Humanin activates integrin αV-TGFß axis and leads to glioblastoma progression.

The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial glioblastoma progression. Our findings demonstrate that the mitochondria-derived peptide, humanin, plays a significant role in enhancing glioblastoma progression through the intratumoral activation of the integrin alpha V (ITGAV)-TGF beta (TGFß) signaling axis. In glioblastoma tissues, humanin showed a significant upregulation in the tumor area compared to the corresponding normal region. Utilizing multiple in vitro pharmacological and genetic approaches, we observed that humanin activates the ITGAV pathway, leading to cellular attachment and filopodia formation. This process aids the subsequent migration and invasion of attached glioblastoma cells through intracellular TGFßR signaling activation. In addition, our in vivo orthotopic glioblastoma model provides further support for the pro-tumoral function of humanin. We observed a correlation between poor survival and aggressive invasiveness in the humanin-treated group, with noticeable tumor protrusions and induced angiogenesis compared to the control. Intriguingly, the in vivo effect of humanin on glioblastoma was significantly reduced by the treatment of TGFBR1 inhibitor. To strengthen these findings, public database analysis revealed a significant association between genes in the ITGAV-TGFßR axis and poor prognosis in glioblastoma patients. These results collectively highlight humanin as a pro-tumoral factor, making it a promising biological target for treating glioblastoma.

Distinguishing thymic cysts from low-risk thymomas via [18F]FDG PET/CT.

BACKGROUND: Thymic cysts are a rare benign disease that needs to be distinguished from low-risk thymoma. [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is a non-invasive imaging technique used in the differential diagnosis of thymic epithelial tumours, but its usefulness for thymic cysts remains unclear. Our study evaluated the utility of visual findings and quantitative parameters of [18F]FDG PET/CT for differentiating between thymic cysts and low-risk thymomas. METHODS: Patients who underwent preoperative [18F]FDG PET/CT followed by thymectomy for a thymic mass were retrospectively analyzed. The visual [18F]FDG PET/CT findings evaluated were PET visual grade, PET central metabolic defect, and CT shape. The quantitative [18F]FDG PET/CT parameters evaluated were PET maximum standardized uptake value (SUVmax), CT diameter (cm), and CT attenuation in Hounsfield units (HU). Findings and parameters for differentiating thymic cysts from low-risk thymomas were assessed using Pearson's chi-square test, the Mann-Whitney U-test, and receiver operating characteristics (ROC) curve analysis. RESULTS: Seventy patients (18 thymic cysts and 52 low-risk thymomas) were finally included. Visual findings of PET visual grade (P < 0.001) and PET central metabolic defect (P < 0.001) showed significant differences between thymic cysts and low-risk thymomas, but CT shape did not. Among the quantitative parameters, PET SUVmax (P < 0.001), CT diameter (P < 0.001), and CT HU (P = 0.004) showed significant differences. In ROC analysis, PET SUVmax demonstrated the highest area under the curve (AUC) of 0.996 (P < 0.001), with a cut-off of equal to or less than 2.1 having a sensitivity of 100.0% and specificity of 94.2%. The AUC of PET SUVmax was significantly larger than that of CT diameter (P = 0.009) and CT HU (P = 0.004). CONCLUSIONS: Among the [18F]FDG PET/CT parameters examined, low FDG uptake (SUVmax ≤ 2.1, equal to or less than the mediastinum) is a strong diagnostic marker for a thymic cyst. PET visual grade and central metabolic defect are easily accessible findings.

Differences in Neuropathology between Nitroglycerin-Induced Mouse Models of Episodic and Chronic Migraine.

Multiple animal models of migraine have been used to develop new therapies. Understanding the transition from episodic (EM) to chronic migraine (CM) is crucial. We established models mimicking EM and CM pain and assessed neuropathological differences. EM and CM models were induced with single NTG or multiple injections over 9 days. Mechanical hypersensitivity was assessed. Immunofluorescence utilized c-Fos, NeuN, and Iba1. Proinflammatory and anti-inflammatory markers were analyzed. Neuropeptides (CGRP, VIP, PACAP, and substance P) were assessed. Mechanical thresholds were similar. Notable neuropathological distinctions were observed in Sp5C and ACC. ACC showed increased c-Fos and NeuN expression in CM (p < 0.001) and unchanged in EM. Sp5C had higher c-Fos and NeuN expression in EM (p < 0.001). Iba1 was upregulated in Sp5C of EM and ACC of CM (p < 0.001). Proinflammatory markers were strongly expressed in Sp5C of EM and ACC of CM. CGRP expression was elevated in both regions and was higher in CM. VIP exhibited higher levels in the Sp5C of EM and ACC of CM, whereas PACAP and substance P were expressed in the Sp5C in both models. Despite similar thresholds, distinctive neuropathological differences in Sp5C and ACC between EM and CM models suggest a role in the EM to CM transformation.

