discovered that plasma Aβ42/40 outperformed the other plasma biomarkers, suggesting its ability to detect early amyloid accumulation. Using the Centiloid scale (CL), Spearman’s rank correlation coefficient between plasma Aβ42/40 and CL was -0.767. Among the 15 participants falling within the CL values indicative of potential future amyloid accumulation (CL between 13.5 and 35.7), plasma Aβ42/40 categorized 61.5% (8/13) as Aβ-positive, whereas visual assessment of amyloid PET identified 20% (3/15) as positive.ConclusionPlasma Aβ42/40 measured using the fully automated HISCL platform showed excellent performance in identifying Aβ accumulation in the brain in a well-characterized cohort. This equipment may be useful for screening amyloid pathology because it has the potential to detect early amyloid pathology and is readily applied in clinical settings.

Postoperative [68Ga]Ga-DOTA-TATE PET/CT imaging is prognostic for progression-free survival in meningioma WHO grade 1

PurposeTumor resection represents the first-line treatment for symptomatic meningiomas, and the extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. In this preliminary study, we evaluate the prognostic relevance of postoperative PET for progression-free survival in meningiomas.MethodsWe conducted a post hoc analysis on a prospective patient cohort with resected meningioma WHO grade 1. Patients received postoperative MRI and [68Ga]Ga-DOTA-TATE PET/CT and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression.ResultsWe included 46 patients with 49 tumors. The mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029), whereas MRI was not. 20 out of 20 patients (100%) with negative PET findings remained recurrence-free. The location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032).ConclusionOur data show that [68Ga]Ga-DOTA-TATE PET/CT is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas.

Lessons from a 3-Year Review of PSMA PET-CT in a Tertiary Setting: Can We Fine Tune Referral Criteria by Identifying Factors Predicting Positivity and Negativity?

To draw inferences from a retrospective evaluation of PSMA PET CT scans performed for the evaluation of biochemical recurrence. A retrospective analysis of 295 PSMA PET CT scans spanning 3 years between 2020 and 2022 was undertaken. Of 295 PET CT scans, 179 were positive, 66 were negative and 50 had indeterminate findings. In the positive group, 67 had radical prostatectomy and PSMA avid lesions were seen most commonly in pelvic lymph nodes. The remaining 112 positive scans were in the non-radical prostatectomy group; 25 had recurrence only in the prostate, 17 had recurrence involving the prostate bed; 28 had no recurrence in the prostate gland, while 42 had recurrence in the prostate as well as in extra-prostatic sites. Overall, in the non-prostatectomy group, 75% of the population was harboring a PSMA avid lesion in the prostate gland while in the remaining 25% of the population, recurrence did not involve the prostate gland. The majority of indeterminate findings were seen in small pelvic or retroperitoneal lymph nodes or skeletal regions (ribs/others) and in nine patients indeterminate focus was seen in the prostate bed only. Follow-up PSMA PET CT was helpful in prior indeterminate findings and unexplained PSA rise. A higher recurrence in the prostate bed while evaluating biochemical recurrence prompts the following: question: should prostatectomy be offered more proactively? Follow-up PSMA PET CT is helpful for indeterminate findings; a PSA rise of 0.7 ng/mL in 6 months can result in positive PSMA PET CT while negative scans can be seen up to a 2 ng/mL PSA rise in 6 months.

18F]FDG PET-MRI provides survival biomarkers in primary central nervous system lymphoma in the elderly: an ancillary study from the BLOCAGE trial of the LOC network.

