Optimization of Metabolic Tumor Volume as a Prognostic Marker in CAR T-Cell Therapy for Aggressive Large B-cell NHL.

BACKGROUND: CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a standard of care in relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphomas (B-NHL) though the majority of recipients do not receive durable disease benefit, prompting the need to better define risk factors for relapse/progression. OBJECTIVES: We performed a single-center, retrospective analysis of patients treated with commercial CAR T-cell therapy to evaluate the impact of tumor burden, as measured by whole-body metabolic tumor volume (MTV) from 18F fluorodeoxyglucose PET imaging, on treatment outcomes. STUDY DESIGN: Sixty-one patients treated with CAR T-cell therapy for R/R B-NHL between May 2016 and November 2021 were included. RESULTS: Using a receiver operating characteristic curve-based MTV optimization cutoff of 450 mL, 1-year progression-free survival (PFS) was 22% for high MTV versus 54% for low MTV (P < .01), and 1-year overall survival (OS) was 37% and 73%, respectively (P = .01). In a subset of 46 patients, residual MTV of less than 106 mL at the day 30 (D30) disease assessment was associated with significantly improved outcomes (1-year OS 85% vs. 13%, P < .01). Incorporation of pretreatment MTV to the International Prognostic Index (IPI) scoring system significantly distinguished 2-year PFS and OS outcomes by 3 risk groups. CONCLUSIONS: Our findings suggest that both pretreatment and D30 MTV are predictive of outcomes among R/R B-NHL patients treated with CAR T-cell therapy. These data indicate that efforts to reduce pretreatment tumor burden may improve longitudinal clinical outcomes. Furthermore, D30 postinfusion MTV quantification may aid clinicians in optimally identifying patients at high-risk for progression, and in whom closer disease monitoring should be considered. MTV also adds prognostic value to patients with high-risk IPI and holds promise for incorporation in novel risk scoring systems which can identify patients prior to CAR T-cell therapy at highest risk of adverse outcomes.

Whole-body tumor segmentation from PET/CT images using a two-stage cascaded neural network with camouflaged object detection mechanisms.

BACKGROUND: Whole-body Metabolic Tumor Volume (MTVwb) is an independent prognostic factor for overall survival in lung cancer patients. Automatic segmentation methods have been proposed for MTV calculation. Nevertheless, most of existing methods for patients with lung cancer only segment tumors in the thoracic region. PURPOSE: In this paper, we present a Two-Stage cascaded neural network integrated with Camouflaged Object Detection mEchanisms (TS-Code-Net) for automatic segmenting tumors from whole-body PET/CT images. METHODS: Firstly, tumors are detected from the Maximum Intensity Projection (MIP) images of PET/CT scans, and tumors' approximate localizations along z-axis are identified. Secondly, the segmentations are performed on PET/CT slices that contain tumors identified by the first step. Camouflaged object detection mechanisms are utilized to distinguish the tumors from their surrounding regions that have similar Standard Uptake Values (SUV) and texture appearance. Finally, the TS-Code-Net is trained by minimizing the total loss that incorporates the segmentation accuracy loss and the class imbalance loss. RESULTS: The performance of the TS-Code-Net is tested on a whole-body PET/CT image data-set including 480 Non-Small Cell Lung Cancer (NSCLC) patients with five-fold cross-validation using image segmentation metrics. Our method achieves 0.70, 0.76, and 0.70, for Dice, Sensitivity and Precision, respectively, which demonstrates the superiority of the TS-Code-Net over several existing methods related to metastatic lung cancer segmentation from whole-body PET/CT images. CONCLUSIONS: The proposed TS-Code-Net is effective for whole-body tumor segmentation of PET/CT images. Codes for TS-Code-Net are available at: https://github.com/zyj19/TS-Code-Net.

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.

The Relative Importance of Clinical and Socio-demographic Variables in Prognostic Prediction in Non-Small Cell Lung Cancer: A Variable Importance Approach.

