Serial PET Research Articles

Assessment of Cardiac Sarcoidosis with PET/CT.

18F-FDG PET with CT is an important advanced imaging modality used to assess patients with suspected or known cardiac sarcoidosis (CS). 18F-FDG PET is indicated for CS work-up in patients with extra-CS and abnormal screening results for cardiac involvement, patients under 60 y old presenting with unexplained high-grade atrioventricular heart block, and patients with suspected CS and idiopathic ventricular arrhythmias. In patients with established CS, serial 18F-FDG PET can be used to assess response to immunosuppressive therapy and long-term surveillance for reactivation of myocardial inflammation in patients with low-grade or quiescent disease. Patient preparation before 18F-FDG PET scanning is key in ensuring adequate suppression of physiologic myocardial 18F-FDG uptake, to maximize the power of the test to detect pathology. Inadequate dietary preparation can cause diffuse or focal-on-diffuse 18F-FDG uptake in the absence of active inflammation. It is important to assess resting myocardial perfusion, typically with 82Rb cardiac PET. Several different patterns of abnormalities have been reported in patients with CS, including normal myocardial perfusion with focal or patchy 18F-FDG uptake suggesting myocardial inflammation without scarring; the presence of a myocardial perfusion defect with abnormal 18F-FDG uptake suggesting myocardial scarring with inflammation; and the presence of a myocardial perfusion defect without 18F-FDG uptake indicating myocardial scarring without inflammation. Prognostically, the presence of myocardial perfusion defects and abnormal 18F-FDG uptake has been shown to be an independent predictor of death or ventricular arrythmias. A high myocardial SUVmax in the left and right ventricles has been shown to be an independent predictor of adverse clinical outcomes. Although the diagnostic performance of 18F-FDG PET has been studied, the reference standard for CS tended to rely on clinical criteria, which may be less sensitive than 18F-FDG PET at detecting CS. Therefore, the diagnosis of CS should rely on a multidisciplinary team approach involving multimodality advanced imaging, including echocardiography, cardiovascular MR, and 18F-FDG PET.

Evaluation of early metabolic changes following vorasidenib using FET PET in patients with IDH-mutant gliomas

SUMMARY The phase-3 INDIGO trial demonstrated that the IDH inhibitor vorasidenib significantly prolonged progression-free survival and delayed intervention in patients with CNS WHO grade 2 gliomas. However, conventional MRI showed limited response, with only 11% of patients having objective responses. Studies suggest that serial PET imaging with radiolabeled amino acids, such as O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET, may provide earlier and more informative assessments of treatment response than MRI. In an initial experience with FET PET, three out of five patients showed metabolic response to vorasidenib. This highlights FET PET’s potential to guide decision-making, though further trials are needed to confirm outcome benefits.

NIMG-34. CXCR4-TARGETED PET IMAGING OF CENTRAL NERVOUS SYSTEM LYMPHOMA AND GLIOMA USING [68GA]GA-PENTIXAFOR

Abstract BACKGROUND Initial results suggest that PET imaging of the chemokine receptor CXCR4 is of considerable interest for differential diagnosis and theranostic approaches. Here, we summarized findings of CXCR4 PET imaging in an institutional series of lymphoma of the central nervous system (CNSL) and glioma. METHODS Twenty-three patients with CNSL and 16 patients with glioma (IDH-wildtype, n=9) underwent PET imaging using the CXCR4-directed tracer [68Ga]Ga-Pentixafor. In 18 patients, serial PET imaging was performed (range, 2-14 scans), resulting in a total of 104 PET scans. For evaluation, PET scans were classified as [68Ga]Ga-Pentixafor-positive and -negative visually, and the maximum standardized uptake value (SUVmax) was obtained from [68Ga]Ga-Pentixafor-PET. RESULTS Twenty-four of all 39 patients (62%) had at least one [68Ga]Ga-Pentixafor-positive PET (CNSL, 57%; glioma, 69%). [68Ga]Ga-Pentixafor-positive PET scans were more common in patients with IDH-wildtype gliomas (89%) than in IDH-mutant gliomas (43%). In patients with [68Ga]Ga-Pentixafor-positive PET, the average SUVmax was 6.4±4.0 in CNSL, and 3.4±1.0 in gliomas (P=0.155). Besides visualization of tumors, [68Ga]Ga-Pentixafor uptake was observed in two patients with radionecrosis. In four CNSL patients who had undergone methotrexate/cytarabine-based first-line therapy, serial PET revealed a significant reduction of SUVmax after chemotherapy completion (average decrease of SUVmax from 4.5±3.8 to 0.6±0.7; P=0.044). In three of those four patients, tumor progression has not been reached (range of time after the follow-up PET, 4-55 months); one patient deceased 44 months after the follow-up PET. In contrast, another patient with an increase in SUVmax from 6.9 to 11.0 after first-line treatment died one month after the follow-up PET. DISCUSSION [68Ga]Ga-Pentixafor PET seems to be of value for non-invasively visualizing and quantifying CXCR4 receptor binding. In CNSL, changes in [68Ga]Ga-Pentixafor uptake following therapy may indicate potential for response assessment. CXCR4-targeting radioligand therapies might be more promising in CNSL than in glioma.

