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.

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.

The Genotype-Phenotype Correlation in Human 5α-Reductase Type 2 Deficiency: Classified and Analyzed from a SRD5A2 Structural Perspective.

The phenotype of the 5α-reductase type 2 deficiency (5αRD2) by the SRD5A2 gene mutation varies, and although there have been many attempts, the genotype-phenotype correlation still has not yet been adequately evaluated. Recently, the crystal structure of the 5α-reductase type 2 isozyme (SRD5A2) has been determined. Therefore, the present study retrospectively evaluated the genotype-phenotype correlation from a structural perspective in 19 Korean patients with 5αRD2. Additionally, variants were classified according to structural categories, and phenotypic severity was compared with previously published data. The p.R227Q variant, which belongs to the NADPH-binding residue mutation category, exhibited a more masculine phenotype (higher external masculinization score) than other variants. Furthermore, compound heterozygous mutations with p.R227Q mitigated phenotypic severity. Similarly, other mutations in this category showed mild to moderate phenotypes. Conversely, the variants categorized as structure-destabilizing and small to bulky residue mutations showed moderate to severe phenotypes, and those categorized as catalytic site and helix-breaking mutations exhibited severe phenotypes. Therefore, the SRD5A2 structural approach suggested that a genotype-phenotype correlation does exist in 5αRD2. Furthermore, the categorization of SRD5A2 gene variants according to the SRD5A2 structure facilitates the prediction of the severity of 5αRD2 and the management and genetic counseling of patients affected by it.

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.

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.

Prediction of amyloid PET positivity via machine learning algorithms trained with EDTA-based blood amyloid-ß oligomerization data.

BACKGROUND: The tendency of amyloid-ß to form oligomers in the blood as measured with Multimer Detection System-Oligomeric Amyloid-ß (MDS-OAß) is a valuable biomarker for Alzheimer's disease and has been verified with heparin-based plasma. The objective of this study was to evaluate the performance of ethylenediaminetetraacetic acid (EDTA)-based MDS-OAß and to develop machine learning algorithms to predict amyloid positron emission tomography (PET) positivity. METHODS: The performance of EDTA-based MDS-OAß in predicting PET positivity was evaluated in 312 individuals with various machine learning models. The models with various combinations of features (i.e., MDS-OAß level, age, apolipoprotein E4 alleles, and Mini-Mental Status Examination [MMSE] score) were tested 50 times on each dataset. RESULTS: The random forest model best-predicted amyloid PET positivity based on MDS-OAß combined with other features with an accuracy of 77.14 ± 4.21% and an F1 of 85.44 ± 3.10%. The order of significance of predictive features was MDS-OAß, MMSE, Age, and APOE. The Support Vector Machine using the MDS-OAß value only showed an accuracy of 71.09 ± 3.27% and F-1 value of 80.18 ± 2.70%. CONCLUSIONS: The Random Forest model using EDTA-based MDS-OAß combined with the MMSE and apolipoprotein E status can be used to prescreen for amyloid PET positivity.

Prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in newly diagnosed multiple myeloma: a systematic review and meta-analysis.

