[18F]FDG PET/CT for predicting triple-negative breast cancer outcomes after neoadjuvant chemotherapy with or without pembrolizumab.

PURPOSE: To determine if pretreatment [18F]FDG PET/CT could contribute to predicting complete pathological complete response (pCR) in patients with early-stage triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy with or without pembrolizumab. METHODS: In this retrospective bicentric study, we included TNBC patients who underwent [18F]FDG PET/CT before neoadjuvant chemotherapy (NAC) or chemo-immunotherapy (NACI) between March 2017 and August 2022. Clinical, biological, and pathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from the PET images. Cut-off values were determined using ROC curves and a multivariable model was developed using logistic regression to predict pCR. RESULTS: N = 191 patients were included. pCR rates were 53 and 70% in patients treated with NAC (N = 91) and NACI (N = 100), respectively (p < 0.01). In univariable analysis, high Ki67, high tumor SUVmax (> 12.3), and low TMTV (≤ 3.0 cm3) were predictors of pCR in the NAC cohort while tumor staging classification (< T3), BRCA1/2 germline mutation, high tumor SUVmax (> 17.2), and low TMTV (≤ 7.3 cm3) correlated with pCR in the NACI cohort. In multivariable analysis, only high tumor SUVmax (NAC: OR 8.8, p < 0.01; NACI: OR 3.7, p = 0.02) and low TMTV (NAC: OR 6.6, p < 0.01; NACI: OR 3.5, p = 0.03) were independent factors for pCR in both cohorts, albeit at different thresholds. CONCLUSION: High tumor metabolism (SUVmax) and low tumor burden (TMTV) could predict pCR after NAC regardless of the addition of pembrolizumab. Further studies are warranted to validate such findings and determine how these biomarkers could be used to guide neoadjuvant therapy in TNBC patients.

Prognostic value of metabolic tumor volume of extranodal involvement in diffuse large B cell lymphoma.

Extranodal involvement predicts poor outcomes of diffuse large B cell lymphoma (DLBCL), but the impact of the metabolic tumor burden (MTV) of extranodal sites using positron emission tomography has not been clarified. This study aimed to assess the impact of extranodal MTV on overall survival (OS). We retrospectively analyzed 145 newly diagnosed DLBCL patients and verified the prognostic impact of each extranodal and nodal MTV. Multivariate Cox hazards modelling using both extranodal and nodal MTV as covariables identified extranodal MTV as a significant factor for OS (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.019-1.129, P = 0.008), but not nodal MTV. Multivariate Cox modelling using restricted cubic splines demonstrated that the impact of total MTV depends on the MTV of extranodal sites, not of nodal sites. When both the number and MTV of extranodal involvements were used as covariables, extranodal MTV remained a significant predictor of OS (HR 1.070, 95%CI 1.017-1.127, P = 0.009), but the number of extranodal sites did not. Extranodal MTV potentially had a more significant role on prognosis than nodal MTV. When considering prognostic impacts, the MTV of extranodal involvement is significantly more important than the number.

Role of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Predicting the Adverse Effects of Chimeric Antigen Receptor T Cell Therapy in Patients with Non-Hodgkin Lymphoma.

CD19-targeting chimeric antigen receptor (CAR)-T cell therapy has shown great efficacy in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) but has been associated with serious adverse effects, such as cytokine release syndrome (CRS). It has been speculated that NHL baseline disease burden might affect clinical outcome and CRS, but this has not been explored in detail in any previous study. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as measured by fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT), are quantitative indicators of baseline tumor burden. Using FDG PET-CT, we calculated baseline and post-CAR-T cell therapy MTV and TLG in 19 patients with NHL. The median MTV was 72 cm3 (range, .02 to 1137.7 cm3), and the median TLG was 555.9 (range, .011 to 8990.3). After a median follow-up of 5 months (range, 1 to 12 months), the best overall response rate was 79.0%. The baseline MTV and TLG did not differ significantly between patients with response and those without response (P = .62 and .95, respectively). On Cox regression analysis, baseline MTV and TLG were not significantly associated with overall survival (P = .67 and .45, respectively). Patients with mild and moderate CRS (grade 0 to 2) had significantly lower MTV and TLG than those with severe CRS (grade 3 to 4) (P = .008 for MTV comparison, P = .011 for TLG comparison). Using FDG PET-CT, we also demonstrated that CAR-T cell therapy in patients with NHL was associated with pseudoprogression and local immune activation. Our data indicate that patients with higher baseline disease burden have more severe CRS, and that CAR-T cell therapy is associated with lymphoma pseudoprogression and local immune activation.