Circulating monocytes decrease significantly following disease-directed therapy and may reflect disease expansion in Langerhans Cell Histiocytosis.

We aimed to examine the association between relative monocytosis and the recurrence of pulmonary Langerhans Cell Histiocytosis. Clinical, laboratory, radiographic and treatment data for 86 patients with a histopathological diagnosis of Langerhans Cell Histiocytosis over a 20-year duration. Parameters such as biological sex, age at diagnosis, time to diagnosis, molecular diagnostic data and imaging were collected. Treatment responses were assessed predominantly through radiography, with RECIST 1.1 criteria applied to MRI or CT scans and PERCIST utilized for serial PET imaging. Investigators also assessed peripheral blood absolute monocyte count at various time points, including initial diagnosis and the most recently available value. While peripheral blood absolute monocyte count between the earliest assessed timepoint and latest value did not differ, the mean value on progression (0.94K/µL), however, was significantly higher than that following re-institution of therapy (0.31, p = 0.000794. Our observation of relative monocytosis on LCH disease progression may be related to an increase in circulating LCH on disease progression or from increased monocyte production for later differentiation into mature dendritic cells that participate in MHC Class 1 upregulation. This trend is especially evident in pulmonary LCH which is incited by tissue trauma and irritation by environmental factors. The phenomena observed in our study parallel other non-LCH cohorts, specifically in published findings from our own group in patients with Rosai Dorfman and Erdheim Chester Disease. To further elucidate the molecular underpinnings of LCH and explore the etiology of this monocyte trend, expanded integrated genomic-transcriptomic sequencing analyses to evaluate the molecular character of LCH and ultimately clarify the origin of this monocyte trend are in progress. These studies are poised to offer invaluable insight to the molecular mechanisms underlying LCH, specifically as they pertain to monocyte signaling and differentiation.

Assessing the Heterogeneity of Response of [68Ga] Ga-PSMA-11 PET/CT Lesions in Patients With Biochemical Recurrence of Prostate Cancer

IntroductionTreatment of men with metastatic prostate cancer can be difficult due to the heterogeneity of response of lesions. [68Ga]Ga-PSMA-11 (PSMA) PET/CT assists with monitoring and directing clinical intervention; however, the impact of response heterogeneity has yet to be related to outcome measures. The aim of this study was to assess the impact of quantitative imaging information on the value of PSMA PET/CT to assess patient outcomes in response evaluation. Patients and MethodsBaseline and follow-up (6 months) PSMA PET/CT of 162 men with oligometastatic PC treated with standard clinical care were acquired between 2015 and 2016 for analysis. An augmentative software medical device was used to track lesions between scans and quantify lesion change to categorize them as either new, increasing, stable, decreasing, or disappeared. Quantitative imaging features describing the size, intensity, extent, change, and heterogeneity of change (based on percent change in SUVtotal) among lesions were extracted and evaluated for association with overall survival (OS) using Cox regression models. Model performance was evaluated using the c-index. ResultsForty-one (25%) of subjects demonstrated heterogeneous response at follow-up, defined as having at least 1 new or increasing lesion and at least 1 decreasing or disappeared lesion. Subjects with heterogeneous response demonstrated significantly shorter OS than subjects without (median OS = 76.6 months vs. median OS not reached, P < .05, c-index = 0.61). In univariate analyses, SUVtotal at follow-up was most strongly associated with OS (HR = 1.29 [1.19, 1.40], P < .001, c-index = 0.73). Multivariable models applied using heterogeneity of change features demonstrated higher performance (c-index = 0.79) than models without (c-index = 0.71-0.76, P < .05). ConclusionAugmentative software tools enhance the evaluation change on serial PSMA PET scans and can facilitate lesional evaluation between timepoints. This study demonstrates that a heterogeneous response at a lesional level may impact adversely on patient outcomes and supports further investigation to evaluate the role of imaging to guide individualized patient management to improve clinical outcomes.

Evaluation of the safety, biodistribution, dosimetry of [18F]AlF-NOTA-LM3 and head-to-head comparison with [68Ga]Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors: an interim analysis of a prospective trial.

