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Purpose: The standardized uptake value (SUV) is a quantitative measure of FDG tumor uptake frequently used as a tool to monitor therapeutic response. This study aims to (i) assess the reproducibility and uncertainty of SUVmax and SUVmean, due to purely statistical, i.e., nonbiological, effects and (ii) to establish the minimum uncertainty below which changes in SUV cannot be expected to be an indicator of physiological changes. Methods: Three sets of measurements were made using a GE Discovery STE PET/CT Scanner in 3D mode: (1) A uniform 68Ge 20 cm diameter cylindrical phantom was imaged. Thirty serial frames were acquired for durations of 3, 6, 10, 15, and 30 min. (2) Esser flangeless phantom (Data Spectrum, ∼6.1 L) with fillable thin-walled cylinders inserts (diameters: 8, 12, 16, and 25 mm; height: ∼3.8 mm) was scanned for five consecutive 3 min runs. The cylinders were filled with 18FDG with a 37 kBq/cc concentration, and with a target-to-background ratio (T/BKG) of 3/1. (3) Eight cancer patients with healthy livers were scanned ∼1.5 h post injection. Three sequential 3 min scans were performed for one bed position covering the liver, with the patient and bed remaining at the same position for the entire length of the scan. Volumes of interest were drawn on all images using the corresponding CT and then transferred to the PET images. For each study (1-3), the average percent change in SUVmean and SUVmax were determined for each run pair. Moreover, the repeatability coefficient was calculated for both the SUVmean and SUVmax for each pair of runs. Finally, the overall ROI repeatability coefficient was determined for each pair of runs. Results: For the 68Ge phantom the average percent change in SUVmax and SUVmean decrease as a function of increasing acquisition time from 4.7 ± 3.1 to 1.1 ± 0.6%, and from 0.14 ± 0.09 to 0.04 ± 0.03%, respectively. Similarly, the coefficients of repeatability also decrease between the 3 and 30 min acquisition scans, in the range of 10.9 ± 3.9% - 2.6 ± 0.9%, and 0.3 ± 0.1% - 0.10 ± 0.04%, for the SUVmax and SUVmean, respectively. The overall ROI repeatability decreased from 18.9 ± 0.2 to 6.0 ± 0.1% between the 3 and 30 min acquisition scans. For the 18FDG phantom, the average percent change in SUVmax and SUVmean decreases with target diameter from 3.6 ± 2.0 to 1.5 ± 0.8% and 1.5 ± 1.3 to 0.26 ± 0.15%, respectively, for targets from 8 - 25 mm in diameter and for a region in the background (BKG). The coefficients of repeatability for SUVmax and SUVmean also decrease as a function of target diameter from 7.1 ± 2.5 to 2.4 ± 0.9 and 4.2 ± 1.5 to 0.6 ± 0.2, respectively, for targets from 8 mm to BKG in diameter. Finally, overall ROI repeatability decreased from 12.0 ± 4.1 to 13.4 ± 0.5 targets from 8 mm to BKG in diameter. Finally, for the measurements in healthy livers the average percent change in SUVmax and SUVmean were in the range of 0.5 ± 0.2% - 6.2 ± 3.9% and 0.4 ± 0.1 and 1.6 ± 1%, respectively. The coefficients of repeatability for SUVmax and SUVmean are in the range of 0.6 ± 0.7% - 9.5 ± 12% and 0.6 ± 0.7% - 2.9 ± 3.6%, respectively. The overall target repeatability varied between 27.9 ± 0.5% and 41.1 ± 1.0%. Conclusions: The statistical fluctuations of the SUVmean are half as large as those of the SUVmax in the absence of biological or physiological effects. In addition, for clinically applicable scan durations (i.e., ∼3 min) and FDG concentrations, the SUVmax and SUVmean have similar amounts of statistical fluctuation for small regions. However, the statistical fluctuations of the SUVmean rapidly decrease with respect tothe SUVmax as the statistical power of the data grows either due to longer scanning times or as the target regions encompass a larger volume. [ABSTRACT FROM AUTHOR]

Purpose: In this study, the authors validated a novel respiratory tracking device, the multidimensional respiratory tracking (MDRT) system, that was designed to assist in correcting for respiratory motion in PET/CT images. The authors also investigated a novel PET acquisition technique, smart gating (SG), that enables to acquire motion-free PET data prospectively, with minimum user interference and with no additional postprocessing of the PET data. Methods: MDRT uses visual tracking techniques to track simultaneously the two-dimensional (in the vertical plane) motion of multiple fiducial markers using a standard video camera. A threshold window is set at the breathing amplitude of interest using the MDRT GUI. A trigger is generated at a rate of 250 Hz as long as the breathing signal is within the threshold window. The triggers are fed into the PET scanner to initialize one single bin of a gated acquisition every 4 ms. No triggers are delivered as the breathing signal drifts outside the threshold window. Consequently, PET data are acquired only whenever the breathing signal is confined within the amplitude threshold window, thus resulting into a motion-free image set. The accuracy of MDRT in tracking the breathing signal was assessed (1) by comparing the period of an oscillating phantom, as measured by MDRT, to that measured with a photogate timer and (2) by comparing the MDRT output to that of the real-time position management (RPM) in ten patients. The SG PET/CT acquisition was validated in phantoms and in two stereotactic body radiosurgery (SBRS) lung DIBH-PET/CT patients. Results: