Machine learning-based diagnostic method of pre-therapeutic 18F-FDG PET/CT for evaluating mediastinal lymph nodes in non-small cell lung cancer.

OBJECTIVES: We aimed to find the best machine learning (ML) model using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for evaluating metastatic mediastinal lymph nodes (MedLNs) in non-small cell lung cancer, and compare the diagnostic results with those of nuclear medicine physicians. METHODS: A total of 1329 MedLNs were reviewed. Boosted decision tree, logistic regression, support vector machine, neural network, and decision forest models were compared. The diagnostic performance of the best ML model was compared with that of physicians. The ML method was divided into ML with quantitative variables only (MLq) and adding clinical information (MLc). We performed an analysis based on the 18F-FDG-avidity of the MedLNs. RESULTS: The boosted decision tree model obtained higher sensitivity and negative predictive values but lower specificity and positive predictive values than the physicians. There was no significant difference between the accuracy of the physicians and MLq (79.8% vs. 76.8%, p = 0.067). The accuracy of MLc was significantly higher than that of the physicians (81.0% vs. 76.8%, p = 0.009). In MedLNs with low 18F-FDG-avidity, ML had significantly higher accuracy than the physicians (70.0% vs. 63.3%, p = 0.018). CONCLUSION: Although there was no significant difference in accuracy between the MLq and physicians, the diagnostic performance of MLc was better than that of MLq or of the physicians. The ML method appeared to be useful for evaluating low metabolic MedLNs. Therefore, adding clinical information to the quantitative variables from 18F-FDG PET/CT can improve the diagnostic results of ML. KEY POINTS: • Machine learning using two-class boosted decision tree model revealed the highest value of area under curve, and it showed higher sensitivity and negative predictive values but lower specificity and positive predictive values than nuclear medicine physicians. • The diagnostic results from machine learning method after adding clinical information to the quantitative variables improved accuracy significantly than nuclear medicine physicians. • Machine learning could improve the diagnostic significance of metastatic mediastinal lymph nodes, especially in mediastinal lymph nodes with low 18F-FDG-avidity.

Total FDG lesion number on PET/CT predicts survival of esophageal carcinoma patients with recurrence following curative surgery.

BACKGROUND: Total lesion number is a prognostic determinant in recurrent esophageal cancer, but this requires multiple tests. Here, we investigated the prognostic value of total FDG lesion number obtained from a single PET/CT study. METHODS: Subjects were 153 esophageal squamous cell carcinoma patients with loco-regional or distant recurrence following curative surgery. FDG PET/CT performed within 30 days was inspected for abnormal FDG uptake lesions using a SUVmax of 3.0 as threshold for significance. Prognostic associations were assessed by Cox proportional hazards regression and Kaplan-Meier analysis. RESULTS: PET/CT showed significant local FDG lesions in 49.0%, regional lesions in 78.4%, and distant lesions in 44.4% of patients. Among 73 patients with loco-regional recurrence, 54 had 0-3 and 19 had ≥4 FDG lesions. Among 80 patients with distant recurrence, 31 had 0-3 and 49 had ≥4 FDG lesions. During a median follow-up of 11.8 months, 99 deaths occurred. Univariate variables associated with poor survival included ≥4 FDG lesions and no treatment for loco-regional recurrence and no treatment for distant recurrence. Kaplan Meier analysis showed worse survival for ≥4 than 0-3 FDG lesions in patients with loco-regional recurrence (15.6 vs. 32.1 months; P=0.009), but not in those with distant recurrence. Significant independent predictors of poor survival were ≥4 FDG lesions and no treatment for loco-regional recurrence and no treatment for distant recurrence. CONCLUSIONS: Total FDG lesion number assessed by PET/CT is a significant independent prognostic factor in esophageal cancer patients with loco-regional recurrence following curative surgery.

Serum uric acid in asymptomatic adults is weakly associated with carotid artery FDG uptake but not intima-media thickness.