BACKGROUND: Prognostic modeling in health care has been predominantly statistical, despite a rapid growth of literature on machine-learning approaches in biological data analysis. We aim to assess the relative importance of variables in predicting overall survival among patients with non-small cell lung cancer using a Variable Importance (VIMP) approach in a machine-learning Random Survival Forest (RSF) model for posttreatment planning and follow-up. METHODS: A total of 935 non-small cell lung cancer patients were randomly and equally divided into 2 training and testing cohorts in an RFS model. The prognostic variables included age, sex, race, the TNM Classification of Malignant Tumors (TNM) stage, smoking history, Eastern Cooperative Oncology Group performance status, histologic type, treatment category, maximum standard uptake value of whole-body tumor (SUVmaxWB), whole-body metabolic tumor volume (MTVwb), and Charlson Comorbidity Index. The VIMP was calculated using a permutation method in the RSF model. We further compared the VIMP of the RSF model to that of the standard Cox survival model. We examined the order of VIMP with the differential functional forms of the variables. RESULTS: In both the RSF and the standard Cox models, the most important variables are treatment category, TNM stage, and MTVwb. The order of VIMP is more robust in RSF model than in Cox model regarding the differential functional forms of the variables. CONCLUSIONS: The RSF VIMP approach can be applied alongside with the Cox model to further advance the understanding of the roles of prognostic factors, and improve prognostic precision and care efficiency.

Computer-assisted Curie scoring for metaiodobenzylguanidine (MIBG) scans in patients with neuroblastoma.

BACKGROUND: Radiolabeled metaiodobenzylguanidine (MIBG) is sensitive and specific for detecting neuroblastoma. The extent of MIBG-avid disease is assessed using Curie scores. Although Curie scoring is prognostic in patients with high-risk neuroblastoma, there is no standardized method to assess the response of specific sites of disease over time. The goal of this study was to develop approaches for Curie scoring to facilitate the calculation of scores and comparison of specific sites on serial scans. PROCEDURE: We designed three semiautomated methods for determining Curie scores, each with increasing degrees of computer assistance. Method A was based on visual assessment and tallying of MIBG-avid lesions. For method B, scores were tabulated from a schematic that associated anatomic regions to MIBG-positive lesions. For method C, an anatomic mesh was used to mark MIBG-positive lesions with automatic assignment and tallying of scores. Five imaging physicians experienced in MIBG interpretation scored 38 scans using each method, and the feasibility and utility of the methods were assessed using surveys. RESULTS: There was good reliability between methods and observers. The user-interface methods required 57 to 110 seconds longer than the visual method. Imaging physicians indicated that it was useful that methods B and C enabled tracking of lesions. Imaging physicians preferred method B to method C because of its efficiency. CONCLUSIONS: We demonstrate the feasibility of semiautomated approaches for Curie score calculation. Although more time was needed for strategies B and C, the ability to track and document individual MIBG-positive lesions over time is a strength of these methods.

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.

Developing and validating a novel metabolic tumor volume risk stratification system for supplementing non-small cell lung cancer staging.

PURPOSE: We hypothesized that whole-body metabolic tumor volume (MTVwb) could be used to supplement non-small cell lung cancer (NSCLC) staging due to its independent prognostic value. The goal of this study was to develop and validate a novel MTVwb risk stratification system to supplement NSCLC staging. METHODS: We performed an IRB-approved retrospective review of 935 patients with NSCLC and FDG-avid tumor divided into modeling and validation cohorts based on the type of PET/CT scanner used for imaging. In addition, sensitivity analysis was conducted by dividing the patient population into two randomized cohorts. Cox regression and Kaplan-Meier survival analyses were performed to determine the prognostic value of the MTVwb risk stratification system. RESULTS: The cut-off values (10.0, 53.4 and 155.0 mL) between the MTVwb quartiles of the modeling cohort were applied to both the modeling and validation cohorts to determine each patient's MTVwb risk stratum. The survival analyses showed that a lower MTVwb risk stratum was associated with better overall survival (all p < 0.01), independent of TNM stage together with other clinical prognostic factors, and the discriminatory power of the MTVwb risk stratification system, as measured by Gönen and Heller's concordance index, was not significantly different from that of TNM stage in both cohorts. Also, the prognostic value of the MTVwb risk stratum was robust in the two randomized cohorts. The discordance rate between the MTVwb risk stratum and TNM stage or substage was 45.1% in the modeling cohort and 50.3% in the validation cohort. CONCLUSION: This study developed and validated a novel MTVwb risk stratification system, which has prognostic value independent of the TNM stage and other clinical prognostic factors in NSCLC, suggesting that it could be used for further NSCLC pretreatment assessment and for refining treatment decisions in individual patients.