18F-labelled somatostatin receptor (SSTR) analogs offer several advantages over 68Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an interim analysis of a prospective trial designed to assess the safety, biodistribution and dosimetry of [18F]AlF-NOTA-LM3, and compare its diagnostic efficacy and clinical management outcomes with [68Ga]Ga-DOTATATE or [68Ga]Ga-NODAGA-LM3 in patients with well-differentiated NETs. Twenty-one patients with histologically confirmed well-differentiated neuroendocrine tumors (G1 and G2) were prospectively recruited. The first eight patients underwent serial PET scans at 5, 15, 30, 45, 60, and 120min after [18F]AlF-NOTA-LM3 injection to assess biodistribution and dosimetry. The remaining patients underwent whole-body PET/CT scans. [18F]AlF-NOTA-LM3 and [68Ga]Ga-DOTATATE PET/CT were done within a week, with a minimum 24-hour interval between the two scans. Focal uptake above the surrounding background activity and could not be explained by physiologic uptake was considered lesions of NETs. Lesion number, tumor uptake, and tumor-to-background ratio (TBR) were compared. In patients with discrepant findings, the size of the smallest lesions (measured on coregistered CT) detected on [68Ga]Ga-DOTATATE and [18F]AlF-NOTA-LM3 was compared. [18F]AlF-NOTA-LM3 was safe and well-tolerated. Physiological uptake of [18F]AlF-NOTA-LM3 was significantly lower than that of [68Ga]Ga-DOTATATE in abdominal organs and bone marrow, but higher in blood pool and lung. The mean effective dose was 0.024 ± 0.014 mSv/MBq. [18F]AlF-NOTA-LM3 detected significantly more liver lesions (457 vs. 291, P = 0.006) and lymph node lesions (30 vs. 22, P = 0.011) compared to [68Ga]Ga-DOTATATE. The tumor uptake was comparable, but TBR was significantly higher with [18F]AlF-NOTA-LM3 for lesions from all sites except for the duodenum. The size of the minimum liver lesions (0.54 ± 0.15 vs. 1.01 ± 0.49, P<0.001) and lymph node lesions (0.50 ± 0.19 vs. 1.26 ± 0.86, P = 0.024) detected on [18F]ALF-NOTA-LM3 were significantly smaller than those detected on [68Ga]Ga-DOTATATE. [18F]AlF-NOTA-LM3 shows favorable biodistribution, higher spatial resolution and superior performance than [68Ga]Ga-DOTATATE in detecting liver and lymph node metastases, with higher TBR. Notably, it is the first SSTR analog to show superiority in detecting lymph node lesions when compared to [68Ga]Ga-DOTATATE. ClinicalTrials.gov identifier NCT06056362.

Using serial 18F-FDG PET/CT PERCIST response to predict responses to immune check point inhibitors in patients with advanced cutaneous squamous cell carcinoma.

9548 Background: The role of serial 18F-FDG-PET/CT imaging in predicting long term efficacy of PD-1 targeted immune checkpoint inhibitor (ICI) in advanced cutaneous squamous cell carcinoma (cSCC) is unknown. This study aims to correlate PET PERCIST response with time to progressive disease. Methods: This was a single-centre retrospective study of patients treated with ICI for advanced cSCC who had baseline and serial FDG-PET/CT within 4-months of commencement of ICI. PERCST 1.0 was calculated by two radiologists independently and classified into complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). The primary endpoint was time to progression from commencement of ICI. Progression was determined by a multidisciplinary team combining clinical and radiological assessments. Results: Of the 242 patients treated with ICI for advanced cSCC during 2018-2023, 83 (34%) patients had a serial FDG PET. Of these, 53 patients met the inclusion criteria of ≤4-months from ICI to second PET. CMR (54.7%), PMR (15.1%), SMD (11.3%) and PMD (18.9%) were seen as initial responses by PERCST 1.0. With a median follow-up of 8-months (1-55), progressive disease as determined by the multidisciplinary team was observed in 11 patients (21%). For these 11 patients, the 4-month PERCST 1.0 response was measured as CMR (n=1), PMR (N=1), SMD (N=2) and PMD (N=7). The median TTP was significantly higher in CMR/ PMR vs SMD/PMD (55 vs 4-Months, P&lt;0.001). At data cut off, 94.6% (N=35) of patients with a 4-month PET PERCST 1.0 CMR/ PMR assessment did not progress clinically. Clinical response was maintained at a minimum of 12-months in 94.7% (n=18) of those responding. Conclusions: Rate of CMR and PMR in advanced cSCC is high with ICI. Early PET CMR/ PMR appears to predict long term durable responses. Incorporation of PET/CT into the assessment of response in cSCC may help guide treatment decisions by early identification of those patients not responding to ICI.

CCR2, CCR4 and CCR9 expression on T cells is required for homing to colon cancer as demonstrated by Zr-89 T cell labeling

Abstract Adoptive T cell therapy relies on trafficking of infused T cells to the tumor. Chemokine gradients and chemokine receptors expressed on T cells mediate this recruitment of T cells. However, due to the high complexity of the tumor microenvironment, regulation of T cell homing to tumors remains poorly understood. We examined how various chemokine receptors expressed on T cells impact their ability to home to cancer using zirconium-89 (89Zr)-oxine cell labeling. Ex vivo activated mouse T cells, wild type (WT) or deficient (KO) for a chemokine receptor, were labeled with 89Zr-oxine and intravenously infused into WT mice bearing subcutaneous syngeneic MC38 colon cancer. Bulk T cells, not tumor antigen specific T cells, were used to determine homing capability of the cells independent of their antigen interaction. Serial PET imaging demonstrated initial lung accumulation of the T cells followed by trafficking to the liver, spleen, and to a much lesser extent other tissues, including the tumor. Ex vivo biodistribution analyses on Day 2 showed CCR2KO, CCR4KO and CCR9KO T cells homed significantly less to the tumor compared to WT T cells, indicating that CCR2, CCR4 and CCR9 expression on T cells is important for homing to colon cancer. Augmenting expression of these chemokine receptors on T cells, or the relevant ligands in the tumor, could enhance T cell homing to colon cancer thereby improving efficacy of T cell therapy.

