Fluorodeoxyglucose Positron Emission Research Articles

Clinical Validation and Correlates of the Cingulate Island Sign Visual Rating Scale for the Diagnosis of Dementia with Lewy Bodies

AbstractBackgroundThe cingulate island sign (CIS) is a metabolic pattern on [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) associated with dementia with Lewy bodies (DLB). The aim of this study was to validate the visual CIS rating scale (CISRs) for the diagnosis of DLB and to explore the clinical correlates.MethodThis single‐center, retrospective study included 166 consecutive patients with DLB and 161 patients with Alzheimer’s disease (AD). The CIS on [18F]FDG‐PET scans was rated using the CISRs (0‐4) independently by three readers blinded to other patient data.ResultThe optimal cut‐off to differentiate DLB from AD was a CISRs score ≥ 1 (sensitivity = 66%, specificity = 84%) whereas a CISRs score ≥ 2 (sensitivity = 58%, specificity = 92%) was optimal to differentiate amyloid positive DLB (n = 43 (82.7%)) and AD. To identify DLB with abnormal (n = 53 (72.6%)) versus normal (n = 20 (27.4%)) dopamine transporter imaging (DaT), a CISRs cut‐off of 4 had a specificity of 95% for abnormal DaT. DLB patients with a CISRs score of 4 performed significantly better in tests of free verbal recall and picture based cued recall, but worse in test of processing speed compared with DLB with a CISRs score of 0.ConclusionThis study confirms the CISRs as a valid marker for the diagnosis of DLB with a high specificity and a lower, but acceptable, sensitivity. Concomitant AD pathology does not influence diagnostic accuracy of the CISRs. In DLB patients, presence of CIS is associated with relative preserved memory function and impaired processing speed.

Synthetic FDG‐PET hypometabolism sensitivity validation in AD

AbstractBackgroundThe availability of 18‐F fluorodeoxyglucose positron emission tomography (FDG‐PET) is not universal. We hypothesized that synthetically generated FDG‐PET images would be as sensitive to detecting the pattern of hypometabolism associated with AD as real images.MethodWe developed a deep learning‐based method to produce synthetic FDG‐PET images from 1,828 T1‐weighted MRI / real FDG‐PET image pairs from the ADNI dataset, and validated the technique on a further 284 image pairs. The technique generated synthetic FDG‐PET images which were then processed to compare Standardized Uptake Value Ratio (SUVR) with the pons as reference in 81 brain regions as defined in the Desikan‐Killiany‐Tourville and subcortical default FreeSurfer atlases.ResultWe tested the differences between synthetic and real FDG‐PET on 745 image pairs (205 controls, 365 mild cognitive impairment (MCI) and 175 AD)(Table 1). Correlations in SUVR values between synthetic and real FDG‐PET ranged between weak (r = 0.13) to strong (r = 0.63), with moderate results in key regions for AD (bilateral precuneus, r = 0.43; bilateral posterior cingulate, r = 0.37). There were significant between‐group (control vs MCI and control vs AD) differences in SUVR values for all regions between synthetic and real PET‐FDG (Figure 1) with synthetic FDG‐PET having lower values. Inter‐group effect sizes were not significantly different in the majority of brain regions (76/81)(Figure 2), with similar effect sizes in the right precuneus (synthetic: ‐0.98 vs original: ‐1.37), left (‐0.77 vs ‐1.0459) and right (‐0.80 vs ‐1.04) posterior cingulate, but different for the left precuneus (‐0.91 vs ‐1.33).ConclusionSynthetic images would increase patients’ accessibility to a meaningful modality for disease assessment while decreasing their exposure to radiation and resources in the health care system.

Neurofunctional Correlates of Activities of Daily Living in Patients with Posterior Cortical Atrophy

AbstractBackgroundResearch on posterior cortical atrophy (PCA) has concentrated on cognitive decline, especially visual processing deficits. However, few studies have focused on the activities of daily living (ADL), and no study has investigated the neurometabolic basis of ADL impairments. We aimed to identify regions of hypometabolism associated with ADL in PCA patients.MethodTwenty‐nine PCA patients, 35 typical Alzheimer’s disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed a scale for total ADL [TADL, including basic ADL (BADL) and instrumental ADL (IADL) subscales] and 18F fluorodeoxyglucose positron emission tomography. Voxel‐wise multivariable regression analysis was conducted at the level of the whole‐brain, PCA‐related hypometabolism patterns, and PCA‐specific hypometabolism patterns.ResultThe general cognitive status of PCA patients was similar to tAD patients; however, they performed worse in TADL, BADL, and IADL. In all analysis levels, TADL was associated with the bilateral parietal lobe, including the right superior parietal lobe, right inferior parietal cortex, right angular gyrus, and left superior parietal lobe. BADL was associated with the bilateral parietal lobe located in the right superior parietal lobe, right inferior parietal cortex, and left superior parietal lobe. IADL was associated with the bilateral superior parietal lobe. Bilateral superior parietal lobe hypometabolism was associated with TADL, BADL, and IADL.ConclusionHypo‐metabolism in the bilateral superior parietal lobes contributes to the decline of ADL in PCA, which is a promising target for future non‐invasive neuromodulation interventions.

