Standardized Uptake Value Threshold Research Articles

Defining the optimal segmentation method for measuring somatostatin receptor expressing tumor volume on 68Ga-DOTATATE positron emission tomography/computed tomography to predict prognosis in patients with gastroenteropancreatic neuroendocrine tumors.

We aimed to compare different segmentation methods used to calculate prognostically valuable volumetric parameters, somatostatin receptor expressing tumor volume (SRETV), and total lesion somatostatin receptor expression (TLSRE), measured by 68Ga-DOTATATE PET/CT and to find the optimal segmentation method to predict prognosis. Images of 34 patients diagnosed with gastroenteropancreatic neuroendocrine tumor (GEPNET) who underwent 68Ga-DOTATATE PET/CT imaging were reanalyzed. Four different threshold-based methods (fixed relative threshold method, normal liver background threshold method, fixed absolute standardized uptake value (SUV) threshold method, and adaptive threshold method) were used to calculate SRETV and TLSRE values. SRETV of all lesions of a patient was summarized as whole body SRETV (WB-SRETV) and TLSRE of all lesions of a patient was computed as whole body TLSRE (WB-TLSRE). WB-SRETVs calculated with all segmentation methods were statistically significantly associated with progression-free survival except WB-SRETVat which was calculated using adaptive threshold method. The fixed relative threshold methods calculated by using 45% (WB-SRETV45%) and 60% (WB-SRETV60%) of the SUV value as threshold respectively, were found to have statistically significant highest prognostic value (C-index = 0.704, CI = 0.622-0.786, P = 0.007). Among WB-TLSRE parameters, WB-TLSRE35%, WB-TLSRE40%, and WB-TLSRE50% had the highest prognostic value (C-index = 0.689, CI = 0.604-0.774, P = 0.008). The fixed relative threshold method was found to be the most effective and easily applicable method to measure SRETV on pretreatment 68Ga-DOTATATE PET/CT to predict prognosis in GEPNET patients. WB-SRETV45% (cutoff value of 11.8 cm3) and WB-SRETV60% (cutoff value of 6.3 cm3) were found to be the strongest predictors of prognosis in GEPNET patients.

Artificial intelligence-based, volumetric assessment of the bone marrow metabolic activity in [18F]FDG PET/CT predicts survival in multiple myeloma.

Multiple myeloma (MM) is a highly heterogeneous disease with wide variations in patient outcome. [18F]FDG PET/CT can provide prognostic information in MM, but it is hampered by issues regarding standardization of scan interpretation. Our group has recently demonstrated the feasibility of automated, volumetric assessment of bone marrow (BM) metabolic activity on PET/CT using a novel artificial intelligence (AI)-based tool. Accordingly, the aim of the current study is to investigate the prognostic role of whole-body calculations of BM metabolism in patients with newly diagnosed MM using this AI tool. Forty-four, previously untreated MM patients underwent whole-body [18F]FDG PET/CT. Automated PET/CT image segmentation and volumetric quantification of BM metabolism were based on an initial CT-based segmentation of the skeleton, its transfer to the standardized uptake value (SUV) PET images, subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, ten different uptake thresholds (AI approaches), based on reference organs or absolute SUV values, were applied for definition of pathological tracer uptake and subsequent calculation of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Correlation analysis was performed between the automated PET values and histopathological results of the BM as well as patients' progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curve analysis was used to investigate the discrimination performance of MTV and TLG for prediction of 2-year PFS. The prognostic performance of the new Italian Myeloma criteria for PET Use (IMPeTUs) was also investigated. Median follow-up [95% CI] of the patient cohort was 110months [105-123months]. AI-based BM segmentation and calculation of MTV and TLG were feasible in all patients. A significant, positive, moderate correlation was observed between the automated quantitative whole-body PET/CT parameters, MTV and TLG, and BM plasma cell infiltration for all ten [18F]FDG uptake thresholds. With regard to PFS, univariable analysis for both MTV and TLG predicted patient outcome reasonably well for all AI approaches. Adjusting for cytogenetic abnormalities and BM plasma cell infiltration rate, multivariable analysis also showed prognostic significance for high MTV, which defined pathological [18F]FDG uptake in the BM via the liver. In terms of OS, univariable and multivariable analysis showed that whole-body MTV, again mainly using liver uptake as reference, was significantly associated with shorter survival. In line with these findings, ROC curve analysis showed that MTV and TLG, assessed using liver-based cut-offs, could predict 2-year PFS rates. The application of IMPeTUs showed that the number of focal hypermetabolic BM lesions and extramedullary disease had an adverse effect on PFS. The AI-based, whole-body calculations of BM metabolism via the parameters MTV and TLG not only correlate with the degree of BM plasma cell infiltration, but also predict patient survival in MM. In particular, the parameter MTV, using the liver uptake as reference for BM segmentation, provides solid prognostic information for disease progression. In addition to highlighting the prognostic significance of automated, global volumetric estimation of metabolic tumor burden, these data open up new perspectives towards solving the complex problem of interpreting PET scans in MM with a simple, fast, and robust method that is not affected by operator-dependent interventions.

Glofitamab Monotherapy in Relapsed or Refractory Large B-Cell Lymphoma: Extended Follow-Up from a Pivotal Phase II Study and Subgroup Analyses in Patients with Prior Chimeric Antigen Receptor T-Cell Therapy and by Baseline Total Metabolic Tumor Volume