Clinical [18F]FSPG Positron Emission Tomography Imaging Reveals Heterogeneity in Tumor-Associated System xc- Activity.

BACKGROUND: (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) positron emission tomography/computed tomography (PET/CT) provides a readout of system xc- transport activity and has been used for cancer detection in clinical studies of different cancer types. As system xc- provides the rate-limiting precursor for glutathione biosynthesis, an abundant antioxidant, [18F]FSPG imaging may additionally provide important prognostic information. Here, we performed an analysis of [18F]FSPG radiotracer distribution between primary tumors, metastases, and normal organs from cancer patients. We further assessed the heterogeneity of [18F]FSPG retention between cancer types, and between and within individuals. METHODS: This retrospective analysis of prospectively collected data compared [18F]FSPG PET/CT in subjects with head and neck squamous cell cancer (HNSCC, n = 5) and non-small-cell lung cancer (NSCLC, n = 10), scanned at different institutions. Using semi-automated regions of interest drawn around tumors and metastases, the maximum standardized uptake value (SUVmax), SUVmean, SUV standard deviation and SUVpeak were measured. [18F]FSPG time-activity curves (TACs) for normal organs, primary tumors and metastases were subsequently compared to 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT at 60 min post injection (p.i.). RESULTS: The mean administered activity of [18F]FSPG was 309.3 ± 9.1 MBq in subjects with NSCLC and 285.1 ± 11.3 MBq in those with HNSCC. The biodistribution of [18F]FSPG in both cohorts showed similar TACs in healthy organs from cancer patients. There was no statistically significant overall difference in the average SUVmax of tumor lesions at 60 min p.i. for NSCLC (8.1 ± 7.1) compared to HNSCC (6.0 ± 4.1; p = 0.29) for [18F]FSPG. However, there was heterogeneous retention between and within cancer types; the SUVmax at 60 min p.i. ranged from 1.4 to 23.7 in NSCLC and 3.1-12.1 in HNSCC. CONCLUSION: [18F]FSPG PET/CT imaging from both NSCLC and HNSCC cohorts showed the same normal-tissue biodistribution, but marked tumor heterogeneity across subjects and between lesions. Despite rapid elimination through the urinary tract and low normal-background tissue retention, the diagnostic potential of [18F]FSPG was limited by variability in tumor retention. As [18F]FSPG retention is mediated by the tumor's antioxidant capacity and response to oxidative stress, this heterogeneity may provide important insights into an individual tumor's response or resistance to therapy.

Lymphatic remapping by long-term lymphoscintigraphy follow-up in secondary lymphedema after breast cancer surgery.

The purpose of the study is to investigate long-term changes on lymphoscintigraphy and their association with clinical factors in breast cancer-related lymphedema (BCRL) patients. This single-center cohort study included BCRL patients who underwent baseline and follow-up lymphoscintigraphy. The percentage of excessive circumference (PEC) of the affected upper limb compared with the unaffected side was used as an indicator of the clinical severity of BCRL. Each 99mTc-phytate lymphoscintigraphy image was categorized according to the Taiwan lymphoscintigraphy staging system. Clinical parameters and the lymphoscintigraphy stage at baseline and follow-up were compared and analyzed. Eighty-seven patients were included. Baseline and follow-up lymphoscintigraphies were performed at median 7 (interquartile range [IQR]: 2‒14) and 78 (IQR: 49‒116) months after surgery, respectively. Both lymphoscintigraphy stage and PEC showed variable change with overall increases in their severity. Stepwise multivariable analysis revealed follow-up lymphoscintigraphy stage (P = 0.001) to be independent variables for PEC at follow-up, however, baseline lymphoscintigraphy stage was not. The clinical courses of BCRL and patients' lymphoscintigraphy patterns showed diverse changes over long-term follow-up. In addition to initial lymphoscintigraphy for diagnosis, lymphatic remapping by follow-up lymphoscintigraphy can be useful to visualize functional changes in the lymphatic system that may guide the optimal management in BCRL.

