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.

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.

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.

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.

Predictive and Prognostic Value of 18F-fluorodeoxyglucose Uptake Combined with Thymidylate Synthase Expression in Patients with Advanced Non-Small Cell Lung Cancer.

We investigated the relationship between tumor 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT) scans and thymidylate synthase (TS) expression. In addition, we evaluated the value of FDG uptake in predicting treatment response and prognosis when combined with TS expression in patients with advanced non-small cell lung cancer (NSCLC). We measured the maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of tumor lesions on pretreatment scan in 234 patients (age: 60.1 ± 9.4 years; males: 56.4%) with stage IV non-squamous NSCLC who were enrolled in the prospective phase II clinical trial. We investigated the correlation of the parameters with TS expression and the predictive values of the parameters compared with other clinical factors. Among these parameters, TLG was the most relevant parameter that had a significant correlation with TS expression (ρ = 0.192, P = 0.008). A multivariable Cox proportional-hazards model revealed that high TLG was a significant independent predictor for treatment response (hazard ratio [HR]: 2.05; P = 0.027), progression-free survival (HR: 1.39; P = 0.043), and overall survival (HR: 1.65; P = 0.035) with other factors. In patients with advanced non-squamous NSCLC, tumor TLG on pretreatment PET/CT scan has predictive and prognostic value.

Development of Predictive Models in Patients with Epiphora Using Lacrimal Scintigraphy and Machine Learning.

PURPOSE: We developed predictive models using different programming languages and different computing platforms for machine learning (ML) and deep learning (DL) that classify clinical diagnoses in patients with epiphora. We evaluated the diagnostic performance of these models. METHODS: Between January 2016 and September 2017, 250 patients with epiphora who underwent dacryocystography (DCG) and lacrimal scintigraphy (LS) were included in the study. We developed five different predictive models using ML tools, Python-based TensorFlow, R, and Microsoft Azure Machine Learning Studio (MAMLS). A total of 27 clinical characteristics and parameters including variables related to epiphora (VE) and variables related to dacryocystography (VDCG) were used as input data. Apart from this, we developed two predictive convolutional neural network (CNN) models for diagnosing LS images. We conducted this study using supervised learning. RESULTS: Among 500 eyes of 250 patients, 59 eyes had anatomical obstruction, 338 eyes had functional obstruction, and the remaining 103 eyes were normal. For the data set that excluded VE and VDCG, the test accuracies in Python-based TensorFlow, R, multiclass logistic regression in MAMLS, multiclass neural network in MAMLS, and nuclear medicine physician were 81.70%, 80.60%, 81.70%, 73.10%, and 80.60%, respectively. The test accuracies of CNN models in three-class classification diagnosis and binary classification diagnosis were 72.00% and 77.42%, respectively. CONCLUSIONS: ML-based predictive models using different programming languages and different computing platforms were useful for classifying clinical diagnoses in patients with epiphora and were similar to a clinician's diagnostic ability.

Synthesis and in vivo characterization of 18F-labeled difluoroboron-curcumin derivative for ß-amyloid plaque imaging.

Positron emission tomography imaging of ß-amyloid (Aß) plaques has proven useful in the diagnosis of Alzheimer's disease. A previous study from our group showed that 4'-O-[18F]fluoropropylcurcumin has poor brain permeability, which is thought to be due to its rapid metabolism. In this study, we synthesized difluoroboron complexes of fluorine-substituted curcumin derivatives (1-4) and selected one of them based on the in vitro binding assays. The selected ligand 2 was found to distinctively stain Aß plaques in APP/PS1 transgenic mouse brain sections. Radioligand [18F]2 was synthesized via a two-step reaction consisting of [18F]fluorination and subsequent aldol condensation. Biodistribution and metabolism studies indicated that radioligand [18F]2 was converted to polar radioactive products and trapped in the normal mouse brain. In contrast, optical images of mice acquired after injection of 2 showed moderate fluorescence signal intensity in the mouse brain at 2 min with a decrease in the signal within 30 min. In the ex vivo optical images, the fluorescence signals in major tissues disappeared within 30 min. Taken together, these results suggest that [18F]2 may be converted to polar 18F-labeled blue-shifted fluorescent products. Further structural modifications are thus needed to render the radioligand metabolically stable.