MDRT was in agreement with the photogate timer in determining the period of motion to less than 2%. The percent errors between MDRT and RPM in the positions of the peaks and troughs of the ten patients' breathing signals were within 10%. In phantoms, SG technique enables to correct for motion-induced artifacts in the PET images and improve the accuracy of PET quantitation. For the SBRS application, in one patient, the patient's CT lesion was not detected in the corresponding clinical PET images, while it exhibited an SUV of 1.8 in the DIBH image set. In the second patient, DIBH-PET images showed an improved PET-to-CT spatial matching and a 52% increase in the lesion SUV. Conclusions: MDRT has been shown to be accurate in tracking breathing motion and assisted in implementing a smart-gating PET acquisition technique that allowed to acquire prospectively motion-free PET images. [ABSTRACT FROM AUTHOR]

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here. [ABSTRACT FROM AUTHOR]

High rates of locoregional control are observed after chemoradiation (CRT) for head and neck squamous cell carcinoma (HNSCC), but distant metastasis (DM) remains a major cause of morbidity and mortality. Improved prediction of adverse oncologic outcomes would facilitate patient selection for escalated therapy. Prior studies have shown that tumor hypoxia on FMISO PET predicts for local failure after CRT, but data showing an association with DM are limited. We combined data from two clinical trials to evaluate whether tumor hypoxia on FMISO PET predicts DM-free survival (DMFS) and overall survival (OS) after CRT for HNSCC. From 2004 to 2020, patients undergoing CRT for nonmetastatic HNSCC who enrolled on two clinical trials investigating the role of FMISO PET (NCT00606294, NCT03323463) were included in this analysis. FMISO PET before and ≥ 7 days after starting CRT were evaluated for tumor hypoxia. Pre- and intra-treatment hypoxia were hypothesized to predict worse DMFS and OS, measured from the end of CRT. DMFS was defined using a composite endpoint, consisting of biopsy-proven HNSCC outside the head and neck or death. Predictors of DMFS and OS were modeled with Cox regression. Among 295 patients, 86% had oropharyngeal primaries, and 89% had HPV+ disease. Per AJCC 7th edition staging, 15% had T ≥ 3, and 18% had N ≥ 2c. De-escalated 30 Gy CRT was delivered to 49% of patients; all others received 70 Gy CRT. Pre- and intra-treatment hypoxia on FMISO PET were identified in 218 (74%) and 69 (23%) patients, respectively. Median follow-up among survivors was 4.4 years. DMFS and OS at 4 years were 89% and 94%, respectively. Among 17 patients with DM, 4 had prior locoregional recurrence. Among 69 patients negative for pre-treatment hypoxia, none experienced DM. In univariable models, worse DMFS was associated with pre-treatment hypoxia (HR 3.37, 95% CI = 1.03-11.1, p = 0.04) and intra-treatment hypoxia (HR 2.57, 95% CI = 1.28-5.15, p = 0.008). In a multivariable model, intra-treatment hypoxia independently predicted worse DMFS (HR 2.94, 95% CI = 1.40-6.21, p = 0.005), alongside T ≥ 3 disease. In univariable models, trends toward worse OS were seen with pre-treatment hypoxia (HR 2.76, 95% CI = 0.84-9.08, p = 0.09) and intra-treatment hypoxia (HR 1.76, 95% CI = 0.85-3.61, p = 0.13). We report the largest clinical series evaluating tumor hypoxia on FMISO PET as a predictor for DMFS and OS after CRT for HNSCC. Pre- and intra-treatment hypoxia on FMISO PET significantly predicted worse DMFS. Intra-treatment hypoxia predicted worse DMFS independent of tumor stage. No patients who were negative for hypoxia on pre-treatment FMISO PET experienced DM. Tumor hypoxia on FMISO PET may aid in selecting patients for escalated treatment strategies aimed at preventing DM. [ABSTRACT FROM AUTHOR]

Greater disease burden is associated with poor outcomes after CAR T. Bridging therapy (BT) is widely used between apheresis and CAR T infusion. We hypothesized that the dynamics of radiomic cytoreduction during the bridging period would be prognostic. Patients with large B-cell lymphoma (LBCL) treated with CD19 CAR T from 2016–2022 were stratified into 5 BT cohorts: 1) no BT 2) radiotherapy (RT) 3) systemic therapy (ST) 4) ST+RT and 5) steroids alone. All patients had a pre apheresis PET. Patients who received BT also had a repeat PET post BT but pre-CAR T infusion. MTV for all scans was analyzed using a semi-automated method with SUV4 threshold. Progression free (PFS) and overall survival (OS) from CAR T infusion were estimated by Kaplan Meier; multivariable analysis was performed using proportional hazards. Patients were stratified by pre-BT disease burden using an absolute MTV cutpoint of 65.4 cc established by a maximally selected log-rank statistic for PFS. "High" and "low" MTV were defined as MTV above or below this cutpoint, respectively. To quantify the impact of effective cytoreduction during BT, we then created 4 BT MTV risk groups: a) "pLow" with persistently low MTV pre and post BT, b) "pHigh" with persistently high MTV pre and post BT, c) "Rising" with baseline low MTV which increased to high post BT and d) "Improved" with baseline high MTV which decreased to low post BT. One hundred ninety-one patients with LBCL (79%), high grade BCL (17%) or primary mediastinal BCL (4%) received CAR T (53% axicabtagene, 22% tisagenlecleucel, 25% lisocabtagene). Forty-seven patients (25%) received no