An experimental rabbit model of symptomatic cerebral vasospasm with in vivo neuroimaging assessment and ex vivo histological validation.

Cerebral vasospasm (CVS) is a severe complication that occurs following aneurysmal subarachnoid hemorrhage (SAH). Magnetic resonance angiography (MRA) has been used to evaluate brain injury following SAH in humans. The present study was designed to assess a rabbit model of symptomatic CVS (SCVS) and the utility of MRA in evaluating SCVS in rabbits. Japanese white rabbits (n=24) were randomly divided into 2 equal groups: A sham group and a SAH group. Neurological scores were evaluated for 7 days following SAH. Basilar artery (BA) diameters were measured using MRA preoperatively and 7 days postoperatively. Rabbits were sacrificed 7 days following SAH and the BA diameter of each rabbit was determined using histological evaluation. Compared with the Sham group, neurological function was significantly reduced in the SAH group at all time points (P<0.05). Furthermore, the BA diameter was significantly smaller in the SAH group on day 7 compared with the baseline measurement (P<0.05). No significant difference was observed between histological and MRA findings in either group at day 7. Histological changes in the hippocampus consistent with ischemia were observed in the SAH group. Hippocampal ischemia was also identified in the SAH group via MRA and there was no difference in detection rates following the use of MRA and histochemistry. MRA appears to be an effective method for assessing vasospasms of the BA and ischemic changes to the hippocampus in a rabbit model of SCVS. Furthermore, the animal model used in the present study may be beneficial for the future study of SCVS.

Pilot Study of 99mTc-labeled Ethylene Dicysteine Deoxyglucose SPECT-CT Imaging in Treatment Response Evaluation in Patients with Locally Advanced Head and Neck Cancer.

BACKGROUND: The purpose of this study is to describe the preliminary findings of 99mTc-labeled ethylene dicysteine deoxyglucose (99mTc-EC-DG) performed four weeks after chemoradiotherapy in patients with locally advanced head and neck squamous cell carcinoma. METHODS: Review of nine patients with locally advanced head and neck squamous cell carcinomas imaged with 99mTc-EC-DG single photon emission computed tomography-computed tomography (SPECT-CT) at baseline before treatment and at four weeks after treatment completion was performed. RESULTS: At four weeks post-treatment, five patients had either decreased activity or no significant activity on 99mTc-EC-DG SPECT-CT and were considered to have responded to treatment, whereas four patients did not have significantly decreased uptake on 99mTc-EC-DG SPECT-CT and were considered to have not adequately responded to treatment. Among the five patients considered to have treatment response at four weeks, all were free of disease (true-negative). Among the four patients considered to have stable activity on 99mTc-EC-DG SPECT-CT at four weeks, two were designated as having no response or incomplete response (true-positive), and two were designated as having complete response (false-positive) on subsequent composite assessment. CONCLUSIONS: The pilot data is promising but warrants further investigation of 99mTc-EC-DG SPECT-CT for the assessment of locoregional treatment response at four weeks in patients with locally advanced head and neck squamous cell carcinomas.

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.

Whole body metabolic tumor volume is a prognostic marker in patients with newly diagnosed stage 3B non-small cell lung cancer, confirmed with external validation.