Prognostic and theranostic 18F-FDG PET biomarkers for anti-PD1 immunotherapy in metastatic melanoma: association with outcome and transcriptomics.

PURPOSE: An imaging-based stratification tool is needed to identify melanoma patients who will benefit from anti Programmed Death-1 antibody (anti-PD1). We aimed at identifying biomarkers for survival and response evaluated in lymphoid tissue metabolism in spleen and bone marrow before initiation of therapy. METHODS: This retrospective study included 55 patients from two institutions who underwent 18F-FDG PET/CT before anti-PD1. Parameters extracted were SUVmax, SUVmean, HISUV (SUV-based Heterogeneity Index), TMTV (total metabolic tumor volume), TLG (total lesion glycolysis), BLR (Bone marrow-to-Liver SUVmax ratio), and SLR (Spleen-to-Liver SUVmax ratio). Each parameter was dichotomized using the median as a threshold. Association with survival, best overall response (BOR), and transcriptomic analyses (NanoString assay) were evaluated using Cox prediction models, Wilcoxon tests, and Spearman's correlation, respectively. RESULTS: At 20.7 months median follow-up, 33 patients had responded, and 29 patients died. Median PFS and OS were 11.4 (95%CI 2.7-20.2) and 28.5 (95%CI 13.4-43.8) months. TMTV (>25cm3), SLR (>0.77), and BLR (>0.79) correlated with shorter survival. High TMTV (>25 cm3), SLR (>0.77), and BLR (>0.79) correlated with shorter survival, with TMTV (HR PFS 2.2, p = 0.02, and HR OS 2.5, p = 0.02) and BLR (HR OS 2.3, p = 0.04) remaining significant in a multivariable analysis. Low TMTV and TLG correlated with BOR (p = 0.03). Increased glucose metabolism in bone marrow (BLR) was associated with transcriptomic profiles including regulatory T cell markers (p < 0.05). CONCLUSION: Low tumor burden correlates with survival and objective response while hematopoietic tissue metabolism correlates inversely with survival. These biomarkers should be further evaluated for potential clinical application.

Risk-stratifying capacity of PET/CT metabolic tumor volume in stage IIIA non-small cell lung cancer.

OBJECTIVES: Stage IIIA non-small cell lung cancer (NSCLC) is heterogeneous in tumor burden, and its treatment is variable. Whole-body metabolic tumor volume (MTVWB) has been shown to be an independent prognostic index for overall survival (OS). However, the potential of MTVWB to risk-stratify stage IIIA NSCLC has previously been unknown. If we can identify subgroups within the stage exhibiting significant OS differences using MTVWB, MTVWB may lead to adjustments in patients' risk profile evaluations and may, therefore, influence clinical decision making regarding treatment. We estimated the risk-stratifying capacity of MTVWB in stage IIIA by comparing OS of stratified stage IIIA with stage IIB and IIIB NSCLC. METHODS: We performed a retrospective review of 330 patients with clinical stage IIB, IIIA, and IIIB NSCLC diagnosed between 2004 and 2014. The patients' clinical TNM stage, initial MTVWB, and long-term survival data were collected. Patients with TNM stage IIIA disease were stratified by MTVWB. The optimal MTVWB cutoff value for stage IIIA patients was calculated using sequential log-rank tests. Univariate and multivariate cox regression analyses and Kaplan-Meier OS analysis with log-rank tests were performed. RESULTS: The optimal MTVWB cut-point was 29.2 mL for the risk-stratification of stage IIIA. We identified statistically significant differences in OS between stage IIB and IIIA patients (p < 0.01), between IIIA and IIIB patients (p < 0.01), and between the stage IIIA patients with low MTVWB (below 29.2 mL) and the stage IIIA patients with high MTVWB (above 29.2 mL) (p < 0.01). There was no OS difference between the low MTVWB stage IIIA and the cohort of stage IIB patients (p = 0.485), or between the high MTVWB stage IIIA patients and the cohort of stage IIIB patients (p = 0.459). Similar risk-stratification capacity of MTVWB was observed in a large range of cutoff values from 15 to 55 mL in stage IIIA patients. CONCLUSIONS: Using MTVWB cutoff points ranging from 15 to 55 mL with an optimal value of 29.2 mL, stage IIIA NSCLC may be effectively stratified into subgroups with no significant survival difference from stages IIB or IIIB NSCLC. This may result in more accurate survival estimation and more appropriate risk adapted treatment selection in stage IIIA NSCLC.