BT, 104 (54%) had ST, 30 (16%) had RT, 5 (3%) had ST+RT, and 5 (3%) steroids alone. Of the 144 patients who received BT, 56% had any degree of quantitative cytoreduction post-BT and only 49% achieved at least 50% MTV reduction. With median follow-up of 21.6 months post CAR T infusion, 12 months PFS was 65% for RT (CI = 47–90%), 50% for no BT (CI = 37–67%), and 39% for ST (CI = 30–50%). Our established MTV cutpoint of 64.5 cc and was significantly associated with PFS (median 20 vs. 2.7 m, P < 0.0001) and OS (unreached vs. 11 m, P < 0.0001). MTV dynamics during BT were further prognostic with 'Improved' patients having significantly better outcomes vs. the "pHigh" patients with PFS of 11 vs. 2.0 m and unreached vs. 7.2 m OS (P < 0.0001 for both). On multivariate analysis, MTV trajectory across the bridging period remained significantly associated with PFS (P < 0.001); importantly, there was no significant difference in PFS between Improved and pLow patients (HR for Improved = 2.74, CI = 0.82-9.18). In our real-world experience, BT was able to reduce disease burden in approximately half of patients. We demonstrate that effective BT can enable initially high disease burden patients to achieve outcomes comparable to low disease burden patients, suggesting BT can convert patients from high to low risk pre-CAR T. [ABSTRACT FROM AUTHOR]

Stereotactic body radiotherapy (SBRT) is increasingly used for oligorecurrent prostate cancer (OPC). Despite excellent local control, distant metastasis free survival rates are more modest. We hypothesized SBRT outcomes could be optimized with improved staging imaging and integration of a well-tolerated targeted radiopharmaceutical therapy (RLT) for microscopic disease. We report initial results of a prospective, single-institution pilot (NCT05079698) of a novel, PSMA-based theranostic strategy for OPC. Men with castrate sensitive OPC and 1-3 sites of PSMA PET avid disease ("index lesions") and no PSMA non-avid sites were eligible. No androgen deprivation therapy was permitted. Subjects first received 2 cycles of 177Lu-PSMA-617 RLT (7.47±0.14 GBq) spaced 6 weeks apart. In vivo dosimetry was performed during cycle 1. Four weeks post-cycle 2, patients were restaged with 68Ga-PSMA PET for an interim (post-RLT) response assessment. Index lesions were then consolidated with SBRT (9 Gy x 3) irrespective of post-RLT PET response. The primary outcome was feasibility defined as successful completion of protocol-mandated therapy without intercurrent distant failure on post-RLT PET. Six men were treated with nine total index lesions (5 nodal, 3 osseous, 1 visceral). The study met its primary endpoint; all completed required interventions and no distant progression was seen on interim PSMA PET. Treatment was well tolerated; no grade 3+ toxicities, 2/6 had grade 2 toxicities (transient anemia and hyperbilirubinemia) and 5/6 had grade 1 toxicities. Median baseline lesion-level PSMA SUVmax was 16.8±8.7. Median interim SUVmax was 6.2±2.5 and declined for all but one lesion post-RLT (median -65%). Median SUVmax at 3-mos post-SBRT was 3.3±2.5 and decreased for all evaluable lesions (median -80%). Median baseline PSA was 2.01 ng/mL (range: 0.72-4.56) which declined in 5/6 post-RLT. The 6th patient experienced biochemical rise with interim PET showing only greater avidity in the known index lesion and SBRT was completed per protocol. All 4 evaluable patients with at least one post-SBRT follow-up have improved PSA at last visit (range 5.5-12 mos from cycle 1), and 2/4 have undetectable PSA. Composite dosimetry, correlatives and quality of life studies are forthcoming. Our pilot study demonstrates the feasibility of a novel PSMA anchored theranostic strategy combining SBRT with targeted RLT for OPC. Preliminary data suggests promising outcomes, including the possibility of achieving an undetectable biochemical disease state without hormone therapy. [ABSTRACT FROM AUTHOR]

Greater tumor burden before CD19-targeted Chimeric Antigen Receptor T Cell (CAR T) therapy predicts lower complete response (CR) rate and shorter survival. Patterns of failure studies have identified baseline lesion characteristics associated with post-CAR T failure. It is not yet known how bridging radiotherapy (BRT) before CAR T alters outcomes and patterns of failure. We reviewed non-Hodgkin lymphoma patients treated with BRT from 30d pre-apheresis to CAR T infusion from 2016-2021. Metabolic tumor volume (MTV) was determined by manual and semiautomatic methods (concordance correlation coefficient >0.98) using threshold SUV 4 pre-BRT and post-BRT/pre-CAR T; maximally selected log-rank established an MTV cut point of 16cc. Patients were stratified by MTV as 'Poor Risk' (>16cc post-BRT), 'Good Risk' (≤16cc pre- and post-BRT) or 'Converted Risk' (>16cc pre-BRT and ≤16cc post-BRT). Response was evaluated by Lugano criteria. Progression (PD) was classified as pre-existing (present pre-CAR T) vs. new and in field, marginal (within 1cm of), or distant with respect to prescription dose region. Progression free and overall survival (PFS/OS) were measured from CAR T infusion by Kaplan Meier. 41 patients with diffuse large B cell (DLBCL; n = 33), mantle cell (n = 7) and Burkitt's lymphoma (n =1) were reviewed. 30 (73%) were advanced stage. Most common BRT sites were head/neck (n=14), pelvis (n=7), and extremity (n=7). BRT sites were bulky (≥7.5cm) in 19 (46%), extranodal in 22 (54%), and SUV>10 in 29 (71%). 