Fully Automatic Quantitative Measurement of Equilibrium Radionuclide Angiocardiography Using a Convolutional Neural Network.

PURPOSE: The aim of this study was to generate deep learning-based regions of interest (ROIs) from equilibrium radionuclide angiography datasets for left ventricular ejection fraction (LVEF) measurement. PATIENTS AND METHODS: Manually drawn ROIs (mROIs) on end-systolic and end-diastolic images were extracted from reports in a Picture Archiving and Communications System. To reduce observer variability, preprocessed ROIs (pROIs) were delineated using a 41% threshold of the maximal pixel counts of the extracted mROIs and were labeled as ground-truth. Background ROIs were automatically created using an algorithm to identify areas with minimum counts within specified probability areas around the end-systolic ROI. A 2-dimensional U-Net convolutional neural network architecture was trained to generate deep learning-based ROIs (dlROIs) from pROIs. The model's performance was evaluated using Lin's concordance correlation coefficient (CCC). Bland-Altman plots were used to assess bias and 95% limits of agreement. RESULTS: A total of 41,462 scans (19,309 patients) were included. Strong concordance was found between LVEF measurements from dlROIs and pROIs (CCC = 85.6%; 95% confidence interval, 85.4%-85.9%), and between LVEF measurements from dlROIs and mROIs (CCC = 86.1%; 95% confidence interval, 85.8%-86.3%). In the Bland-Altman analysis, the mean differences and 95% limits of agreement of the LVEF measurements were -0.6% and -6.6% to 5.3%, respectively, for dlROIs and pROIs, and -0.4% and -6.3% to 5.4% for dlROIs and mROIs, respectively. In 37,537 scans (91%), the absolute LVEF difference between dlROIs and mROIs was <5%. CONCLUSIONS: Our 2-dimensional U-Net convolutional neural network architecture showed excellent performance in generating LV ROIs from equilibrium radionuclide angiography scans. It may enhance the convenience and reproducibility of LVEF measurements.

Erratum: A Patient With Fahr's Disease Who Presented Prominent Visuospatial Dysfunction.

[This corrects the article on p. 117 in vol. 22, PMID: 37545866.].

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.

Association between tumor 18F-fluorodeoxyglucose metabolism and survival in women with estrogen receptor-positive, HER2-negative breast cancer.

We examined whether 18F-fluorodeoxyglucose metabolism is associated with distant relapse-free survival (DRFS) and overall survival (OS) in women with estrogen receptor (ER)-positive, HER2-negative breast cancer. This was a cohort study examining the risk factors for survival that had occurred at the start of the study. A cohort from Asan Medical Center, Korea, recruited between November 2007 and December 2014, was included. Patients received anthracycline-based neoadjuvant chemotherapy. The maximum standardized uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) was measured. The analysis included 466 women. The median (interquartile range) follow-up period without distant metastasis or death was 6.2 (5.3-7.6) years. Multivariable analysis of hazard ratio (95% confidence interval [CI]) showed that the middle and high tertiles of SUV were prognostic for DRFS (2.93, 95% CI 1.62-5.30; P < 0.001) and OS (4.87, 95% CI 1.94-12.26; P < 0.001). The 8-year DRFS rates were 90.7% (95% CI 85.5-96.1%) for those in the low tertile of maximum SUV vs. 73.7% (95% CI 68.0-79.8%) for those in the middle and high tertiles of maximum SUV. 18F-fluorodeoxyglucose PET/CT may assess the risk of distant metastasis and death in ER-positive, HER2-negative patients.

PET Imaging of System xC - in Immune Cells for Assessment of Disease Activity in Mice and Patients with Inflammatory Bowel Disease.

We aimed to explore whether the imaging of antiporter system xC - of immune cells with (4S)-4-(3-18F-fluoropropyl)-l-glutamate (18F-FSPG) PET can assess inflammatory bowel disease (IBD) activity in murine models and patients (NCT03546868). Methods: 18F-FSPG PET imaging was performed to assess IBD activity in mice with dextran sulfate sodium-induced and adoptive T-cell transfer-induced IBD and a cohort of 20 patients at a tertiary care center in South Korea. Immunohistochemical analysis of system xC - and cell surface markers was also studied. Results: Mice with experimental IBD showed increased intestinal 18F-FSPG uptake and xCT expression in cells positive (+) for CD11c, F4/80, and CD3 in the lamina propria, increases positively associated with clinical and pathologic disease activity. 18F-FSPG PET studies in patients, most of whom were clinically in remission or had mildly active IBD, showed that PET imaging was sufficiently accurate in diagnosing endoscopically active IBD and remission in patients and bowel segments. 18F-FSPG PET correctly identified all 9 patients with superficial or deep ulcers. Quantitative intestinal 18F-FSPG uptake was strongly associated with endoscopic indices of IBD activity. The number of CD68+xCT+ and CD3+xCT+ cells in 22 bowel segments from patients with ulcerative colitis and the number of CD68+xCT+ cells in 7 bowel segments from patients with Crohn disease showed a significant positive association with endoscopic indices of IBD activity. Conclusion: The assessment of system xC - in immune cells may provide diagnostic information on the immune responses responsible for chronic active inflammation in IBD. 18F-FSPG PET imaging of system xC - activity may noninvasively assess the IBD activity.