Metabolic tumor burden predicts prognosis of ovarian cancer patients who receive platinum-based adjuvant chemotherapy.

Volumetric parameters of positron emission tomography-computed tomography using 18F-fludeoxyglucose ((18) F-FDG PET/CT) that comprehensively reflect both metabolic activity and tumor burden are capable of predicting survival in several cancers. The aim of this study was to investigate the predictive performance of metabolic tumor burden measured by (18) F-FDG PET/CT in ovarian cancer patients who received platinum-based adjuvant chemotherapy after cytoreductive surgery. Included in this study were 37 epithelial ovarian cancer patients. Metabolic tumor burden in terms of metabolic tumor volume (MTV) and total lesion glycolysis (TLG), clinical stage, histological type, residual tumor after primary cytoreductive surgery, baseline serum carbohydrate antigen 125 (CA125) level, and the maximum standardized uptake value (SUVmax ) were determined, and compared for their performance in predicting progression-free survival (PFS). Metabolic tumor volume correlated with CA125 (r = 0.547, P < 0.001), and TLG correlated with SUVmax and CA125 (SUVmax , r = 0.437, P = 0.007; CA125, r = 0.593, P < 0.001). Kaplan-Meier analysis showed a significant difference in PFS between the groups categorized by TLG (P = 0.043; log-rank test). Univariate analysis indicated that TLG was a statistically significant risk factor for poor PFS. Multivariate analysis adjusted according to the clinicopathological features was carried out for MTV, TLG, SUVmax , tumor size, and CA125. Only TLG showed a significant difference (P = 0.038), and a 3.915-fold increase in the hazard ratio of PFS. Both MTV and TLG (especially TLG) could serve as potential surrogate biomarkers for recurrence in patients who undergo primary cytoreductive surgery followed by platinum-based chemotherapy, and could identify patients at high risk of recurrence who need more aggressive treatment.

Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B-cell lymphoma.

The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F-18] fluorodeoxyglucose ((18) F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with bendamustine-rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of (18) F-FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty-five patients with relapsed or refractory DLBCL were enrolled. The (18) F-FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value-volume histogram was significantly greater in complete response patients than in non-complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression-free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression-free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine-rituximab.

Combination of Circulating Cell-Free DNA and Positron Emission Tomography to Distinguish Non-Small Cell Lung Cancer from Tuberculosis.

OBJECTIVE: Non-small cell lung cancer (NSCLC) holds high metabolic tumor burden and circulating cell-free DNA (cfDNA) levels, and the relationship between metabolic tumor burden and cfDNA in NSCLC and the underlying mechanism of their interaction therein remain poorly characterized. Our aim was to evaluate the clinical value of cfDNA and metabolic tumor burden by positron emission tomography-computed tomography (PET/CT) for NSCLC differential diagnosis from tuberculosis in patients with solitary pulmonary nodules. METHODS: Metabolic tumor burden values in humans (subjects with NSCLC, subjects with tuberculosis, and healthy control subjects) and relevant mouse models were detected by preoperative 18F-fluorodeoxyglucose PET (18F-FDG PET/CT) and [3H]-2-deoxy-DG uptake, respectively. The cfDNA levels were detected by quantifying serum cfDNA fragments from the ALU (115 bp) gene using reverse transcription-polymerase chain reaction. RNA sequence was performed to determine the underlying target genes and knocked down or inhibited the target genes in vivo and in vitro to determine the mechanism therein. RESULTS: Metabolic tumor burden correlated with serum cfDNA levels in NSCLC subjects but not in tuberculosis subjects or healthy controls. Mouse models showed a similar phenomenon. In addition, the RNA sequence showed that glucose transporter 1 (GLU1), factor-related apoptosis ligand (FasL), caspase 8, and caspase 3 were significantly increased in NSCLC mouse tumors compared with those in tuberculosis mouse masses. Inhibiting the metabolic tumor burden by blocking or knocking down GLU1 markedly reduced the expression of FasL, the phosphorylation of caspase 8/caspase 3, and serum cfDNA levels/apoptosis percentage in vivo and in vitro. Furthermore, the use of a combination of cfDNA and metabolic tumor burden allowed better ability to distinguish NSCLC subjects from those with tuberculosis or healthy controls than either method used alone. CONCLUSION: Metabolic tumor burden promotes the formation of circulating cfDNA through GLU1-mediated apoptosis in NSCLC, and the combination of cfDNA and metabolic tumor burden could be valuable for distinguishing NSCLC from tuberculosis.