39% of BRT treated all active disease. Median dose was 30Gy (4 - 54). 17 (41%) also received systemic therapy during the bridging period. Patients received axicabtagene (n=19), tisagenlecleucel (n=10), lisocabtagene (n=9), or brexucabtagene (n=3). In 33 patients with interim PET after BRT: 85% had PR/CR in field (CR=10), 58% had out of field PD. Despite median 13d from BRT to PET, there was a significant reduction in overall max diameter (p=0.006) and SUV (p=0.03) and in field MTV (p<0.001). At median post-CAR T follow up of 20.3mo, 19 DLBCL patients progressed. Most PD (12/19) involved pre-existing sites; 8 were in field/marginal. In DLBCL, median PFS was 20mo; median OS was not reached. In 25 DLBCL patients with post-BRT PET, median PFS was 26, 31, and 2.7mo in Good, Converted, and Poor risk groups. Median OS was unreached for Good/Converted and 11mo for Poor risk. BRT significantly reduced maximum diameter, SUV, and MTV – all predictors of poor post-CAR T prognosis. Patterns of failure in this cohort were similar to published failure patterns after CAR T without bridging therapy, which may suggest improved control of higher-risk lesions. Similar PFS and OS in patients with initially low MTV and those who achieved low MTV post-BRT suggests the ability to improve patient risk; larger cohorts are needed to confirm this finding. [ABSTRACT FROM AUTHOR]

De-escalation strategies for the treatment of HPV-associated OPC show promise for effective, less toxic treatment. However, identifying accurate markers of more aggressive subsets of HPV OPC remains challenging. The 30 Reduction in Radiation for OPC (ROC) trial prospectively used intra-treatment 18F-FMISO imaging to selectively de-escalate patients to 30Gy chemoradiotherapy, however, a subset of patients still developed nodal recurrence. We hypothesized that diffusion-weighted (DW) MRI-derived quantitative imaging metrics, such as apparent diffusion coefficient (ADC), a surrogate marker of tumor cellularity based on water diffusion patterns, might help identify patients at high risk of recurrence and enable broader use of de-escalation strategies. The 30 ROC trial enrolled patients with p16-positive OPC, cT0-2, N1-2c (AJCC 7th ed). All patients had pre-treatment 18F-FMISO (fluoromisonidazole) PET scan and those with baseline nodal hypoxia underwent a 2nd intra-treatment scan. All patients underwent primary site surgery where negative margin was not required. All patients had gross neck nodal disease. Those with intra-treatment resolution of nodal hypoxia or without initial hypoxia were de-escalated to 30Gy (non-hypoxic group) with 2 cycles of concurrent chemotherapy, while those with persistent radiographic hypoxia (hypoxic group) were treated to 70Gy. Standard T1, T2 weighted, and multiple b-value DW-MRI data were acquired pre-treatment and weekly during the first 4 weeks of treatment. Two radiation oncologists delineated nodal tumor regions of interest (ROIs) in a blinded fashion with ITK-SNAP on DW images (b= 0 s/mm2). Multiple b-value DW data were fitted to a monoexponential model to calculate ADC (mm2/s). The data analysis was performed on ROIs and voxel-wise using the in-house developed tool MRI-QAMPER. Standard statistical analysis was performed using MRI and clinical response data based on RECISTv1.1 provided by a radiologist. 158 patients were enrolled, of whom 95 had pre-treatment DW-MRI data available with tumor ROI with ADC values. Based on overall 18F-FMISO imaging, 12.6% (12/95) exhibited persistent hypoxia and 87.4% (83/95) had resolved/no hypoxia. All patients with nodal recurrences were in the de-escalated non-hypoxic group (8/83). Pre-treatment ADC was not different between overall hypoxic and non-hypoxic groups. Among de-escalated patients, those who developed nodal recurrence exhibited significantly different intra-treatment ADC at week 3 (before completing 30Gy) relative to those who did not recur (P<0.05, Wilcoxon rank-sum test). The quantitative imaging metric, ADC, reflects both the restricted and hindered Brownian motion of water molecules in tumor tissue. Thus, ADC may be a useful intra-treatment marker to identify patients at risk for nodal recurrence to benefit from the incorporation of an upfront planned neck dissection after 30Gy as part of the de-escalation strategy. [ABSTRACT FROM AUTHOR]

F-18 Fluoromisonidazole (FMISO) is a robust imaging biomarker for tumor hypoxia. Hypoxia limits effective cancer treatment, specifically radiotherapy in head and neck cancers. We have completed and have ongoing trials using hypoxia imaging to guide radiation dose de-escalation. To ensure wide applicability, we sought to develop and validate standardized qualitative and quantitative criteria to accurately and reliably interpret clinical FMISO PET/CT images. All HPV+ oropharyngeal cancer patients who had FMISO PET/CT imaging before and about 2 weeks into chemoradiation therapy and pre-treatment F-18 FDG PET/CT were included. 