Primary central nervous system lymphoma (PCNSL) incidence is rising among elderly patients, presenting challenges due to poor prognosis and treatment-related toxicity risks. This study explores the potential of combining [18F]fluorodeoxyglucose ([18F]FDG) PET scans and multimodal MRI for improving management in elderly patients with de novo PCNSL. Immunocompetent patients over 60years with de novo PCNSL were prospectively enrolled in a multicentric study between January 2016 and April 2021. Patients underwent brain [18F]FDG PET-MRI before receiving high-dose methotrexate-based chemotherapy. Relationships between extracted PET (metabolic tumor volume (MTV), sum of MTV for up to five lesions (sumMTV), metabolic imaging lymphoma aggressiveness score (MILAS)) and MRI parameters (tumor contrast-enhancement size, cerebral blood volume (CBV), cerebral blood flow (CBF), apparent diffusion coefficient (ADC)) and treatment response and outcomes were analyzed. Of 54 newly diagnosed diffuse large B-cell PCNSL patients, 52 had positive PET and MRI with highly [18F]FDG-avid and contrast-enhanced disease (SUVmax: 27.7 [22.8-36]). High [18F]FDG uptake and metabolic volume were significantly associated with low ADCmean values and high CBF at baseline. Among patients, 69% achieved an objective response at the end of induction therapy, while 17 were progressive. Higher cerebellar SUVmean and lower sumMTV at diagnosis were significant predictors of complete response: 6.4 [5.7-7.7] vs 5.4 [4.5-6.6] (p = 0.04) and 5.5 [2.1-13.3] vs 15.9 [4.2-19.5] (p = 0.01), respectively. Two-year overall survival (OS) was 71%, with a median progression-free survival (PFS) of 29.6months and a median follow-up of 37months. Larger tumor volumes on PET or enhanced T1-weighted MRI were significant predictors of poorer OS, while a high MILAS score at diagnosis was associated with early death (< 1year). Baseline cerebellar metabolism and sumMTV may predict response to end of chemotherapy in PCNSL. Tumor volume and MILAS at baseline are strong prognostic factors.

Unsupervised [18F]Flortaucipir cutoffs for tau positivity and staging in Alzheimer’s disease

PurposeSeveral [18F]Flortaucipir cutoffs have been proposed for tau PET positivity (T+) in Alzheimer’s disease (AD), but none were data-driven. The aim of this study was to establish and validate unsupervised T+ cutoffs by applying Gaussian mixture models (GMM).MethodsAmyloid negative (A−) cognitively normal (CN) and amyloid positive (A+) AD-related dementia (ADRD) subjects from ADNI (n=269) were included. ADNI (n=475) and Geneva Memory Clinic (GMC) cohorts (n=98) were used for validation. GMM-based cutoffs were extracted for the temporal meta-ROI, and validated against previously published cutoffs and visual rating.ResultsGMM-based cutoffs classified less subjects as T+, mainly in the A− CN (<3.4% vs >28.5%) and A+ CN (<14.5% vs >42.9%) groups and showed higher agreement with visual rating (ICC=0.91 vs ICC<0.62) than published cutoffs.ConclusionWe provided reliable data-driven [18F]Flortaucipir cutoffs for in vivo T+ detection in AD. These cutoffs might be useful to select participants in clinical and research studies.

Genetic risk scores enhance the diagnostic value of plasma biomarkers of brain amyloidosis.

Blood-based biomarkers offer strong potential to revolutionize diagnosis, trial enrolment and treatment monitoring in Alzheimer's disease (AD). However, further advances are needed before these biomarkers can achieve wider deployment beyond selective research studies and specialty memory clinics, including the development of frameworks for optimal interpretation of biomarker profiles. We hypothesized that integrating Alzheimer's disease genetic risk score (AD-GRS) data would enhance the diagnostic value of plasma AD biomarkers by better capturing extant disease heterogeneity. Analysing 962 individuals from a population-based sample, we observed that an AD-GRS was independently associated with amyloid PET levels (an early marker of AD pathophysiology) over and above APOE ε4 or plasma p-tau181, amyloid-β42/40, glial fibrillary acidic protein or neurofilament light chain. Among individuals with a high or moderately high plasma p-tau181, integrating AD-GRS data significantly improved classification accuracy of amyloid PET positivity, including the finding that the combination of a high AD-GRS and high plasma p-tau181 outperformed p-tau181 alone in classifying amyloid PET positivity (88% versus 68%; P = 0.001). A machine learning approach incorporating plasma biomarkers, demographics and the AD-GRS was highly accurate in predicting amyloid PET levels (90% training set; 89% test set) and Shapley value analyses (an explainer method based in cooperative game theory) indicated that the AD-GRS and plasma biomarkers had differential importance in explaining amyloid deposition across individuals. Polygenic risk for AD dementia appears to account for a unique portion of disease heterogeneity, which could non-invasively enhance the interpretation of blood-based AD biomarker profiles in the population.