Characterizing the effects of COVID‐19 on the brain using FDG PET imaging before and after COVID‐19 infection

AbstractBackgroundIndividuals diagnosed with COVID‐19 have been found to have changes in brain structure as well as dramatic neuropsychiatric effects such as dementia, Parkinsonism, and greater likelihood of stroke (Taquet, 2021). Infection has also been shown to result in hypometabolic changes on 18F ‐fluorodeoxyglucose positron emission tomography (FDG PET) when compared to normal controls (Guedj, 2021). This study will seek to determine which brain regions are most affected by COVID‐19 with FDG PET. To our knowledge, we are the first study to compare pre‐ and post‐infection FDG PET imaging within patients. These patients were coincidentally infected with COVID‐19 between standard of care longitudinal FDG PET imaging for cancer.MethodPatients with COVID‐19 who had FDG PET imaging that included the brain before and after serologic COVID‐19 diagnosis were identified from an internal COVID‐19 registry. Clinical data was mined from the electronic health record. Images were processed with well‐established SPM12 methods (Friston, 1995). A voxel‐wise ANCOVA was performed on FDG PET images before and after COVID‐19 infection, including covariates of age, sex, ethnicity, and time between chemotherapy and follow‐up imaging using p < 0.001 and voxel extent threshold of 10.Result29 patients met inclusion criteria (Table 1). Compared to baseline, 4 clusters of voxels were significantly decreased after COVID‐19 infection in the temporal lobes, anterior cingulate gyrus, and superior cerebellum (Table 2). In a post‐hoc analysis, spherical regions of interest (radius = 5 mm) surrounding these clusters were tested for post‐infection hypometabolism. The bilateral temporal lobes, anterior lobe of cerebellum, and right caudate head showed significant decrease in glucose metabolism following COVID‐19 infection (p < 0.05).ConclusionCurrently, this is the first study to leverage a pre‐COVID‐19 infection FDG PET for comparison to imaging post‐infection. We discovered regions in the temporal lobe, frontal lobe, and cerebellum that showed hypometabolic changes following infection, important for determining spatial localization of the effects of this viral infection.

Characterizing the effects of chemotherapy on the brain of patients with head and neck cancer using FDG PET

AbstractBackgroundChemotherapy has known adverse effects on the brain. From small (N<30) studies primarily in breast cancer, we know that post‐chemotherapy brain changes can be detected with 18F ‐fluorodeoxyglucose positron emission tomography (FDG PET), but this has been relatively unexplored in other cancers, and has not been explored in patients with head and neck cancer (HNCa) (Chen, 2018). Patients with HNCa have 2‐3 times the risk of dementia after therapy compared to controls and may be particularly vulnerable given underlying lower levels of education and heavy tobacco and alcohol use (Zer, 2018). We will determine which areas of the brain are most vulnerable to the chemotherapy in HNCa with FDG PET.MethodPatients with HNCa were identified from Vanderbilt’s Cancer Registry, limited to patients with FDG PET in the last year (2021). Clinical data was mined from the electronic health record. Images were processed with well‐established SPM12 methods (Friston, 1995). A voxel‐wise ANCOVA was performed on FDG PET images before and after chemotherapy, including covariates of age, sex, ethnicity, and time between chemotherapy and follow‐up imaging using conservative family wise error of <0.05 and voxel extent threshold of 10.Result68 patients with HNCa met inclusion criteria and all patients received Carboplatin‐based chemotherapy (Table 1). Compared to baseline, 17 clusters met conservative significance thresholds with decreases in glucose metabolism following treatment (Figure 1). These included large regions (46397 1.5mm3 voxels) in the frontal and temporal lobes (pFWE = <0.001). Specifically, there was significantly decreased glucose metabolism in the dorsolateral prefrontal cortex (BA 9), frontoparietal cortex (BA 10), orbital frontal cortex (BA 11), medial and superior temporal gyri (BA 21, 22), dorsal (BA 24), and the subgenual (BA 25), pregenual (BA 32), and rostral (BA 33) anterior cingulate cortex post‐chemotherapy.ConclusionTo our knowledge, this is the first study to explore the effects of chemotherapy in HNCa, a population particularly vulnerable to these effects. We found that regions in the forebrain and temporal lobes are most vulnerable. Studies like these are important to establish and confirm spatial distributions of these effects which will be crucial for development of diagnostics and monitoring tools for these effects.

Catalan Early Onset Dementia Network 2021 Report

AbstractBackgroundThe Catalan Early Onset Neurodegenerative Dementia Network is a multicenter project launched in 2020 with the aim of understanding the epidemiology and clinical care of people with early‐onset neurodegenerative dementia and their caregivers.MethodsNeurologists and geriatricians visiting patients with cognitive impairment in Catalonia were invited to prospectively collect demographical and clinical data from patients with age at onset (AAO) less than 65 years visited during the year 2021.ResultWe registered information of 1221 subjects from 14 centers. Mean age was 56,2 years (SD 8.7), 64% were woman. Mean age at symptom onset was 53,9 years (SD 9.1). The most frequent cognitive symptoms at onset were memory impairment (72,9%) and dysexecutive difficulties (21,8%). Mean Mini Mental State Examination (MMSE) score was 26,7 (range 7‐30). Initial clinical diagnose was a non‐neurodegenerative disorder in 81,4% of cases and a neurodegenerative disorder in 17,81%. Genetic counseling accounted for 0,8% of visits. The suspected non‐neurodegenerative and neurodegenerative patients were studied with a neuropsychological test (85,5% vs 86,7%, respectively), magnetic resonance imaging (MRI) (39,9% vs 55,6%), computerized tomography (CT) scan (33,2% vs 34,4%), fluorodeoxyglucose positron emission tomography (FDG‐PET) (6,8% vs 39,0%), amyloid‐PET (3,9% vs 34,4%) and lumbar puncture (7,1%, vs 44,8%). 16,6% of participants had a final diagnose of a neurodegenerative cognitive disorder (10,9% Alzheimer’s disease, 2,3% frontotemporal lobular degeneration, 2,1% MCI of suspected neurodegenerative etiology, 0,58% other neurodegenerative dementias); 83,4% were diagnosed with a non‐degenerative disorder (28,4% subjective cognitive decline (SCD), 25,0% mild cognitive impairment of non‐neurodegenerative etiology, 19,8% cognitive impairment after Covid‐19, 10,2% other dementias). Diagnostic delay was higher for neurodegenerative disorders (17 months: median 12 months (interquartile range (IQR) 19) between AAO and first visit +5 months (IQR 8) between first visit and diagnose) than non‐degenerative disorders (12 months: 9 months (IQR 19,6) + 3 months (IQR 7) respectively).ConclusionOf 1221 patients under 65 years old visited in cognitive disorders units, only 16,6% had a final diagnose of neurodegenerative cognitive disorder. More than a quarter of subjects were diagnosed as SCD and a fifth as cognitive impairment after Covid‐19. In 2021, diagnosis delay was higher in neurodegenerative disorders (median 17 months).