OBJECTIVES: We performed a systematic review and meta-analysis on the prognostic values of 18F-FDG PET/CT in patients with newly diagnosed multiple myeloma (MM). METHODS: PubMed and Embase were searched until July 10, 2019, for studies that reported the prognostic significance of 18F-FDG PET in patients with newly diagnosed MM, with overall (OS) and progression-free survival (PFS) included as outcomes. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were meta-analytically pooled using a random-effects model. RESULTS: Fifteen studies (1670 patients) were included for qualitative synthesis. Among multiple PET parameters, the presence of extramedullary disease (EMD), more than three focal lesions (FLs), and high FDG uptake were widely evaluated and significantly associated with shorter OS and PFS in most of the included studies. Among 11 studies included in quantitative synthesis, the overall HRs of EMD, more than three FLs, and high FDG uptake on PFS were 2.12 (95% CI, 1.52-2.96), 2.38 (95% CI, 1.84-3.07), and 2.02 (95% CI, 1.51-2.68), respectively. The pooled HRs of those three parameters on OS were 2.37 (95% CI, 1.77-3.16), 3.29 (95% CI, 2.38-4.56), and 2.28 (95% CI, 1.67-3.13). No statistical differences were found across parameters for either PFS (p = 0.6822) or OS (p = 0.2147). CONCLUSIONS: Pretreatment 18F-FDG PET/CT is a significant predictor for disease progression and survival in patients with MM. It may be a useful prognostic biomarker capable of accurate risk stratification and application in clinical decision-making for newly diagnosed MM. KEY POINTS: • There remain unmet clinical needs for reliable prognostic biomarkers in patients with newly diagnosed multiple myeloma. • This meta-analysis shows that the presence of extramedullary disease, more than three focal lesions, and high FDG uptake from baseline 18F-FDG PET are significant prognostic factors. • These imaging biomarkers might help the accurate stratification of patient prognosis which is required for choosing an appropriate therapeutic strategy in clinical practice.

Prognostic value of 18F-FDG PET and PET/CT for assessment of treatment response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis to evaluate the prognostic significance of 18F-FDG PET and PET/CT for evaluation of responses to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: We searched PubMed, Embase, and the Cochrane Library databases until June 2020 to identify studies that assessed the prognostic value of 18F-FDG PET scans during or after NAC with regard to overall (OS) and disease-free survival (DFS). Hazard ratios (HRs) and their 95% confidence intervals (CIs) were pooled meta-analytically using a random-effects model. RESULTS: Twenty-one studies consisting of 1630 patients were included in the qualitative synthesis. Twelve studies investigated the use of PET scans for interim response evaluation (during NAC) and 10 studies assessed post-treatment PET evaluation (after NAC). The most widely evaluated parameter distinguishing metabolic responders from poor responders on interim or post-treatment PET scans was %ΔSUVmax, defined as the percent reduction of SUVmax compared to baseline PET, followed by SUVmax and complete metabolic response (CMR). For the 17 studies included in the meta-analysis, the pooled HR of metabolic responses on DFS was 0.21 (95% confidence interval [CI], 0.14-0.32) for interim PET scans and 0.31 (95% CI, 0.21-0.46) for post-treatment PET scans. Regarding the influence of metabolic responses on OS, the pooled HRs for interim and post-treatment PET scans were 0.20 (95% CI, 0.09-0.44) and 0.26 (95% CI, 0.14-0.51), respectively. CONCLUSIONS: The currently available literature suggests that the use of 18F-FDG PET or PET/CT for evaluation of response to NAC provides significant predictive value for disease recurrence and survival in breast cancer patients and might allow risk stratification and guide rational management.

Hepatobiliary phase hypointense nodule without arterial phase hyperenhancement: are they at risk of HCC recurrence after ablation or surgery? A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis to determine intrahepatic distant recurrence (IDR) risk of hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) on pretreatment gadoxetic acid-enhanced MRI in patients with hepatocellular carcinoma (HCC) treated with either hepatectomy or radiofrequency ablation (RFA). METHODS: PubMed and EMBASE databases were searched up to April 6, 2019. We included studies that evaluated HBP hypointense nodules without APHE as risk factors for IDR in HCC patients treated with either hepatectomy or RFA. Hazard ratios (HR) were meta-analytically pooled using random effects model. Subgroup analyses stratified to clinicopathologic variables were performed to explore heterogeneity. Methodological quality of included studies was assessed using Quality in Prognostic Studies (QUIPS) tool. RESULTS: Eight studies with 842 patients were analyzed. The overall pooled HR for IDR was 2.44 (95% CI, 1.99-2.98) and were 2.14 (95% CI, 1.66-2.76) and 3.07 (95% CI, 2.19-4.31) for patients that underwent hepatectomy and RFA, respectively. No significant heterogeneity was present (I2 = 0%). The presence of these nodules was consistently shown to be significant factors for IDR in other subgroups (HR = 1.74-3.07). Study quality was generally moderate. CONCLUSIONS: HBP hypointense nodules without APHE are risk factors for IDR in HCC patients treated with either RFA or hepatectomy. Stratification of patient management with regard to performing additional tests or treatment for these nodules and modification of proper follow-up strategies may be required in patients with HCC who have these nodules on pretreatment gadoxetic acid-enhanced MRI. KEY POINTS: • HBP hypointense nodules without APHE constitute an entity that is unique in gadoxetic acid-enhanced MRI. • HBP hypointense nodules without APHE are risk factors for IDR in HCC patients treated with either RFA or hepatectomy. • Stratification of management and modification of proper follow-up strategies may be required in HCC patients who have these nodules on pretreatment gadoxetic acid-enhanced MRI.