Performance of deep learning models for response evaluation on whole-body bone scans in prostate cancer.

OBJECTIVE: We aimed to develop deep learning classifiers for assessing therapeutic response on bone scans of patients with prostate cancer. METHODS: A set of 3791 consecutive bone scans coupled with their last previous scan (1528 patients) was evaluated. Bone scans were labeled as "progression" or "nonprogression" on the basis of clinical reports and image review. A 2D-convolutional neural network architecture was trained with three different preprocessing methods: 1) no preprocessing (Raw), 2) spatial normalization (SN), and 3) spatial and count normalization (SCN). Data were allocated into training, validation, and test sets in the ratio of 72:8:20, with the 20% independent test set rotating all scans over a five-fold testing procedure. A Grad-CAM algorithm was employed to generate class activation maps to visualize the lesions contributing to the decision. Diagnostic performance was compared using area under the receiver operating characteristics curves (AUCs). RESULTS: The data consisted of 791 scans labeled as "progression" and 3000 scans labeled as "nonprogression." The AUCs of the classifiers were 0.632-0.710 on the Raw dataset, were significantly higher with the use of SN at 0.784-0.854 (p < 0.001 for Raw versus SN), and higher still with SCN at 0.954-0.979 (p < 0.001 for SN versus SCN). Class activation maps of the SCN model visualized lesions contributing to the model's decision of progression. CONCLUSION: With preprocessing of spatial and count normalization, our deep learning model achieved excellent performance in classifying the therapeutic response of bone scans in patients with prostate cancer.

Associations of cardiovascular and diabetes-related risk factors with myocardial perfusion reserve assessed by 201Tl/99mTc-tetrofosmin single-photon emission computed tomography in patients with diabetes mellitus and stable coronary artery disease.

We aimed to examine the associations of cardiovascular risk factors with myocardial perfusion reserve (MPR) in patients with type 2 diabetes and stable coronary artery disease. The study patients were retrospectively identified from a database of patients with diabetes and stable coronary artery disease at Asan Medical Center (Seoul, Republic of Korea), covering the period from 2017 to 2019. The primary outcome variable was MPR assessed by dynamic stress 201Tl/rest 99mTc-tetrofosmin SPECT. Univariable and stepwise multivariable analyses were performed to assess the associations of cardiovascular risk factors with MPR. A total of 276 patients (236 men and 40 women) were included. The median global MPR was 2.4 (interquartile range 1.9-3.0). Seventy-five (27.2%) patients had an MPR < 2.0. Multivariable linear regression showed that smoking (ß = - 0.44, 95% confidence interval - 0.68 to - 0.21, P < 0.001), hypertension (ß = - 0.24, 95% confidence interval - 0.47 to - 0.02, P = 0.033), and summed difference score (ß = - 0.05, 95% confidence interval - 0.07 to - 0.03, P < 0.001) were independently associated with MPR. Abnormal MPR (< 2.0) was associated with a higher incidence of cardiac death or myocardial infarction (P = 0.034). MPR assessed by dynamic stress 201Tl/rest 99mTc-tetrofosmin SPECT was impaired in a large cohort of patients with diabetes. After adjusting for risk variables, including standard myocardial perfusion imaging characteristics, smoking, and hypertension were associated with MPR. Our results may aid in identifying patients with impaired MPR and stratifying patients with type 2 diabetes.

Prognostic significance of pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with T2N1 hormone receptor-positive, ERBB2-negative breast cancer who underwent adjuvant chemotherapy.