PURPOSE: TNM Stage 3B encompasses a wide range of primary tumor and nodal metastatic tumor burden. This study aimed to evaluate the prognostic value of quantitative FDG PET/CT parameters in patients with newly diagnosed Stage 3B Non-Small Cell Lung Cancer (NSCLC). MATERIALS AND METHODS: Institutional review board approved retrospective study identified patients diagnosed with Stage 3B NSCLC (8th edition TNM classification) on baseline FDG PET/CT at two medical centers (Medical centers A and B), between Feb 2004 and Dec 2014. Patients were excluded if they had prior NSCLC treatment or recent diagnosis of a second primary cancer. Quantitative FDG PET/CT parameters including whole body metabolic tumor volume (MTVwb), total lesion glycolysis (TLGwb), and maximum standardized uptake value (SUVmaxwb) were measured from baseline PET/CT using Edge method with Mimvista software. The primary endpoint was overall survival (OS). Cox proportional hazard regression and Kaplan-Meier overall survival analyses were used to test for an association between OS and quantitative FDG PET/CT parameters. The distributions of MTVwb, TLGwb, SUVmaxwb were skewed, so a natural logarithm transformation was applied and the transformed variables [(ln(MTVwb), ln(TLGwb), and ln(SUVmaxwb)] were used in the analysis. RESULTS: The training set included 110 patients from center A with Stage 3B NSCLC. 78.2% of patients expired during follow-up. Median OS was 14 months. 1-year, 2-year, and 5-year OS was 56.5%, 34.6% and 13.9%, respectively. Univariate Cox regression analysis showed no significant difference in OS on the basis of age, gender, histology, ln(TLGwb), or ln(SUVmaxwb). ln(MTVwb) was positively associated with OS [hazard ratio (HR) of 1.23, p = 0.037]. This association persisted on multivariate Cox regression analysis (HR 1.28, p = 0.043), with adjustments for age, gender, treatment and tumor histology. External validation with 44 patients from center B confirmed increasing MTVwb was associated significantly worse OS. An MTVwb cut-off point of 85.6 mL significantly stratified Stage 3B NSCLC patient prognosis. CONCLUSION: MTVwb is a prognostic marker for OS in patients with Stage 3B NSCLC, independent of age, gender, treatment, and tumor histology.

Prognostic value of quantitative PET/CT in patients with a nonsmall cell lung cancer and another primary cancer.

OBJECTIVE: The staging and management of patients with newly diagnosed nonsmall cell lung cancer (NSCLC) in the setting of recently diagnosed other (metachronous or synchronous) primary cancer are challenging. This retrospective cohort study was carried out to test our hypothesis that baseline 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) PET/CT parameters, including whole-body metabolic tumor volume (MTVWB), total lesion glycolysis (TLGWB), and maximum standardized uptake value (SUVmaxWB), are associated with the overall survival (OS) of such patients. PATIENTS AND METHODS: A total of 110 NSCLC patients (52 men and 58 women, aged 68.6±7.8 years) with other primary malignant cancers who had baseline F-FDG PET/CT scans were retrospectively reviewed. MTVWB, TLGWB, and SUVmaxWB were measured. Kaplan-Meier analysis with the log-rank test and Cox regression models were used to assess the association of OS with F-FDG PET/CT parameters and clinical risk factors. RESULTS: Kaplan-Meier analysis and univariate Cox regression models showed significant associations of OS with ln(MTVWB), ln(TLGWB), ln(SUVmaxWB), TNM stage, and treatment type (surgery vs. no treatment). Multivariable Cox regression models showed a significant relationship of OS with ln(MTVWB) [hazard ratio (HR)=1.368, P=0.001], ln(TLGWB) (HR=1.313, P<0.001), and ln(SUVmaxWB) (HR=1.739, P=0.006), adjusted for age, treatment type, tumor histology, and TNM stage. The TNM stage was not associated significantly with OS when MTVWB, TLGWB, or SUVmaxWB were included in the multivariable models. CONCLUSION: MTVWB, TLGWB, and SUVmaxWB from baseline F-FDG PET/CT are associated individually with OS of patients with both NSCLC and other primary malignant tumors independent of age, treatment type, tumor histology, and TNM stage.

Evaluation of parkinsonism and striatal dopamine transporter loss in patients with spinocerebellar ataxia type 6.