Background: Glofitamab is a CD20xCD3 bispecific antibody with a 2:1 (CD20:CD3) format that engages and redirects T cells to eliminate B cells. In a pivotal Phase II study (NCT03075696), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and had a manageable safety profile in patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL; Dickinson et al. N Engl J Med 2022). Here, we present an extended follow up, as well as subgroup analyses in patients with prior chimeric antigen receptor (CAR) T-cell therapy and by baseline total metabolic tumor volume (TMTV). Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D) 1 of Cycle (C) 1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles; total of 8.3 months). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson et al. J Clin Oncol 2014). Cytokine release syndrome (CRS) events were assessed using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Exploratory analyses were performed to investigate the association between TMTV at baseline and progression-free survival (PFS) and CRS. As there is currently no consensus on the method for standardized uptake value (SUV) thresholding in non-Hodgkin's lymphoma, a variety of methods are used in clinical studies (Keijzer et al. Comput Struct Biotechnol J 2023). Here, we used IRC-assessed TMTV derived from baseline positron emission tomography images using a semi-automatic method with a threshold for TMTV of 2x the SUV mean of the liver. Results: As of May 1, 2023, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics were as previously presented (Dickinson et al. N Engl J Med 2022): median prior therapies received was 3 (range: 2-7); 33% of patients had received prior CAR T-cell therapy, and 85% were refractory to their most recent regimen. Median time on study was 25.8 months (range: 0-35). The IRC-assessed overall response and CR rates were 52% and 40%, respectively. The majority of CRs (40/62; 65%) were ongoing at data cut-off. Median duration of CR (DoCR) was 26.9 months (95% confidence interval [CI]: 18.4-not evaluable [NE]); an estimated 67% of patients with a CR at any time remained in remission at 18 months. PFS and overall survival rates at 12 months in patients with a CR at end of treatment (EOT) were 80% and 90%, respectively. In patients with prior CAR T-cell therapy (n=52), CR rates were consistent with the overall population (N=155; 37% vs 40%, respectively) and median DoCR was 22.0 months (95% CI: 6.7-NE). The safety profile of glofitamab was consistent with what has been described previously, with no new safety signals observed. Baseline TMTV was available for 144 patients and the median was 128.7mL (range: 0-3820; data cut-off: January 16, 2023). Higher TMTV was associated with an increased risk of experiencing a Grade ≥2 CRS event. The proportion of patients with Grade ≥2 CRS events in the first, second, third, and fourth TMTV quartiles was 2.8%, 11.1%, 16.7%, and 38.9%, respectively (Chi-square=16.273; degrees of freedom=1; p<0.0001). Patients with a baseline TMTV above or equal to the median (n=72) had a 12-month PFS rate of 16.8% (95% CI: 9.7-29.1), compared with 50.1% (95% CI: 39.5- 63.7) amongst patients with a baseline TMTV below the median (n=72; hazard ratio: 2.6, 95% CI: 1.7-3.9; Figure). Conclusions: Glofitamab continued to demonstrate durable responses in patients with R/R LBCL, with most patients with CR at EOT still in remission, and no new safety signals observed. These data indicate that there may be potential for favorable long-term outcomes with fixed-duration glofitamab for R/R LBCL. CR rates in patients with prior CAR T-cell therapy were durable and consistent with the overall population. Data from the subgroup analyses showed that higher baseline TMTV was associated with an increased risk of Grade ≥2 CRS and suggested that baseline TMTV may be prognostic for PFS. Updated analyses, with a follow-up of approximately 24 months post EOT, and further TMTV exploratory analyses will be presented.

Metabolic bulk volume from FDG PET as an independent predictor of progression-free survival in follicular lymphoma.

Total metabolic tumor volume (TMTV) in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) predicts patient outcome in follicular lymphoma (FL); however, it requires laborious segmentation of all lesions. We investigated the prognostic value of the metabolic bulk volume (MBV) obtained from the single largest lesion. Pretreatment FDG PET/computed tomography (CT) scans of 201 patients were analyzed for TMTV and MBV using a 41% maximum standardized uptake value (SUVmax) threshold. During a median follow-up of 3.2 years, 54 events, including 14 deaths, occurred. Optimal cut-offs were 121.1 cm3 for TMTV and 24.8 cm3 for MBV. Univariable predictors of progression-free survival (PFS) included a high Follicular Lymphoma International Prognostic Index 2 (FLIPI2) score, TMTV, and MBV. In the multivariable analysis, high TMTV and MBV were independent predictors of worse PFS (P =0.015 and 0.033). Furthermore, in a sub-group with FLIP2 scores of 0-2 (n = 132), high MBV could identify patients with worse PFS (P = 0.007). . Readily measurable MBV is useful for stratifying risk in FL patients.

Prognostic Value of Somatostatin Receptor-Derived Volumetric Parameters from a Hybrid Standardized Uptake Value Thresholding Method in Patients with 68Ga-DOTATATE-Avid Stage IV Neuroendocrine Neoplasms: A Preliminary Study

Introduction: The ability of PET/CT imaging to delineate neuroendocrine neoplasms (NENs) and predict prognosis in affected patients is often compromised by substantial uptake heterogeneity. We hereby proposed a hybrid standardized uptake value (SUV) thresholding algorithm to extract volumetric parameters from somatostatin receptor (SSTR) PET/CT imaging and investigate their prognostic performance in patients with 68Ga-DOTATATE-avid stage IV NENs. Methods: For 38 retrospectively enrolled patients, we used either fixed SUV thresholding of normal liver parenchyma (method A), 41% of the SUVmax for each lesion (method B), or a hybrid method (method A for liver metastases; fixed SUV threshold of normal bone for bone metastases; method B for primary tumors and other metastases) to quantify the whole-body SSTR-expressing tumor volume (SRETVwb) and total lesion SSTR expression (TLSREwb). Patient survival was also recorded and analyzed. Results: PET/CT images revealed heterogeneous uptake of 68Ga-DOTATATE at primary and metastatic sites. Progression-free survival (PFS) and overall survival (OS) were negatively correlated with the extent of liver or bone metastases (p 18F-FDG PET/CT positivity. By the hybrid method, PFS was significantly shorter in patients with high SRETVwb, and OS was significantly shorter in those with high SRETVwb and TLSREwb (p wb nor TLSREwb could predict patient outcomes. Conclusion: Compared with other methods used in 68Ga-DOTATATE-avid stage IV NENs, our hybrid SUV thresholding method demonstrated robustness, with greater precision, reliability, and prognostic power.

Assessment of 18F-DCFPyL PSMA PET/CT and PET/MR quantitative parameters for reference standard organs: Inter-reader, inter-modality, and inter-patient variability.