Prospective evaluation of the utility of concurrent 18F-FDG PET/CT and 68Ga-DOTA-TOC imaging in gastroenteropancreatic neuroendocrine neoplasms (GEPNENs): The PETNET study.

4022 Background: Somatostatin receptor imaging (SRI) is a standard of care for patients with GEPNETs. The additional value of concurrent 18F-FDG PET/CT (FDG PET) remains unclear. We reviewed a prospective functional imaging study to determine the utility of FDG PET in GEPNENs. Methods: PETNET is a prospective study in British Columbia, Canada, which provides all 68Ga-DOTA-TOC (DOTA PET) imaging in the province. Every patient receives a DOTA PET scan and an FDG PET within 30 days. PETNET enrolls all patients with an indication for SRI. Scans are ordered per treating physician discretion at any point in the disease course. This abstract focuses on the WD-GEPNEN population. Only the first dual functional imaging scans were analyzed and FDG was interpreted qualitatively (positive/negative). Results: From 04/2017-01/2023, 375 patients with NEN were enrolled, 165 (44%) with metastatic GEPNENs. Baseline characteristics are described. Median time between scans was 4 days (IQR 1-11). The proportion of patients with positive FDG PET at baseline increased with WHO grade. For patients with well differentiated G1 to G3 GEPNENs (N=161), overall survival was significantly lower with a positive FDG PET (HR: 4.22; 95%CI 1.61-11.02 p=0.001). FDG remained prognostic when G3 tumors were excluded (N=148) (HR 3.52; 95%CI 1.32-9.42 p= 0.007). When analyzing dual tracer PET imaging, patients with DOTA+/FDG- had reduced risk of dying in comparison with DOTA+/FDG+ (HR:0.26; 95%CI 0.09-0.67 p=0.01). After multivariate analysis, FDG positivity remained independently associated with reduced survival (HR 2.87; 95%CI 1.06-7.75 p=0.04) when controlling for grade of tumor and age. Conclusions: In this prospective cohort of metastatic GEPNENs, a positive FDG PET was significantly associated with reduced overall survival. These results provide additional evidence to support dual tracer functional imaging use in metastatic well differentiated GEPNEN’s. [Table: see text]

False positive PET scan in patients with treated malignancy following COVID-19 vaccination.