BACKGROUND: This study investigated the association of serum uric acid (UA) with carotid fluoro-2-deoxyglucose (FDG) uptake as a marker of inflammatory atherosclerosis. METHODS AND RESULTS: In this cross-sectional retrospective study of 970 otherwise healthy adults, subjects in the greater serum UA quartiles had higher triglyceride (P < .001), lower high-density lipoprotein cholesterol (P < .05), and lower estimated GFR (P < .001). Mean and maximum Target-to-background ratios (TBRs) of carotid FDG uptake measured by positron emission tomography were significantly increased across greater serum UA quartiles (1.35 and 1.57 for Q1, 1.38 and 1.60 for Q2, 1.39 and 1.62 for Q3, and 1.39 and 1.61 for Q4; P = .001 and < .001). Carotid intima-media thickness was not different. Serum UA showed weak but significant correlations with estimated GFR (P < .001), and with mean (P < .001) and maximum carotid TBR (P = .004). Serum UA correlated with mean TBR in male (P = .008) and female subjects (P = .011), in high (≥ 70; P = .015) and low estimated GFR (< 70; P = .035), and in normotensive (P = .001) but not in hypertensive subjects. CONCLUSIONS: Elevated serum UA in asymptomatic adults is associated with increased carotid FDG uptake, which suggests a potential role of UA in carotid inflammatory atherosclerosis.

Synthesis and characterization of 64Cu- and Cy5.5-labeled tetraiodothyroacetic acid derivatives for tumor angiogenesis imaging.

It was previously reported that tetraiodothyroacetic acid (tetrac) inhibits angiogenesis by binding to the cell surface receptor for thyroid hormone on integrin αVß3. Therefore, we synthesized and evaluated two 64Cu-labeled tetrac derivatives and a Cy5.5-labeled tetrac derivative for tumor angiogenesis imaging. Tetrac was structurally modified to conjugate with 1,4,7,10-tetraazacyclododecane-N,N',N″,N″'-tetraacetic acid (DOTA) via its hydroxy or carboxylic acid end, and the resulting DOTA-conjugated tetrac derivatives were then labeled with 64Cu. Tetrac was also conjugated with Cy5.5 via its carboxylic acid end. All three tetrac derivatives (1-3) exhibited greater inhibitory activity than tetrac against endothelial cell tube formation. The U87MG cell binding of [64Cu]2 showed a time-dependent increase over 24 h and it was inhibited by 38% at 4 h in the presence of tetrac, indicating specificity of [64Cu]2 to the thyroid hormone receptor site on integrin αVß3. Positron emission tomography (PET) images of U87MG tumor-bearing mice injected with [64Cu]1 and [64Cu]2 revealed that high radioactivity accumulated in the tumors, and that the tumor uptake and tumor-to-nontarget uptake ratio were higher in small tumors than in large tumors. In addition, the Cy5.5-labeled tetrac derivative (3) displayed a strong near-infrared (NIR) signal in the tumors. Taken together, these results suggest that these ligands hold promise as imaging agents for visualization of tumor angiogenesis.

Correlations between metabolic texture features, genetic heterogeneity, and mutation burden in patients with lung cancer.

PURPOSE: This study investigated the correlations between parameters of 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scan and indices of genetic properties, heterogeneity index (HI), and tumor mutation burden (TMB), in patients with lung cancer. METHODS: We produced 106 PET indices for each tumor site that underwent genomic analysis in a total of 176 study subjects (age, 62.0 ± 10.0 y; males, 68.2%), comprising 101 adenocarcinoma (ADC), 29 squamous cell carcinoma (SQCC), and 46 small cell lung cancer (SCLC) patients. We then examined the correlations of the PET parameters with genetic properties of HI and TMB, according to pathology and tumor site. RESULTS: Comparisons between PET parameters and the genetic properties with false discovery rate (FDR) correction revealed that the surface standard uptake value (SUV) entropy of SUV statistics had a significant correlation with HI only in patients with SCLC who underwent a genetic test in lymph nodes (r = 0.592, p = 0.028), whereas PET parameters did not show a significant correlation with HI or TMB in patients with SCLC who underwent a genetic test in lung tissue. In patients with ADC and SQCC, there was no significant correlation between PET parameters and the genetic properties. Although SUVmax showed raw p values less than 0.05 in correlation with HI (r = 0.315, raw p = 0.048) and TMB (r = 0.206, raw p = 0.043) in ADC, and SUVpeak had a raw p value less than 0.05 in correlation with HI (r = 0.394, raw p = 0.046) in SQCC, these parameters were not significant when corrected by FDR. CONCLUSIONS: In this study, surface SUV entropy had a significant correlation with HI in SCLC. Regarding other PET parameters and tumors, no significant correlation with genetic parameters existed.

PET/CT features discriminate risk of metastasis among single-bone FDG lesions detected in newly diagnosed non-small-cell lung cancer patients.