Prognostic Value of Pretreatment MRI in Patients With Prostate Cancer Treated With Radiation Therapy: A Systematic Review and Meta-Analysis.

OBJECTIVE. Despite a substantial increase in the use of MRI for pretreatment evaluation of prostate cancer, its prognostic value in patients undergoing radiation therapy (RT) is not well known. Therefore, the purpose of this study was to systematically review the literature and perform a meta-analysis on the prognostic value of pretreatment MRI in patients with prostate cancer who underwent external beam radiation therapy (EBRT) or brachytherapy. MATERIALS AND METHODS. PubMed and Embase databases were searched for studies published on or before March 13, 2019. We included studies that evaluated pretreatment MRI as a prognostic factor in prostate cancer regarding biochemical recurrence (BCR), metastatic failure, and overall or cancer-specific mortality. Effect sizes were measured in terms of the hazard ratio (HR) and were meta-analytically pooled using the random-effects model. The quality of the studies was independently evaluated using the Quality in Prognostic Studies tool. RESULTS. Twelve studies (2205 patients) were included. All studies assessed BCR; metastasis was evaluated in three studies, and mortality was evaluated in one study. Extraprostatic extension (EPE), seminal vesicle invasion (SVI), large tumor size or volume, number of sextants involved, and tumor involvement of prostatic apex were significant prognostic factors of BCR (pooled HRs = 1.50-4.47). EPE, larger tumor size, greater tumor volume, presence of metastatic pelvic lymph nodes (LNs), and presence of SVI were significant risk factors for metastasis (pooled HRs = 1.12-11.96). Pelvic LN metastasis was significantly predictive of cancer-specific mortality (HR = 4.45 [95% CI, 1.30-15.23]). CONCLUSION. Several pretreatment MRI findings were significant prognostic factors in patients with prostate cancer who underwent RT.

Modifications to a LATE MERISTEM IDENTITY1 gene are responsible for the major leaf shapes of Upland cotton (Gossypium hirsutum L.).

Leaf shape varies spectacularly among plants. Leaves are the primary source of photoassimilate in crop plants, and understanding the genetic basis of variation in leaf morphology is critical to improving agricultural productivity. Leaf shape played a unique role in cotton improvement, as breeders have selected for entire and lobed leaf morphs resulting from a single locus, okra (l-D1), which is responsible for the major leaf shapes in cotton. The l-D1 locus is not only of agricultural importance in cotton, but through pioneering chimeric and morphometric studies, it has contributed to fundamental knowledge about leaf development. Here we show that an HD-Zip transcription factor homologous to the LATE MERISTEM IDENTITY1 (LMI1) gene of Arabidopsis is the causal gene underlying the l-D1 locus. The classical okra leaf shape allele has a 133-bp tandem duplication in the promoter, correlated with elevated expression, whereas an 8-bp deletion in the third exon of the presumed wild-type normal allele causes a frame-shifted and truncated coding sequence. Our results indicate that subokra is the ancestral leaf shape of tetraploid cotton that gave rise to the okra allele and that normal is a derived mutant allele that came to predominate and define the leaf shape of cultivated cotton. Virus-induced gene silencing (VIGS) of the LMI1-like gene in an okra variety was sufficient to induce normal leaf formation. The developmental changes in leaves conferred by this gene are associated with a photosynthetic transcriptomic signature, substantiating its use by breeders to produce a superior cotton ideotype.