Hypofractionated re-irradiation with bevacizumab for relapsed chemorefractory glioblastoma after prior high dose radiotherapy: a feasible option for patients with large-volume relapse.

There remains no standard of care for patients with recurrent and chemorefractory glioblastoma. Re-irradiation (reRT) provides an additional management option. However, published series predominantly focus on small reRT volumes utilizing stereotactic hypofractionated regimens. Concerns regarding toxicity have limited utilisation of reRT for larger recurrences, however this may be mitigated with use of bevacizumab (BEV). A prospective database of patients managed with the EORTC-NCIC (Stupp) protocol 60Gy chemoradiotherapy protocol for glioblastoma between 2007 and 2021 was reviewed for those patients receiving reRT for chemorefractory relapse. Serial MRI and PET were used to establish true progression and exclude patients with pseudoprogression or radionecrosis from reRT. The primary endpoint was overall survival (OS) from date of reRT. Prognostic factors were also assessed. 447 patients managed for glioblastoma under the Stupp protocol were identified, of which 372 had relapsed and were thus eligible for reRT. 71 patients underwent reRT. Median relapse-free survival from diagnosis for the reRT and overall cohorts were similar at 11.6 months (95%CI:9.4-14.2) and 11.8 months (95%CI:9.4-14.2) respectively. 60/71 (85%) reRT patients had received BEV prior to reRT and continued concurrent BEV during reRT. Of the 11 patients not managed with BEV during reRT, 10 required subsequent salvage BEV. ReRT patients were younger (median 53 vs. 59 years, p < 0.001), had better performance status (86% vs. 69% ECOG 0-1, p = 0.002) and more commonly had MGMT promoter-methylated tumours (54% vs. 40%, p = 0.083) compared to non-reRT patients. Median reRT PTV volume was 135cm3 (IQR: 69-207cm3). Median OS from reRT to death was 7.1 months (95%CI:6.3-7.9). Patients aged < 50, 50-70 and > 70 years had post-reRT median OS of 7.7, 6.4 and 6.0 months respectively (p = 0.021). Median post-reRT survival was longer for patients with ECOG performance status 0-1 compared to 2-3 (8.1 vs. 6.3 months, p = 0.039). PTV volume, site of relapse, MGMT promoter-methylation status and extent of initial surgical resection were not associated with post-reRT survival. ReRT was well-tolerated. Out of the 6 patients (8%) admitted to hospital after reRT, only one was for reRT toxicity. This was a CTCAE grade 3 radiation necrosis event in a patient managed without prior BEV. Patients with recurrent glioblastoma who have been previously treated with 60Gy radiotherapy have a meaningful survival benefit from large volume re-irradiation which is well tolerated. ReRT should not be ignored as a salvage treatment option in patients with chemorefractory progressive disease.

Anti-LGI1 autoimmune encephalitis: insights from three cases with serial PET imaging

BackgroundAutoimmune encephalitis (AE) can be a disabling condition, but it is manageable when identified in its early phases. Multiple diagnostic modalities can aid the diagnosis and delineation of areas of involvement in the brain, which is essential in correlating the symptoms to their pathology.Case presentationThis case series focuses on three cases of anti-LGI1 encephalitis in their 3rd and 5th decades, each displaying facio-brachial dystonic seizures (FBDS) and varying symptoms, such as behavioural changes and hyperhidrosis. Their MRI brains were not conclusive, but when the patients underwent a PET scan, all three of them showed involvement of the Basal Ganglia, which reversed along with clinical improvement after standard treatment for AE.ConclusionsAE can be a morbid condition for a long time, but some factors that might predispose to better patient outcomes might be early diagnosis and treatment. A PET scan is a modality that might help pick up functional changes before structural changes set in, and so should be considered in the diagnostic workup. Patterns of involvement of brain areas in Anti LGI1 AE need delineation, and basal ganglia seems to be a consistent region of involvement.