It is unclear whether patients with spinocerebellar ataxia type 6 (SCA6) have parkinsonism and striatal dopamine transporter (DAT) loss, based on previously small size studies without well-matched controls. A study with a larger number of patients and both age- and gender-matched healthy controls (HCs) is needed for a better answer to this question. Twelve genetically confirmed ataxic SCA6 patients (six male six female, age 65.3 ± 11.2 years), and eight age- and gender-matched HCs (five male three female, age 71.3 ± 8.6 years) were enrolled during 2013-2015 from tertiary movement disorders and ataxia clinics. Clinical assessment for parkinsonism, and qualitative and quantitative assessment of DAT level on DaTscan™ imaging were conducted in SCA6 patients compared to HCs. We found no convincing parkinsonism in SCA6 patients, given generalized bradykinesia in the context of significant ataxia in all, with mild symmetric rigidity in five without resting tremor. Furthermore, we found no striatal DAT loss in anterior, posterior, and total putamen and caudate on imaging, assessed independently by qualitative visual inspection in a blinded manner by the nuclear medicine specialist and movement disorder specialist (kappa = 1). Additional quantitative analysis on these areas did not reveal significant DAT loss either in SCA6 patients compared to HCs. We conclude that there is no convincing parkinsonism or DAT loss in SCA6 patients in this unique study with a larger than previously reported number of patients compared to both age- and gender-matched HCs, suggesting that dopaminergic dysfunction is not usually involved in SCA6.

Consistency of metabolic tumor volume of non-small-cell lung cancer primary tumor measured using 18F-FDG PET/CT at two different tracer uptake times.

OBJECTIVES: The objective of this study was to test the hypothesis that the metabolic tumor volume (MTV) of primary non-small-cell lung cancer is not sensitive to differences in F-fluorodeoxyglucose (F-FDG) uptake time, and to compare this consistency of MTV measurements with that of standardized uptake value (SUV) and total lesion glycolysis (TLG). METHODS: Under Institutional Review Board approval, 134 consecutive patients with histologically proven non-small-cell lung cancer underwent F-FDG PET/computed tomography scanning at about 1 h (early) and 2 h (delayed) after intravenous injection of F-FDG. MTV, SUV, and TLG of the primary tumor were all measured. Student's t-test and Wilcoxon's signed-rank test for paired data were used to compare MTV, SUV, and TLG between the two scans. The intraclass correlation coefficient (ICC) was used to assess agreement in PET parameters between the two scans and between the measurements made by two observers. RESULTS: MTV was not significantly different (P=0.17) between the two scans. However, SUVmax, SUVmean, SUVpeak, and TLG increased significantly from the early to the delayed scans (P<0.0001 for all). The median percentage change between the two scans in MTV (1.65%) was smaller than in SUVmax (11.76%), SUVmean(10.57%), SUVpeak(13.51%), and TLG (14.34%); the ICC of MTV (0.996) was greater than that of SUVmax (0.933), SUVmean (0.952), SUVpeak (0.928), and TLG (0.982). Interobserver agreement between the two radiologists was excellent for MTV, SUV, and TLG on both scans (ICC: 0.934-0.999). CONCLUSION: MTV is not sensitive to common clinical variations in F-FDG uptake time, its consistency is greater than that of SUVmax, SUVmean, SUVpeak, and TLG, and it has excellent interobserver agreement.

A new PET/CT volumetric prognostic index for non-small cell lung cancer.

OBJECTIVES: Whole-body metabolic tumor volume (MTVWB) has been shown of prognostic value for non-small cell lung cancer (NSCLC) beyond that of TNM stage, age, gender, performance status, and treatment selection. The current TNM staging system does not incorporate tumor volumetric information. We propose a new PET/CT volumetric prognostic (PVP) index that combines the prognostic value of MTVWB and TNM stage. MATERIALS AND METHODS: Based on 328 consecutive NSCLC patients with a baseline PET/CT scan before treatment, from which MTVWB was measured semi-automatically, we estimated hazard ratios (HRs) for ln(MTVWB) and TNM stage from a Cox proportional hazard regression model that consisted of only ln(MTVWB) and TNM stage as prognostic variables of overall survival. We used the regression coefficients, which gave rise to the HRs, as weights to formulate the PET/CT volumetric prognostic (PVP) index. We also compared the prognostic value of the PVP index against that of TNM stage alone and ln(MTVWB) alone with univariate and multivariate survival analyses and C-statistics. RESULTS: Univariate analysis C-statistic for the PVP index (C=0.71) was statistically significantly greater than those for TNM stage alone (C=0.67, p<0.01) and for ln(MTVWB) alone (C=0.69, p=0.033). Multivariate analyses showed that the PVP index yielded significantly greater discriminatory power (C=0.74) than similar models based on either TNM stage (C=0.72, p<0.01) or ln(MTVWB) (C=0.73, p<0.01). Lower values of the PVP index were associated with significantly better overall survival (adjusted HR=2.70, 95%CI [2.16, 3.37]). CONCLUSION: The PVP index provides a practical means for clinicians to combine the prognostic value of MTVWB and TNM stage and offers significantly better prognostic accuracy for overall survival of NSCLC patients than the current TNM staging system or metabolic tumor burden alone.