Solitary Nodular Invasive Mucinous Adenocarcinoma of the Lung: Imaging Diagnosis Using the Morphologic-Metabolic Dissociation Sign.

OBJECTIVE: To evaluate the efficacy of the morphologic-metabolic (M-M) dissociation sign based on computed tomography (CT) and fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/CT in discriminating invasive mucinous adenocarcinoma (IMA) from invasive non-mucinous adenocarcinomas (ADCs) of the lung. MATERIALS AND METHODS: The Institutional Review Board approved this retrospective study. Among surgically resected solitary pulmonary nodule (SPN)-type ADCs (< 3 cm in diameter), 35 patients with IMAs and 329 with invasive non-mucinous ADCs were included. Morphologic malignancy was established if the tumor with lobulated or spiculated margin on CT presented a tumor shadow disappearance rate of < 0.5. The M-M dissociation sign was determined when a malignant-morphologic nodule on CT showed maximum standardized uptake value (SUVmax) < 3.5 on PET/CT. RESULTS: Among 35 IMAs (size: 21 ± 7 mm, SUVmax: 1.8 ± 2.0) and 329 invasive non-mucinous ADCs (size: 21 ± 6 mm, SUVmax: 4.6 ± 4.2), the M-M dissociation sign was observed in 54% of IMAs (19/35) and 10% of invasive non-mucinous ADCs (34/329) (p < 0.001). The diagnostic performance of the sign in discriminating IMA from invasive non-mucinous ADCs showed a sensitivity of 54.3% (95% confidence interval [CI], 36.7-71.2), specificity 89.7% (95% CI, 85.9-92.7), positive predictive value 35.8% (95% CI, 26.5-46.5), and negative predictive value 94.9% (95% CI, 92.8-96.4). Multivariate analyses revealed metabolic benignity (odds ratio [OR] 2.99; 95% CI, 1.01-8.93; p = 0.047) and M-M dissociation sign (OR 6.35; 95% CI, 2.76-14.62; p < 0.001) to be significant predictors of SPN-type IMAs. CONCLUSION: Identification of the absence of M-M dissociation sign is an accurate indicator for excluding IMA from SPN-type lung ADCs.

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.

18F-Labeled BODIPY Dye: A Potential Prosthetic Group for Brain Hybrid PET/Optical Imaging Agents.

There are few hybrid positron emission tomography (PET)/fluorescence imaging agents available for brain imaging. For this purpose, BODIPY dye is very attractive because one of its fluorine atoms can be readily exchanged with 18F, and it can be modified to produce red-shifted fluorescence. In this study, therefore, we synthesized and investigated a 18F-labeled red-shifted BODIPY dye as a prosthetic group for brain hybrid PET/optical imaging agents and determined the optimal dose of this radioligand for hybrid imaging. The red-shifted BODIPY dye (1) was synthesized, and one of its fluorine atoms was exchanged with 18F using SnCl4 in high yield. Partition coefficients of 18F-labeled BODIPY dye ([18F]1) and 1 were measured using its radioactivity and fluorescence, respectively, which were shown to be suitable for brain penetration. Optimal dose for hybrid imaging was determined by analysis of PET/CT and optical images of Balb/C nude mice injected with [18F]1 and 1, respectively. Hybrid PET/optical images of mice injected with optimal dose of [18F]1 showed strong radioactivity and fluorescence signal in the brain at 2 min after injection, with rapid clearance by 30 min. Tissue distribution data confirmed the in vivo and ex vivo PET/optical imaging data, indicating desirable brain pharmacokinetics of the radioligand. Taken together, the results of this study suggest that [18F]1 can be widely used as a prosthetic group for brain hybrid PET/optical imaging agents.