Predictive Value of Total Metabolic Tumor Burden Prior to Treatment in NSCLC Patients Treated with Immune Checkpoint Inhibition.

OBJECTIVES: We aimed to assess the predictive value of the total metabolic tumor burden prior to treatment in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs). METHODS: Pre-treatment 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) scans performed in two consecutive years for staging in adult patients with confirmed NSCLC were considered. Volume, maximum/mean standardized uptake value (SUVmax/SUVmean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed per delineated malignant lesion (including primary tumor, regional lymph nodes and distant metastases) in addition to the morphology of the primary tumor and clinical data. Total metabolic tumor burden was captured by totalMTV and totalTLG. Overall survival (OS), progression-free survival (PFS) and clinical benefit (CB) were used as endpoints for response to treatment. RESULTS: A total of 125 NSCLC patients were included. Osseous metastases were the most frequent distant metastases (n = 17), followed by thoracal distant metastases (pulmonal = 14 and pleural = 13). Total metabolic tumor burden prior to treatment was significantly higher in patients treated with ICIs (mean totalMTV ± standard deviation (SD) 72.2 ± 78.7; mean totalTLG ± SD 462.2 ± 538.9) compared to those without ICI treatment (mean totalMTV ± SD 58.1 ± 233.8; mean totalTLG ± SD 290.0 ± 784.2). Among the patients who received ICIs, a solid morphology of the primary tumor on imaging prior to treatment was the strongest outcome predictor for OS (Hazard ratio HR 28.04, p < 0.01), PFS (HR 30.89, p < 0.01) and CB (parameter estimation PE 3.46, p < 0.01), followed by the metabolic features of the primary tumor. Interestingly, total metabolic tumor burden prior to immunotherapy showed a negligible impact on OS (p = 0.04) and PFS (p = 0.01) after treatment given the hazard ratios of 1.00, but also on CB (p = 0.01) given the PE < 0.01. Overall, biomarkers on pre-treatment PET/CT scans showed greater predictive power in patients receiving ICIs, compared to patients without ICI treatment. CONCLUSIONS: Morphological and metabolic properties of the primary tumors prior to treatment in advanced NSCLC patients treated with ICI showed great outcome prediction performances, as opposed to the pre-treatment total metabolic tumor burdens, captured by totalMTV and totalTLG, both with negligible impact on OS, PFS and CB. However, the outcome prediction performance of the total metabolic tumor burden might be influenced by the value itself (e.g., poorer prediction performance at very high or very low values of total metabolic tumor burden). Further studies including subgroup analysis with regards to different values of total metabolic tumor burden and their respective outcome prediction performances might be needed.

Tumor metabolic and secondary lymphoid organ metabolic markers on 18F-fludeoxyglucose positron emission tomography predict prognosis of immune checkpoint inhibitors in advanced lung cancer.

Background: The purpose of this study was to investigate the predictive value of tumor metabolic parameters in combination with secondary lymphoid metabolic parameters on positron emission tomography (PET)/computed tomography (CT) for immune checkpoint inhibitor (ICI) prognosis in advanced lung cancer. Methods: This study retrospectively included 125 patients who underwent 18F-fludeoxyglucose (FDG) PET/CT before ICI therapy, including 41 patients who underwent a second PET/CT scan during ICI treatment. The measured PET/CT parameters included tumor metabolism parameters [maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG), and total metabolic tumor volume (TMTV)] and secondary lymphoid organ metabolism parameters [spleen-to-liver SUVmax ratio (SLR) and bone marrow-to-liver SUVmax ratio (BLR)]. The correlation of PET/CT metabolic parameters with early ICI treatment response, progression-free survival (PFS), and overall survival (OS) was analyzed. Results: Within a median follow-up of 28.7 months, there were 44 responders and 81 non-responders. The median PFS was 8.6 months (95% confidence interval (CI): 5.872-11.328), and the median OS was 20.4 months (95% CI: 15.526-25.274). Pretreatment tumor metabolic parameters were not associated with early treatment responses. The high bone marrow metabolism (BLR >1.03) was significantly associated with a shorter PFS (p = 0.008). Patients with a high TMTV (>168 mL) and high spleen metabolism (SLR >1.08) had poor OS (p = 0.019 and p = 0.018, respectively). Among the 41 patients who underwent a second PET/CT scan, the ΔSUVmax was significantly lower (p = 0.01) and the SLR was significantly higher (p = 0.0086) in the responders. Populations with low-risk characteristics (low TMTV, low SLR, and ΔSLR > 0) had the longest survival times. Conclusion: High pretreatment TMTV and SLR are associated with poor OS, and increased spleen metabolism after ICI therapy predicts treatment benefit. This indicates that the combination of tumor and spleen metabolic parameters is a valuable prognostic strategy.