Improvement of motion artifacts using dynamic whole-body 18F-FDG PET/CT imaging

PurposeSerial dynamic whole-body PET imaging is valuable for assessing serial changes in tracer uptake. The purpose of this study was to evaluate the improvement of motion artifacts in patients using serial dynamic whole-body 18F-fluorodeoxyglyucose (FDG) PET/CT imaging.Materials and methodsIn 797 consecutive patients, serial 3-min dynamic whole-body FDG PET imaging was performed seven times, at 60 or 90 min after FDG administration. In cases with large body motion during imaging, we tried to improve the images by summing the images before body motion. An image quality study was performed on another 50 patients without obvious body motion using the same acquisition mode.ResultsObvious body movement was observed in 106 of 797 cases (13.3%), and severe motion artifacts which interfered image interpretation were observed in 18 (2.3%). In these 18 cases, summation of the images before the body movement enabled us to obtain images that excluded the effect of the body motion. In the visual evaluation of the image quality in another 50 patients studied, acceptable image quality was obtained when 2 or more times the serial 3-min image data were added.ConclusionSerial dynamic whole-body FDG PET imaging can minimize body motion artifacts by summation of the images before the body motion. Such serial dynamic study may be a choice for PET imaging to eliminate motion artifacts.

Serial fractional flow reserve, coronary flow reserve and index of microcirculatory resistance after percutaneous coronary intervention in patients treated for stable angina pectoris assessed with PET.

Cardiac 15 O-water PET is a noninvasive method to evaluate epicardial and microvascular dysfunction and further quantitate absolute myocardial blood flow (MBF). The aim of this study was to assess the impact of revascularization on MBF and myocardial flow reserve (MFR) assessed with 15 O-water PET and invasive flow and pressure measurements. In 21 patients with single-vessel disease referred for percutaneous coronary intervention (PCI), serial PET perfusion imaging and fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were performed during PCI and after 3 months. In the affected myocardium, stress MBF and MFR increased significantly from before revascularization to 3 months after revascularization: stress MBF 2.4 ± 0.8 vs. 3.2 ± 0.8; P < 0.001 and MFR 2.5 ± 0.8 vs. 3.4 ± 1.1; P = 0.004. FFR and CFR increased significantly from baseline to after revascularization and remained stable from after revascularization to 3-month follow-up: FFR 0.64 ± 0.20 vs. 0.91 ± 0.06 vs. 0.91 ± 0.07; P < 0.001; CFR 2.4 ± 1.2 vs. 3.6 ± 1.9 vs. 3.6 ± 1.9; P < 0.001, whereas IMR did not change significantly: 30.3 ± 22.9 vs. 30.1 ± 25.3 vs. 31.9 ± 25.2; P = ns. After revascularization, an increase in stress MBF was associated with an increase in FFR ( r = 0.732; P < 0.001) and an increase in MFR ( r = 0.499; P = 0.021). IMR measured before PCI was inversely associated with improvement in stress MBF, ( r = -0.616; P = 0.004). Recovery of myocardial perfusion after PCI was associated with an increase in FFR 3 months after revascularization. Microcirculatory dysfunction was associated with less improvement in myocardial perfusion.

Development of [89Zr]Zr-hCD103.Fab01A and [68Ga]Ga-hCD103.Fab01A for PET imaging to noninvasively assess cancer reactive T cell infiltration: Fab-based CD103 immunoPET

BackgroundCD103 is an integrin specifically expressed on the surface of cancer-reactive T cells. The number of CD103+ T cells significantly increases during successful immunotherapy and might therefore be an attractive biomarker for noninvasive PET imaging of immunotherapy response. Since the long half-life of antibodies preclude repeat imaging of CD103+ T cell dynamics early in therapy, we therefore here explored PET imaging with CD103 Fab fragments radiolabeled with a longer (89Zr) and shorter-lived radionuclide (68Ga).MethodsAntihuman CD103 Fab fragment Fab01A was radiolabeled with 89Zr or 68Ga, generating [89Zr]Zr-hCD103.Fab01A and [68Ga]Ga-hCD103.Fab01A, respectively. In vivo evaluation of these tracers was performed in male nude mice (BALB/cOlaHsd-Foxn1nu) with established CD103-expressing CHO (CHO.CD103) or CHO-wildtype (CHO.K1) xenografts, followed by serial PET imaging and ex vivo bio-distribution.Results[89Zr]Zr-hCD103.Fab01A showed high tracer uptake in CD103+ xenografts as early as 3 h post-injection. However, the background signal remained high in the 3- and 6-h scans. The background was relatively low at 24 h after injection with sufficient tumor uptake. [68Ga]Ga-hCD103.Fab01Ashowed acceptable uptake and signal-to-noise ratio in CD103+ xenografts after 3 h, which decreased at subsequent time points.Conclusion[89Zr]Zr-hCD103.Fab01A demonstrated a relatively low background and high xenograft uptake in scans as early as 6 h post-injection and could be explored for repeat imaging during immunotherapy in clinical trials. 18F or 64Cu could be explored as alternative to 68Ga in optimizing half-life and radiation burden of the tracer.