OBJECTIVES: We investigated the capacity of fluorodeoxyglucose (FDG) PET/CT features for stratifying probability of metastasis for single-bone FDG lesions in non-small-cell lung cancer (NSCLC). METHODS: Subjects were 118 newly diagnosed NSCLC patients with a solitary bone FDG lesion and no evidence of other distant metastasis based on PET/CT, brain MRI, and contrast-enhanced chest CT. Bone lesion SUVmax and CT findings, primary tumor SUVmax, clinical T stage, and N stage were analyzed. RESULTS: The bone lesions were determined by biopsy, characteristic MRI findings and clinical follow-up to be metastatic in 33 (28.0%) and benign in 85 cases (72.0%). A cutoff bone SUVmax of 4.3 showed good diagnostic performance (81.8% sensitivity, 84.7% specificity, and 83.9% accuracy), but there was considerable overlap. Bone lesion PET/CT features of SUVmax ≤ 2, osteosclerotic rim or fracture correctly diagnosed 20/20 benign, while SUVmax > 10, soft-tissue mass or bone destruction correctly diagnosed 18/18 metastatic cases. In the remaining 80 cases, bone features of SUVmax > 4.3 and osteolytic change, and lung tumor features of SUVmax > 6.4, ≥ T2 stage (n = 70), and ≥ N1 stage (n = 43) favored metastasis. The presence of one or less of these features correctly diagnosed 38/38 benign, while the presence of four or more features correctly diagnosed 5/5 metastatic cases. The 37 cases with two or three features had either benign (n = 27) or metastatic bone disease (n = 10). CONCLUSION: Combining bone lesion and lung tumor PET/CT features can help stratify risk of bone metastasis in these patients. KEY POINTS: • In NSCLC with a single-bone FDG lesion, lesion SUVmaxis useful for differential diagnosis. • CT features of the single-bone FDG lesions provide additional diagnostic value. • High NSCLC SUVmax, greater T stage, and FDG positive nodes also favor metastasis.

Strong association of epidermal growth factor receptor status with breast cancer FDG uptake.

PURPOSE: Imaging tumor FDG uptake could complement breast cancer biomarkers of risk and treatment response. Although breast cancer FDG uptake is reputedly influenced by major biomarker states, the role of epidermal growth factor receptor (EGFR) expression remains largely unexplored. METHODS: This is a retrospective study that included 499 patients with primary breast cancer at initial presentation. Tumor FDG uptake was measured on pretreatment PET/CT as maximum standardized uptake value (SUVmax), and biomarkers were assessed by immunohistochemistry of tumor tissue. Regression analysis was performed for predictors of high tumor FDG uptake (SUVmax ≥ 8.6). RESULTS: SUVmax was higher in ER- (36.5%; 11.2 ± 6.0 vs. 8.3 ± 5.3), PR- (42.3%; 10.9 ± 6.0 vs. 8.2 ± 5.2), and triple-negative tumors (19.8%; 12.0 ± 6.9 vs. 8.7 ± 5.2; all p < 0.0001). EGFR expression (28.5%) was more frequent in ER-, PR-, triple-negative, cytokeratin 5/6 (CK5/6) + and mutant P53 (mP53) + tumors (all p < 0.0001). EGFR+ was associated with higher SUVmax among all tumors (11.9 ± 6.0 vs. 8.3 ± 5.3), ER- tumors (p < 0.0001), PR- and + tumors (p < 0.0001 and 0.027), hormone receptor- and + tumors (p < 0.0001 and 0.004), human epidermal growth factor receptor 2 (HER2)- and + tumors (p < 0.0001 and 0.006), non-triple negative tumors (p < 0.0001), CK5/6- and + tumors (p = 0.021 and <0.0001), and mP53- and + tumors (p < 0.0001 and 0.008). Tumors had high FDG uptake in 73.2% of EGFR+ and 40.6% of EGFR- tumors. On regression analysis, significant multivariate predictors of high tumor FDG uptake were large size, EGFR+ and CK5/6+ for the entire subjects, and EGFR+ and CK5/6+ for ER- and hormone receptor negative subgroups. High FDG uptake was able to sub-stratify EGFR+ tumors that were more likely to be ER- and CK5/6+, and EGFR- tumors more likely to be mP53 +. CONCLUSIONS: Primary breast tumor FDG uptake is strongly influenced by EGFR status beyond that by other major biomarkers including hormone receptor and HER2 status, and EGFR expression is a strong independent predictor of high breast tumor FDG uptake.