Prostate specific membrane antigen (PSMA)-based radiotracers have shown promise for prostate cancer assessment. Evaluation of quantitative variability and establishment of reference standards are important for optimal clinical and research utility. This work evaluates the variability of PSMA-based [18F]DCFPyL (PyL) PET quantitative reference standards. Consecutive eligible patients with biochemically recurrent prostate cancer were recruited for study participation from August 2016-October 2017. After PyL tracer injection, whole body PET/CT (wbPET/CT) was obtained with subsequent whole body PET/MR (wbPET/MR). Two readers independently created regions of interest (ROIs) including a 40% standardized uptake value (SUV) threshold ROI of the whole right parotid gland and separate spherical ROIs in the superior, mid, and inferior gland. Additional liver (right lobe) and blood pool spherical ROIs were defined. Bland-Altman analysis, including limits of agreement (LOA), as well as interquartile range (IQR) and coefficient of variance (CoV) was used. Twelve patients with prostate cancer were recruited (mean age, 61.8 yrs; range 54-72 years). One patient did not have wbPET/MR and was excluded. There was minimal inter-reader SUVmean variability (bias±LOA) for blood pool (-0.13±0.42; 0.01±0.41), liver (-0.55±0.82; -0.22±1.3), or whole parotid gland (-0.05±0.31; 0.08±0.24) for wbPET/CT and wbPET/MR, respectively. Greater inter-reader variability for the 1-cm parotid gland ROIs was present, for both wbPET/CT and wbPET/MR. Comparing wbPET/CT to the subsequently acquired wbPET/MR, blood pool had a slight decrease in SUVmean. The liver as well as parotid gland showed a slight increase in activity although the absolute bias only ranged from 0.45-1.28. The magnitude of inter-subject variability was higher for the parotid gland regardless of modality or reader. In conclusion, liver, blood pool, and whole parotid gland quantitation show promise as reliable reference normal organs for clinical/research PET applications. Variability with 1-cm parotid ROIs may limit its use.

Quantitative assessment of 99mTc-methylene diphosphonate bone SPECT/CT for assessing bone metastatic burden and its prognostic value in patients with castration-resistant prostate cancers: initial results in a single-center retrospective study

To evaluate the prognostic value of the quantitative assessment of 99mTc-methylene diphosphonate (99mTc-MDP) bone SPECT/CT in castration-resistant prostate cancer (CRPC) patients with bone metastases. A total of 103 patients who underwent 99mTc-MDP bone SPECT/CT imaging from the neck to the proximal femur were included. First, in 65 patients without bone metastases, the normal range of standardized uptake value (SUV) of non-pathological bone was evaluated to determine an SUV threshold to reliably exclude most normal osseous activity. Then, in 38 CRPC patients with bone metastases, lesion uptake volume (LUV), which is the extracted volume of bone metastases exhibiting high accumulation above the SUV threshold, was calculated. The relation between LUV and prostate-related mortality was statistically evaluated. Based on the SUV measurements of non-pathological bones, the optimal SUV threshold, which defines abnormal bone SPECT uptake, was determined to be 8. Median LUV was 39mL (interquartile range 4.0-104.3mL) in the CRPC subjects with bone metastases. Kaplan-Meier survival analysis showed a significant relation between prostate cancer-specific survival and LUV (cut-off value, 19.95mL; P = 0.001). Multivariate analysis revealed LUV as an independent prognostic factor for the survival (P = 0.008, hazard ratio 23.424). Global chi-square test showed that LUV had significant incremental prognostic value in addition to prostate-specific antigen and the interval from progression to CRPC until bone SPECT/CT (P = 0.022). Quantitative assessment of 99mTc-MDP bone SPECT images can provide valuable prognostic information in CRPC patients with bone metastases.

Semi-automated 18F-FDG PET segmentation methods for tumor volume determination in Non-Hodgkin lymphoma patients: a literature review, implementation and multi-threshold evaluation

In the treatment of Non-Hodgkin lymphoma (NHL), multiple therapeutic options are available. Improving outcome predictions are essential to optimize treatment. The metabolic active tumor volume (MATV) has shown to be a prognostic factor in NHL. It is usually retrieved using semi-automated thresholding methods based on standardized uptake values (SUV), calculated from 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) images. However, there is currently no consensus method for NHL. The aim of this study was to review literature on different segmentation methods used, and to evaluate selected methods by using an in house created software tool.A software tool, MUltiple SUV Threshold (MUST)-segmenter was developed where tumor locations are identified by placing seed-points on the PET images, followed by subsequent region growing. Based on a literature review, 9 SUV thresholding methods were selected and MATVs were extracted. The MUST-segmenter was utilized in a cohort of 68 patients with NHL. Differences in MATVs were assessed with paired t-tests, and correlations and distributions figures.High variability and significant differences between the MATVs based on different segmentation methods (p < 0.05) were observed in the NHL patients. Median MATVs ranged from 35 to 211 cc.No consensus for determining MATV is available based on the literature. Using the MUST-segmenter with 9 selected SUV thresholding methods, we demonstrated a large and significant variation in MATVs. Identifying the most optimal segmentation method for patients with NHL is essential to further improve predictions of toxicity, response, and treatment outcomes, which can be facilitated by the MUST-segmenter.

Brentuximab Vedotin Combined with Chemotherapy in Newly Diagnosed, Early-Stage, Unfavorable-Risk Hodgkin Lymphoma: Extended Follow-up with Evaluation of Baseline Metabolic Tumor Volume and PET2