Characterizing the effects of COVID‐19 on the brain using FDG PET imaging before and after COVID‐19 infection

AbstractBackgroundIndividuals diagnosed with COVID‐19 have been found to have changes in brain structure as well as dramatic neuropsychiatric effects such as dementia, Parkinsonism, and greater likelihood of stroke (Taquet, 2021). Infection has also been shown to result in hypometabolic changes on 18F ‐fluorodeoxyglucose positron emission tomography (FDG PET) when compared to normal controls (Guedj, 2021). This study will seek to determine which brain regions are most affected by COVID‐19 with FDG PET. To our knowledge, we are the first study to compare pre‐ and post‐infection FDG PET imaging within patients. These patients were coincidentally infected with COVID‐19 between standard of care longitudinal FDG PET imaging for cancer.MethodPatients with COVID‐19 who had FDG PET imaging that included the brain before and after serologic COVID‐19 diagnosis were identified from an internal COVID‐19 registry. Clinical data was mined from the electronic health record. Images were processed with well‐established SPM12 methods (Friston, 1995). A voxel‐wise ANCOVA was performed on FDG PET images before and after COVID‐19 infection, including covariates of age, sex, ethnicity, and time between chemotherapy and follow‐up imaging using p < 0.001 and voxel extent threshold of 10.Result29 patients met inclusion criteria (Table 1). Compared to baseline, 4 clusters of voxels were significantly decreased after COVID‐19 infection in the temporal lobes, anterior cingulate gyrus, and superior cerebellum (Table 2). In a post‐hoc analysis, spherical regions of interest (radius = 5 mm) surrounding these clusters were tested for post‐infection hypometabolism. The bilateral temporal lobes, anterior lobe of cerebellum, and right caudate head showed significant decrease in glucose metabolism following COVID‐19 infection (p < 0.05).ConclusionCurrently, this is the first study to leverage a pre‐COVID‐19 infection FDG PET for comparison to imaging post‐infection. We discovered regions in the temporal lobe, frontal lobe, and cerebellum that showed hypometabolic changes following infection, important for determining spatial localization of the effects of this viral infection.

Synthetic FDG‐PET hypometabolism sensitivity validation in AD

AbstractBackgroundThe availability of 18‐F fluorodeoxyglucose positron emission tomography (FDG‐PET) is not universal. We hypothesized that synthetically generated FDG‐PET images would be as sensitive to detecting the pattern of hypometabolism associated with AD as real images.MethodWe developed a deep learning‐based method to produce synthetic FDG‐PET images from 1,828 T1‐weighted MRI / real FDG‐PET image pairs from the ADNI dataset, and validated the technique on a further 284 image pairs. The technique generated synthetic FDG‐PET images which were then processed to compare Standardized Uptake Value Ratio (SUVR) with the pons as reference in 81 brain regions as defined in the Desikan‐Killiany‐Tourville and subcortical default FreeSurfer atlases.ResultWe tested the differences between synthetic and real FDG‐PET on 745 image pairs (205 controls, 365 mild cognitive impairment (MCI) and 175 AD)(Table 1). Correlations in SUVR values between synthetic and real FDG‐PET ranged between weak (r = 0.13) to strong (r = 0.63), with moderate results in key regions for AD (bilateral precuneus, r = 0.43; bilateral posterior cingulate, r = 0.37). There were significant between‐group (control vs MCI and control vs AD) differences in SUVR values for all regions between synthetic and real PET‐FDG (Figure 1) with synthetic FDG‐PET having lower values. Inter‐group effect sizes were not significantly different in the majority of brain regions (76/81)(Figure 2), with similar effect sizes in the right precuneus (synthetic: ‐0.98 vs original: ‐1.37), left (‐0.77 vs ‐1.0459) and right (‐0.80 vs ‐1.04) posterior cingulate, but different for the left precuneus (‐0.91 vs ‐1.33).ConclusionSynthetic images would increase patients’ accessibility to a meaningful modality for disease assessment while decreasing their exposure to radiation and resources in the health care system.

18F]FDG PET-MR characterization of aortitis in the IL1rn−/− mouse model of giant-cell arteritis

BackgroundMetabolic imaging is routinely used to demonstrate aortitis in patients with giant-cell arteritis. We aimed to investigate the preclinical model of aortitis in BALB/c IL1rn−/− mice using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography–magnetic resonance (PET-MR), gamma counting and immunostaining. We used 15 first-generation specific and opportunistic pathogen-free (SOPF) 9-week-old IL1rn−/− mice, 15 wild-type BALB/cAnN mice and 5 s-generation specific pathogen-free (SPF) 9-week-old IL1rn−/−. Aortic [18F]FDG uptake was assessed as the target-to-background ratio (TBR) using time-of-flight MR angiography as vascular landmarks.Results[18F]FDG uptake measured by PET or gamma counting was similar in the first-generation SOPF IL1rn−/− mice and the wild-type group (p > 0.05). However, the first-generation IL1rn−/− mice exhibited more interleukin-1β (p = 0.021)- and interleukin-6 (p = 0.019)-positive cells within the abdominal aorta than the wild-type mice. In addition, the second-generation SPF group exhibited significantly higher TBR (p = 0.0068) than the wild-type mice on the descending thoracic aorta, unlike the first-generation SOPF IL1rn−/− mice.ConclusionsIn addition to the involvement of interleukin-1β and -6 in IL1rn−/− mouse aortitis, this study seems to validate [18F]FDG PET-MR as a useful tool for noninvasive monitoring of aortitis in this preclinical model.