PURPOSE: To determine whether tumor uptake of 18F-fluorodeoxyglucose (18F-FDG) is associated with invasive disease-free survival (IDFS) in patients with hormone receptor (HR)-positive ERBB2-negative early-stage breast cancer treated with adjuvant chemotherapy. METHODS: This is a single-center cohort study of women with breast cancer who underwent surgery between 2008 and 2015 at Asan Medical Center, Seoul, Korea. Patients were enrolled if they were diagnosed with HR-positive ERBB2-negative breast cancer with histology of invasive ductal carcinoma, had an American Joint Committee on Cancer pathologic tumor stage of T2N1 with 1-3 positive axillary nodes, underwent preoperative 18F-FDG positron emission tomography/computed tomography (PET/CT), and underwent breast cancer surgery followed by anthracycline- or taxane-based adjuvant chemotherapy. The primary outcome measure was IDFS. The maximum standardized uptake value (SUVmax) was dichotomized using a predefined cut-off of 4.14. RESULTS: A total of 129 patients were included. The median follow-up period for IDFS in those without recurrence was 82 months (interquartile range, 65-106). Multivariable Cox analysis showed that SUVmax was independently associated with IDFS [adjusted hazard ratio 2.49; 95% confidence interval (CI), 1.06-5.84]. Ten-year IDFS estimates via the Kaplan-Meier method were 0.60 (95% CI, 0.42-0.74) and 0.82 (95% CI, 0.65-0.91) for high and low SUVmax groups, respectively. The overall association between SUVmax and IDFS appeared to be consistent across subgroups divided according to age, progesterone receptor status, histologic grade, or presence of lymphovascular invasion. CONCLUSION: High SUVmax on preoperative 18F-FDG PET/CT was independently associated with reduced long-term IDFS in T2N1 HR-positive ERBB2-negative breast cancer patients who underwent adjuvant chemotherapy.

FDG metabolic parameter-based models for predicting recurrence after upfront surgery in synchronous colorectal cancer liver metastasis.

OBJECTIVE: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM). METHODS: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS). RESULTS: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms. CONCLUSIONS: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM. KEY POINTS: • In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. • The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. • The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making.

Fully Automatic Quantitative Measurement of 18F-FDG PET/CT in Thymic Epithelial Tumors Using a Convolutional Neural Network.

OBJECTIVES: The aim of this study was to develop a deep learning (DL)-based segmentation algorithm for automatic measurement of metabolic parameters of 18F-FDG PET/CT in thymic epithelial tumors (TETs), comparable performance to manual volumes of interest. PATIENTS AND METHODS: A total of 186 consecutive patients with resectable TETs and preoperative 18F-FDG PET/CT were retrospectively enrolled (145 thymomas, 41 thymic carcinomas). A quasi-3D U-net architecture was trained to resemble ground-truth volumes of interest. Segmentation performance was assessed using the Dice similarity coefficient. Agreements between manual and DL-based automated extraction of SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and 63 radiomics features were evaluated via concordance correlation coefficients (CCCs) and linear regression slopes. Diagnostic and prognostic values were compared in terms of area under the receiver operating characteristics curve (AUC) for thymic carcinoma and hazards ratios (HRs) for freedom from recurrence. RESULTS: The mean Dice similarity coefficient was 0.83 ± 0.34. Automatically measured SUVmax (slope, 0.97; CCC, 0.92), MTV (slope, 0.94; CCC, 0.96), and TLG (slope, 0.96; CCC, 0.96) were in good agreement with manual measurements. The mean CCC and slopes were 0.88 ± 0.06 and 0.89 ± 0.05, respectively, for the radiomics parameters. Automatically measured SUVmax, MTV, and TLG showed good diagnostic accuracy for thymic carcinoma (AUCs: SUVmax, 0.95; MTV, 0.85; TLG, 0.87) and significant prognostic value (HRs: SUVmax, 1.31 [95% confidence interval, 1.16-1.48]; MTV, 2.11 [1.09-4.06]; TLG, 1.90 [1.12-3.23]). No significant differences in the AUCs or HRs were found between automatic and manual measurements for any of the metabolic parameters. CONCLUSIONS: Our DL-based model provides comparable segmentation performance and metabolic parameter values to manual measurements in TETs.

Diagnostic and prognostic values of 2-[18F]FDG PET/CT in resectable thymic epithelial tumour.