INTRODUCTION: While the majority of patients with early-stage (ES), bulky Hodgkin lymphoma (HL) can be cured with modern approaches, approximately 15% of patients with bulky HL relapse. Improving upfront approaches while minimizing long-term adverse effects remains integral. We previously reported the results of a multicenter pilot study of 4 cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD) followed by 1 of 4 approaches if positron emission tomography (PET)-4 negative. The treatment program was highly active and well-tolerated. We now present extended results and prognostic evaluation of baseline metabolic tumor volume (MTV) and PET2 results. METHODS: Full methodology has been published (Kumar et al., J. Clin Oncol. 2021). Briefly, patients with untreated HL were enrolled into 1 of 4 sequential cohorts. In cohort 1 (C1), eligible patients had any of the following unfavorable (UF) risk factors: bulky mediastinal mass, ESR ≥ 50 mm/h or ≥ 30 mm/h if B symptoms, extranodal involvement, > 2 lymph node sites, or infradiphragmatic disease. The same criteria applied to C2, except for bulk being defined by the Memorial Sloan Kettering (MSK) definition (maximal transverse or coronal diameter of the largest mass > 7 cm). In C3 and C4, all patients were required to have MSK criteria bulk. All cohorts received BV-AVD x 4. Patients with a PET-negative response after 4 cycles received 30-Gy involved site radiation therapy (ISRT) in C1, 20-Gy ISRT in C2, 30-Gy consolidative-volume RT (CVRT) in C3, and no RT in C4. For 84 patients at MSK, baseline MTV was measured using the 41% maximum standard uptake value (SUV) threshold method. Interim PET after 2 cycles was interpreted using the 5-point scale with scores ≤ 3 considered negative. Survival data was updated through July 1, 2022. Progression-free (PFS) and overall survival (OS) probabilities were estimated by the Kaplan-Meier method and compared for various features using the log-rank test, with a p-value of ≤ 0.05 statistically significant. RESULTS: Of 117 patients enrolled, 116 completed chemotherapy. With a median followup of 4.6 years (6.7, 5.3, 4.5, and 3.3 years for C1-4), there were 8 progression events and 2 deaths. Since original publication, 1 further progression occurred amongst a patient in C4. The median PFS and OS have not been reached in either group. The overall 4-year PFS and OS were 93% and 98%, respectively. The 4-year PFS for C1-4 was 93%, 96%, 90%, and 93%, respectively (p=0.78). Next, outcomes were compared by MTV and PET2. Among 84 patients assessed for baseline MTV, median MTV was 150 (range 13-827) cm3. Using the median MTV to stratify patients, overall 4-year PFS in the MTV-high (n=43) versus MTV-low (n=41) group was 91% versus 100%, respectively (p=0.047). Fourteen patients (12%) had positive PET2. Four-year PFS in the PET2 positive versus negative group was 79% versus 95%, respectively (p=0.02). By MTV and PET2, 4-year PFS for the MTV-low/PET2-negative (n=36), MTV-low/PET2-positive (n=5), MTV-high/PET2-negative (n=38), and MTV-high/PET2-positive (n=5) groups was 100%, 100%, 95%, and 60%, respectively (p=0.001) (Figure 1). Within these 4 groups, there were 4 progression events, 2 within the MTV-high/PET2-negative group and 2 within the MTV-high/PET2-positive group. The 2 patients in the MTV-high/PET2-negative group had Deauville score (DS) 2 on PET2 and then developed DS4 on PET4; 1 received salvage R-ICE (concomitant CD20 expression) followed by autologous transplant (autoSCT), and 1 received salvage pembrolizumab-GVD followed by autoSCT. The 2 patients within the MTV-high/PET2-positive group had DS4 on PET2 and PET4. One patient received salvage augmented ICE followed by radiation and autoSCT. The other patient had a negative biopsy of PET4 disease and completed CVRT, but relapsed 2 months later and received salvage augmented ICE and autoSCT. All 4 of these patients remain without disease after a median follow-up post autoSCT of 65 (28-86) months. CONCLUSIONS: We report extended followup of short-course BV-AVD followed by various doses/fields of RT, including no RT, in ES, bulky HL. The BV-AVD program remains highly active and well-tolerated, including in the absence of consolidative RT for certain patients. Baseline MTV and PET2 identifies an unfavorable cohort at higher risk of treatment failure. Trials in ES, bulky HL should evaluate stratified treatment paradigms using baseline MTV and PET2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Influence of the methodological aspects of the dichotomization of total metabolic tumor volume measured through baseline fluorine-18 fluorodeoxyglucose PET on survival prediction in lymphoma.

The total metabolic tumor volume (TMTV) measured from fluorine-18 fluorodeoxyglucose (18F-FDG) PET can be useful for determining the prognosis of patients with lymphoma. Stratifying patients into high- and low-TMTV risk groups requires a cutoff point, which is determined through the dichotomization method. This study investigated whether different TMTV dichotomization methods influenced survival prediction in patients with lymphoma. We retrospectively enrolled 129 patients with lymphoma who had undergone baseline 18F-FDG PET. TMTV was calculated using a fixed standardized uptake value threshold of 4.0. A total of six methods were employed to determine the optimal TMTV cutoff point using receiver-operating characteristic curve analyses, X-Tile bioinformatics software, and the Cutoff Finder web application. The prognostic performance of each method in survival prediction was examined. The median (interquartile range) TMTV was 123 cm3 (21-335 cm3). The optimal TMTV cutoff values for predicting progression-free survival (PFS) and overall survival (OS) were in the range of 144-748 cm3. The cutoff points were used to dichotomize patients into two groups with distinct prognoses. All TMTV dichotomizations were significantly predictive of PFS and OS. The survival curves showed significant differences between the high- and low-TMTV groups. The C-indices of the survival models did not significantly differ in any of the dichotomizations. The prognostic significance of TMTV was maintained regardless of the methodological aspects of dichotomization. However, the optimal TMTV cutoff point varied according to the chosen dichotomization method. Care should be taken when establishing an optimal TMTV cutoff point for clinical use.

Variable Relative Biological Effectiveness of Proton Therapy Increases PET-Visible Mucosal Injury in Head and Neck Cancer Patients

Despite dosimetric advantages of proton therapy in head and neck cancers, there is concern for increased end of range relative biologic effectiveness (RBE) and subsequent dose enhancement and mucosal toxicity with proton therapy. Herein, we evaluated differences in mucosal PET avidity on post-treatment scans as a surrogate for mucosal injury between proton and photon therapy patients. We further assessed the relationship between PET changes and RBE. The cohort comprised 9 proton and 10 photon patients who received ≥50 Gy adjuvant radiotherapy to oropharyngeal mucosa who remained loco-regional disease free ≥6 months post-treatment. All patients underwent follow-up fluorodeoxyglucose (FDG) PET-CT scans 3 months post-radiotherapy. PET-CTs were fused to planning CTs using deformable registration. High- and low-uptake regions were auto-contoured using a ≥150% mean liver standard uptake value (SUV) threshold and intersected with mucosal targets with/without a 5mm margin. SUV maximum (SUVMAX) values, linear energy transfer (LET) statistics, and RBE statistics based on McNamara, Jones, and linear LET models were extracted and compared. The mucosal target SUVMAX values on post-treatment PET-CTs for proton patients averaged 6.78 compared to 4.83 for photon patients (p=0.0267). Near maximum (LETd1%) LET for mucosal targets with a 5mm margin averaged 5.232 keV/µm. RBE in high-uptake regions exceeded that of low-uptake regions (p=0.0039), with mean biologic dose exceeding clinical dose by 11.05%, 18.67%, and 15.65%, respectively, using different RBE models. Post-radiotherapy PET avidity was more commonly observed in proton patients. Within proton patient mucosal targets, the location of increased PET avidity corresponded to areas with higher RBE. This is the first report of differential PET findings based on RBE. These results suggest that elevated RBE was associated with PET avidity and mucosal injury.