Neuroimaging Characteristics of Hearing Loss in the Mayo Clinic Study of Aging.

To investigate the association between standard pure tone and speech audiometry with neuroimaging characteristics reflective of aging and dementia in older adults. Prospective population-based study. Single tertiary care referral center. Participants from the Mayo Clinic Study of aging 60 years old or older with normal cognition or mild cognitive impairment, baseline neuroimaging, and a behavioral audiogram associated with neuroimaging were eligible for study. Imaging modalities included structural MRI (sMRI) and fluid-attenuated inversion recovery MRI (FLAIR-MRI; N = 605), diffusion tensor imaging MRI (DTI-MRI; N = 444), and fluorodeoxyglucose-positron emission tomography (FDG-PET; N = 413). Multivariable logistic and linear regression models were used to evaluate associations with neuroimaging outcomes. Mean (SD) pure tone average (PTA) was 33 (15) dB HL and mean (SD) word recognition score (WRS) was 91% (14). There were no significant associations between audiometric performance and cortical thinning assessed by sMRI. Each 10-dB increase in PTA was associated with increased likelihood of abnormal white-matter hyperintensity (WMH) from FLAIR-MRI (odds ratio 1.26, P = .02). From DTI-MRI, participants with <100% WRSs had significantly lower fractional anisotropy in the genu of the corpus callosum (parameter estimate [PE] -0.012, P = .008) compared to those with perfect WRSs. From FDG-PET, each 10% decrease in WRSs was associated with decreased uptake in the anterior cingulate cortex (PE -0.013, P = .001). Poorer audiometric performance was not significantly associated with cortical thinning but was associated with white matter damage relevant to cerebrovascular disease (increased abnormal WMH, decreased corpus callosum diffusion). These neuroimaging results suggest a pathophysiologic link between hearing loss and cerebrovascular disease.

Ultra Low Dose 4 Gy Radiation for Definitive Therapy of Gastric MALT Lymphoma

Introduction Definitive treatment for early-stage gastric MALT (mucosa-associated lymphoid tissue) lymphoma typically includes radiation therapy (RT) to doses of 24-30 Gy. Given the favorable prognosis of this disease, there is considerable interest in decreasing the toxicity profile of treatment. We prospectively investigated outcomes using a response-adapted (RA) approach giving an initial 4 Gy (ultra-low dose (ULD)) RT with an additional 20 Gy only for incomplete response (Figure 1). We hypothesized that this RA-approach would maintain excellent outcomes with limited toxicity. Methods We performed a single-arm prospective trial of ULD RT in 24 patients (age ≥18 years) with newly diagnosed or relapsed stage I-IV H. pylori (HP) negative gastric MALT lymphoma (NCT03680586). Patients with residual lymphoma after HP eradication were eligible. Patients with bulky disease (&amp;gt;10 cm) were excluded. Patients were treated with 4 Gy in 2 fractions and assessed with endoscopy and imaging at 3-4 months post-RT. Patients with a complete response (CR) assessed by endoscopy with biopsies and imaging were observed. Patients with a partial response (PR) by endoscopic, pathologic or radiographic evaluations were re-evaluated in 6-9 months. Biopsy-confirmed residual disease at the second timepoint (9-13 months) or stable disease (SD)/progressive disease (PD) at any time point prompted treatment with an additional 20 Gy in 10 fractions. Systemic therapy was permitted if clinically indicated. Results We enrolled 24 patients from 2019-2021. Median age was 67 (range 40-85) with 15 female patients (63%). Patients had stage I (n=20, 83%), II (n=1, 4%), and IV (n=3, 13%) disease. Of 15 tested patients, 4 were positive for t(11;18). Patients had pre-treatment imaging with fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) (n=21), contrasted CT (n=2), and contrasted magnetic resonance imaging (MRI) (n=1). Eight patients had prior treatment including systemic therapy (n=2, 8%) or antibiotics for HP positive (n=3, 13%) or HP negative (n=3, 13%) disease. Of 3 patients with prior HP positive disease, residual lymphoma was documented after eradication at 18 months (PR), 11 months (SD), and 8 months (disease relapse after CR) post-diagnosis. Median follow-up for the entire cohort was 34 months (95% CI 22-40) based on the reverse Kaplan-Meier estimator. Sixteen patients had a CR at first evaluation (3-4 months) after 4 Gy, and an additional 4 patients had disease conversion to CR at second evaluation (9-13 months), for a total of 20 patients (83%) who had a CR to 4 Gy at a median time of 4 months (range 3-12). No patients had positive imaging findings with a pathologic CR. One local relapse occurred 14 months post-treatment after a CR to 4 Gy. This patient received 20 Gy and again experienced a CR. Four patients received an additional 20 Gy for SD/PD or residual disease after 4 Gy. Two patients received 20 Gy for symptomatic SD at 3-4 months, both with a CR following RA therapy. Two patients received 20 Gy for residual disease at 10 and 13 months. One patient had a CR and one is pending last follow-up. Two of the 4 patients (50%) with a positive t(11;18) required an additional 20 Gy RT compared with 3 of 11 (27%) patients without the translocation (p=0.56) The rate of 3-year LC for 23 patients who had complete follow-up was 100%, with 19 of 24 patients (79%) with a CR at last follow-up after only the initial 4 Gy. One patient with stage IV disease experienced distant relapse with diffuse large B cell lymphoma and is in CR after systemic therapy. No additional patients received systemic therapy after RT. RT was well tolerated with no grade 3 or higher acute or late toxicities. Conclusions Most patients with gastric MALT lymphoma experienced a CR after only 4 Gy RT; for those requiring an additional 20 Gy with completed follow-up, all experienced a CR. This strategy could be considered to select only those patients who benefit from longer RT courses and spare most patients from unnecessary treatment toxicity. It is important to allow adequate time for response with this indolent disease. Additional follow-up is required to confirm long-term excellent outcomes with RA ULD treatment.