OBJECTIVES: We aimed to evaluate the diagnostic ability for the prediction of histologic grades and prognostic values on recurrence and death of pretreatment 2-[18F]FDG PET/CT in patients with resectable thymic epithelial tumours (TETs). METHODS: One hundred and fourteen patients with TETs who underwent pretreatment 2-[18F]FDG PET/CT between 2012 and 2018 were retrospectively evaluated. TETs were classified into three histologic subtypes: low-risk thymoma (LRT, WHO classification A/AB/B1), high-risk thymoma (HRT, B2/B3), and thymic carcinoma (TC). Area under the receiver operating characteristics curve (AUC) was used to assess the diagnostic performance of PET/CT variables (maximum standardised uptake value [SUVmax], metabolic tumour volume [MTV], total lesion glycolysis [TLG], maximum diameter). Cox proportional hazards models were built using PET/CT and clinical variables. RESULTS: The tumours included 52 LRT, 33 HRT, and 29 TC. SUVmax showed good diagnostic ability for differentiating HRT/TC from LRT (AUC 0.84, 95% confidence interval [CI] 0.76 - 0.92) and excellent ability for differentiating TC from LRT/HRT (AUC 0.94, 95% CI 0.90 - 0.98), with significantly higher values than MTV, TLG, and maximum diameter. With an optimal cut-off value of 6.4, the sensitivity, specificity, and accuracy for differentiating TC from LRT/HRT were 69%, 96%, and 89%, respectively. In the multivariable Cox proportional hazards analyses for freedom-from-recurrence, SUVmax was an independent prognostic factor (p < 0.001), whereas MTV and TLG were not. SUVmax was a significant predictor for overall survival in conjunction with clinical stage and resection margin. CONCLUSION: SUVmax showed excellent diagnostic performance for prediction of TC and significant prognostic value in terms of recurrence and survival. KEY POINTS: • Maximum standardised uptake value (SUVmax) shows excellent performance in the differentiation of thymic carcinoma from low- and high-risk thymoma. • SUVmax is an independent prognostic factor for freedom-from-recurrence in the multivariable Cox proportional hazard model and a significant predictor for overall survival. • 2-[18F]FDG PET/CT can provide a useful diagnostic and prognostic imaging biomarker in conjunction with histologic classification and stage and help choose appropriate management for thymic epithelial tumours.

Risk Factors for Hypervascularization in Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement: A Systematic Review and Meta-analysis.

RATIONALE AND OBJECTIVES: To perform a systematic review and meta-analysis to determine risk factors for hypervascularization in hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Pubmed and EMBASE databases were searched up to May 7, 2020. Studies which evaluated radiologic and clinical risk factors for hypervascularization in HBP hypointense nodules without APHE were included. Hazard ratios were meta-analytically pooled using random-effects model. Methodological quality of included studies was assessed using Quality in Prognostic Studies (QUIPS) tool. RESULTS: Sixteen studies with 934 patients were included. HBP hypointense nodules without APHE with baseline size greater than 10 mm, T2 hyperintensity, and restricted diffusion showed risk for hypervascularization with pooled HRs of 2.95 (95% confidence interval [CI], 1.94-4.20), 4.21 (95% CI, 1.15-15.40), 5.83 (95% CI, 1.42-23.95), respectively. Previous HCC history contributed to hypervascularization of the nodules with hazard ratio of 2.06 (95% CI, 1.23-3.44). T1 hyperintensity, intralesional fat, Child-Pugh Class B, sex, alfa-fetoprotein, hepatitis B or C infection were not significant risk factors for hypervascularization (p ≥0.05). Study quality was generally moderate. CONCLUSION: HBP hypointense nodules without APHE on gadoxetic acid-enhanced MRI with baseline size greater than 10 mm, T2 hyperintensity, restricted diffusion and previous hepatocellular carcinoma history pose higher risk for hypervascularization. Proper patient management in patients with HBP hypointense nodules without APHE on gadoxetic acid-enhanced MRI may need to be tailored according to these risk factors.

Diagnostic performance of deep learning models for detecting bone metastasis on whole-body bone scan in prostate cancer.

PURPOSE: We evaluated the performance of deep learning classifiers for bone scans of prostate cancer patients. METHODS: A total of 9113 consecutive bone scans (5342 prostate cancer patients) were initially evaluated. Bone scans were labeled as positive/negative for bone metastasis using clinical reports and image review for ground truth diagnosis. Two different 2D convolutional neural network (CNN) architectures were proposed: (1) whole body-based (WB) and (2) tandem architectures integrating whole body and local patches, here named as "global-local unified emphasis" (GLUE). Both models were trained using abundant (72%:8%:20% for training:validation:test sets) and limited training data (10%:40%:50%). The allocation of test sets was rotated across all images: therefore, fivefold and twofold cross-validation test results were available for abundant and limited settings, respectively. RESULTS: A total of 2991 positive and 6142 negative bone scans were used as input. For the abundant training setting, the receiver operating characteristics curves of both the GLUE and WB models indicated excellent diagnostic ability in terms of the area under the curve (GLUE: 0.936-0.955, WB: 0.933-0.957, P > 0.05 in four of the fivefold tests). The overall accuracies of the GLUE and WB models were 0.900 and 0.889, respectively. With the limited training setting, the GLUE models showed significantly higher AUCs than the WB models (0.894-0.908 vs. 0.870-0.877, P < 0.0001). CONCLUSION: Our 2D-CNN models accurately classified bone scans of prostate cancer patients. While both showed excellent performance with the abundant dataset, the GLUE model showed higher performance than the WB model in the limited data setting.