e18698 Background: The COVID-19 pandemic led to mass vaccination across the globe and resulted in several unintended consequences, one of which being reactive lymphadenopathy mimicking malignancy. A large study reported hypermetabolic lymphadenopathy (HLN) in over 45% of patients after receiving at least one dose of COVID-19 vaccine. A study on breast cancer patients noted a near-400% increase in lymphadenopathy on MRI and ultrasonography over the two years prior to mass vaccination. These findings present a dilemma in patients with treated malignancy while under surveillance. As vaccination became more commonplace, a case series reported on patients with PET-detected lymphadenopathy, with biopsies confirming VRLN. These investigations contributed to general recommendations on the importance of clinical context in patient care after COVID-19 vaccination. We present a unique study that evaluates patients with treated solid and hematological malignancies that presented with HLN after COVID-19 vaccination which emphasizes the importance of clinical acumen in the management of oncological patients in the pandemic era. Methods: We identified 6 patients aged 39-95 with prior malignancy. 5 were diagnosed with metastatic melanoma, and one had a diagnosis of high-grade B-cell lymphoma. Patients were managed with chemotherapy, immunotherapy, surgery, radiotherapy, or a combination of modalities, and were in complete radiological remission. All patients received at least two doses of a COVID-19 vaccine, with one dose at least three weeks prior to a routine surveillance PET-CT. Each patient exhibited HLN. Results: Of six patients, three underwent biopsy. There was no evidence of malignancy in any biopsy, and VRLN was confirmed. The remaining patients were followed with surveillance, and all had resolution of HLN without intervention. Time between COVID-19 vaccination and PET evidence of HLN ranged from 19 to 232 days. Time between first positive and first resolved PET ranged from 92 to 463 days. All patients were alive at the time of abstract submission. Conclusions: Our study emphasizes the importance of a focused history when suspecting recurrent malignancy, especially after sustained remission in our vulnerable populations. Acknowledging that COVID-19 vaccination can lead to HLN is becoming more common, and we show that this can occur, persist, and resolve even months after vaccination. While high suspicion for recurrence should be maintained, all efforts should be taken to protect patients and prevent unnecessary procedures. Records of recent vaccinations should be available and reviewed prior to radiological studies and clinical decisions, which can reduce avoidable interventions and harm. Surveillance of our patients proved to be an appropriate approach, and our study shows that similar patient presentations can have different paths of care depending on the awareness of treating physicians.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Patients (pts) with cHL with slow early response (SER) to initial chemotherapy (chemo) have a high risk of relapse. Current treatments such as chemo dose intensification and radiotherapy (RT) can increase the risk of secondary malignancies and cause long-term toxicity. KEYNOTE-667 (NCT03407144) is an open-label, phase 2 study being conducted to evaluate pembrolizumab (pembro) plus chemo in pts with cHL and SER to front-line chemo. We present results of an interim analysis of pts with high-risk cHL and SER (group 2). Methods: Pts eligible for group 2 were aged 3–17 (children) or 18–25 y (young adults) with newly diagnosed high-risk (stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB) cHL. Pts in group 2 received induction therapy with 2 cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Response was then assessed by PET/MRI/CT. Pts with rapid early response to OEPA received nonstudy therapy and pts with SER to OEPA (Deauville score, 4/5) received consolidation with 4 cycles of cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28) plus pembro 2 mg/kg up to 200 mg IV Q3W (3–17 y) or 200 mg IV Q3W (18–25 y). After consolidation, pts with PET positivity (Deauville score, 4/5 at late response assessment [LRA]) received involved-site RT (28.8 Gy) to late PET-positive residua. RT was omitted in pts with PET negativity. All pts with SER continued to receive pembro Q3W for 17 doses. The primary end point was ORR in pts with SER by blinded independent central review (BICR) per Cheson 2007 International Working Group criteria. Secondary end points included PET negativity at LRA and safety. Results: 49 pts with high-risk cHL with SER to OEPA were included in group 2. The median age was 15 y (range, 6–22), 24 pts (49%) had bulky disease, and 31 (63%) had Ann Arbor stage IV disease. At data cutoff (2 September 2022), the median follow-up was 15.3 mo (range, 3.2–30.5); 22 pts (45%) had completed treatment and 24 (49%) were ongoing on consolidation/maintenance. Median time on pembrolizumab was 10.4 mo (range, 0.5–11.8). 42 pts (86%) had an LRA, of whom 27 (64%) were PET negative by BICR (30 pts [71%] were PET negative by investigator review). Adverse events (AEs) occurred in 42 pts (86%), with grade 3/4 AEs in 13 pts (27%). Serious AEs were reported in 7 pts (14%). No pts died because of an AE. Treatment-related AEs occurred in 30 pts (61%), with grade 3/4 treatment-related AEs in 6 pts (12%). 4 pts (8%) had immune-mediated AEs: 2 grade 1 hypothyroidism and 2 grade 2 hypothyroidism. Conclusions: The results showed that pembro plus COPDAC-28 consolidation had manageable safety and promising efficacy in children and young adults with high-risk cHL and SER to front-line chemo. 64% of pts with a LRA had a PET-negative response and were spared RT. These findings suggest that adding pembro to COPDAC-28 consolidation may augment responses in this high-risk cHL population. Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Keywords: Hodgkin lymphoma, immunotherapy Conflicts of interests pertinent to the abstract L. Vinti Consultant or advisory role: Amgen, Clinigen Research funding: Merck, Sharp & Dohme Educational grants: Takeda, Neon Other remuneration: Amgen, Takeda F. Fagioli Employment or leadership position: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Consultant Or Advisory Role: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Honoraria: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Educational Grants: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Other Remuneration: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi D. Plaza Lopez de Sabando Research funding: MERCK J. Landman-Parker Research funding: BMS, MSD J. Shen Employment or leadership position: Merck P. Pillai Employment or leadership position: Merck Stock ownership: Merck P. Marinello Employment or leadership position: Merck Stock ownership: Merck C. Mauz-Koerholz Consultant or advisory role: MSD Research funding: MSD