Optimization of Adaptive Threshold in Tumor Segmentation Based on I-124 PET/CT NEMA Phantom Study

Numerous methods have been introduced to segment the thyroid tumors in iodine-124 (124I) Positron Emission Tomography/Computer Tomography (PET/CT) imaging. An adaptive threshold-based is preferable to a manual and fixed threshold-based approach for forecasting accurate and precise tumor volume in real-patient studies, as it was reported to be more resistant to noise and resolution. Manual segmentation was reported to be time-consuming, subjective, subject to inter- and intra-observer variability and prone to segmentation errors [1]. This study aimed to determine the optimal adaptive threshold for thyroid tumor segmentation in 124I PET/CT imaging.&#x0D; &#x0D; The objective of this study was firstly to determine the segmented volume using the standardized uptake value threshold method. Secondly, to compare the adaptive threshold and recovery coefficient (RC) value between the time of flight (TOF) and non-time of flight (non-TOF) PET/CT reconstructions in 124I phantom studies. Finally, to determine the accuracy and RC for 124I PET/CT studies. This study was done by placing NEMA 2012/IEC 2008 PET IQ Phantom and filled with 1 kBq/ml and 20 kBq/ml in its background and sphere each to model tumor background ratio (TBR) 20:1 of 124I PET/CT imaging. The phantom was scanned using TOF and non-TOF PET at 3, 4 and 5 minutes per bed position and reconstructed using 600, 1200 and 2000 beta penalization factors. Image registration, contouring and segmentation were performed using MIM Encore Software. A set of different adaptive thresholds (Tadaptive: 10%-50%) was applied to each sphere in the TBR image of the phantom using the tri-dimensional automatic segmentation tool. The optimal Tadaptive for each of the parameter assessed was defined based on the lowest goodness value calculated. The RC was calculated using mean value and known activity. Finally, the RC against the percentage of maximum was plotted to analyse the descending order of beta penalization factors for time per bed position.&#x0D; &#x0D; Figure 1 shows the image of 124I contoured VOIs on the spheres. The results showed that segmented volumes were not affected by the time per bed position in 124I PET/CT imaging. Table 1 shows the descending order beta penalization factors for time per bed position. Beta penalization factors of 600 to 2000 resulted in either underestimation or overestimation of the measured volume. Comparing TOF to non-TOF PET/CT 124I imaging, consistent and reproducible data were observed for the TOF PET for the three beta penalization factors. Tadaptive of 28.0% consistently gave the lowest goodness value shown by the closest R2 value to one, thus can produce lowest error if it is being used to reconstruct images.&#x0D; As a conclusion, 28% Tadaptive is suggested as the optimal threshold for 124I TOF PET/CT imaging due to consistent data obtained for all beta penalization factors assessed in this study. The inconsistent data obtained by non-TOF PET thus requires further optimization.

Prospective Evaluation of Different Methods for Volumetric Analysis on [18F]FDG PET/CT in Pediatric Hodgkin Lymphoma.

Rationale: Therapy response evaluation by 18F-fluorodeoxyglucose PET/CT (FDG PET) has become a powerful tool for the discrimination of responders from non-responders in pediatric Hodgkin lymphoma (HL). Recently, volumetric analyses have been regarded as a valuable tool for disease prognostication and biological characterization in cancer. Given the multitude of methods available for volumetric analysis in HL, the AIEOP Hodgkin Lymphoma Study Group has designed a prospective analysis of the Italian cohort enrolled in the EuroNet-PHL-C2 trial. Methods: Primarily, the study aimed to compare the different segmentation techniques used for volumetric assessment in HL patients at baseline (PET1) and during therapy: early (PET2) and late assessment (PET3). Overall, 50 patients and 150 scans were investigated for the current analysis. A dedicated software was used to semi-automatically delineate contours of the lesions by using different threshold methods. More specifically, four methods were applied: (1) fixed 41% threshold of the maximum standardized uptake value (SUVmax) within the respective lymphoma site (V41%), (2) fixed absolute SUV threshold of 2.5 (V2.5); (3) SUVmax(lesion)/SUVmean liver >1.5 (Vliver); (4) adaptive method (AM). All parameters obtained from the different methods were analyzed with respect to response. Results: Among the different methods investigated, the strongest correlation was observed between AM and Vliver (rho > 0.9; p < 0.001 for SUVmean, MTV and TLG at all scan timing), along with V2.5 and AM or Vliver (rho 0.98, p < 0.001 for TLG at baseline; rho > 0.9; p < 0.001 for SUVmean, MTV and TLG at PET2 and PET3, respectively). To determine the best segmentation method, we applied logistic regression and correlated different results with Deauville scores at late evaluation. Logistic regression demonstrated that MTV (metabolic tumor volume) and TLG (total lesion glycolysis) computation according to V2.5 and Vliver significantly correlated to response to treatment (p = 0.01 and 0.04 for MTV and 0.03 and 0.04 for TLG, respectively). SUVmean also resulted in significant correlation as absolute value or variation. Conclusions: The best correlation for volumetric analysis was documented for AM and Vliver, followed by V2.5. The volumetric analyses obtained from V2.5 and Vliver significantly correlated to response to therapy, proving to be preferred thresholds in our pediatric HL cohort.