NIMG-05. CHARACTERIZATION OF LONG-TERM METABOLIC CHANGES OF BRAIN METASTASES AFTER TREATMENT WITH STEREOTACTIC RADIOSURGERY USING SERIAL FET PET IMAGING

Abstract BACKGROUND In the present study, we characterized the long-term metabolic changes of brain metastases after treatment with stereotactic radiosurgery (SRS) by serial PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value in differentiating between radiation-induced changes and local brain metastasis relapse. Patients and METHODS From 2010-2020, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal MRI findings after SRS, and (iii) subsequently underwent two or more additional FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed by neuropathological evaluation (29%) or clinicoradiologically (71%). RESULTS We identified 14 patients with 42 FET PET scans (median number, 3; range, 2-4). Concurrent to SRS, 4 patients (29%) were treated with checkpoint inhibitors. Following SRS, equivocal MRI findings occurred after a median time of 7 months (range, 2-62 months). Subsequently, FET PET scans were acquired over a median 16 months (range, 7-99 months). Nine patients (64%) had radiation-induced changes, and five had local brain metastases relapse. TBRs calculated from the last available FET PET scan showed the highest accuracy (93%) in identifying radiation-induced changes (threshold, 1.95; P=0.011). In lesions consistent with local brain metastases relapse, TBR increased considerably over time (median increase, 17%; range, 11% - 32%). In contrast, in lesions considered as radiation-induced changes, TBR remained stable or even decreased (median change, -4%; range, -44% - 11%). The TBR evolution over time significantly differed between the two groups (P=0.011). CONCLUSIONS Serial FET PET imaging has a high diagnostic accuracy for characterizing long-term changes of brain metastases after treatment with stereotactic radiosurgery.

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer

PurposeTo investigate combined MRI and 18F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer.MethodsPatients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K1) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated.ResultsThirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31–66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18F-FDG PET (K1) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS.ConclusionMid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

Relative Monocytosis Is Predictive of Disease Progression and Confirmatory of Response Assessment in Langerhans Cell Histiocytosis

Introduction Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm, which arises when myeloid precursors expressing CD207 (Langerin) and CD1a expand and circulate as mature dendritic cells, clinically manifesting in multisystemic eosinophilic granulomas at osseous sites (notably the cranium), lungs, cutaneous tissue, and visceral structures (pituitary gland, liver, spleen). Molecular alterations in MAP kinase signaling are common, specifically in BRAFV600E, which is identified in greater than 50% of patients. Limited LCH is commonly managed with local therapies, such as surgery and radiation, while disseminated disease is managed with systemic therapies, including multi-agent chemotherapy or targeted agents, such as BRAF inhibitors. While diagnostic and management paradigms are well-established in LCH, clinical studies evaluating indicators of disease progression are lacking. Methods Clinical, laboratory, radiographic and treatment data for 49 patients with a histopathologic diagnosis of Langerhans Cell Histiocytosis treated at a single institution over a 20-year period was reviewed by multiple study investigators. Specific parameters reviewed included biological sex, age at and time to diagnosis, molecular diagnostic data by immunohistochemistry and/or next generation sequencing, diagnostic imaging utilized, treatment rendered, clinical and/or radiographic response. Radiography in all but 1/49 patients was used to assess treatment responses, by RECIST 1.1 where MRI, or CT was utilized and PERCIST for serial PET imaging. The peripheral blood absolute monocyte count (in K/µL) was also assessed in each patient at various timepoints, including at initial diagnosis and the most recent value. We also performed a more focused assessment of absolute monocytes at the time of disease progression (when applicable) and again following reinstitution of therapy. Statistical analyses to compare sets of data were conducted using unpaired two-sided t-tests. Results Of the 49 patients included in this analysis, 28 were female and 21 male, with an average age at diagnosis of approximately 38 years; time between symptom onset and diagnosis varied widely across the cohort but was generally less than 12 months. Molecular diagnostics were employed in only 8/49 patients, 3 by IHC, 4 by NGS and 1 by both; BRAFV600E was assessed in 6 patients and was positive in 2. Approach to imaging at diagnosis and throughout treatment varied but most commonly included conventional CT (25), followed by MRI (17) and PET (16). LCH was observed as a primary pulmonary disease in 18 patients (36.7%), as involvement of skull/CNS/ocular structures in 10 and as localized cutaneous involvement in 5. Complete responses were observed in 17 of 49 patients, 11/17 of whom underwent local therapy (radiation and/or surgery) at ≥1 point in his or her treatment course. On the other end of the spectrum, 5 patients never achieved any response and always had progressive/persistent disease, all of whom had been diagnosed with pulmonary LCH in the setting of chronic tobacco use. Peripheral blood absolute monocyte count between the earliest-assessed timepoint and latest value, lastly, did not differ. The mean value on progression (0.94 K/µL), however, was significantly higher than that following re-institution of therapy (0.31, p=0.0005) as depicted in Figure 1. Discussion The identification of relative monocytosis at the time of LCH progression was an unexpected finding in this study. LCH pathogenesis has been felt to berelated to dysregulated hematopoiesis and acquisition of somatic mutations during monocyte differentiation, ultimately driving clonal expansion of CD1a+/CD207+ histiocytes. Within this working model of disruption to monocyte differentiation, one explanation of our observed findings is a simple expansion in circulating monocytes as a manifestation of disease progressing throughout various tissues. Another possibility is that circulating monocytes are upregulated and later differentiate into mature dendritic cells for MHC Class I presentation. Similar observations have been made at our institution in cohorts of non-LCH histiocytosis, specifically Rosai Dorfman and Erdheim Chester Disease. Expanded integrated genomic-transcriptomic sequencing analyses to evaluate the molecular character of LCH and ultimately clarify the origin of this monocyte trend are currently underway.