Correlation between the presence of herniation pit and femoroacetabular impingement: a systematic review and meta-analysis.

PURPOSE: The purpose of this systematic review and meta-analysis was to evaluate the correlation between the incidence of herniation pits (HPs) and femoroacetabular impingement (FAI)-related morphologies. METHODS: A systematic search of the MEDLINE, EMBASE, and Cochrane Library databases was performed for studies evaluating the relationship between the incidence of HPs and FAI-related morphologies published up to August 16, 2019. Subgroup analyses were also performed to determine the differences in the relationship between the presence/absence of hip symptoms and cam-/pincer-type FAI. RESULTS: Seven studies involving 7950 hips were included. The pooled odds ratio (OR) for the incidence of HPs in the presence of an FAI-related morphology was 1.64 (95% confidence interval [CI] = 1.09-2.46; P = 0.02). In the subgroup analyses, the ORs for the incidence of HPs in the symptomatic and asymptomatic hips were 1.00 (95% CI 0.40-2.51; P = 1.00) and 1.59 (95% CI 1.42-1.77; P < 0.0001), respectively; the ORs for the incidence of HPs in the cam- and pincer-type FAI were 1.61 (95% CI 1.43-1.81; P < 0.0001) and 1.42 (95% CI 0.77-2.61; P = n.s.), respectively. CONCLUSIONS: The incidence of HPs has a significant relationship with FAI-related morphology, especially in asymptomatic patients and those with cam-type FAI morphology. LEVEL OF EVIDENCE: III.

Correction to: Correlation between the presence of herniation pit and femoroacetabular impingement: a systematic review and meta-analysis.

Authors would like to correct the errors in figure 4 legend.

Diagnostic accuracy and safety of 16α-[18F]fluoro-17ß-oestradiol PET-CT for the assessment of oestrogen receptor status in recurrent or metastatic lesions in patients with breast cancer: a prospective cohort study.

BACKGROUND: A biopsy of first recurrence or metastatic disease is recommended to re-evaluate oestrogen receptor status in patients with breast cancer and to select appropriate treatment. However, retesting for oestrogen receptor status with rebiopsy is not always feasible, depending on lesion location and the risk associated with biopsy, and in these cases clinicians continue to treat patients according to the oestrogen receptor status of the primary tumour. Consequently suboptimal therapy might be offered to these patients. We assessed the diagnostic accuracy and safety of 16α-[18F]fluoro-17ß-oestradiol (18F-FES) PET-CT to assess oestrogen receptor status in patients with recurrent or metastatic breast cancer. METHODS: We did a prospective cohort study at the Asan Medical Center, Seoul, South Korea. Eligible patients had breast cancer, with first recurrence or metastatic disease at presentation, were 19 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-2. The primary objective was to show the agreement between qualitative 18F-FES PET-CT interpretation and the results of oestrogen receptor expression by immunohistochemical assay, a non-reference standard test. Whole-body 18F-FES PET-CT imaging was done after intravenous injection of 111-222 MBq of 18F-FES, with dosing primarily determined by radiation dosimetry analysis. 18F-FES uptake above background intensity was interpreted as positive. Efficacy was assessed in all patients with histologically confirmed recurrent or metastatic breast cancer who received 18F-FES and had PET-CT images available (intention-to-diagnose analysis), and safety was assessed in all patients who received 18F-FES. This study is registered with ClinicalTrials.gov, number NCT01986569. FINDINGS: Between Nov 27, 2013, and Nov 10, 2016, 93 patients were enrolled. Of the 85 patients included in the efficacy analysis, 47 (55%) were oestrogen receptor-positive and 38 (45%) were oestrogen receptor-negative. Positive status percent agreement between the 18F-FES PET-CT results and oestrogen receptor status by immunohistochemical assay was 76·6% (95% CI 62·0-87·7) and the negative status percent agreement was 100·0% (90·8-100·0). Patients who were oestrogen receptor-positive and had a positive 18F-FES PET-CT result had a significantly higher progesterone receptor expression than those who were oestrogen receptor-positive and had a negative 18F-FES PET-CT result (23 [68%] of 34 patients vs 0 of 11 patients; p<0·0001). The most common adverse event was procedural pain in nine (10%) of 90 patients injected with 18F-FES. No adverse events were related to the study drug except injection site pain in one (1%) patient. No serious adverse events were recorded. INTERPRETATION: The high negative percent agreement between 18F-FES PET-CT and oestrogen receptor status by immunohistochemical assay in this cohort suggests that positive 18F-FES uptake by recurrent or metastatic oestrogen receptor-positive breast cancer lesions could be an alternative to oestrogen receptor assays in this setting. Staging assessment should include 18F-FES PET-CT when retesting oestrogen receptor status is not feasible. FUNDING: Asan Institute for Life Sciences, Ministry of Health and Welfare, South Korea.