The Impact of Segmentation Method and Target Lesion Selection on Radiomic Analysis of 18F-FDG PET Images in Diffuse Large B-Cell Lymphoma

Radiomic analysis of 18F[FDG] PET/CT images might identify predictive imaging biomarkers, however, the reproducibility of this quantitative approach might depend on the methodology adopted for image analysis. This retrospective study investigates the impact of PET segmentation method and the selection of different target lesions on the radiomic analysis of baseline 18F[FDG] PET/CT images in a population of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. The whole tumor burden was segmented on PET images applying six methods: (1) 2.5 standardized uptake value (SUV) threshold; (2) 25% maximum SUV (SUVmax) threshold; (3) 42% SUVmax threshold; (4) 1.3∙liver uptake threshold; (5) intersection among 1, 2, 4; and (6) intersection among 1, 3, 4. For each method, total metabolic tumor volume (TMTV) and whole-body total lesion glycolysis (WTLG) were assessed, and their association with survival outcomes (progression-free survival PFS and overall survival OS) was investigated. Methods 1 and 2 provided stronger associations and were selected for the next steps. Radiomic analysis was then performed on two target lesions for each patient: the one with the highest SUV and the largest one. Fifty-three radiomic features were extracted, and radiomic scores to predict PFS and OS were obtained. Two proportional-hazard regression Cox models for PFS and OS were developed: (1) univariate radiomic models based on radiomic score; and (2) multivariable clinical–radiomic model including radiomic score and clinical/diagnostic parameters (IPI score, SUVmax, TMTV, WTLG, lesion volume). The models were created in the four scenarios obtained by varying the segmentation method and/or the target lesion; the models’ performances were compared (C-index). In all scenarios, the radiomic score was significantly associated with PFS and OS both at univariate and multivariable analysis (p &lt; 0.001), in the latter case in association with the IPI score. When comparing the models’ performances in the four scenarios, the C-indexes agreed within the confidence interval. C-index ranges were 0.79–0.81 and 0.80–0.83 for PFS radiomic and clinical–radiomic models; 0.82–0.87 and 0.83–0.90 for OS radiomic and clinical–radiomic models. In conclusion, the selection of either between two PET segmentation methods and two target lesions for radiomic analysis did not significantly affect the performance of the prognostic models built on radiomic and clinical data of DLBCL patients. These results prompt further investigation of the proposed methodology on a validation dataset.

Feasibility of biology-guided radiotherapy using PSMA-PET to boost to dominant intraprostatic tumour

BackgroundBiology-guided radiotherapy (BgRT) delivers dose to tumours triggered from positron emission tomography (PET) detection. Prostate specific membrane antigen (PSMA) PET uptake is abundant in the dominant intraprostatic lesion (DIL). This study investigates the feasibility of BgRT to PSMA-avid subvolume in the prostate region. MethodsPatients enrolled in the prospective randomized trial ProPSMA at our institution were included (ID: ANZCTR12617000005358). Gross tumour volumes (GTVs) were delineated on the PET component of a PET/CT scan from a standardized uptake value (SUV) threshold technique. Suitability for BgRT requires a strong signal-to-background ratio with a surrounding tissue free of significant PSMA uptake. The signal-to-background ratio was quantified from the calculation of the normalized SUV (nSUV), defined as the ratio between SUVmax within the GTV and SUVmean inside a 3D margin expansion of the GTV. The PSMA distribution surrounding the tumour was quantified as a function of the distance from the GTV. ResultsIn this cohort of 84 patients, 83 primary tumours were included. Prostate volume ranged from 19 cm3 to 148 cm3 (median = 52 cm3; IQR = 39 cm3 – 63 cm3). SUVmax inside the prostate was between 2 and 125 (median = 19; IQR = 11 – 30). More than 50% of GTVs generated with threshold between 25%SUVmax (median volume = 10.0 cm3; IQR = 4.5 cm3 – 20.0 cm3) and 50%SUVmax (median volume = 1.9 cm3; IQR = 1.1 cm3 – 3.8 cm3) were suitable for BgRT by using nSUV ≥ 3 and a margin expansion of 5 mm. ConclusionsIt is feasible to identify GTVs suitable for BgRT in the prostate. These GTVs are characterized by a strong signal-to-background ratio and a surrounding tissue free of PSMA uptake.

Positron emission tomography/computed tomography differentiates resectable thymoma from anterior mediastinal lymphoma

ObjectiveDiscrete anterior mediastinal masses most often represent thymoma or lymphoma. Lymphoma treatment is nonsurgical and requires biopsy. Noninvasive thymoma is ideally resected without biopsy, which may potentiate pleural metastases. This study sought to determine if clinical criteria or positron emission tomography/computed tomography could accurately differentiate the 2, guiding a direct surgery versus biopsy decision. MethodsA total of 48 subjects with resectable thymoma and 29 subjects with anterior mediastinal lymphoma treated from 2006 to 2019 were retrospectively examined. All had pretreatment positron emission tomography/computed tomography and appeared resectable (solitary, without clear invasion or metastasis). Reliability of clinical criteria (age and B symptoms) and positron emission tomography/computed tomography maximum standardized uptake value were assessed in differentiating thymoma and lymphoma using Wilcoxon rank-sum test, chi-square test, and logistic regression. Receiver operating characteristic analysis identified the maximum standardized uptake value threshold most associated with thymoma. ResultsThere was no association between tumor type and age group (P = .183) between those with thymoma versus anterior mediastinal lymphoma. Patients with thymoma were less likely to report B symptoms (P < .001). The median maximum standardized uptake value of thymoma and lymphoma differed dramatically: 4.35 versus 18.00 (P < .001). Maximum standardized uptake value was independently associated with tumor type on multivariable regression. On receiver operating characteristic analysis, lower maximum standardized uptake value was associated with thymoma. Maximum standardized uptake value less than 12.85 was associated with thymoma with 100.00% sensitivity and 88.89% positive predictive value. Maximum standardized uptake value less than 7.50 demonstrated 100.00% positive predictive value for thymoma. ConclusionsPositron emission tomography/computed tomography maximum standardized uptake value of resectable anterior mediastinal masses may help guide a direct surgery versus biopsy decision. Tumors with maximum standardized uptake value less than 7.50 are likely thymoma and thus perhaps appropriately resected without biopsy. Tumors with maximum standardized uptake value greater than 7.50 should be biopsied to rule out lymphoma. Lymphoma is likely with maximum standardized uptake value greater than 12.85.