Hepatic FDG uptake is associated with future cardiovascular events in asymptomatic individuals with non-alcoholic fatty liver disease.

BACKGROUND: Hepatic F-18 fluoro-2-deoxyglucose (FDG) uptake is associated with non-alcoholic fatty liver disease (NAFLD) which is an independent risk factor for cardiovascular disease. However, the value of hepatic FDG uptake for predicting future cardiovascular events has not been explored. METHODS AND RESULTS: Study participants were 815 consecutive asymptomatic participants who underwent a health screening program that included FDG positron emission tomography/computed tomography (PET/CT), abdominal ultrasonography, and carotid intima-media thickness (CIMT) measurements (age 51.8 ± 6.0 year; males 93.9%). We measured hepatic FDG uptake and assessed the prognostic significance of this parameter with other cardiovascular risk factors including Framingham risk score and CIMT. Multivariate Cox proportional hazards analyses including all study participants revealed that NAFLD with high-hepatic FDG uptake was the only independent predictor for future cardiovascular events [hazard ratio (HR) 4.23; 95% CI 1.05-17.04; P = .043). Subgroup analysis conducted in the NAFLD group showed that high-hepatic FDG uptake was a significant independent predictor of cardiovascular events (HR 9.29; 95% CI 1.05-81.04; P = .045). CONCLUSIONS: This exploratory study suggests that high-hepatic FDG uptake may be a useful prognostic factor for cardiovascular events in individuals with NAFLD.

Pulmonary Intravascular Lymphomatosis: Clinical, CT, and PET Findings, Correlation of CT and Pathologic Results, and Survival Outcome.

Purpose To describe clinical, computed tomographic (CT), and positron emission tomographic (PET) features, correlation of CT and pathologic results, and survival of patients with pulmonary intravascular lymphomatosis. Materials and Methods The institutional review board approved this retrospective study with waiver of patient consent. Forty-two patients with pulmonary intravascular lymphomatosis were identified, 11 (26%) of whom showed lung involvement. CT features were correlated with histopathologic results. Clinical and survival outcomes were compared between patients with and those without pulmonary involvement by adopting the χ(2), Student t, or Kaplan-Meier analysis with log-rank tests. Results At clinical presentation, all 11 patients showed B symptoms (systemic symptoms of fever, night sweats, and weight loss), 10 had respiratory and four had neurologic symptoms, and two had skin lesions. Patients received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with (n = 5) or without (n = 6) rituximab, and seven (64%) patients died. Patients with lung involvement showed reduced overall and recurrence-free survival (median; 10.8 and 18.9 months, respectively) compared with those without lung involvement (median, 18.4 and 31.0 months, respectively) (P = .338 and .065, respectively). The most common CT abnormality was bilateral ground-glass opacity (GGO, n = 10), with increased fluorodeoxyglucose uptake at PET/CT (seven of seven patients). GGO correlated histopathologically with the expanded alveolar septal vasculatures and perivascular spaces filled with neoplastic lymphoid cells. Conclusion Pulmonary intravascular lymphomatosis appeared as bilateral GGO on CT images, with increased fluorodeoxyglucose uptake on PET/CT images. GGO on CT images correlated with the area of expanded alveolar septae because of distended vessels filled with neoplastic lymphoid cells. (©) RSNA, 2016 Online supplemental material is available for this article.

Intratumoral heterogeneity of (18)F-FDG uptake predicts survival in patients with pancreatic ductal adenocarcinoma.

PURPOSE: To assess whether intratumoral heterogeneity measured by (18)F-FDG PET texture analysis has potential as a prognostic imaging biomarker in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We evaluated a cohort of 137 patients with newly diagnosed PDAC who underwent pretreatment (18)F-FDG PET/CT from January 2008 to December 2010. First-order (histogram indices) and higher-order (grey-level run length, difference, size zone matrices) textural features of primary tumours were extracted by PET texture analysis. Conventional PET parameters including metabolic tumour volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) were also measured. To assess and compare the predictive performance of imaging biomarkers, time-dependent receiver operating characteristic (ROC) curves for censored survival data and areas under the ROC curve (AUC) at 2 years after diagnosis were used. Associations between imaging biomarkers and overall survival were assessed using Cox proportional hazards regression models. RESULTS: The best imaging biomarker for overall survival prediction was first-order entropy (AUC = 0.720), followed by TLG (AUC = 0.697), MTV (AUC = 0.692), and maximum SUV (AUC = 0.625). After adjusting for age, sex, clinical stage, tumour size and serum CA19-9 level, multivariable Cox analysis demonstrated that higher entropy (hazard ratio, HR, 5.59; P = 0.028) was independently associated with worse survival, whereas TLG (HR 0.98; P = 0.875) was not an independent prognostic factor. CONCLUSION: Intratumoral heterogeneity of (18)F-FDG uptake measured by PET texture analysis is an independent predictor of survival along with tumour stage and serum CA19-9 level in patients with PDAC. In addition, first-order entropy as a measure of intratumoral metabolic heterogeneity is a better quantitative imaging biomarker of prognosis than conventional PET parameters.