Importance of FDG-PET (Fluorodeoxyglucose Positron Emission Tomography) in Staging and Response Assessment of Hairy Cell Leukemia (HCL)

Alessandro Mancini and Luca De Carolis are Co-first authors. Nicodemo Baffa, Brunangelo Falini and Enrico Tiacci are Co-last authors. INTRODUCTION HCL is an indolent BRAF-mutated leukemia usually presenting with cytopenias, splenomegaly, little or no lymphadenopathy, heavy bone marrow (BM) infiltration and few circulating leukemic cells. Imaging exams for staging include abdominal echography and computed tomography (CT), while the role of PET is largely unknown. METHODS 84 patients (pts) with relapsed/refractory HCL participating to our clinical trials of BRAF inhibitor-based therapies prospectively underwent PET/CT pre- and post-treatment, in addition to usual examinations for response assessment. Since FDG uptake is normally higher in liver than spleen, BM and lymph nodes, uptake in the latter tissues was considered abnormal if equal to or higher than the liver. Splenomegaly was defined by a longest spleen diameter &amp;gt;13 cm on PET/CT. The standard definition of complete remission (CR) in HCL just requires no palpable splenomegaly on physical examination, in addition to resolution of cytopenias as well as no hairy cells visible in the blood smear and the BM biopsy by non-immunological stains. RESULTS Pre-therapy, 58/77 (75%) non-splenectomized pts showed abnormal splenic FDG uptake (maximal standardized uptake value/SUVmax: median 4.8, vs 3.9 for the liver), which was always diffuse without focal lesions. Conversely, focal splenic uptake is not infrequent in splenic marginal zone lymphoma (18%, 7/39 pts - Abdom Radiol 2018;43:2721; vs of 0/58 HCL pts, p=0.0003), which may aid in the differential diagnosis with this HCL-mimicker. Moreover, 14/58 (24%) HCL pts. with a PET+ spleen did not have splenomegaly, and splenic uptake returned to normal in 10/11 evaluable cases (91%) achieving at least a partial response post-therapy, which suggests leukemic spleen involvement even without splenomegaly. Abnormal diffuse BM uptake was observed in 41/82 evaluable pts (50%; median SUVmax 5, vs 3.4 for the liver). In these cases, leukemic involvement in the BM biopsy was greater (median 80%) than in the other 41 pts (median 65%; p-value &amp;lt;0.01), pointing to HCL infiltration as the cause of abnormal BM uptake rather than to reactive hyperplasia of non-involved BM. Post-therapy, pathologic spleen uptake normalized in 46/51 evaluable pts (90%), and their CR rate was higher (32/46 pts, 70%) than in the other 5 pts remaining PET+ (1/5, 20%; p=0.047). Among the 46 PET- cases, 31 (67%) were not splenomegalic while 15 (33%) had residual splenomegaly (up to 17 cm; Fig. 1A); interestingly, within PET- cases relapse-free survival (RFS) was similar not only in conventionally defined CR cases with (n=8) vs without (n=24) residual non-palpable splenomegaly (p=0.84 after a median follow-up of 19 months), but also when the 6 cases meeting all conventional CR criteria except for still palpable splenomegaly were added to the 8 CR pts with residual non-palpable splenomegaly (p=0.7 after a median follow-up of 20.5 months - Fig. 1B). These findings suggest that metabolic status reflects splenic HCL involvement more reliably than spleen size or palpability, a concept that could improve the current definition of CR in HCL. Abnormal BM uptake resolved after treatment in 34/37 evaluable pts (92%), and their CR rate was again higher (23/34, 68%) than in the other 3 pts remaining PET+ (0/3; p=0.047). Leukemic infiltration of the BM biopsy was lower in the 34 PET- vs the 3 PET+ pts (median 5% vs 70%-80%, respectively; p=0.0004), indicating that BM abnormal uptake reflects HCL infiltration load rather than reactive BM hyperplasia post-therapy. Finally, abnormal lymph node uptake was observed pre-therapy in 9/84 (11%) pts (median SUVmax 7.1, vs 3.4 for the liver) and normalized after treatment in 7/8 evaluable pts (88%), including one case with residual lymph node enlargement (2.2 cm); all these 7 pts had achieved a CR while the remaining pt had no response to therapy. CONCLUSIONS PET is potentially useful in the differential diagnosis with splenic marginal zone lymphoma and may aid in the clinical management of HCL pts by detecting metabolic involvement of the main disease sites even in the absence of organomegaly. Importantly, PET signal tracks with response to therapy even in case of persistent organomegaly, which may lead to refine the definition of CR in HCL.