4 independent nuclear medicine (NM) physicians with varying clinical experience of 1, 3, 5, and 15 years with no FMISO experience interpreted images. Training and reference interpretations were performed by a 5th NM physician with 30 years of clinical and 15 years of FMISO experience. Suspicious cervical lymph nodes (LN) > 1 cm in short axis with abnormal FDG avidity on FDG PET/CT were categorized as positive or negative for FMISO uptake. A LN was considered positive if it demonstrated SUVmax visually greater than floor of mouth (FOM). FMISO SUVmax of the LN and FOM were obtained using a 3D VOI. The training and validation process consisted of: (1) initial instruction; (2) practice interpretation; (3) one on one re-training on contentious group reads; (4) final group training; (5) validation interpretation of new scans. Qualitative, visual comparison of FMISO uptake in LN to FOM, and quantitative, ratio of FMISO SUVmax of LN to FOM, were analyzed. The Fleiss κ coefficient (κ) was calculated to measure inter-reader agreement. 192 FMISO scans were included. Qualitative criteria mean sensitivity and specificity (SE/SP) after initial instruction were 0.773 and 0.809. κ was 0.338. Mean SE/SP after additional training were 0.976 and 0.869. κ was 0.864 [95%CI: 0.782 to 0.944]. For the quantitative criteria, ROC curve analysis was used to estimate the best threshold by maximizing the Youden index, which was determined to be SUVmax LN/SUVmax FOM > 1.2. Quantitative criteria mean SE/SP after additional training were 0.896 and 0.953. κ was 0.859 (95%CI: 0.761 to 0.944). The quantitative criteria alone demonstrated a lower sensitivity than the qualitative, 0.896 vs. 0.976. Therefore, we suggest using a hybrid method with quantitative criteria as a guide with the ultimate decision based on qualitative assessment to minimize the number of patients with false negatives and subsequent undertreatment. The hybrid qualitative/quantitative diagnostic interpretation criteria developed for evaluating FMISO PET/CT in combination with dedicated training has substantial inter-reader agreement and excellent diagnostic performance. This suggests that multi-institutional studies that employ FMISO PET for patient stratification in prospective trials are feasible and can be implemented. [ABSTRACT FROM AUTHOR]

The 30 ROC Trial utilizes functional imaging, specifically pre-treatment (Tx) and intra-Tx fluorine-18-labeled fluoromisonidazole positron emission tomography (18F-FMISO PET) to select appropriate human papillomavirus positive (HPV+) OPC patients for major de-escalation to 30 Gy. In this trial, patients also underwent pre-Tx and weekly multiparametric magnetic resonance imaging (MRI) scans to correlate with hypoxia status. The aim of the present study was to assess the value of MRI tumor volume to predict baseline hypoxia status in HPV+OPC patients who underwent major dose de-escalation. A total (N = 158) patients with cT0-2,N1-2b (AJCC 7th ed.) p16+ OPC were enrolled. All patients had pre-Tx 18F-FMISO PET scans to assess baseline hypoxia status, and only those with baseline hypoxia underwent a repeat intra-Tx scan. Pre-Tx and weekly intra-Tx MRI scans were acquired on technology company's 3T MRI scanner using a neurovascular phased array coil. Radiation oncologists delineated gross nodal disease as regions of interest on T 2 w images. Tumor volume (cm3) was calculated in ITK SNAP for each patient using the segmentation software. All standard statistical analyses were performed on RStudio 2021.09.2. Of the 158 patients, N=95 patients had analyzable pre-Tx and weekly on-Tx MRI scans. Based on pre-Tx 18F-FMISO PET results, increased tumor volume was associated with baseline nodal hypoxia (N=69, median 18.55 cm3, range: 3.15- 60.62) compared to initially non-hypoxic tumors (N= 26, median 6.44 cm3, range: 0.48 – 47.74, p<0.001). After the intra-Tx 18F-FMISO PET result, patients were further stratified into converted negative (N= 57), persistently hypoxic (N=12), and never hypoxic (N=26). We found that the median pre-Tx nodal volume for the persistently hypoxic (median 17.75 cm3, range 5.54- 42.93, p=0.006) and converted negative (median 18.55 cm3, range 3.15 – 60.62, p<0.001) groups was significantly (P= <0.05) increased compared to the initially hypoxia negative patients (6.44 cm3, range 0.48 – 47.74). We performed further assessment of this pattern with intra-Tx MRIs (weeks 1-4) and found that this correlation of groups with baseline hypoxia (converted negative and persistently hypoxic) continued to exhibit larger nodal volume compared to the never hypoxic group. Pre-Tx nodal volume on MRI correlates with pre-Tx hypoxia status where the larger the volume, the higher the likelihood of hypoxia. This correlation continued throughout radiation Tx as evidenced by the weekly MRI scans. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate how changes in tumor hypoxia, according to serial fluorine-18-labeled fluoro-misonidazole (18F-FMISO) positron emission tomography (PET) imaging, affect the efficacy of intensity-modulated radiotherapy (IMRT) dose painting.Methods and Materials: Seven patients with head and neck cancers were imaged twice with FMISO PET, separated by 3 days, before radiotherapy. Intensity-modulated radiotherapy plans were designed, on the basis of the first FMISO scan, to deliver a boost dose of 14 Gy to the hypoxic volume, in addition to the 70-Gy prescription dose. The same plans were then applied to hypoxic volumes from the second FMISO scan, and the efficacy of dose painting evaluated by assessing coverage of the hypoxic volumes using Dmax, Dmin, Dmean, D95, and equivalent uniform dose (EUD).Results: Similar hypoxic volumes were observed in the serial scans for 3 patients but dissimilar ones for the other 4. There was reduced coverage of hypoxic volumes of the second FMISO scan relative to that of the first scan (e.g., the average EUD decreased from 87 Gy to 80 Gy). The decrease was dependent on the similarity of the hypoxic volumes of the two scans (e.g., the average EUD decrease was approximately 4 Gy for patients with similar hypoxic volumes and approximately 12 Gy for patients with dissimilar ones).Conclusions: The changes in spatial distribution of tumor hypoxia, as detected in serial FMISO PET imaging, compromised the coverage of hypoxic tumor volumes achievable by dose-painting IMRT. However, dose painting always increased the EUD of the hypoxic volumes. [ABSTRACT FROM AUTHOR]