Quantification of metabolic tumor activity and burden in patients with non-small-cell lung cancer: Is manual adjustment of semiautomatic gradient-based measurements necessary?

PURPOSE: Metabolic tumor burden (MTB) measurements including metabolic tumor volume and total lesion glycolysis have been shown to have prognostic value in non-small-cell lung cancer (NSCLC). The calculation of MTB typically utilizes software to semiautomatically draw volumes of interest around the tumor, which are subsequently manually adjusted by the radiologist to include the entire tumor. The manual adjustment step can be time-consuming and observer-dependent. We compared the agreement of MTB values obtained using the semiautomatic method with and without manual adjustment in NSCLC patients. METHODS: This IRB-approved prospective study included 134 patients with histologically proven NSCLC who underwent fluorine-18 fluorodeoxyglucose PET/computed tomography. The MTB of the primary tumor was measured with a semiautomatic gradient-based method without manual adjustment (the semiautomatic gradient method) and with manual adjustment (the manually adjusted semiautomatic gradient method) by two radiologists using the MIM PETedge tool. The paired t-test, Wilcoxon signed-rank test, and concordance correlation coefficient (CCC) were calculated to evaluate the agreement between MTB measures obtained with these two methods, as well as agreement between the two radiologists for each method. RESULTS: Maximum standardized uptake value was identical between the two methods. No statistically significant difference was present for peak standardized uptake value, metabolic tumor volume, and total lesion glycolysis values between the two methods (P=0.23, 0.45, and 0.37, respectively). Excellent agreement between the two methods was found in terms of CCC (CCC>0.98 for all measures). Interobserver reliability was excellent for all measures (CCC>0.90). CONCLUSION: The semiautomatic gradient-based tumor-segmentation method can be used without the additional manual adjustment step for MTB quantification of primary NSCLC tumors.

Relationship between Overall Survival of Patients with Non-Small Cell Lung Cancer and Whole-Body Metabolic Tumor Burden Seen on Postsurgical Fluorodeoxyglucose PET Images.

PURPOSE: To test the hypothesis that whole-body metabolic tumor burden (MTBWB) on postsurgical fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) images in patients with non-small cell lung cancer (NSCLC) is associated with their overall survival (OS). MATERIALS AND METHODS: The institutional review board approved this study and waived the requirement for obtaining informed consent. One hundred forty-two patients with NSCLC (69 men, 73 women; median age, 67.7 years) who underwent postsurgical FDG PET/CT were retrospectively reviewed. The whole-body metabolic tumor volume (MTVWB), whole-body total lesion glycolysis (TLGWB), and whole-body maximum standardized uptake value (SUVWBmax) were measured. OS served as the primary end point of the study. Kaplan-Meier curves and Cox regression were used to assess the association between PET/CT markers and OS. RESULTS: The interobserver variability was low, as demonstrated with intraclass correlation coefficients higher than 0.94 for SUVWBmax, MTVWB, and TLGWB. When compared with those with negative postsurgical FDG PET/CT findings, a significant decrease of OS was found in patients with the presence of FDG-avid tumor on the basis of both a log-rank test (P = .001) and a univariate Cox model (hazard ratio = 2.805, P = .001). In patients with FDG-avid tumor, there was a significant association between OS and ln MTVWB (P < .001), ln TLGWB (P < .001), and ln SUVWBmax (P < .010) in either univariate or multivariate analysis, after adjusting for patient age, sex, TNM restage, and therapy after postsurgical PET/CT studies. The OS differences between the groups dichotomized by the median value of MTVWB (11.54 mL, P = .004), TLGWB (32.38 mL, P < .001), or SUVWBmax (4.93, P = .023) were significant. CONCLUSION: MTBWB and tumor maximum standardized uptake at postsurgical FDG PET/CT are related to the patient's OS in NSCLC, independent of age, sex, TNM restaging, and therapy after postsurgical PET/CT studies.