EPCORE FL-1: Phase 3 Trial of Subcutaneous Epcoritamab with Rituximab and Lenalidomide (R 2) Vs R 2 Alone in Patients with Relapsed or Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including rituximab + lenalidomide (R 2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces potent and selective T-cell-mediated killing of malignant CD20 + B cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N=68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet 2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55-100) and complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R 2 for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%. Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1-2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management. These encouraging data, and the distinct mechanisms of action of epcoritamab and R 2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study. Study Design and Methods: EPCORE FL-1 (NCT05409066) is a global, randomized, open-label, multicenter phase 3 trial designed to evaluate efficacy and safety of epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL. Adult patients must have histologically confirmed classic FL (previously grades 1 to 3a FL) stage II, III, or IV with a CD20 + tumor on a representative biopsy based on local pathology report and no evidence of histologic transformation. Patients must have R/R disease after ≥1 prior anti-lymphoma regimen that contained an anti-CD20 monoclonal antibody in combination with chemotherapy; patients receiving only prior anti-CD20 monoclonal antibody monotherapy and/or radiation are not eligible. Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and ≥1 measurable disease site per Lugano 2014 criteria. Lenalidomide-refractory FL (best response to lenalidomide of stable or progressive disease or progressive disease within 6 months of completion of lenalidomide) is excluded. Approximately 520 patients will be enrolled and randomized 1:1 to receive a full dose of epcoritamab in combination with R 2 or R 2 alone ( Figure); the trial is currently enrolling in 2 arms, Arms A &amp; C. Based on emerging safety and efficacy data, Arm B has been closed to enrollment and the recommended dose of epcoritamab in combination with R 2 is 48 mg. Epcoritamab will be subcutaneously administered using a step-up dosing regimen to full dose in cycle 1 (28 days/cycle). Full dose of epcoritamab will be administered weekly in cycles 2-3 and monthly from cycle 4 onward for up to 12 cycles of treatment. Patients will be serially assessed for disease progression at prespecified intervals. The primary endpoint is progression-free survival assessed by independent review committee (IRC) per Lugano criteria. Key secondary efficacy endpoints include CR rate (by IRC per Lugano criteria), overall survival, and minimal residual disease negativity. Other efficacy endpoints include best overall response, duration of response, duration of complete response, time to progression, event-free survival, time to next anti-lymphoma treatment, and patient-reported outcomes. Safety endpoints include incidence and severity of treatment-emergent adverse events and adverse events of special interest. Exploratory endpoints include assessments of pharmacodynamic and pharmacokinetic data. The study opened for enrollment in 2022 in North America, South America, Europe, Africa, Asia, and Australia.

CART-AI-Radiomics: Survival and Neurotoxicity Prediction in B-Cell Lymphoma Patients Treated with CAR-T Cells through an Imaging Features-Based Model

Background: Despite clinical outcome improvements observed in relapsed/refractory (R/R) B-cell lymphoma patients (pts) treated with antigen receptor modified T-cells (CAR-T cells), a sizeable proportion still progress or relapse after infusion. Besides, this procedure is associated with significant morbidity primarily due to the immune effector cell-associated neurotoxicity syndrome (ICANS). The main goal of the CART-AI-Radiomics study is to apply artificial intelligence to develop new imaging-based prognostic and predictive models that integrate molecular and imaging biomarkers towards improved stratification of pts at high risk of R/R. In this sub-study, we retrospectively assessed the ability of imaging features and clinical data to predict survival and neurotoxicity. Methods: Consecutive pts diagnosed of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) treated with anti-CD19 CAR-T cells from 2019-2022 in Valencia Clinic Hospital and La Fe Hospital were included (cut-off date: July 2023). All the pre-infusion flourine18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18F-FDG PET/CT) scans and clinical data were collected. The volume of interest (VOI) was manually contoured for all visible lesions in the PET/CT imaging exams. A subsequent imaging features extraction was performed. Features included PET conventional parameters-maximum standardized uptake value (SUV max), metabolic tumor volume (MTV; defined as the volume of voxels with SUVs higher than the threshold of 41% × SUV max) and total lesion glycolysis (TLG)-and radiomic features. Imaging parameters were calculated for all lesions (total) and for the dominant lesion (DL), whereas clinical variables were measured before lymphodepletion (LD). Univariate and multivariate analyses were carried out using Cox proportional-hazards models for survival prediction and logistic regression for neurotoxicity assessment. Survival analyses were conducted according to MTV total values. Results: A total of 29 pts (median age 63.2 [range 21.8-79.3] years; 18 [62.1%] females) who received CAR-T cell therapy were included. Twenty-six (89.7%) pts had DLBCL and 3 (10.3%) had PMBCL. At the time of pre-LD, 22 (75.9%) pts had increased lactate dehydrogenase (LDH) levels 18 (62.1%), presented with stage IV disease, 16 (55.17%) with an International Prognostic Index (IPI) score of 3-5, 8 (27.6%) had bulky disease. Median number of prior treatment lines was 2 (range 2-6). Twenty-three (79.3%) pts were treated with axicabtagene ciloleucel and 6 (20.7%) with tisagenlecleucel. Bridging therapy before LD was required by 26 (89.6%) pts. For survival analyses, a cut-off MTV total value of 236.03 mL that maximized the Log-Rank statistic was selected to divide pts into high MTV total and low MTV total categories. Median overall survival (OS) was 5.7 [3.2-NA, 95% CI] months and 36.2 [13.9-NA, 95% CI] months for the high and low MTV total, respectively (Fig. 1). In multivariate analyses, a model including MTV total, SUV max and TLG total as imaging feature, and ICANS, C-reactive protein LD (CRP LD), LDH LD, lymphocytes count LD (Li LD) as clinical variables was able to successfully predict OS ( p = 0.019). Median progression-free survival (PFS) was 3 [1.31-NA, 95% CI] months and 11.06 [5.81-NA, 95% CI] months for the high and low MTV total, respectively. In multivariate analysis, a successful prediction of PFS ( p = 0.007) was achieved with a model including the same predictors that were used for OS. For the neurotoxicity assessment, a logistic regression model including six conventional PET parameters-MTV total, MTV DL,TLG total, TLG DL, median SUV DL, SUV max-two radiomic features,-entropy and entropy DL-and four clinical variables-CRP LD, LDH LD, Li LD and type of CAR-T cell treatment-was able to successfully predict the development of ICANS with an area under the curve of 0.971, a sensitivity of 0.813, a specificity of 0.846 and an accuracy of 0.828 (Fig. 2). Conclusions: Imaging features extracted from pre-infusion 18F-FDG PET/CT images in combination with several clinical features could predict survival and neurotoxicity in pts with DLBCL or PMBCL treated with CAR-T cell therapy. Quantitative features extracted from the PET/CT imaging exams may be useful for patient risk stratification and neurotoxicity prediction. Validation of these classifiers in independent datasets is warranted.