AI Transformers for Radiation Dose Reduction in Serial Whole-Body PET Scans

To develop a deep learning approach that enables ultra-low-dose, 1% of the standard clinical dosage (3 MBq/kg), ultrafast whole-body PET reconstruction in cancer imaging.In this Health Insurance Portability and Accountability Act-compliant study, serial fluorine 18-labeled fluorodeoxyglucose PET/MRI scans of pediatric patients with lymphoma were retrospectively collected from two cross-continental medical centers between July 2015 and March 2020. Global similarity between baseline and follow-up scans was used to develop Masked-LMCTrans, a longitudinal multimodality coattentional convolutional neural network (CNN) transformer that provides interaction and joint reasoning between serial PET/MRI scans from the same patient. Image quality of the reconstructed ultra-low-dose PET was evaluated in comparison with a simulated standard 1% PET image. The performance of Masked-LMCTrans was compared with that of CNNs with pure convolution operations (classic U-Net family), and the effect of different CNN encoders on feature representation was assessed. Statistical differences in the structural similarity index measure (SSIM), peak signal-to-noise ratio (PSNR), and visual information fidelity (VIF) were assessed by two-sample testing with the Wilcoxon signed rank t test.The study included 21 patients (mean age, 15 years ± 7 [SD]; 12 female) in the primary cohort and 10 patients (mean age, 13 years ± 4; six female) in the external test cohort. Masked-LMCTrans-reconstructed follow-up PET images demonstrated significantly less noise and more detailed structure compared with simulated 1% extremely ultra-low-dose PET images. SSIM, PSNR, and VIF were significantly higher for Masked-LMCTrans-reconstructed PET (P < .001), with improvements of 15.8%, 23.4%, and 186%, respectively.Masked-LMCTrans achieved high image quality reconstruction of 1% low-dose whole-body PET images.Keywords: Pediatrics, PET, Convolutional Neural Network (CNN), Dose Reduction Supplemental material is available for this article. © RSNA, 2023.

Radioimmunoscintigraphy and Pretreatment Dosimetry of 131I-Omburtamab for Planning Treatment of Leptomeningeal Disease.

Radiolabeled antibody treatment with 131I-omburtamab, administered intraventricularly into the cerebrospinal fluid (CSF) space, can deliver therapeutic absorbed doses to sites of leptomeningeal disease. Assessment of distribution and radiation dosimetry is a key element in optimizing such treatments. Using a theranostic approach, we performed pretreatment 131I-omburtamab imaging and dosimetric analysis in patients before therapy. Methods: Whole-body planar images were acquired 3 ± 1, 23 ± 2, and 47 ± 2 h after intracranioventricular administration of 75 ± 5 MBq of 131I-omburtamab via an Ommaya reservoir. Multiple blood samples were also obtained for kinetic analysis. Separate regions of interest (ROIs) were manually drawn to include the lateral ventricles, entire spinal canal CSF space, and over the whole body. Count data in the ROIs were corrected for background and physical decay, converted to activity, and subsequently fitted to an exponential clearance function. The radiation absorbed dose was estimated to the CSF, separately to the spinal column and ventricles, and to the whole body and blood. Biodistribution of the injected radiolabeled antibody was assessed for all patients. Results: Ninety-five patients were included in the analysis. Biodistribution showed prompt localization in the ventricles and spinal CSF space with low systemic distribution, noted primarily as hepatic, renal, and bladder activity after the first day. Using ROI analysis, the effective half-lives were 13 ± 11 h (range, 5-75 h) for CSF in the spinal column, 8 ± 3 h (range, 3-17 h) for ventricles, and 41 ± 11 (range, 23-81 h) for the whole body. Mean absorbed doses were 0.63 ± 0.38 cGy/MBq (range, 0.24-2.25 cGy/MBq) for CSF in the spinal column, 1.03 ± 0.69 cGy/MBq (range, 0.27-5.15 cGy/MBq) for the ventricular CSF, and 0.45 ± 0.32 mGy/MBq (range, 0.05-1.43 mGy/MBq) for the whole body. Conclusion: Pretherapeutic imaging with 131I-omburtamab allows assessment of biodistribution and dosimetry before the administration of therapeutic activity. Absorbed doses to the CSF compartments and whole body derived from the widely applicable serial 131I-omburtamab planar images had acceptable agreement with previously reported data determined from serial 124I-omburtamab PET scans.