Developing a clinical and PET/CT volumetric prognostic index for risk assessment and management of NSCLC patients after initial therapy.

BACKGROUND: Currently, individual clinical prognostic variables are used sequentially with risk-stratification after TNM staging in clinical practice for the prognostic assessment of patients with NSCLC, which is not effective for estimating the collective impact of multiple individual variables on patient outcomes. Here, we developed a clinical and PET/CT volumetric prognostic (CPVP) index that integrates the prognostic power of multiple clinical variables and metabolic tumor volume from baseline FDG-PET, for use immediately after definitive therapy. PATIENTS AND METHODS: This retrospective cohort study included 998 NSCLC patients diagnosed between 2004 and 2017, randomly assigned to two cohorts for modeling the CPVP index using Cox regression models examining overall survival (OS) and subsequent validation. RESULTS: The CPVP index generated from the model cohort included pretreatment variables (whole-body metabolic tumor volume [MTVwb], clinical TNM stage, tumor histology, performance status, age, race, gender, smoking history) and treatment type. A clinical variable (CV) index without MTVwb and PET/CT volumetric prognostic (PVP) index without clinical variables were also generated for comparison. In the validation cohort, univariate Cox modeling showed a significant association of the index with overall survival (OS; Hazard Ratio [HR] 3.14; 95% confidence interval [95% CI] = 2.71 to 3.65, p < 0.001). Multivariate Cox regression analysis demonstrated a significant association of the index with OS (HR = 3.13, 95% CI = 2.66 to 3.67, p < 0.001). The index showed greater prognostic power (C-statistic = 0.72) than any of its independent variables including clinical TNM stage (C-statistic ranged from 0.50 to 0.69, all p < 0.003), CV index (C-statistic = 0.68, p < 0.001) and PVP index (C-statistic = 0.70, p = 0.006). CONCLUSIONS: The CPVP index for NSCLC patients has moderately strong prognostic power and is more prognostic than its individual prognostic variables and other indices. It provides a practical tool for quantitative prognostic assessment after initial treatment and therefore may be helpful for the development of individualized treatment and monitoring strategy for NSCLC patients.

Prognostic Value of 18F-FDG PET/CT Volume-Based Metabolic Parameters in Patients with Node-Negative Stage II Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a major cancer prevalent in Asian males. Pretreatment tumor burden can be prognostic for ESCC. We studied the prognostic value of metabolic parameters of 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) and the serum squamous cell carcinoma antigen (SCC-Ag) level in node-negative stage II ESCC patients. Eighteen males underwent staging evaluation were included. The volume-based metabolic parameters derived from 18F-FDG PET/CT, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were obtained using the PET Volume Computer Assisted Reading application. The Spearman correlation coefficients were calculated to assess the relationship between metabolic parameters and pretreatment serum SCC-Ag levels. Based on the 5-year follow-up, patients were sub-divided into the demised and the stable groups. Potential prognostic value was assessed by independent t-test and the Mann-Whitney U test. The association of overall survival was assessed using univariate and multivariate Cox regression analyses. The demised group showed significant higher values in serum SCC-Ag, as well as in MTV and TLG, but not SUVmax and SUVmean. The SUVmax, MTV, TLG, and serum SCC-Ag showed significant association with overall survival. Our findings suggest potential usage of pretreatment volume-based metabolic parameters of 18F-FDG PET/CT and serum SCC-Ag as prognostic factors for node-negative stage II ESCC patients.

The Value of 18F-FDG PET/CT in Predicting the Response to PD-1 Blocking Immunotherapy in Advanced NSCLC Patients with High-Level PD-L1 Expression.