Catabolism of (64)Cu and Cy5.5-labeled human serum albumin in a tumor xenograft model.

Human serum albumin (HSA), the most abundant protein in blood plasma, has been used as a drug carrier for the last few decades. Residualizingly radiolabeled serum albumin has been reported to be avidly taken up by tumors of sarcoma-bearing mice and to most likely undergo lysosomal degradation. In this study, we prepared (64)Cu-1,4,7,10-tetraazacyclododecane-N,N',N″,N'″-tetraacetic acid (DOTA) and Cy5.5-conjugated HSA (dual probe), and evaluated its tumor uptake and catabolism. Two dual probes were prepared using different DOTA conjugation sites of HSA (one via Lys residues and the other via the Cys residue). (64)Cu-DOTA-Lys-HSA-Cy5.5 (dual probe-Lys) exhibited higher uptake by RR1022 sarcoma cells in vitro than (64)Cu-DOTA-Cys-HSA-Cy5.5 (dual probe-Cys). In RR1022 tumor-bearing mice, the two dual probes showed a similar level of tumor uptake, but uptake of dual probe-Lys was reduced in the liver and spleen compared to dual probe-Cys, probably because of the presence of a higher number of DOTA molecules in the former. At 24 and 48 h after injection, dual probe-Lys was intact or partially degraded in blood, liver, kidney, and tumor samples, but (64)Cu-DOTA-Lys was observed in the urine using radioactivity detection. Similarly, Cy5.5-Lys was observed in the urine using fluorescence detection. These results indicate that dual probe-Lys may be useful for predicting the catabolic fate of drug-HSA conjugates.

Prognostic value of lymphoscintigraphy in patients with gynecological cancer-related lymphedema.

BACKGROUND AND OBJECTIVES: We investigated the prognostic value of qualitative lymphoscintigraphy in gynecological cancer-related lymphedema, which is a common complication after treatment. METHODS: All 152 patients underwent (99m) Tc tin-colloid lymphoscintigraphy before complex decongestive therapy (CDT). We analyzed the uptake patterns of the inguinal lymph nodes, main lymphatic vessel and collateral lymphatic vessels, as well as dermal back flow. We compared these lymphoscintigraphic findings and other clinical variables between good and poor therapeutic responders using Pearson's Chi-squared test, Fisher's exact test and multiple logistic regression analysis. RESULTS: Eighty-nine patients (58.6%) had a poor therapeutic response to CDT. In univariate analysis, there were significant differences between good and poor responders in clinical stage (P < 0.001), therapy compliance (P < 0.001), main lymphatic vessel uptake pattern (P < 0.01), collateral lymphatic vessel uptake pattern (P < 0.01) and severity of dermal back flow (P < 0.001). After multivariate analysis, only severity of dermal back flow (P < 0.005), clinical stage (P < 0.05) and therapy compliance (P < 0.001) were found to be independent predictors of therapeutic response. CONCLUSIONS: Lymphoscintigraphy may be useful to predict the outcome of patients with gynecological cancer-related lymphedema undergoing CDT along with clinical stage and compliance.

Hepatic glucose uptake is increased in association with elevated serum γ-glutamyl transpeptidase and triglyceride.