Brown Adipose Tissue Prevalence Is Lower in Obesity but Its Metabolic Activity Is Intact.

Due to its high metabolic activity, brown adipose tissue (BAT) has become a promising target for the development of novel treatment concepts for metabolic disease. Despite several reports of a negative association between the presence of active BAT and obesity, very little is known about the quantitative and qualitative differences of BAT in lean and obese individuals. Systematic studies directly comparing cold-induced BAT activity in leanness and obesity are currently lacking. Here we studied BAT mass and function in 31 lean and 64 obese men and women. After a standardized cooling protocol using a water-perfused vest, 18F-FDG-positron emission tomography/computed tomography scans were performed, and BAT was delineated using lean body-mass adjusted standardized uptake value (SUV) thresholds in anatomic regions with fat radiodensity. Cold-induced thermogenesis (CIT), a functional readout of BAT activity, was quantified by indirect calorimetry. Active BAT was present in a significantly higher proportion of lean than obese individuals (58% vs. 33%, p=0.019). In these participants with active BAT, however, BAT volume and activity did not differ between leanness and obesity. Accordingly, CIT was similar in both weight groups. BAT metrics were not related to adiposity or total fat mass per se. However, in obese participants a strong negative correlation existed between visceral adipose tissue and BAT volume, 18F-FDG uptake and CIT. In summary, despite a significantly lower prevalence of BAT, the metabolic activity and thermogenic capacity of BAT appears to be still intact in obesity and is inversely associated with visceral fat mass.

Pre-treatment total metabolic tumour volumes in lymphoma: Does quantity matter?

Positron emission tomography/computed tomography (PET/CT) is used for the staging of lymphomas. Clinical information, such as Ann Arbor stage and number of involved sites, is derived from baseline staging and correlates with tumour volume. With modern imaging software, exact measures of total metabolic tumour volumes (tMTV) can be determined, in a semi- or fully-automated manner. Several technical factors, such as tumour segmentation and PET/CT technology influence tMTV and there is no consensus on a standardized uptake value (SUV) thresholding method, or how to include the volumes in the bone marrow and spleen. In diffuse large B-cell lymphoma, follicular lymphoma, peripheral T-cell lymphoma, and Hodgkin lymphoma, tMTV has been shown to predict progression-free survival and/or overall survival, after adjustments for clinical risk scores. However, most studies have used receiver operating curves to determine the optimal cut-off for tMTV and many studies did not include a training-validation approach, which led to the risk of overestimation of the independent prognostic value of tMTV. The identified cut-off values are heterogeneous, even when the same SUV thresholding method is used. Future studies should focus on testing tMTV in homogeneously-treated cohorts and seek to validate identified cut-off values externally so that a prognostic value can be documented, over and above currently used clinical surrogates for tumour volume.

Pre-Infusion Neurofilament Light Chain (NfL) Levels Predict the Development of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) - a Multicenter Retrospective Study

Chimeric antigen receptor (CAR) T-cell therapy is often associated with neurological complications termed immune effector cell-associated neurotoxicity syndrome (ICANS). There remains a critical need to identify patients most at risk for ICANS. Yet a biomarker for the development of ICANS is lacking. This retrospective multicenter study evaluates pre-infusion levels of plasma neurofilament light chain (NfL), a marker of neurodegeneration, as a predictive biomarker the development of ICANS.Study inclusion criteria included available pre-infusion (up to 4 weeks prior to lymphodepletion) plasma from patients treated with a CAR T cell therapy (n = 30, 36% with ICANS, ASTCT consensus ICANS grade range 1-4). Exclusion criteria included confounding diagnoses known to elevate NfL levels (e.g. dementia, recent stroke). Plasma NfL was assayed using a Simoa HD-X kit (Quanterix TM). Demographic (age, sex), oncologic (primary, stage, mean tumor volume (MTV), and history of central nervous system (CNS) involvement), and medical history (history of non-oncologic CNS disease or neuropathy) were obtained from the medical record. MTV was derived from total lesion burden on pre-infusion positron emission tomography (PET) scans using a 41% maximum standard uptake value (SUV) threshold. Pre-infusion (i.e. during lymphodepletion) and Post-infusion Day 1 (D1) platelet count, C-reactive protein (CRP), fibrinogen, lactate dehydrogenase (LDH), and ferritin levels were also obtained from the medical record. Group comparisons used log-rank testing, followed by receiver operating characteristic (ROC) curve classification and hierarchical clustering. Validation testing used a 10,000 fold cross-validation on 80% of the data. Finally, demographic and clinical characteristics correlated with pre-infusion biomarkers using point-biserial and Spearman (rank) correlation.Our results demonstrated that individuals who would go on to develop ICANS had elevations in pre-infusion NfL ([87.6 v 29.4 pg/ml; Fig 1A], p = 0.00004) with excellent classification accuracy for the development of ICANS (AUC 0.96; Fig 1B), sensitivity (0.91) and specificity (0.95). NfL further correlated with ICANS development (r = 0.74, p < 0.0001; Fig 1C). Among known post-infusion risk factors, D1 ferritin had the highest classification accuracy, but was inferior to baseline NfL (p < 0.05; Fig 1B). Both baseline NfL and D1 ferritin elevations clustered with ICANS grade (Fig 1D).Our findings show that pre-infusion plasma NfL levels are a robust early marker for the development of ICANS that exceeds known post-infusion markers. This suggests the risk of developing ICANS reflects pre-existing latent neuroaxonal injury. Predictive identification of patients at risk of developing ICANS prior to cellular infusion would permit early, preemptive or prophylactic ICANS-directed therapies, thereby improving patient outcomes.Figure 1: Baseline (pre-infusion) NfL Levels in ICANS (A) Baseline (pre-infusion) levels of NfL in patients who develop Grade 0 ICANS, Grade 1-2 ICANS, and Grade 3+ ICANS. (B) Receiver operating characteristic curve classification of patients who developed any grade ICANS (1+) vs grade 0 for baseline NfL and post-infusion day 1 (D1) markers. (C) Correlation between pre-treatment factors and pre-infusion biomarkers. All significant relationships after correction for multiple comparisons using false discovery rate (FDR) are outlined (*). (D) Hierarchical clustering of age, baseline NfL, and D1 markers. Clusters associating with ICANS are labeled in red, while those associating with cytokine release syndrome (CRS) are in blue. [Display omitted] DisclosuresCaimi: Verastem: Consultancy; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; XaTek: Patents & Royalties: Royalties from patents (wife); Kite Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Amgen Therapeutics.: Consultancy; TG Therapeutics: Honoraria. de Lima: BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding. Campian: AbbVie, Inc.: Speakers Bureau; NeoImmuneTech: Research Funding. Ghobadi: Amgen: Consultancy, Research Funding; Atara: Consultancy; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding.