BACKGROUND: The objective of this study was to evaluate if 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)-derived parameters are useful in predicting response and survival after programmed cell death protein 1 (PD-1) blocking immunotherapy in patients with advanced NSCLC characterized by a high programmed death-ligand 1 (PD-L1) expression (≥50%) on immunohistochemistry. PATIENTS AND METHODS: In 30 patients with advanced stage IV non-small-cell lung cancer (NSCLC) and high PD-L1 expression, 18F-FDG PET/CT parameters before start of treatment with PD-1 blocking immunotherapy were evaluated retrospectively. In 24 out of the 30 patients, 18F-FDG PET/CT was available 8 to 9 weeks after start of the treatment. Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and metabolic responses assessed on 18F-FDG PET/CT were compared. RESULTS: Median follow-up was 20 months (range, 4.2-37.6). Median PD-L1 expression was 80%. The objective response rate with RECIST 1.1 was 53.3%. Median progression-free survival (PFS) was 12.4 months (95% confidence interval [CI], 1.0-37.8), and median overall survival (OS) was 14.9 months (95% CI, 2.4-38.2). Baseline 18F-FDG PET/CT parameters did not differ between responders and non-responders (all P > .05). The maximum standardized uptake value (SUVmax) was the only 18F-FDG PET/CT parameter associated with PFS (P = .04), with a trend for OS (P = .06). At first evaluation, response according to total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were associated with PFS and OS (both P < .0001). This was not the case for RECIST 1.1 (P = .29 for PFS and P = .38 for OS). CONCLUSION: Clinical response and survival were independent from metabolic tumor volume at baseline. Reduction of metabolic tumor volume after 8 to 9 weeks of treatment was a better predictor for prolonged survival than RECIST 1.1.

Tumor Burden Measured by 18F-FDG PET/CT in Predicting Efficacy and Adverse Effects of Chimeric Antigen Receptor T-Cell Therapy in Non-Hodgkin Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has exhibited promising clinical outcomes in treating relapsed/refractory (R/R) B-cell hematologic malignancies. Current studies have shown a close correlation between baseline tumor burden and therapeutic response in CAR-T cell therapy. However, the roles of PET/CT metabolic parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), remain unclear in this setting. In this study, we retrospectively reviewed 41 R/R NHL patients. 18F-FDG PET/CT was used to measure the average standardized uptake value (SUVavg), MTV, and TLG of the lymphomatous lesions. These patients were divided into two groups according to the optimal cutoff values of respective PET/CT metabolic parameters. The multivariate analysis depicted that early post-therapy SUVavg (HR: 1.418, 95% CI: 1.029, 1.955; p = 0.033) and MTV (HR: 1.001, 95% CI: 1.000, 1.002; p = 0.041) were independent risk factors associated with OS and PFS, respectively. Patients with baseline SUVavg < 4.36 achieved a superior 1-year OS rate than the SUVavg ≥ 4.36 group (100.0% vs. 44.9%, p = 0.019). For the patients with lower values in early post-therapy SUVavg (<2.60) (51.1% vs. 0%, p < 0.001), MTV (<0.55 cm3) (53.6% vs. 0.0%, p = 0.001), and TLG (<1.54) (53.6% vs. 0.0%, p = 0.001), their 1-year PFS rates were higher than the compared groups. Moreover, patients with higher baseline tumor burdens were found to have significantly increased CRS incidence and cytokine levels. In conclusion, the PET/CT metabolic parameters are closely related to OS, PFS, and CRS in R/R NHL patients treated with CAR-T cells. This study may pave the way for building a comprehensive assessment system of tumor burden using 18F-FDG PET/CT, which can optimize therapeutic and supportive approaches in CAR-T cell therapy.

Value of metabolic parameters in distinguishing primary mediastinal lymphomas from thymic epithelial tumors.

Objective: A high rate of unnecessary thymectomies has been reported. This study aimed to distinguish primary mediastinal lymphomas (PMLs) from thymic epithelial tumors (TETs) by evaluating volumetric and metabolic parameters with 18F-FDG PET/CT. Methods: A total of 136 patients who were pathologically diagnosed with TETs or PMLs were enrolled, and 18F-FDG PET/CT was performed before therapy. Volumetric parameters, including the mean SUV (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax, were determined and compared between the 2 subtypes. The diagnostic performance of these parameters was evaluated with receiver operating characteristic (ROC) curve analysis. Results: All parameters significantly differed between patients with PMLs and TETs. Patients with lymphomas were younger and had higher SUVmean, SUVmax, TLG, and MTV values than patients with TETs. The MTV and TLG values had similar diagnostic performance. ROC analysis indicated that the areas under the curves of the SUVmean and SUVmax values performed similarly (approximately 0.76) in differentiating patients with PMLs from TETs, and both values were better than the MTV and TLG values. When age was included with the SUVmax in differentiating TETs from PMLs, the AUC was 0.91, and the sensitivity and specificity increased to 80% and 93%, respectively. Conclusions: The SUVmax and volumetric parameters of 18F-FDG PET/CT can be used to distinguish patients with PMLs versus TETs, and thus may aid in preventing unnecessary thymectomies or other invasive operations.