COMBINED USE OF MINIMAL RESIDUAL DISEASE MONITORING AND FDG‐PET FOR OUTCOME PREDICTION IN FOLLICULAR LYMPHOMA: RESULTS FROM THE FONDAZIONE ITALIANA LINFOMI (FIL) FOLL12 TRIAL

Introduction: In follicular lymphoma (FL), FDG-PET is routinely employed to evaluate response at the end of induction (EoI), while minimal residual disease (MRD) analysis is highly reliable in predicting relapse over the entire disease history. Nonetheless, scant data are available describing the integration of these powerful prognostic tools for response evaluation in FL. This issue was investigated in the phase III FIL “FOLL12” trial [Luminari, JCO 2022]. Methods: Only patients with an available molecular marker for MRD and centrally reviewed EoI PET were included. MRD was systematically assessed by RQ-PCR with BCL2::IGH consensus primers in peripheral blood (PB) and bone marrow (BM), as previously reported with inferior follow-up [Ladetto ASH 2021]. PET scans were classified according to Deauville score (DS) criteria: DS1–3 was negative and DS4–5 positive. Results: Overall, 394 patients out of 780 were included (51%), as expected based on the MRD marker availability. These patients had a slightly better outcome than excluded cases (CR rate 82% vs. 73%, p = 0.003, 5y PFS 66% vs. 61%, p = 0.046). At EoI, both BM MRD and PET positivity were independent predictors of poor PFS in multivariate analysis (HR 1.66, CI: 1.01–2.71 and HR 2.03, CI: 1.30–3.18). The 68 discordant cases (i.e., MRD+/PET− or MRD−/PET+) showed an intermediate outcome (PFS HR 1.93, CI: 1.28–2.92) between the 314 double negative (reference) and the 10 double positive ones (HR 6.22, CI: 2.99–12.9), Figure 1A. Moreover, both EoI PET+ and the persistence/reappearance of MRD positivity in BM during the 18 months of rituximab maintenance/observation were independently associated to a higher risk of POD24 (HR 5.61, CI: 2.59–12.1, and HR 2.37, CI: 1.15–4.84, respectively). On the other hand, MRD kinetic analysis by non-invasive PB sampling during the rituximab maintenance/observation period substantially updated the risk status over PET results. Indeed, the marginal PFS HR for an MRD+ after an EoI PET negative result increased from 1.36 (CI: 0.47–3.96) at 6 months, to 2.09 (CI: 1.01–4.18) at 12 months, up to 3.60 (CI: 2.30–5.64) at 24 months (Figure 1B, blue curve). This means that patients scoring PET- at EoI but showing a persistent or reappearing MRD+ signal during the following 24 months had a dismal PFS, superimposable to that of PET+ patients (Figure 1C). Accordingly, in landmark multivariate analysis PB MRD+ either at 12 or 24 months predicted adverse PFS (HR 3.79, CI: 1.60–8.96 and HR 5.21, CI: 1.88–14.4, respectively), independently from EoI PET result. Keywords: indolent non-Hodgkin lymphoma, minimal residual disease, PET-CT Conflicts of interests pertinent to the abstract S. Ferrero Consultant or advisory role: Janssen, EUSA Pharma, Abbvie, Incyte, Clinigen, Sandoz, Italfarmaco Honoraria: Janssen, EUSA Pharma, Servier, Gentili Research funding: Morphosys, Janssen, Gilead, Beigene Educational grants: Takeda, Janssen, EUSA Pharma