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has recently been approved as second-line treatment for relapsed/refractory large B-cell lymphoma (LBCL). This study compares patterns of disease relapse and progression across patients receiving CAR-T as second-line (early administration) versus third or subsequent lines (late administration). We analyzed 354 patients treated with Axicabtagene ciloleucel (71%) and Lisocabtagene maraleucel (29%); 80 (23%) received early administration, and 274 (77%) late administration. One-year overall survival was higher in the early group (82% [95% CI 72-93] vs. 71% [95% CI 66-77], p = 0.048). However, the survival benefit was not sustained in multivariable Cox regression modeling and propensity score matching. One-year cumulative incidences of relapse were similar (37% [95% CI 24-50] vs. 43% [95% CI 37-49], p = 0.2), as were 1-year progression-free survival probabilities (62% [95% CI 50-76] vs. 50% [95% CI 44-57], p = 0.14). The early group exhibited a favorable toxicity profile, with lower rate of grade ≥2 cytokine release syndrome (26% vs. 39%, p = 0.031) and reduced cumulative incidence of severe neutropenia (41% [95% CI 30-52] vs. 55% [95% CI 49-60], p = 0.027). Our results indicate favorable outcomes with CAR-T irrespective of treatment line. The equivalence in disease control suggests that CAR-T resistance mechanisms persist in LBCL failing first-line therapy., Competing Interests: Competing interests: Perales reports honoraria from Adicet, Allogene, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Sanofi, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics and Sellas Life Sciences, and the scientific advisory board of NexImmune. He has ownership interests in NexImmune, Omeros, and OrcaBio. He has received institutional research support for clinical trials from Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. Lori Leslie reports honoraria/consulting/speaker bureau from Gilead/Kite, SeaGen, ADC Therapeutics, Celgene/BMS, Janssen/J&J, Pharmacyclics, Beigene, Abbvie, Genmab, AstraZeneca, TG Therapeutics, Epizyme, Karyopharm, Merck, Eli Lily. Gunjan Shah has research funding to the institution from Janssen, Amgen, BMS, Beyond Spring, and GPCR, and is on the DSMB for ArcellX. K.R. Kite/Gilead: Research Funding, Consultancy, Honoraria, and travel support; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria; Pierre-Fabre: travel support. Lori A Leslie reports honoraria/consulting/speaker bureau from Gilead/Kite, SeaGen, ADC Therapeutics, Celgene/BMS, Janssen/J&J, Pharmacyclics, Beigene, Abbvie, Genmab, AstraZeneca, TG Therapeutics, Epizyme, Karyopharm, Merck, Eli Lily. Michael Scordo has served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, and Omeros; has received research funding from Angiocrine Bioscience and Omeros; has served on ad hoc advisory boards for Kite Pharma; and has received honoraria from i3Health and Medscape for CME related activity. Dr. Sergio A. Giralt is a consultant for and receives research funding from Amgen, Actinium, Celgene, Johnson & Johnson, and Takeda and is a consultant for Jazz Pharmaceuticals, Novartis, Kite Pharma, and Spectrum Pharmaceuticals. Samantha Brown receives salary support from AACR Project GENIE Biopharma Collaborative. The remaining authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: We designed a CD19-targeted chimeric antigen receptor (CAR) comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3ζ and 4-1BB/CD3ζ CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities., Methods: In this first-in-human, phase I, dose escalation and expansion clinical trial, patients with relapsed or refractory large B-cell lymphoma received 19(T2)28z-1XX CAR T cells at four dose levels (DLs), ranging from 25 to 200 × 10 6 ., Results: Twenty-eight patients underwent apheresis and received CAR T cells. Sixteen and 12 patients were treated in the dose escalation and expansion cohorts, respectively. The overall response rate (ORR) was 82% and complete response (CR) rate was 71% in the entire cohort. The lowest dose of 25 × 10 6 was selected for dose expansion. In 16 patients treated at this DL, 88% achieved ORR and 75% CR. With the median follow-up of 24 months, the 1-year event-free survival was 61% (95% CI, 45 to 82) and 14 patients remain in continuous CR beyond 12 months. In all cohorts, grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome rates were low at 4% and 7%, respectively. 1XX CAR T-cell products contain a higher proportion of CD8 T cells with memory features, and CAR T-cell persistence has been detected beyond 1-2 years in patients with ongoing remission., Conclusion: The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profiles and may benefit the treatment of other hematologic malignancies, solid tumors, and autoimmunity.