BACKGROUND: Subjects with fatty liver disease (FLD) can show increased hepatic 2-deoxy-2-((18)F)fluoro-D-glucose (FDG) uptake, but the role of hepatic inflammation has not been explored. AIMS: We investigated whether hepatic inflammatory response, as implicated by elevated serum markers, is associated with increased liver FDG uptake in FLD. METHODS: Liver sonography and FDG positron emission tomography was performed in 331 asymptomatic men with nonalcoholic FLD (NAFLD), 122 with alcoholic FLD (AFLD), and 349 controls. Mean standard uptake value (SUV) of liver FDG uptake was compared to cardiac risk factors and serum markers of liver injury. RESULTS: Hepatic FDG mean SUV was increased in NAFLD (2.40 ± 0.25) and AFLD groups (2.44 ± 0.25) compared to controls (2.28 ± 0.26; both P < 0.001). Both FLD groups also had higher serum γ-glutamylranspeptidase (GGT), triglyceride (TG), hepatic transaminases, and LDL. High GGT and TG levels were independent determinants of increased FDG uptake for both FLD groups. Hepatic mean SUV significantly increased with high compared to low GGT for NAFLD (2.48 ± 0.28 vs. 2.37 ± 0.24), AFLD (2.51 ± 0.27 vs. 2.39 ± 0.23), and control groups (2.39 ± 0.22 vs. 2.26 ± 0.26). High TG increased hepatic mean SUV in AFLD and control groups. Furthermore, serum GGT and TG levels significantly correlated to hepatic mean SUV in all three groups. CONCLUSIONS: Hepatic FDG uptake is closely associated with elevated TG and GGT regardless of the presence of FLD. Thus, inflammation response may play a major role in increased hepatic glucose uptake.

Diagnosis and whole body screening using blood pool scintigraphy for evaluating congenital vascular malformations.

BACKGROUND: Because magnetic resonance imaging and angiography are inappropriate for whole-body screening because of high cost or invasiveness, we investigated the potential of whole-body blood pool scintigraphy (WBBPS) as a screening and diagnostic tool for congenital vascular malformations (CVMs). METHODS: The subjects of the study were 137 patients (mean age: 20 ± 16 years; range: 0.3-68 years) with suspected CVM. Whole-body anterior and posterior images were acquired twenty minutes after injection of 760 MBq (99m)Tc-labeled red blood cells (pediatric dose: 13 MBq/kg). The final diagnosis was determined by clinical findings, magnetic resonance imaging, angiography, Doppler sonography, and lymphoscintigraphy. RESULTS: Of these patients, 124 had venous malformations, and 13 had lymphatic malformations. WBBPS successfully detected abnormal blood pooling lesions in 96.8% (120/124) of the patients with venous malformations. None of the patients with lymphatic malformation showed abnormal uptake on WBBPS. In addition, WBBPS detected 41 additional abnormal vascular lesions that were not found during initial clinical evaluation in 16.9% (21/124) of the patients with venous malformations. CONCLUSION: WBBPS is a valuable diagnostic and screening modality for the initial evaluation of CVM because of its high characterizing accuracy of 97.1% and the ability to image the whole body.

Coregistered whole body magnetic resonance imaging-positron emission tomography (MRI-PET) versus PET-computed tomography plus brain MRI in staging resectable lung cancer: comparisons of clinical effectiveness in a randomized trial.

BACKGROUND: The objective of this study was to assess whether coregistered whole brain (WB) magnetic resonance imaging-positron emission tomography (MRI-PET) would increase the number of correctly upstaged patients compared with WB PET-computed tomography (PET-CT) plus dedicated brain MRI in patients with nonsmall cell lung cancer (NSCLC). METHODS: From January 2010 through November 2011, patients with NSCLC who had resectable disease based on conventional staging were assigned randomly either to coregistered MRI-PET or WB PET-CT plus brain MRI (ClinicalTrials.gov trial NCT01065415). The primary endpoint was correct upstaging (the identification of lesions with higher tumor, lymph node, or metastasis classification, verified with biopsy or other diagnostic test) to have the advantage of avoiding unnecessary thoracotomy, to determine appropriate treatment, and to accurately predict patient prognosis. The secondary endpoints were over staging and under staging compared with pathologic staging. RESULTS: Lung cancer was correctly upstaged in 37 of 143 patients (25.9%) in the MRI-PET group and in 26 of 120 patients (21.7%) in the PET-CT plus brain MRI group (4.2% difference; 95% confidence interval, -6.1% to 14.5%; P = .426). Lung cancer was over staged in 26 of 143 patients (18.2%) in the MRI-PET group and in 7 of 120 patients (5.8%) in the PET-CT plus brain MRI group (12.4% difference; 95% confidence interval, 4.8%-20%; P = .003), whereas lung cancer was under staged in 18 of 143 patients (12.6%) and in 28 of 120 patients (23.3%), respectively (-10.7% difference; 95% confidence interval, -20.1% to -1.4%; P = .022). CONCLUSIONS: Although both staging tools allowed greater than 20% correct upstaging compared with conventional staging methods, coregistered MRI-PET did not appear to help identify significantly more correctly upstaged patients than PET-CT plus brain MRI in patients with NSCLC.