Inverse Prognostic Relationships of 18F-FDG PET/CT Metabolic Parameters in Patients with Distal Bile Duct Cancer Undergoing Curative Surgery.

PURPOSE: As there were few previous studies with a small number of subjects, the purpose of this was to evaluate the prognostic significance of 18F-FDG PET/CT in patients with distal bile duct cancer undergoing curative surgery. METHODS: The study included 40 patients (M/F = 24:16; age 68.0 ± 8.0 years) who underwent preoperative 18F-FDG PET/CT followed by curative surgical resection. The participant's age, sex, Eastern Cooperative Oncology Group performance-status score, baseline serum CA 19-9 level, stage, pathologic T and N stages, tumor size, tumor grade, tumor growth pattern, R0 resection, and adjuvant therapy were included as clinicopathological variables for predicting overall survival. The PET variables were maximum standardized uptake value (SUVmax), average SUV (SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the tumor. The Kaplan-Meyer method and Cox proportional hazards model were used for the survival analysis. RESULTS: A total of 15 of 40 patients (37.5%) died during the follow-up period. In univariate analysis, low SUVmax (≤ 2.7, p = 0.0005) and low SUVavg (≤ 2.6, p = 0.0034) were significant predictors of poor overall survival. In multivariate analyses, only low SUVmax (HR = 6.7016, 95% CI 1.9961-22.4993, p = 0.0047) was an independent prognostic factor associated with poor overall survival. CONCLUSION: The SUVmax of the primary tumor measured by 18F-FDG PET/CT was an independent significant prognostic factor for overall survival in patients with distal bile duct cancer. However, different results from a previous study warrant further large sample-sized study.

Role of 18F-FDG PET/CT in patients without known primary malignancy with skeletal lesions suspicious for cancer metastasis.

BACKGROUND: When subjects without a known malignancy present with suspicious skeletal lesions, differential diagnosis and primary cancer identification is important. Here, we investigated the role of FDG PET/CT in this clinical situation. METHODS: We enrolled 103 patients with no known malignancies who were referred for FDG PET/CT because of bone lesions that were suspicious for cancer metastasis. Each extra-skeletal FDG lesion was categorized as consistent with primary cancer or with metastasis based on the distribution and pattern of all abnormal lesions in the individual. RESULTS: Final diagnosis revealed that bone lesions represented cancer metastasis in 75 patients (72.8%). In the remaining 28 patients (27.2%), they were from other causes including multiple myeloma or lymphoma, malignant primary bone tumor, and benign bone disease. PET/CT indicated a primary cancer in 70 patients (68.0%). This was the correct primary site in 46 cases and the incorrect site in 13 cases (including 6 cases with cancer of unknown primary, CUP). In the remaining 11 cases, the bone lesions were due to other causes. PET/CT did not indicate a primary cancer in 33 patients (32.0%). Of these cases, 17 did not have a primary cancer, 8 had CUP, and 8 had primary cancers that were missed. Thus, PET/CT had a sensitivity of 61.3% and specificity of 60.7% for primary cancer identification in the entire population. Excluding patients with CUP, PET/CT sensitivity was 75.4%. PET/CT also provided information useful for recognizing multiple myeloma and benign bone disease as the cause of the skeletal lesions. CONCLUSIONS: In patients without known malignancies with suspected skeletal cancer metastasis, FDG PET/CT can help identify the primary cancer and provide useful information for differential diagnosis.

Clinical Significance of Incidental Focal 18F-FDG Uptake in the Spinal Cord of Patients with Cancer.