Lymphoma Severity and Type Are Associated With Aortic FDG Uptake by 18F-FDG PET/CT Imaging.

BACKGROUND: There is evidence that metabolic disease burden in lymphoma influences patient outcome. However, the impact of disease severity on the cardiovascular system is unknown. OBJECTIVES: The aim of this study was to examine whether lymphoma is associated with arterial inflammation by investigating the relationship between disease metabolic burden and arterial fluorodeoxyglucose (FDG) uptake. METHODS: Sixty-two chemotherapy-naïve patients with active Hodgkin's or non-Hodgkin's lymphoma were matched (2:1) to individual control groups of lymphoma patients previously treated and free of active disease. All groups underwent 18F-FDG position emission tomography-computed tomography imaging. Disease severity was quantified by metabolic tumor volume (MTV) and total lesion glycolysis corresponding to standardized uptake values (SUVs) ≥41% or ≥2.5 of the maximum SUV within lymphoma regions, and aortic FDG uptake was quantified through the target-to-background ratio (TBR). Inflammatory and disease severity biomarkers were also measured. RESULTS: MTV and total lesion glycolysis measurements were significantly correlated with inflammatory and disease biomarkers. Aortic TBR was higher in patients with active non-Hodgkin's lymphoma compared with control subjects (median difference 0.51; 95% confidence interval [CI]: 0.28 to 0.78; p < 0.001). Similarly, patients with active Hodgkin's lymphoma had higher values of aortic TBR compared with control subjects (median difference 0.31; 95% CI: 0.15 to 0.49; p < 0.001). In addition, aortic TBR was modestly increased in patients with stage III to IV disease compared with those with stage I to II disease (median aortic TBR: 2.23 [interquartile range: 2.01 to 2.54] vs. 2.06 [interquartile range: 1.83 to 2.27; p = 0.050). In multivariable analysis, aortic FDG uptake and MTV≥2.5 values were independently associated (ß = 0.425; 95% CI: 0.189 to 0.662; p = 0.001; R2 = 0.208), as were aortic FDG uptake and MTV≥41% (ß = 0.407; 95% CI: 0.167 to 0.649, p = 0.001; R2 = 0.191). CONCLUSIONS: Aortic wall FDG uptake is related with disease severity indicative of a possible vascular effect of lymphoma. This work highlights a new potential role of molecular imaging in cardio-oncology for evaluating disease severity and its consequences on the vasculature.

Prognostic value of metabolic tumor burden calculated using dual-time-point 18F-fluorodeoxyglucose positron emission tomography/CT in patients with oropharyngeal or hypopharyngeal cancer.

BACKGROUND: This study investigates the prognostic value of metabolic tumor burden calculated using dual-time-point 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT in patients with locally advanced cancer. METHODS: This study examines 42 patients (35 men and 7 women, 38-73 years old) with locally advanced oropharyngeal or hypopharyngeal cancer who had undergone FDG-PET/CT before receiving chemoradiotherapy. Maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for the early and delayed phases. Statistical analyses included receiver operating characteristic curve, univariate and multivariate analysis. RESULTS: ΔSUVmax , both phases of MTV2.5 and TLG2.5 , early TLG40% , ΔTLG2.5 , and ΔTLG40% were significantly associated with progression-free survival (PFS). In multivariate analysis, early TLG2.5 (P = .005) was an independent prognostic factor of PFS. CONCLUSION: Not the percent change but the value calculated in the early phase in several parameters using dual-time-point FDG-PET/CT is significantly associated with the outcomes of patients with locally advanced oropharyngeal or hypopharyngeal cancer.

Metabolic tumor burden on postsurgical PET/CT predicts survival of patients with gastric cancer.