ITA-IMMUNO-PET: The Role of [18F]FDG PET/CT for Assessing Response to Immunotherapy in Patients with Some Solid Tumors.

To examine the role of [18F]FDG PET/CT for assessing response to immunotherapy in patients with some solid tumors. Data recorded in a multicenter (n = 17), retrospective database between March and November 2021 were analyzed. The sample included patients with a confirmed diagnosis of a solid tumor who underwent serial [18F]FDG PET/CT (before and after one or more cycles of immunotherapy), who were >18 years of age, and had a follow-up of at least 12 months after their first PET/CT scan. Patients enrolled in clinical trials or without a confirmed diagnosis of cancer were excluded. The authors classified cases as having a complete or partial metabolic response to immunotherapy, or stable or progressive metabolic disease, based on a visual and semiquantitative analysis according to the EORTC criteria. Clinical response to immunotherapy was assessed at much the same time points as the serial PET scans, and both the obtained responses were compared. The study concerned 311 patients (median age: 67; range: 31-89 years) in all. The most common neoplasm was lung cancer (56.9%), followed by malignant melanoma (32.5%). Nivolumab was administered in 46.3%, and pembrolizumab in 40.5% of patients. Baseline PET and a first PET scan performed at a median 3 months after starting immunotherapy were available for all 311 patients, while subsequent PET scans were obtained after a median 6, 12, 16, and 21 months for 199 (64%), 102 (33%), 46 (15%), and 23 (7%) patients, respectively. Clinical response to therapy was recorded at around the same time points after starting immunotherapy for 252 (81%), 173 (56%), 85 (27%), 40 (13%), and 22 (7%) patients, respectively. After a median 18 (1-137) months, 113 (36.3%) patients had died. On Kaplan-Meier analysis, metabolic responders on the first two serial PET scans showed a better prognosis than non-responders, while clinical response became prognostically informative from the second assessment after starting immunotherapy onwards. [18F]FDG PET/CT could have a role in the assessment of response to immunotherapy in patients with some solid tumors. It can provide prognostic information and thus contribute to a patient's appropriate treatment. Prospective randomized controlled trials are mandatory.

Longitudinal pathologic course of older individuals with medial temporal tau deposition in the absence of amyloid‐β pathology

AbstractBackgroundAlzheimer’s disease (AD)‐like tau pathology in the medial temporal lobe (MTL) is also commonly observed in older individuals without amyloid‐β (Aβ) pathology, a condition termed primary age‐related tauopathy (PART). Little is known about the longitudinal course of this condition and its association with the AD continuum remains controversial. We used serial PET, MRI, and CSF data to study the longitudinal pathologic course of older individuals who show PET‐measured MTL tau pathology in the absence of Aβ pathology.MethodWe included older individuals with varying degrees of cognitive performance from the Alzheimer’s Disease Neuroimaging Initiative, the Harvard Aging Brain Study, and AVID’s A05 Study who had undergone baseline (n=1097) and follow‐up [18F]flortaucipir (FTP) (n=489, follow‐up: 1.83±0.84 years) and Aβ‐PET scanning (n=398, follow‐up: 2.36±0.76 years). Participants were separated into three groups according to Aβ and tau positivity (A‐T‐, A‐T+, A+T+), using a cut‐off of 12 centiloids for A+ and the 95th percentile of entorhinal (ERC) FTP SUVR values in healthy young controls (n=16, ≤39y) for T+. In complementary analyses we also assessed longitudinal changes in CSF biomarkers (n=99, follow‐up: 2.34±1.05 years) and cortical atrophy on MRI (n=650, follow‐up: 2.00±0.86 years).Result43% of A‐ individuals and 81% of A+ individuals were ERC‐tau positive. Cross‐sectionally, A‐T+ showed elevated FTP SUVR restricted to the medial/inferior temporal lobe, while A+T+ displayed a more AD‐characteristic pattern of widespread cortical FTP uptake (Fig. 1A). A‐T+ showed moderate FTP SUVR increases over time largely limited to the temporal lobe, whereas FTP SUVR increases were widespread in A+T+ (Fig. 1B). Notably, A‐T+ individuals did not increase Aβ accumulation over time (Fig. 1C). CSF analysis confirmed longitudinal tau increases in A‐T+ in the absence of increased Aβ accumulation (Fig. 1D). Compared to A‐T‐, A‐T+ individuals demonstrated accelerated MTL atrophy, whereas A+T+ showed more widespread AD‐typical cortical atrophy (Fig. 2).ConclusionElevated MTL tau‐PET signal is frequently observed in older individuals without notable Aβ pathology, reminiscent of pathology‐defined PART. These A‐T+ individuals exhibit a comparably slow course of progressive tau accumulation and neurodegeneration confined to the temporal lobe and do not appear to be on a pathologic trajectory towards AD.