Volume-based parameters of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography improve outcome prediction in early-stage non-small cell lung cancer after surgical resection.

OBJECTIVE: To evaluate the prognostic significance and predictive performance of volume-based parameters of F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) in early-stage non-small cell lung cancer (NSCLC). BACKGROUND: Although surgical resection remains the optimal treatment for early-stage NSCLC, approximately 40% of patients with stage I and 60% of patients with stage II NSCLC relapse and die within 5 years after curative resection. Therefore, identification of additional prognostic biomarkers is needed to develop risk-adapted treatment strategies. METHODS: We retrospectively reviewed 529 consecutive patients with pathologically proven early-stage NSCLC who underwent preoperative F-FDG PET/CT. Maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for the primary tumors were measured. Overall survival (OS) and disease-free survival (DFS) were assessed by the Kaplan-Meier method. The prognostic significance of PET parameters and other clinicopathological variables was assessed by Cox proportional hazards regression analysis. To evaluate and compare the predictive performance of PET parameters, time-dependent receiver operating characteristic (ROC) curve analysis was used. RESULTS: In the multivariate analyses, volume-based parameters of PET (MTV and TLG) that were analyzed as continuous variables were significantly associated with an increased risk of recurrence (P = 0.001 for MTV, P < 0.001 for TLG) and death (P = 0.009 for MTV, P = 0.007 for TLG), after adjusting for age, sex, histology, tumor stage, and type of surgery. SUVmax analyzed as a continuous variable was not a significant prognostic factor for both DFS (P = 0.056) and OS (P = 0.525). In the time-dependent ROC curve analysis, the volume-based parameter of PET showed better predictive performance than SUVmax (P < 0.001). CONCLUSIONS: The volume-based parameter of PET is an independent prognostic factor for survival in addition to pathological tumor-node-metastasis stage and a promising tool for better prediction of outcome in patients with early-stage NSCLC.

Histopathology of lung adenocarcinoma based on new IASLC/ATS/ERS classification: prognostic stratification with functional and metabolic imaging biomarkers.

PURPOSE: To correlate the results of histopathologic subtyping and grading of lung adenocarcinoma with maximum standardized uptake values (SUVmax) on positron emission tomography (PET)/computed tomography and apparent diffusion coefficient (ADC) values on diffusion-weighted MRI (DWI). MATERIALS AND METHODS: Forty-three patients were included. The SUVmax and mean ADC values of tumors were measured and correlated with the histologic subtypes and grades of lung adenocarcinomas based on the IASLC/ATS/ERS classification scheme. Disease-free survival (DFS) was estimated by using the Kaplan-Meier method, and the log-rank test was used to evaluate differences among three histologic grades or subgroups classified with imaging biomarker study results. RESULTS: Five (12.5%) tumors belonged to low grade, 30 (70%) to intermediate grade, and 8 (18.5%) to high grade, and patients with low-grade histology had lower risk of recurrence than those with intermediate- or high-grade histology (P = 0.048). A significant difference in SUVmax and mean ADC values was observed among three histologic grades (Ps < 0.001). Regarding DFS, lower metabolic (PET) activity or higher functional (DWI) diffusivity showed longer DFS. When patients (n = 30; 70% of patients) with intermediate histologic grade were subgrouped in consideration of both SUVmax and mean ADC results, combining metabolic and functional criteria helped stratify patients more precisely (P = 0.006). CONCLUSION: SUVmax and mean ADC value correlate well with the histologic grades in lung adenocarcinomas, and combining both imaging biomarker study results leads to more useful stratification of patients into different prognostic subsets than the results of each study.

Factors affecting 18F-FDG uptake by metastatic lymph nodes in gastric cancer.