PURPOSE: We investigated the incidence, location, and clinical significance of focal 18F-FDG uptake of the spinal cord in patients with cancer. METHODS: We reviewed the medical records of 22,937 consecutive adult patients with known or suspicious malignancy who underwent 18F-FDG PET/CT. PET/CT scans with incidental focal spinal cord uptake were selected and retrospectively reviewed to determine the presence, location, number, and maximum standardized uptake value (SUVmax) of any focal hypermetabolic lesions of the spinal cord. In subjects with focal spinal uptake, clinical characteristics and clinical follow-up results, including follow-up PET/CT, were reviewed. RESULTS: Incidental focal spinal cord uptake was observed in 69 of 22,937 adult patients (incidence = 0.3%; M:F = 31:38; age, 55.8 ± 14.7 years). Seventy-eight focal hypermetabolic lesions on spinal cord in the PET/CT scans of the 69 study subjects were analyzed. The most common sites of focal spinal cord uptake were the T12 vertebra (47/78; 60.3%) and L1 vertebra (20/78; 25.6%). Multifocal cord uptake was found in 8 of 69 patients (11.6%). The average SUVmax for cord uptake was 2.5 ± 0.5 (range, 1.4∼3.9). There was no clinical or imaging evidence of abnormalities in the spinal cord, both at the time of PET/CT and during clinical follow-up. CONCLUSIONS: Although incidental focal 18F-FDG uptake of the spinal cord is rare in patients with cancer, it may be physiological or benign, but it should not be considered as malignant involvement. Common sites for the uptake were in the T12 and L1 spine levels.

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.

Relation between tumor FDG uptake and hematologic prognostic indicators in stage I lung cancer patients following curative resection.

Hematologic parameters of systemic inflammation are receiving attention as promising prognostic indicators in cancer patients. Here, we investigated the relation and compared the prognostic values of circulating blood cell-based parameters and tumor F-fluoro-2-deoxyglucose (FDG) uptake in patients with stage I nonsmall cell lung cancers (NSCLC).Subjects were 1034 patients with newly diagnosed stage I NSCLC who underwent FDG positron emission tomography/computed tomography (PET/CT) followed by curative resection. Total white blood cell (WBC) count, absolute neutrophil, lymphocyte and platelet counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were obtained. Tumor FDG uptake was measured as SUVmax.WBC, neutrophil and lymphocyte counts, and NLR demonstrated weak but significant correlation to tumor SUVmax. Using the upper quartile as cutoff, patients with high tumor SUVmax had significantly higher WBC, neutrophil and lymphocyte counts, and greater NLR. There were 144 recurrences (13.9%) over a median follow-up of 29.5 months. On Cox proportional hazards regression analysis, WBC count, tumor SUVmax, age, gender, smoking, cell type, and tumor stage were significant univariate prognostic factors. On multivariate analysis, high tumor SUVmax (HR = 2.22; 95% CI, 1.52-3.25; P < 0.001), tumor stage 1B (HR = 2.11; 95% CI, 1.47-3.01; P < 0.001), and old age (HR = 1.03; 95% CI, 1.01-1.05; P = 0.002) were significant independent predictors of poor survival. Finally, high tumor SUVmax remained a significant predictor of prognosis in both low and WBC count groups.Circulating blood counts showed significant correlation to tumor FDG uptake in early stage NSCLC. WBC count was a significant univariate variable, but tumor FDG uptake was a superior and independent predictor of outcome. Hence, tumor FDG uptake effectively stratified prognosis in patients with low as well as high WBC count.

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.

Value of interim FDG PET/CT for predicting outcome of patients with angioimmunoblastic T-cell lymphoma.

Subjects were 45 patients with angioimmunoblastic T-cell lymphoma (AITL) who underwent 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography/computed tomography (PET/CT) at baseline and interim after 2-4 cycles. Predictors of progression-free survival (PFS) and overall survival (OS) were assessed. Positive interim PET/CT (Deauville score ≥3) was a significant independent predictor of poor PFS (Hazard ratio, 4.42; p=.028), and showed marginal significance to predict OS (p=.065). Less than 60% decrease in the average change of maximum standardized uptake value normalized by lean body mass (SULmax) also was a significant independent predictor of poor PFS (Hazard ratio, 12.96; p=.001) and poor OS (Hazard ratio, 24.11; p=.006). Interim PET/CT has a significant prognostic value for predicting PFS and OS in patients with AITL. Deauville score and percent decrease of SULmax have the potential to be useful parameter in classifying patients into good and poor responders.