Prognostic Value of 18F-FDG PET in Neuroendocrine Neoplasm: A Systematic Review and Meta-analysis.

OBJECTIVES: Accurate assessment of the prognosis is critical for the rational treatment of neuroendocrine neoplasms (NENs). We performed a systematic review and meta-analysis of the prognostic value of 18F-FDG PET for NENs. PATIENTS AND METHODS: PubMed and Embase databases were searched up to September 2020 for studies that evaluated 18F-FDG PET as prognostic factors in patients with NENs with overall survival (OS) and event-free survival (EFS) as outcomes. Hazards ratios (HRs) comparing high and low FDG uptakes were pooled using the DerSimonian-Laird method. Publication bias was assessed and adjusted for using the trim-and-fill method. Metaregression and subgroup analyses were performed to explore the cause of heterogeneity. RESULTS: Twenty-three studies (1799 patients) were included. The overall pooled HRs of high FDG uptake on EFS and OS were 2.84 (95% confidence interval [CI], 2.21-3.64) and 3.50 (95% CI, 2.42-4.12), respectively. Publication biases were present regarding both EFS and OS (P = 0.0342 and 0.0009, respectively). After adjustment, effect sizes remained significant for EFS and OS (adjusted HR, 2.26 [95% CI, 1.76-2.89]; 3.16 [95% CI, 2.42-4.12]). In metaregression analyses, the proportion of grade 3 tumors positively correlated with the HR of OS (adjusted P = 0.0422). CONCLUSIONS: 18F-FDG PET is a significant prognostic factor in patients with NENs. 18F-FDG PET might be a useful prognostic biomarker in conjunction with the histologic grade and can help select the optimal treatment.

A practical individualized radiation precaution based on the dose rate at release time after inpatient 131I ablation therapy.

INTRODUCTION: Retained radioactivity of 131I after ablation therapy largely differs in each patient according to factors including the amount of remnant thyroid tissue, renal function, and use of recombinant human thyroid-stimulating hormone. To reduce unnecessary restriction of patient's daily life after inpatient 131I ablation therapy, we propose a practical individualized method for radiation precaution based on dose rate at release time. METHODS: We evaluated 215 patients with differentiated thyroid cancer who underwent inpatient 131I ablation therapy following total thyroidectomy. Effective dose equivalent rates at 1-m distance were measured upon release (EDRR) on day 2 and during delayed whole-body scan (EDRD) visits on day 6‒8 after 131I administration. The biexponential model was designed to estimate total effective dose equivalent to others. To assess conservativeness of our model, EDRD estimated by our model was compared with measured EDRD. EDRR-based periods of precaution not to receiving 1 mSv of radiation exposure were estimated and compared with those based on administered radioactivities on American Thyroid Association (ATA) recommendations. RESULTS: The EDRR ranged from 1.0-48.9 µSv/hr. The measured EDRD were equal to or lower than estimated EDRD in all patients, except for one, indicating that our model is sufficiently conservative. According to our model, no subjects needed additional daytime restriction after release. The maximum permissible times for public transportation use were longer in all patients compared with those based on administered radioactivities. Nighttime restriction periods were significantly shorter than those based on administered radioactivity; median periods requiring sleeping apart were 0 (range, 0‒5), 4 (range, 1‒14), and 3 (range, 2‒13) days after release in patients treated with radioactivity doses of 2.96, 5.50, and 7.40 GBq, respectively, needing 8, 16, and 19 additional days, respectively, based on administered radioactivity. CONCLUSIONS: Radiation safety instructions using proposed method based on EDRR of individual patient could safely reduce the burden of radiation precaution.