OBJECTIVE: We assessed factors affecting fluorine F 18 fluorodeoxyglucose (F-FDG) uptake of metastatic lymph nodes (LNs) in advanced gastric cancer (AGC) due to low F-FDG uptake of metastatic LNs in gastric cancer. METHODS: Retrospective analyses were performed on 31 patients with AGCs who underwent preoperative F-FDG positron emission tomography (PET) and subsequent gastrectomy. Metastatic LNs were compared with primary tumors (on a one-to-one basis) with respect to maximum standardized uptake values, glucose transporter type 1 (GLUT-1) expression, proliferation indices (using Ki-67), microvessel density, and lymphatic vessel density. RESULTS: Maximum standardized uptake values of metastatic LNs were significantly correlated with % GLUT-1 expression (ρ = 0.80, P < 0.0001) and Ki-67 labeling index (ρ = 0.57, P = 0.001) in LNs. These uptake values were also significantly correlated with SUVs (ρ = 0.54; P = 0.002), % GLUT-1 expression (ρ = 0.71, P < 0.0001), and Ki-67 labeling index (ρ = 0.43, P = 0.019) in primary tumors. In multiple regression analysis, only % GLUT-1 expression in primary tumors and metastatic LNs were significant factors in predicting maximum standardized uptake value of metastatic LNs. CONCLUSIONS: In AGCs, GLUT-1 expression and Ki-67 labeling index are important factors in predicting F-FDG uptake by metastatic LNs.

Comparison of 18F-fluorodeoxyglucose uptake with the expressions of glucose transporter type 1 and Na+/I- symporter in patients with untreated papillary thyroid carcinoma.

PURPOSE: Discrepancies between the uptakes of (18)F-fluorodeoxyglucose ((18)F-FDG) and (131)I in papillary thyroid carcinoma have been reported. We compared 18F-FDG uptake with the expressions of glucose transporter type 1 (GLUT1) and sodium-iodide symporter (NIS) in untreated papillary thyroid carcinoma. MATERIALS AND METHODS: A total of 33 consecutive patients (male:female = 12:21; mean age, 46.6 ± 13.0 years) with initially diagnosed papillary thyroid carcinoma were prospectively included in the study. All subjects underwent preoperative (18)F-FDG positron emission tomography/computerized tomography scans followed by surgery. The expressions of GLUT1 and NIS were evaluated in resected primary tumors and metastatic lymph nodes by immunohistochemical staining and were compared with the maximum standard uptake value of each lesion, respectively. RESULTS: None of the 40 primary tumors showed significant expressions of GLUT1. Significant expressions of NIS were found in 14 primary tumors (35.0%). Among 36 metastatic lymph nodes, only 1 showed GLUT1 expression. Significant expression of NIS was found in 13 (36.1%) metastatic nodes. The maximum standard uptake value of both primary tumors and metastatic nodes with negative expression of NIS was significantly higher than those with a positive expression of NIS (10.6 ± 10.8 vs. 4.9 ± 5.2, p = 0.011). CONCLUSIONS: The 18F-FDG uptake of untreated papillary thyroid carcinoma has an inverse correlation with NIS expression. However, GLUT1 expression does not appear to be associated with 18F-FDG uptake in untreated papillary thyroid carcinoma.

Solitary pulmonary nodular lung adenocarcinoma: correlation of histopathologic scoring and patient survival with imaging biomarkers.

PURPOSE: To evaluate the usefulness of histopathologic scoring for survival prediction in patients with solitary pulmonary nodular (SPN) lung adenocarcinomas and to correlate the histopathologic scoring with the results of computed tomography (CT) and fluorine 18 fluorodeoxyglucose positron emission tomography (PET)/CT. MATERIALS AND METHODS: This retrospective study was institutional review board approved and the requirement for informed consent was waived. A total of 148 patients with SPN lung adenocarcinoma underwent PET/CT and CT. Correlations between histopathologic scores estimated by using two predominant histologic subtypes from each surgically resected specimen and the mass of the nodule at CT or maximum standardized uptake value (SUV(max)) at PET/CT were assessed. Disease-free survival (DFS) was estimated by using the Kaplan-Meier method, and the log-rank test was used to evaluate differences in each histopathologic subtype. RESULTS: In 135 (91%) patients, tumors had a mixed subtype. The most frequently observed histologic subtypes, in decreasing order, were acinar (51%), lepidic (18%), solid (10%), and papillary (9%). DFS rates at 5 years were higher than 90% for the group of patients with nodules that showed the lepidic growth pattern, and 50% for patients with nodules that showed the micropapillary pattern. The pathologic score proved to be a significant predictor of DFS (P < .001). Both SUV(max) and the mass of the nodule were closely correlated with pathologic score. CONCLUSION: Pathologic scoring appears to help predict DFS in patients with SPN lung adenocarcinoma and shows close correlation with imaging biomarkers including the mass of the nodule at CT and SUV(max) at PET/CT.