Low Tmtv Influences Response and Outcomes in R/R DLBCL 3L+ Patients Treated with CAR-T Cells : First Results of FDG-PET/CT Analysis in the French Descar-T Registry

Context : DESCAR-T is a French national registry designed by LYSA/LYSARC including real-life patients receiving commercial CAR T-cells for hematologic malignancies. We initiated a project to conduct a centralized review of Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography (FDG-PET/CT) performed before CAR T-cells infusion, and during follow-up, to evaluate the impact of several metabolic imaging parameters at baseline and response assessment. Materials and methods : Patients with relapsed/refractory (R/R) DLBCL who initiated at least a third line of therapy (3L+) from the DESCAR-T registry and treated with commercial anti-CD19 CAR T-cells, with at least one central reviewed PET before CAR T-cell infusion (PRE-CAR T), at one month (M1) or three months (M3) after infusion, were included. For each visit, Total Metabolic Tumor Volume (TMTV) and SUVmax of the tumor were measured. Deauville score (DS) and response according to 2014 Lugano classification were registered on follow-up FDG-PET/CT. TMTV optimal cut-off for survival prediction (PFS and OS) was determined using X-tile analysis and association of DS with prognosis was studied. Progression-free survival (PFS) was defined as the time between CAR T-cell infusion and progression during follow-up. Overall survival (OS) was defined as the time between CAR T-cell treatment and death during follow-up. Results : Our analysis included FDG-PET/CT data from 212 R/R DLBCL patients (59 treated with tisagenlecleucel and 153 with axicabtagene ciloleucel). Median follow-up was 24.1 months and overall response rate was 47.1% with 112 patients presenting progression or relapse. On PRECAR-T FDG-PET/CT, the median SUVmax was 16.1 (25th-75th percentiles, 8.55-25.30) and median TMTV was 43.91 cm3 (25th-75th percentiles, 12.79-140.43 cm3). Tumor burden significantly affected survival using a TMTV optimal cut-off of 30 cm3. It was associated with a shorter PFS in patients with PRECAR-T TMTV ≥30 cm3 compared with &amp;lt;30 cm3 (median of 3 vs 22.2 months; p=0.0001; respectively) and a shorter OS (median of 9.4 vs 32 months ; p=0.0001; respectively). Regarding metabolic response at M1, reported in 192 patients, DS 1-3 (n=120; 62.5%) was significantly associated with better PFS and OS than DS4-5 (n=72; 37.5%) (for PFS: median of 1.3 vs 21.8 months ; p&amp;lt;0.0001; for OS: median of 4.5 vs 30.6 months; p&amp;lt;0.0001). Of note, considering only DS5 (n=46; 24%) as unequivocally insufficient response onM1 evaluation, identified patients with the poorest outcomes (for PFS: median of 0 month vs 21.2 months ; p&amp;lt;0.0001; for OS: median of 4.5 months vs 31.1 months; p&amp;lt;0.0001). Conclusion : Low PRECAR-T TMTV influences response and retains its predictive and prognostic value in R/R DLBCL patients treated with anti-CD19 CAR T-cells. Moreover, metabolic response assessed with DS is significantly associated with patients' outcome.

Impact of Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography on Therapeutic Decisions and Radiotherapy Planning in Head and Neck Squamous Carcinoma: A Retrospective Study of 46 Patients.

BACKGROUND Positron emission tomography/computed tomography (PET/CT) using fluorodeoxyglucose (FDG) is essential in oncology for precise tumor delineation. This study evaluated FDG PET/CT's impact on therapeutic decisions in head and neck cancer, comparing metabolic tumor volumes (MTV) measured by different methods with radiotherapy targets, crucial for treatment planning and patient outcomes. MATERIAL AND METHODS We retrospectively analyzed 46 patients with histologically confirmed head and neck cancer who underwent FDG PET/CT examination before radiotherapy. The mean age was 62 years (46-78 years). Then, we calculated MTV of the primary tumor or local recurrence using a local threshold of 41% of the standard uptake volume (SUV) corrected for lean body mass (SULmax) of the lesion and absolute threshold of SUV 2.5. Descriptive analysis of the recruited patients was assessed based on the clinical database (Medsol). RESULTS The study included 45 patients with squamous carcinoma and 1 with sarcoid cell carcinoma. PET/CT examination led to therapeutic decision changes in 11 cases. No significant difference was found in median values of Gross Tumor Volume (GTV) and MTV absolute (p=0.130). However, significant differences were observed in MTV local, MTV absolute, and GTV median values (p<0.001), with both MTVs showing significant correlation with GTV (p<0.01), especially MTV absolute (r=0.886). CONCLUSIONS FDG PET/CT examination prior to radiotherapy significantly influences therapeutic decisions in head and neck cancer patients. Based on our findings, the absolute threshold method (SUV: 2.5) appears to be an effective approach for calculating MTV for radiotherapy planning purposes.