BACKGROUND: The prognostic value of postoperative 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) to patients with gastric cancer remains unclear. This study aims to investigate the prognostic value of whole body (WB) metabolic tumor burden (MTBWB) on postsurgical 18F-FDG PET/CT to patients with gastric cancer. METHODS: A total of 376 patients with surgeries-confirmed gastric cancer were enrolled. Clinicopathologic information, overall survival (OS) and MTBWB parameters on postsurgical PET/CT, in terms of WB maximum standardized uptake value (SUVWBmax), WB metabolic tumor volume (MTVWB), and WB total lesion glycolysis (TLGWB) were collected. In-between differences of patient clinicopathologic characteristics, OS and MTBWB measurements were compared using chi-square test, Fisher's exact test, Student's t test or the Kaplan-Meier survival analysis. The optimal cutoffs of MTBWB measurements were calculated through the receiver operating characteristic (ROC) curve analysis. Univariable and multivariable Cox proportional hazard regression were performed to test the predictive value of the clinicopathologic factors and MTBWB measurements to patient survival. RESULTS: The PET-positive patients had significantly decreased OS based on either Kaplan-Meier survival analysis (P <  0.001) or univariable Cox regression (hazard ratio [HR] = 2.850, P <  0.001). In patients with PET-positive tumors, the associations between OS and SUVWBmax, MTVWB and TLGWB were significant, both in univariable analysis (P <  0.001, P <  0.001 and P = 0.001, respectively) and in multivariable analysis (P = 0.002, P <  0.001 and P = 0.005, respectively). Patient OS among groups dichotomized by cutoffs of SUVWBmax > 8.6, MTVWB > 91.5 cm3, and TLGWB > 477.6 cm3 were significantly different (P = 0.001, P <  0.001 and P = 0.001, respectively). CONCLUSIONS: MTBWB, in terms of SUVWBmax, MTVWB and TLGWB, on postsurgical 18F-FDG PET/CT provides prognostic value to patients with gastric cancer after curative resection.

An updated and validated PET/CT volumetric prognostic index for non-small cell lung cancer.

OBJECTIVES: Whole-body metabolic tumor volume (MTVWB) and TNM staging are independent prognostic factors for overall survival (OS) in non-small cell lung cancer (NSCLC). We aimed to update and validate the PET/CT volumetric prognostic index (PVP index) using the new 8th edition TNM staging system to evaluate its prognostic power versus TNM staging and MTVWB alone. MATERIALS AND METHODS: This study was a retrospective analysis of 949 non-small cell lung cancer (NSCLC) patients diagnosed between 2004 and 2014. Clinical TNM stage, MTVWB, age and gender, tumor histology type at the initial staging PET/CT exam, as well as treatment history and long-term survival data were obtained. Patients were randomly assigned to modeling or validation group. Univariate and multivariate Cox regression analyses were performed to compare PVP index, TNM stage, and MTVWB in the validation group. RESULTS: The updated PVP index included the 3 variables TNM stage, and MTVWB and age. Univariate Cox models showed significant association of PVP index with overall survival (OS) in patients with NSCLC (with Hazard ratio HR = 2.88 in the validation group, p < 0.001). The C-statistic of the PVP index (C-statistic = 0.71 in the validation group) was significantly greater than that of 8th edition TNM staging (C-statistic = 0.68, p = 0.029), MTVWB (C-statistic = 0.68, p = 0.001), and patient age (C-statistic = 0.53, p < 0.001). Multivariate Cox regression analyses demonstrated significant association of PVP index with OS (with HR = 2.80, p < 0.001) after adjusting patient's gender and tumor histology. CONCLUSIONS: The updated PVP index provides a quantitative risk assessment for NSCLC patients using 8th edition TNM staging, MTVWB, and age. The index provides a simple and practical way for the care team to incorporate the independent prognostic value of both the TNM stage and MTVWB. This approach can further improve the accuracy of overall survival prognosis.

Prognostic evaluation of percentage variation of metabolic tumor burden calculated by dual-phase (18) FDG PET-CT imaging in patients with head and neck cancer.

BACKGROUND: The purpose of this study was to investigate the prognostic value of percentage variation of metabolic tumor burden in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Patients referred to undergo (18) fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT for staging of HNSCC were included in this study. Using a dual-phase method, standardized uptake value maximum (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were recorded and respectively used to calculate retention index (RI), %ΔMTV, and %ΔTLG. Recurrence-free survival (RFS) was determined by Kaplan-Meier method and compared with studied PET parameters in univariate and multivariate. RESULTS: Seventy patients (61 men/9 women; 62.9 ± 9.1 years old) were included. In univariate, SUVmax, RI, MTV, and TLG (p ≤ .0001) were significantly correlated with RFS, unlike %ΔMTV (p = 137) and %ΔTLG (p = .517). In multivariate, RI (p = .005) and MTV (p = .022) persisted as independent prognostic factors. CONCLUSION: Our results did not prove a prognostic interest of percentage variation of metabolic tumor burden in patients with HNSCC but confirmed that RI and MTV are independently correlated with RFS. © 2015 Wiley Periodicals, Inc. Head Neck 38: E600-E606, 2016.