Concordance between Response Assessment Using Prostate-Specific Membrane Antigen PET and Serum Prostate-Specific Antigen Levels after Systemic Treatment in Patients with Metastatic Castration Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

Prostate-specific membrane antigen positron emission tomography (PSMA PET) has recently gained interest as a promising tool for treatment response evaluation in metastatic castration-resistant prostate cancer (CRPC). We performed a systematic review and meta-analysis assessing the concordance between response evaluation using PSMA PET and serum prostate-specific antigen (PSA) level after systemic treatment and the association between PSMA PET and overall survival in metastatic CRPC patients. PubMed, Embase, and Cochrane library databases were searched until August 2020. Studies that reported the concordance between PSMA PET and PSA response were included. PSMA PET and PSA response evaluation were dichotomized into response vs. non-response to construct two-by-two contingency tables; an ≥30% increase in PSMA PET according to PET Response Criteria in Solid Tumors 1.0 and as an increase in serum PSA level of ≥25% as per Prostate Cancer Working Group 3 guidelines were defined as non-response. The percent agreement rates were pooled using random-effect model. Ten studies (268 patients) were included. The concordance rates ranged 0.50-0.84 with a pooled proportion of 0.73 (95% confidence interval 0.67-0.79). Patients were treated with 177Lu-PSMA therapy in five, chemotherapy in three, 223Ra in one, and more than one type in one study. Various PET parameters were used: the most widely evaluated was PSMA tumor volume (PSMA-TV). Similar proportions were found across different therapeutic agents, PET response parameters, and regarding directionality of discordance (PSA response/PSMA non-response vs. PSMA response/PSA non-response). Two studies reported that a decrease in PSMA-TV was associated with better overall survival. PSMA PET and PSA response assessments were discordant in nearly a fourth of metastatic CRPC patients. Further studies are warranted to establish the clinical meaning of this discordance and define appropriate management for such clinical situation.

Impact of 18F-FDG PET, PET/CT, and PET/MRI on Staging and Management as an Initial Staging Modality in Breast Cancer: A Systematic Review and Meta-analysis.

OBJECTIVES: We performed a systematic review and meta-analysis to evaluate the impact of 18F-FDG PET, PET/CT, and PET/MRI on staging and management during the initial staging of breast cancer. METHODS: We searched the PubMed, Embase, Cochrane Library, and KoreaMed databases until March 2020 to identify studies that reported the proportion of breast cancer patients whose clinical stage or management were changed after PET scans. The proportion of changes was pooled using a random-effects model. Subgroup and metaregression analyses were performed to explore heterogeneity. RESULTS: We included 29 studies (4276 patients). The pooled proportions of changes in stage and management were 25% (95% confidence interval [CI], 21%-30%) and 18% (95% CI, 14%-23%), respectively. When stage changes were stratified according to initial stage, the pooled proportions were 11% (95% CI, 3%-22%) in stage I, 20% (95% CI, 16%-24%) in stage II, and 34% (95% CI, 27%-42%) in stage III. The relative proportions of intermodality and intention-to-treat changes were 74% and 70%, respectively. Using metaregression analyses, the mean age and the proportion of initial stage III to IV and histologic grade II to III were significant factors affecting the heterogeneity in changes in stage or management. CONCLUSIONS: Currently available literature suggests that the use of 18F-FDG PET, PET/CT, or PET/MRI leads to significant modification of staging and treatment in newly diagnosed breast cancer patients. Therefore, there may be a role for routine clinical use of PET imaging for the initial staging of breast cancer.

Prognostic and predictive values of interim 18F-FDG PET during neoadjuvant chemoradiotherapy for esophageal cancer: a systematic review and meta-analysis.

PURPOSE: To determine the prognostic and predictive value of early metabolic response assessed by a change in standardized uptake value (SUV) on interim 18F-FDG PET in patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy. METHODS: PubMed and Embase were searched up until 10 September, 2020, for studies evaluating a change in SUV on interim 18F-FDG PET for predicting a pathologic response, progression-free survival (PFS), or overall survival (OS) in patients with esophageal cancer. The sensitivity and specificity for predicting a pathologic response were pooled using bivariate and hierarchical summary receiver operating characteristic (HSROC) models. Meta-analytic pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were derived using a random-effects model. RESULTS: A total of 11 studies (695 patients) were included in the meta-analysis. For nine studies assessing predictive accuracy, the pooled sensitivity and specificity of an early metabolic response for predicting a pathologic response were 0.80 (95% CI 0.61-0.91) and 0.54 (95% CI 0.45-0.63), respectively. The area under the HSROC curve was 0.64 (95% CI 0.60-0.68). Across the nine studies assessing prognostic value, an early metabolic response determined by interim PET showed pooled HRs for predicting PFS and OS of 0.44 (95% CI, 0.30-0.63) and 0.42 (95% CI, 0.31-0.56), respectively. CONCLUSION: Change in SUV on interim 18F-FDG PET had significant prognostic value and moderate predictive value for a pathologic response in esophageal cancer treated with neoadjuvant chemoradiotherapy. Interim 18F-FDG PET may help prognostic stratification and guide treatment planning in oncologic practice.