Fine needle aspiration as a diagnostic modality for Warthin tumors identified as fluorodeoxyglucose positron emission tomography/computed tomography-positive.

Limited evidence exists regarding the 2-deoxy-2-[fluorine-18]-fluoro-D-glucose (FDG) avidity of Warthin tumors, the second most common benign parotid gland tumor. This study aims to clarify this aspect by analyzing patients who underwent FDG positron emission tomography/computed tomography (PET/CT) and quantifying tumor standardized uptake values (SUV). Medical records of 29 patients with fine needle aspiration (FNA)-confirmed Warthin tumors who underwent FDG-PET/CT near the diagnosis of Warthin tumor were reviewed. Key parameters included cancer history, cytologic diagnosis of Warthin tumor, maximum SUV on FDG PET/CT, and tumor localization. Among the cohort, 18 males and 11 females (average age: 67.9 years) were included. Most patients had malignant neoplasms (lung, head and neck, breast, others). One patient had synchronous liver cancer. Three individuals had bilateral Warthin tumors, and three had bifocal tumors, resulting in 35 tumors for analysis. Tumors were located in the parotid gland (28) and vicinity (7). SUVmax for the Warthin tumors ranged from 3.6 to 26.8, with an average SUVmax of 10.1. Warthin tumors exhibit significant and variable FDG accumulation, exceeding expectations and mimicking high-grade malignancies. Awareness of this phenomenon is crucial for accurate staging and timely management. In cases of positive FDG PET/CT uptake in periparotid, perimandibular, and upper jugular areas, FNA is recommended to avoid misinterpretation or delays in management.

An Innovative Non-Linear Prediction Model for Clinical Benefit in Women with Newly Diagnosed Breast Cancer Using Baseline FDG-PET/CT and Clinical Data.

Objectives: We aimed to develop a novel non-linear statistical model integrating primary tumor features on baseline [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), molecular subtype, and clinical data for treatment benefit prediction in women with newly diagnosed breast cancer using innovative statistical techniques, as opposed to conventional methodological approaches. Methods: In this single-center retrospective study, we conducted a comprehensive assessment of women newly diagnosed with breast cancer who had undergone a FDG-PET/CT scan for staging prior to treatment. Primary tumor (PT) volume, maximum and mean standardized uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured on PET/CT. Clinical data including clinical staging (TNM) but also PT anatomical site, histology, receptor status, proliferation index, and molecular subtype were obtained from the medical records. Overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) were assessed as endpoints. A logistic generalized additive model was chosen as the statistical approach to assess the impact of all listed variables on CB. Results: 70 women with newly diagnosed breast cancer (mean age 63.3 ± 15.4 years) were included. The most common location of breast cancer was the upper outer quadrant (40.0%) in the left breast (52.9%). An invasive ductal adenocarcinoma (88.6%) with a high tumor proliferation index (mean ki-67 expression 35.1 ± 24.5%) and molecular subtype B (51.4%) was by far the most detected breast tumor. Most PTs displayed on hybrid imaging a greater volume (12.8 ± 30.4 cm3) with hypermetabolism (mean ± SD of PT maximum SUVmax, SUVmean, MTV, and TLG, respectively: 8.1 ± 7.2, 4.9 ± 4.4, 12.7 ± 30.4, and 47.4 ± 80.2). Higher PT volume (p < 0.01), SUVmax (p = 0.04), SUVmean (p = 0.03), and MTV (<0.01) significantly compromised CB. A considerable majority of patients survived throughout this period (92.8%), while five women died (7.2%). In fact, the OS was 31.7 ± 14.2 months and PFS was 30.2 ± 14.1 months. A multivariate prediction model for CB with excellent accuracy could be developed using age, body mass index (BMI), T, M, PT TLG, and PT volume as predictive parameters. PT volume and PT TLG demonstrated a significant influence on CB in lower ranges; however, beyond a specific cutoff value (respectively, 29.52 cm3 for PT volume and 161.95 cm3 for PT TLG), their impact on CB only reached negligible levels. Ultimately, the absence of distant metastasis M displayed a strong positive impact on CB far ahead of the tumor size T (standardized average estimate 0.88 vs. 0.4). Conclusions: Our results emphasized the pivotal role played by FDG-PET/CT prior to treatment in forecasting treatment outcomes in women newly diagnosed with breast cancer. Nevertheless, careful consideration is required when selecting the methodological approach, as our innovative statistical techniques unveiled non-linear influences of predictive biomarkers on treatment benefit, highlighting also the importance of early breast cancer diagnosis.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Application ofthe 2022 ACR/EULAR criteria forTakayasu arteritis to previously diagnosed patients based onthe 1990 ACR criteria.

Recently, a joint group of the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) proposed new criteria for Takayasu arteritis (TAK) (the 2022 ACR/EULAR criteria). This study applied the 2022 ACR/EULAR criteria to patients with previously diagnosed TAK based on the 1990 ACR criteria and investigated the concordance rate between the two criteria according to the four imaging modalities. This study reviewed the medical records of 179 patients who met the 1990 ACR criteria for TAK. The imaging modalities included conventional angiography, computed tomography angiography, fluorodeoxyglucose-positron emission tomography, and magnetic resonance angiography. Regardless of the imaging modalities, the concordance rate between the two criteria was 85.5% when including all patients, whereas it increased to 98.1% when only patients aged ≤60 years were included. Among the four imaging modalities, computed tomography angiography exhibited the highest concordance rate between the two criteria (85.6%). The concordance rate among patients aged >60 years was 95.7%. Only one patient aged 50-60 years was reclassified as having both TAK and giant cell arteritis. The concordance rate was 85.5% regardless of the imaging modalities and increased to 86.9% on simultaneous computed tomography angiography and fluorodeoxyglucose-positron emission tomography imaging.