Risk Stratification for Relapsed/Refractory Classical Hodgkin Lymphoma Integrating Pretransplant Deauville Score and Residual Metabolic Tumor Volume

IntroductionPositron emission tomography (PET) positivity before autologous stem cell transplantation (ASCT) predicts poor prognosis in relapsed/refractory (rel/ref) classical Hodgkin lymphoma (cHL). However, there is limited data regarding the value of pre-ASCT residual metabolic tumor volume (rMTV) assessed by PET to predict post-ASCT outcomes. We aimed to evaluate the role of pre-ASCT Deauville score (DS) combined with rMTV in patients with rel/ref cHL who underwent salvage ASCT, and also to establish a risk model integrating pre-ASCT DS, rMTV, and other clinical risk factors.MethodsThis is a retrospective cohort study using clinical data of patients with rel/ref cHL identified from the lymphoma database and the ASCT database of the Princess Margaret Cancer Center, Toronto, Canada. Following criteria were required: (1) patients (≥18 yrs) with histologically confirmed rel/ref cHL between January 2014 to March 2019; (2) treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or ABVD-equivalent regimens; (3) chemosensitive disease after salvage therapy; (4) restaging PET before ASCT clearance. Pre-ASCT PET scans were assessed using the Deauville 5-point scale, and rMTV was computed in the scans with DS 4 or 5 using the 41% maximum standardized uptake value threshold method. Receiver operating characteristics analysis was used to determine an optimal cutoff of rMTV 41% for event prediction. The primary endpoint was event-free survival (EFS), defined as time form ASCT to first documented disease progression, any new lymphoma therapy, death from any cause, or last follow-up.ResultsA total of 106 patients fulfilled the eligibility criteria and were included. Median age was 33.5 yrs (range, 18-70), and 72 (68%) were male. The cohort characteristics at time of progression were 55 (52%) patients with advanced stage, 28 (26%) with B symptoms, 39 (37%) with extranodal disease, and 39 (37%) with primary refractory disease, defined as achieving less than a complete response, disease progression during first-line therapy, or time to relapse (TTR) 3 months or less. All patients received gemcitabine, dexamethasone, cisplatin (GDP) regimen as salvage therapy. Based on the response to GDP therapy, 24 patients required second (N=20) or third (N=4) salvage regimens before ASCT (brentuximab vedotin [BV] alone or combination with bendamustine [N=16], pembrolizumab [N=9], and mini-BEAM [N=3]). 32 patients (30%) received planned pre- or post-ASCT involved field radiation for DS 4-5 lesions. 4 patients received post-ASCT BV consolidation.With a median follow-up of 26.2 months (interquartile range [IQR], 14.4-49.2), 2-year EFS and overall survival rates were 72.1% and 93.1%, respectively. Pre-ASCT DS was determined as 1-3 (N=63, 59%) and 4-5 (N=43, 41%). None of the patients with DS 5 had new lesions. Patients with pre-ASCT DS 1-3 had significantly better EFS than those with DS 4-5 (2-year; 80.8% vs 59.2%; P=0.002; Fig 1A).Median rMTV 41% of the 43 patients with DS 4-5 was 5.1 cm 3 (IQR, 2.0-24.7). The optimal cutoff of rMTV 41% was 4.4 cm 3. Patients with rMTV low (< 4.4cm 3, N=21) had better EFS than those with rMTV high (N=22; 2-year, 75.0% vs 45.4%; P=0.009), but had similar 2-year EFS when compared with patients with DS 1-3 (80.8%, P=0.280; Fig 1B)In the multivariable analysis for EFS, a combined assessment of pre-ASCT DS/rMTV 41% and rel/ref status at time of progression were independently associated with EFS (for DS 4-5/rMTV low, hazard ratio [HR] 1.58; for DS 4-5/rMTV high, HR 4.72; P<0.001: for primary refractory disease, HR 2.26; P=0.026). Based on these results, we stratified patients into 3 groups according to the post-ASCT outcomes: low-risk (relapsed disease [i.e., TTR > 3 months] and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=54), intermediate-risk (refractory disease and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=30), and high-risk (pre-ASCT DS 4-5/rMTV high irrespective of rel/ref status, N=22) groups. The risk model was significantly associated with EFS (intermediate vs low, HR 3.26, 95%CI 1.20-8.83, P=0.020; high vs low, HR 7.61, 95% CI 2.89-20.01, P<0.001; Fig 1C).ConclusionWe propose a risk stratification model integrating a combination of DS and rMTV 41% on pre-ASCT PET and rel/ref status at time of progression, which allow discrimination of post-ASCT outcomes in patients with rel/ref cHL. The model may serve as a tool to facilitate risk-stratified treatment decisions. [Display omitted] DisclosuresMetser: POINT Biopharm Inc: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Crump: Roche: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees. Kuruvilla: Seattle Genetics: Honoraria; Amgen: Honoraria; Antengene: Honoraria; AbbVie: Honoraria; Janssen: Honoraria, Research Funding; BMS: Honoraria; Medison Ventures: Honoraria; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Roche: Honoraria, Research Funding; Novartis: Honoraria; Merck: Honoraria; Pfizer: Honoraria. Kridel: Gilead Sciences: Research Funding.