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [ 89 Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer., Methods: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [ 89 Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [ 89 Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [ 89 Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [ 89 Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741., Findings: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [ 89 Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [ 89 Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort., Interpretation: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [ 89 Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies., Funding: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation., Competing Interests: Declaration of interests NJC received grants from AbbVie, Amgen, Harpoon Therapeutics, Merck, Monte Rosa Therapeutics, and Roche/Genentech, royalties from Wolters Kluwer, and consulting fees from G1 Therapeutics and Sanofi, and participated on data safety and monitoring boards for AbbVie and Harpoon Therapeutics. AKe received travel support from the American Association of Physicists in Medicine and has ownership interest in patent US9814431B2. AM filed patent PCT/US2022/031066. LB declares nonremunerated consultancies for AAA-Novartis, Ipsen, Clovis, ITM, Iba, Great Point Partners, PointBiopharma, and RayzeBio; grant support from AAA-Novartis; participation on the data safety and monitoring board for AAA-Novartis, PointBiopharma, and Precirix; and the following leadership roles: Board of Directors of American Board of Nuclear Medicine and Member of the Scientific Advisory Board of the Neuroendocrine Tumor Research Foundation. MJM received honoraria from Mashup Media; declares patent application 18/448,609; has participated on data safety and monitoring boards for Lantheus, AstraZeneca, Daiichi, Convergent Therapeutics, Pfizer, ITM Isotope Technologies, Clarity Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Telix, Progenics, Z-Alpha, Ambrx, Flare Therapeutics, Fusion Pharmaceuticals, Curium, TransThera, Bristol Myers Squibb, Arvinas, Core Medica, Exelixis, Corcept, Janssen, Novartis, and Astellas; and has stock options in Doximity. JSL has consulted for Clarity Pharmaceuticals, Curie, Therapeutics Inc, Earli, Evergreen Theragnostics, NexTech Invest, Telix Pharmaceuticals, Suba Therapeutics, Inhibrx, Precirix, Alpha-9, Solve, and TPG Capital; a leadership role in the Society of Nuclear Medicine; stock in Curie Therapeutics, Summit Biomedical Imaging, Telix Pharmaceuticals, and Evergreen Theragnostics; and receipt of materials from Clarity Pharmaceuticals and Avid Radiopharmaceuticals. CMR has consulted for Amgen, AstraZeneca, Daiichi Sankyo, Hoffman-La Roche, Jazz, Legend, Bridge Medicines, and Harpoon Therapeutics; has a leadership role on the LUNGevity Foundation Board of Directors; and has stock options for Auron, DISCO, and Earli. JTP has consulted for GLG and DISCO. JSL, CMR, and JTP are inventors on patents WO2021007371A1, WO2022153194A, and WO2023034557A1, and have received royalty payments from Memorial Sloan Kettering Cancer Center. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: PET-CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care., Methods: Staging PET-CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET-CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUV mean of liver to the average SUV mean of the bilateral rectus femoris muscles. Kaplan-Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS., Results: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET-CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56-0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009)., Conclusions: Elevated LRF ratio, a patient-specific PET-CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Anti-programmed death 1 (PD-1) inhibitors are the standard of care for advanced gastroesophageal cancer. Although recommendations and approval by regulatory agencies are often based on programmed death ligand 1 (PD-L1) expression, pathologic assessments of PD-L1 status have several limitations. Single-site biopsies do not adequately capture disease heterogeneity within individual tumor lesions or among several lesions within the same patient, the PD-L1 combined positive score is a dynamic biomarker subject to evolution throughout a patient's disease course, and repeated biopsies are invasive and not always feasible. Methods: This was a prospective pilot study of the PD-L1-targeting radiotracer, 18 F-BMS-986229, with PET imaging (PD-L1 PET) in patients with gastroesophageal cancer. Patients were administered the 18 F-BMS-986229 radiotracer intravenously at a dose of 370 MBq over 1-2 min and underwent whole-body PET/CT imaging 60 min later. The primary objective of this study was to evaluate the safety and feasibility of 18 F-BMS-986229. The trial is registered with ClinicalTrials.gov (NCT04161781). Results: Between February 3, 2020, and February 2, 2022, 10 patients with gastroesophageal adenocarcinoma underwent PD-L1 PET. There were no adverse events associated with the 18 F-BMS-986229 tracer, and imaging did not result in treatment delays; the primary endpoint was achieved. Radiographic evaluation of PD-L1 expression was concordant with pathologic assessment in 88% of biopsied lesions, and 18 F-BMS-986229 uptake on PET imaging correlated with pathologic evaluation by the combined positive score (Spearman rank correlation coefficient, 0.64). Seventy-one percent of patients with 18 F-BMS-986229 accumulation on PET imaging also had lesions without 18 F-BMS-986229 uptake, highlighting the intrapatient heterogeneity of PD-L1 expression. Patients treated with frontline programmed death 1 inhibitors who had 18 F-BMS-986229 accumulation in any lesions on PET imaging had longer progression-free survival than patients without tracer accumulation in any lesions (median progression-free survival, 28.4 vs. 9.9 mo), though the small sample size prevents any definitive conclusions. Conclusion: PD-L1 PET imaging was safe, feasible, and concordant with pathologic evaluation and offers a potential noninvasive tool to assess PD-L1 expression., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response., Methods: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [ 89 Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [ 89 Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16)., Findings: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [ 89 Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [ 89 Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted., Interpretation: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [ 89 Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies., Funding: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [ 177 Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177 Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177 Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [ 177 Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis., (© 2023. The Author(s).)