Genetic alterations associated with 18F-fluorodeoxyglucose positron emission tomography/computed tomography in head and neck squamous cell carcinoma.

BACKGROUND: We investigated the relationship between genetic alterations and 18F-FDG PET/CT findings in head and neck squamous cell carcinoma (HNSC). METHODS: Using mRNA-sequences of HNSC samples (480 patients) from the Cancer Genome Atlas (TCGA) portal, gene coexpression networks were constructed via a weighted correlation network analysis (WGCNA) algorithm, and their association with the tumor-to-blood signal ratio on 18F-FDG PET/CT data (21 patients) was explored. An elastic-net regression model was developed to estimate the PET tumor-to-blood ratio from the gene networks and to derive an FDG signature score (FDGSS). The FDGSS was evaluated with regard to clinical variables and general mutational profiles, as well as alterations to oncogenic signaling pathways. FINDINGS: The FDGSS values differed across clinical stages (p = 0.027), HPV-status (p< 0.001), and molecular subtypes of HNSC (p< 0.001). Multivariate Cox regression demonstrated that FDGSS was an independent predictor for overall (p = 0.019) and progression-free survival (p = 0.024). FDGSS positively correlated with total mutation rate (p = 0.016), aneuploidy (p < 0.001), and somatic copy number alteration scores (p < 0.001). CDKN2A in the cell cycle pathway (q = 0.014) and the TP53 gene in the TP53 pathway (q = 0.005) showed significant differences between high and low FDGSS patients. CONCLUSION: FDGSS based on the gene coexpression network was associated with the mutational landscape of HNSC. 18F-FDG PET/CT is therefore a valuable tool for the in vivo imaging of these cancers, being able to visualize the glucose metabolism of the tumor and allow inferences to be made on the underlying genetic alterations in the tumor.

Immune microenvironment of the gene signature reflecting the standardised uptake value on 18F-fluorodeoxyglucose positron emission tomography/computed tomography in head and neck squamous cell carcinoma.

OBJECTIVE: A comprehensive understanding of the link between 18F-FDG PET/CT and the tumor immune microenvironment (TIM) is lacking. We, therefore, investigated the TIM in regard to the gene signature of 18F-FDG PET/CT in head and neck squamous cell carcinoma (HNSC). METHODS: The mRNA sequence data of 480 HNSC patients on The Cancer Genome Atlas portal were used to explore genes showing high associations with maximum standardised uptake value (SUVmax) on 18F-FDG PET/CT based on Pearson correlation test. Hierarchical clustering of the selected gene signature was performed and divided patients into high and low SUV clusters. Principal component analysis was performed to derive the summarised expression profile of the gene signature and defined the first principal component scores as the SUV signature scores (SUVSSs). The SUV clusters and SUVSS based on the gene signature were characterised by overall survival, clinical variables, and the immune microenvironment in terms of overall immune score, immune cell type enrichment score, expression of immunomodulator genes as well as somatic copy number alterations (SCNA) possibly contributing to immune cell recognition. RESULTS: The high SUV cluster classified by the gene signature (191 genes) was an independent predictor of overall survival (adjusted hazard ratio 1.40, p = 0.022). The SUVSS values differed across the molecular subtypes of HNSC (p < 0.001), and HPV status (p = 0.024). Tumors in the low SUV cluster exhibited significantly higher overall immune score and lower SCNA scores (p < 0.05 for all) compared with tumors in the high SUV cluster. The low SUV cluster showed an immune cell composition consisting of high levels of T cells, B cells, mast cells, neutrophils, monocytes, and eosinophils, but lower basophils and similar macrophage levels to the high SUV cluster. Differential gene expression analysis demonstrated SUV cluster-distinct expression of several immunomodulators including PD-1, CD40LG, IL2RA, TLR4, BTLA, and TIGIT. CONCLUSION: HNSC exhibited the distinct TIM according to the gene signature reflecting SUVmax on 18F-FDG PET/CT. Our results support an understanding of the close relationship between FDG uptake and tumor immune response, and suggest that 18F-FDG PET/CT could be clinically usable as a biomarker for assisting immunotherapy.