The Diagnostic Performance of MRI for Detection of Extramural Venous Invasion in Colorectal Cancer: A Systematic Review and Meta-Analysis of the Literature.

OBJECTIVE. The purpose of this article is to perform a systematic review and meta-analysis regarding the diagnostic test accuracy of MRI for detecting extramural venous invasion (EMVI) in patients with colorectal cancer. MATERIALS AND METHODS. PubMed and EMBASE were searched up to November 9, 2018. We included diagnostic accuracy studies that used MRI for EMVI detection in patients with colorectal cancer, using pathologic analysis as the reference standard. The methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Sensitivity and specificity were pooled and plotted in a hierarchic summary ROC plot. Metaregression analysis using several clinically relevant covariates was performed. RESULTS. Fourteen studies (n = 1751 patients) were included. Study quality was moderate in general. Pooled sensitivity was 0.61 (95% CI, 0.49-0.71), and pooled specificity was 0.87 (95% CI, 0.79-0.92). There was substantial heterogeneity according to the Cochran Q test (p < 0.01) and Higgins I2 heterogeneity index (98% and 95% for sensitivity and specificity, respectively). Publication bias was present (p = 0.01). Higher rates of advanced T category, use of high-resolution MRI, and use of antispasmodic drugs were shown to significantly affect heterogeneity (p < 0.01). Location of primary tumor, preoperative treatment status, study design, definition of reference standard, magnetic field strength, and use of functional MRI were not statistically significant (p = 0.17-0.92). CONCLUSION. MRI shows moderate sensitivity and good specificity for the detection of EMVI in colorectal cancer. The use of high-resolution MRI may improve diagnostic performance.

CT Characteristics of Non-Small Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangement: A Systematic Review and Meta-Analysis.

OBJECTIVE. The purpose of this study was to perform a systematic review and meta-analysis regarding CT features of non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement. MATERIALS AND METHODS. The PubMed and Embase databases were searched up to February 20, 2019. Studies that evaluated CT features of NSCLC with and without ALK rearrangement was included. Methodologic quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. The association between CT features and ALK rearrangement was pooled in the form of the odds ratio (OR) or the mean difference (MD) using the random-effects model. Heterogeneity was examined using the inconsistency index (I2). Publication bias was examined using funnel plots and Egger tests. RESULTS. Sixteen studies were included, consisting of 3113 patients with NSCLC. The overall prevalence of patients with ALK rearrangement was 17% (528/3113). Compared with NSCLC without ALK rearrangement, on CT images those with ALK rearrangement were more frequently solid (OR = 2.86), central in location (OR = 2.72), and 3 cm or smaller (OR = 0.57); had lower contrast-enhanced CT attenuation (MD = -4.79 HU); more frequently had N2 or N3 disease (OR = 5.63), lymphangitic carcinomatosis (OR = 3.46), pleural effusion (OR = 1.91), or pleural metastasis (OR = 1.81); and less frequently had lung metastasis (OR = 0.66). Heterogeneity varied among CT features (I2 = 0-80%). No significant publication bias was seen (p = 0.15). CONCLUSION. NSCLC with ALK rearrangement had several distinctive CT features compared with that without ALK rearrangement. These CT biomarkers may help identify patients likely to have ALK rearrangement.