Intra-patient Variability of FDG Standardized Uptake Values in Mediastinal Blood Pool, Liver, and Myocardium during R-CHOP Chemotherapy in Patients with Diffuse Large B-cell Lymphoma.

PURPOSE: 18F-fluorodeoxyglucose (FDG) PET/CT is useful for staging and evaluating treatment response in patients with diffuse large B-cell lymphoma (DLBCL). A five-point scale model using the mediastinal blood pool (MBP) and liver as references is a recommended method for interpreting treatment response. We evaluated the variability in standardized uptake values (SUVs) of the MBP, liver, and myocardium during chemotherapy in patients with DLBCL. METHODS: We analyzed 60 patients with DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) treatment and underwent baseline, interim, and final FDG PET/CT scans. The FDG uptakes of lymphoma lesions, MBP, liver, and myocardium were assessed, and changes in the MBP and liver SUV and possible associated factors were evaluated. RESULTS: The SUV of the liver did not change significantly during the chemotherapy. However, the SUVmean of MBP showed a significant change though the difference was small (p = 0.019). SUVmean of MBP and liver at baseline and interim scans was significantly lower in patients with advanced Ann Arbor stage on diagnosis. The SUVmean of the MBP and liver was negatively correlated with the volumetric index of lymphoma lesions in baseline scans (r = -0.547, p < 0.001; r = -0.502, p < 0.001). Positive myocardial FDG uptake was more frequently observed in interim and final scans than in the baseline scan, but there was no significant association between the MBP and liver uptake and myocardial uptake. CONCLUSIONS: The SUV of the liver was not significantly changed during R-CHOP chemotherapy in patients with DLBCL, whereas the MBP SUV of the interim scan decreased slightly. However, the SUV of the reference organs may be affected by tumor burden, and this should be considered when assessing follow-up scans. Although myocardial FDG uptake was more frequently observed after R-CHOP chemotherapy, it did not affect the SUV of the MBP and liver.

Body Mass Index with Tumor 18F-FDG Uptake Improves Risk Stratification in Patients with Breast Cancer.

PURPOSE: To investigate the combined prognostic impact of body mass index (BMI) and tumor standardized uptake value (SUV) measured on pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in patients with breast cancer. METHODS: We evaluated a cohort of 332 patients with newly diagnosed breast cancer (stage I-III) who underwent pretreatment FDG PET/CT followed by curative resection. Patients were categorized as overweight (BMI ≥ 23 kg/m2) or normal weight (BMI < 23 kg/m2). Primary tumor maximum SUV was measured by FDG PET/CT. Associations between BMI and tumor SUV with disease recurrence were assessed using Cox regression models. RESULTS: Median follow-up was 39 months. There were 76 recurrences and 15 cancer-related deaths. Multivariable Cox regression analysis demonstrated that high tumor SUV (hazard ratio [HR] = 1.75; 95% CI, 1.02-3.02; P = 0.044) and overweight (HR = 1.84; 95% CI, 1.17-2.89; P = 0.008) were independent poor prognostic factors. Positive hormone receptor status was an independent predictor of favorable outcome (HR = 0.42; 95% CI, 0.26-0.68; P < 0.001). Overweight patients with high tumor SUV had a two-fold risk of recurrence compared to patients with normal weight or low tumor SUV after adjusting for clinical stage and tumor subtype (HR = 2.06; 95% CI, 1.30-3.27; P = 0.002). CONCLUSIONS: In patients with breast cancer, higher tumor SUV was associated with a more adverse outcome particularly in overweight women. BMI status combined with tumor SUV data allows better risk-stratification of breast cancer, independent of clinical stage and tumor subtype.