Treatment of two cases with refractory, metastatic intermediate-risk neuroblastoma with isotretenoin alone or observation.

Patients <12 months with favorable biology, metastatic neuroblastoma have >90% overall survival following treatment with chemotherapy and surgery. We report two infants with favorable biology, stage 4 neuroblastoma with refractory disease after standard intermediate-risk chemotherapy and additional retrieval chemotherapy. One patient was treated with six additional cycles of isotretinoin and the other observed. Both remain clinically well with persistent disease but no evidence of tumor progression for 28 and 13 months following completion of cytotoxic treatment. Similar to residual tumor in primary sites, refractory metastatic disease may not portend a poor outcome in patients with favorable biology, intermediate-risk neuroblastoma.

Prognostic value of metabolic tumor burden from (18)F-FDG PET in surgical patients with non-small-cell lung cancer.

OBJECTIVE: To assess the prognostic value of metabolic tumor burden as measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT), independent of current Union Internacional Contra la Cancrum/American Joint Committee on Cancer tumor, node, and metastasis (TNM) stage; in comparison with that of standardized uptake value (SUV) in surgical patients with non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: This study retrospectively reviewed 104 consecutive surgical patients (47 males, 57 females, median age at PET/CT scan of 67.92 years) with diagnosed stage I to IV NSCLC who had baseline (18)F-FDG PET/CT scans. The (18)F-FDG PET/CT scans were performed in accordance with National Cancer Institute guidelines. The MTV of tumors in the whole body (MTV(WB)), TLG of tumors in the whole body (TLG(WB)), the maximum standardized uptake value of tumors in the whole body (SUV(maxWB)) as well as the mean standardized uptake value of tumor in the whole body (SUV(meanWB)) were measured. The median follow-up among 67 survivors was 42.07 months from the PET/CT (range 2.82-80.95 months). Statistical methods included Kaplan-Meier curves, Cox regression, and C-statistics. The interobserver variability of SUV(maxWB), SUV(meanWB), MTV(WB), and TLG(WB) between two observers was analyzed using concordance correlation coefficients (CCCs). RESULTS: The interobserver variability of SUV(maxWB), SUV(meanWB), MTV(WB) and TLG(WB) was very low with CCCs greater than 0.882. There was a statistically significant association of stage with overall survival (OS). The hazard ratio (HR) of stage III and stage IV as compared with stage I was 3.60 (P = .001) and 4.00 (P = .013), respectively. The MTV(WB) was significantly associated with OS with a HR for 1-unit increase of ln(MTV(WB)) of 1.40/1.32 (P = .004/.039), before/after adjusting for stage and other prognostic factors including chemoradiation therapy, and surgical procedure, respectively. TLG(WB) had a statistically significant association with OS before and after adjusting for stage and the other prognostic factors. The HR for 1-unit increase in ln(TLG(WB)) was 1.26 (P = .011) and 1.25 (P = .031), before and after the adjustment, respectively. Subjects with conditions that led to pneumonectomy (HR = 2.82, P = .035) or segmental resection (HR = 3.44, P = .044) had significantly worse survival than those needing lobectomy. There was no statistically significant association between OS and age, gender, tumor histology, ln(SUV(maxWB)), and ln(SUV(meanWB)) (all P > .05). There were 37 deaths during follow-up. CONCLUSION: Baseline whole-body metabolic tumor burden as measured with MTV(WB) and TLG(WB) on FDG PET is a prognostic measure independent of clinical stage and other prognostic factors including chemoradiation therapy and surgical procedure with low interobserver variability and may be used to further risk stratify surgical patients with NSCLC. This study also suggests that MTV and TLG are better prognostic measures than SUV(max) and SUV(mean). These results will need to be validated in larger cohorts in a prospective study.