Feasibility of dynamic stress 201Tl/rest 99mTc-tetrofosmin single photon emission computed tomography for quantification of myocardial perfusion reserve in patients with stable coronary artery disease.

PURPOSE: We evaluated the feasibility of dynamic stress 201Tl/rest 99mTc-tetrofosmin SPECT imaging using a cardiac camera equipped with cadmium-zinc-telluride detectors for the quantification of myocardial perfusion reserve (MPR). METHODS: Subjects with stable known or suspected coronary artery disease (CAD) who had undergone or were scheduled to undergo fractional flow reserve (FFR) measurement were prospectively enrolled. Dynamic stress 201Tl/rest 99mTc-tetrofosmin SPECT imaging was performed using a dedicated multiple pinhole SPECT camera with cadmium-zinc-telluride detectors. MPR was derived using Corridor4DM software. RESULTS: A total of 34 subjects were enrolled (25 men and 9 women; mean age 60.4 years). FFR was measured in 65 coronary arteries with intermediate lesions. The average global MPR was 2.58 ± 1.03. Global MPR was associated with the extent of CAD (P = 0.028) and global summed stress score (r = -0.60, P < 0.001). Regional MPR showed a significant correlation with diameter stenosis (r = -0.57, P < 0.001), minimum lumen diameter (r = 0.50, P < 0.001), summed stress score (r = -0.52, P < 0.001) and FFR (r = 0.52, P < 0.001). The area under the receiver operating characteristic curve of MPR for the diagnosis of functionally significant stenosis (FFR ≤0.8) was 0.79 (P < 0.001). The sensitivity and specificity of regional MPR were 67% and 83%, respectively, using a cut-off value of 2.0. CONCLUSION: Dynamic stress 201Tl/rest 99mTc-tetrofosmin SPECT imaging and quantification of MPR is feasible in patients with stable CAD. The preliminary results of this study in a small number of patients require confirmation in a larger cohort to determine their implications for bolstering the role of SPECT imaging in the diagnosis and risk prediction of CAD.

Prognostic Value of Volume-Based Metabolic Parameters of 18F-FDG PET/CT in Uterine Cervical Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study is to perform a systematic review and meta-analysis of volume-based 18F-FDG PET/CT parameters regarding the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with uterine cervical cancer. MATERIALS AND METHODS: The PubMed and EMBASE databases were systematically searched until January 19, 2018. We included studies that evaluated pretreatment MTV or TLG as a prognostic factor in uterine cervical cancer with event-free (EFS) and overall survival (OS) as the endpoints. Effect sizes of the prognostic value of MTV and TLG were measured in terms of hazard ratio (HR) and were meta-analytically pooled. Multiple subgroup analyses stratified to clinicopathologic and PET/CT variables were performed to explore heterogeneity. RESULTS: Twelve studies including 660 patients were included. Prognoses were worse in patients with high MTV and TLG, with pooled HRs of 5.89 (95% CI, 3.85-9.01; p < 0.00001) and 5.82 (95% CI, 3.62-9.35; p < 0.00001), respectively, for EFS and 6.62 (95% CI, 3.44-12.73; p < 0.00001) and 7.75 (95% CI, 3.48-17.27; p < 0.00001), respectively, for OS. At multiple subgroups analyses, the prognostic values of MTV and TLG for EFS were consistently significant, with pooled HRs of 5.08-7.30 and 4.80-15.83, respectively. CONCLUSION: Volume-based FDG PET/CT parameters were significant prognostic factors in patients with uterine cervical cancer. In spite of clinical and methodologic differences across the studies, patients with high MTV or TLG had a higher risk of adverse events or death.

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.