Greater tumor burden before CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy predicts lower complete response rate and shorter overall survival (OS) in patients with aggressive non-Hodgkin lymphoma (NHL). Recent patterns of failure studies have identified lesion characteristics, including size, standard uptake value (SUV), and extranodal location, as associated with post-CAR-T therapy failure. Here we analyzed the effect of bridging radiation-containing treatment (BRT) on pre-CAR-T therapy lesion- and patient-level characteristics and post-CAR-T therapy outcomes, including patterns of failure. Consecutive NHL patients who received radiation therapy from 30 days before leukapheresis until CAR T cell infusion were reviewed. Metabolic tumor volume (MTV) was contoured with a threshold SUV of 4. The first post-CAR-T therapy failures were categorized as preexisting/new/mixed with respect to pre-CAR-T therapy disease and in-field/marginal/distant with respect to BRT. Forty-one patients with diffuse large B cell lymphoma (DLBCL; n = 33), mantle cell lymphoma (n = 7), or Burkitt lymphoma (n = 1) were identified. BRT significantly improved established high-risk parameters of post-CAR-T therapy progression, including in-field median MTV (45.5 cc to .2 cc; P < .001), maximum SUV (18.1 to 4.4; P < .001), diameter (5.5 cm to 3.2 cm; P < .001), and lactate dehydrogenase (LDH; 312 to 232; P = .025). DLBCL patients with lower LDH levels post-BRT had improved progression-free survival (PFS; P = .001). In DLBCL, first failures were new in 7 of 19 patients, preexisting in 5 of 19, and mixed in 7 of 19; with respect to BRT, 4 of 19 were in-field and 4 of 19 were marginal. Post-CAR-T therapy survival was similar in patients with initially low MTV and those with newly low MTV post-BRT using a statistically determined threshold of 16 cc (PFS, 26 months versus 31 months; OS unreached for both). BRT produced significant cytoreductions in diameter, SUV, MTV, and LDH, all predictors of poor post-CAR-T therapy outcomes. Similar PFS and OS in patients with initially low MTV and those who achieved newly low MTV after BRT suggest that BRT may "convert" poor-risk patients to better risk. In the future, the response to BRT may allow for risk stratification and individualization of bridging strategies., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Immunotherapy offers the potential for durable clinical benefit but calls into question the association between tumor size and outcome that currently forms the basis for imaging-guided treatment. Artificial intelligence (AI) and radiomics allow for discovery of novel patterns in medical images that can increase radiology's role in management of patients with cancer, although methodological issues in the literature limit its clinical application. Using keywords related to immunotherapy and radiomics, we performed a literature review of MEDLINE, CENTRAL, and Embase from database inception through February 2022. We removed all duplicates, non-English language reports, abstracts, reviews, editorials, perspectives, case reports, book chapters, and non-relevant studies. From the remaining articles, the following information was extracted: publication information, sample size, primary tumor site, imaging modality, primary and secondary study objectives, data collection strategy (retrospective vs prospective, single center vs multicenter), radiomic signature validation strategy, signature performance, and metrics for calculation of a Radiomics Quality Score (RQS). We identified 351 studies, of which 87 were unique reports relevant to our research question. The median (IQR) of cohort sizes was 101 (57-180). Primary stated goals for radiomics model development were prognostication (n=29, 33.3%), treatment response prediction (n=24, 27.6%), and characterization of tumor phenotype (n=14, 16.1%) or immune environment (n=13, 14.9%). Most studies were retrospective (n=75, 86.2%) and recruited patients from a single center (n=57, 65.5%). For studies with available information on model testing, most (n=54, 65.9%) used a validation set or better. Performance metrics were generally highest for radiomics signatures predicting treatment response or tumor phenotype, as opposed to immune environment and overall prognosis. Out of a possible maximum of 36 points, the median (IQR) of RQS was 12 (10-16). While a rapidly increasing number of promising results offer proof of concept that AI and radiomics could drive precision medicine approaches for a wide range of indications, standardizing the data collection as well as optimizing the methodological quality and rigor are necessary before these results can be translated into clinical practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

68 Ga-labeled somatostatin analog (SSA) PET/CT is now a standard-of-care component in the management of neuroendocrine tumors (NETs). However, treatment response for NETs is still assessed with morphologic size measurements from other modalities, which can result in inaccuracy about the disease burden. Functional tumor volume (FTV) acquired from SSA PET/CT has been suggested as a possible metric, but no validated measurement tool to measure FTV exists. We tested the precision of multiple FTV computational approaches compared with morphologic volume measurements to identify a candidate for incorporation into future FTV studies to assess tumor burden more completely and accurately. Methods: The clinical and imaging data of 327 NET patients were collected at Memorial Sloan Kettering Cancer Center between December 2016 and April 2018. Patients were required to have SSA PET/CT and dedicated CT scans within 6 wk and were excluded if they had any intervention between scans. When paired studies were evaluated, 150 correlating lesions demonstrated SSA. Lesions were excluded if they contained necrotic components or were lobulated. This exclusion resulted in 94 lesions in 20 patients. The FTV for each lesion was evaluated with a hand-drawn assessment and 3 automated techniques: 50% threshold from SUV max , 42% threshold from SUV max , and background-subtracted lesion activity. These measurements were compared with volume calculated from morphologic volume measurements. Results: The FTV calculation methods showed varying correlations with morphologic volume measurements. FTV using a 42% threshold had a 0.706 correlation, hand-drawn volume from PET imaging had a 0.657 correlation, FTV using a 50% threshold had a 0.645 correlation, and background-subtracted lesion activity had a 0.596 correlation. The Bland-Altman plots indicated that all FTV methods had a positive mean difference from morphologic volume, with a 50% threshold showing the smallest mean difference. Conclusion: FTV determined with thresholding of SUV max demonstrated the strongest correlation with traditional morphologic lesion volume assessment and the least bias. This method was more accurate than FTV calculated from hand-drawn volume assessments. Threshold-based automated FTV assessment promises to better determine disease extent and prognosis in patients with NETs., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)