Assessment of naive indolent lymphoma using whole-body diffusion-weighted imaging and T2-weighted MRI: results of a prospective study in 30 patients.

BACKGROUND: We prospectively evaluated the diagnostic utility of whole-body diffusion-weighted imaging with background body signal suppression and T2-weighted short-tau inversion recovery MRI (WB-DWIBS/STIR) for the pretherapeutic staging of indolent lymphoma in 30 patients. METHODS: This prospective study included 30 treatment-naive patients with indolent lymphomas who underwent WB-DWIBS/STIR and conventional imaging workup plus biopsy. The pretherapeutic staging agreement, sensitivity, and specificity of WB-DWIBS/STIR were investigated with reference to the multimodality and multidisciplinary consensus review for nodal and extranodal lesions excluding bone marrow. RESULTS: In the pretherapeutic staging, WB-DWIBS/STIR showed very good agreement (κ = 0.96; confidence interval [CI], 0.88-1.00), high sensitivity (93.4-95.1%), and high specificity (99.0-99.4%) for the whole-body regions. These results were similar to those of 18F-FDG-PET/CT, except for the sensitivity for extranodal lesions. For extranodal lesions, WB-DWIBS/STIR showed higher sensitivity compared to 18F-FDG-PET/CT for the whole-body regions (94.9-96.8% vs. 79.6-86.3%, P = 0.058). CONCLUSION: WB-DWIBS/STIR is an effective modality for the pretherapeutic staging of indolent lymphoma, and it has benefits when evaluating extranodal lesions, compared with 18F-FDG-PET/CT.

Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-glutamate (18F-FSPG) for PET/CT Imaging in Patients with Newly Diagnosed and Recurrent Prostate Cancer.

PURPOSE: (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a radiopharmaceutical for PET imaging of system xC - activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical. EXPERIMENTAL DESIGN: Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of 18F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples. RESULTS: 18F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUVmax) for cancer was significantly higher than both normal (P < 0.005) and benign pathology (P = 0.011), while there was no significant difference between normal and benign pathology (P = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. 18F-FSPG accumulation showed moderate correlation with CD44 expression. CONCLUSIONS: 18F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.

Comparison of diagnostic sensitivity of [18F]fluoroestradiol and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for breast cancer recurrence in patients with a history of estrogen receptor-positive primary breast cancer.

BACKGROUND: To compare the diagnostic sensitivity of [18F]fluoroestradiol ([18F]FES) and [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) for breast cancer recurrence in patients with estrogen receptor (ER)-positive primary breast cancer. METHODS: Our database of consecutive patients enrolled in a previous prospective cohort study to assess [18F]FES PET/CT was reviewed to identify eligible patients who had ER-positive primary breast cancer with suspected first recurrence at presentation and who underwent [18F]FDG PET/CT. The sensitivity of qualitative [18F]FES and [18F]FDG PET/CT interpretations was assessed, comparing them with histological diagnoses. RESULTS: Of the 46 enrolled patients, 45 were confirmed as having recurrent breast cancer, while one was diagnosed with chronic granulomatous inflammation. Forty (89%) patients were ER-positive, four (9%) were ER-negative, and one (2%) patient did not undergo an ER assay. The sensitivity of [18F]FES PET/CT was 71.1% (32/45, 95% CI, 55.7-83.6), while that of [18F]FDG PET/CT was 80.0% (36/45, 95% CI, 65.4-90.4) with a threshold of positive interpretation, and 93.3% (42/45, 95% CI, 81.7-98.6) when a threshold of equivocal was used. There was no significant difference in sensitivity between [18F]FES and [18F]FDG PET/CT (P = 0.48) with a threshold of positive [18F]FDG uptake, but the sensitivity of [18F]FDG was significantly higher than [18F]FES (P = 0.013) with a threshold of equivocal [18F]FDG uptake. One patient with a benign lesion showed negative [18F]FES but positive [18F]FDG uptake. CONCLUSIONS: The restaging of patients who had ER-positive primary breast cancer and present with recurrent disease may include [18F]FES PET/CT as an initial test when standard imaging studies are equivocal or suspicious.

Clinicopathological characteristics of primary central nervous system lymphoma with low 18F-fludeoxyglucose uptake on brain positron emission tomography.

Primary central nervous system lymphoma (PCNSL) typically shows a strong uptake of F-fludeoxyglucose (FDG) imaged by positron emission tomography (PET). Uncommonly, PCNSL demonstrates a low uptake on FDG PET. We investigated the clinicopathological characteristics of the unusual cases of PCNSL with low FDG uptake.We retrospectively enrolled 104 consecutive patients with newly diagnosed PCNSL who underwent baseline brain FDG PET. The degree of FDG uptake of PCNSL was visually scored by 4 grades (0, ≤contralateral white matter; 1, >contralateral white matter and contralateral gray matter). Grades 0-2 were considered as PCNSL with low uptake. We investigated association of low uptake of PCNSL with the following clinicopathological factors: age, sex, steroid treatment, lactate dehydrogenase level, cerebrospinal fluid protein level, condition of PET scanning, immunohistochemical markers (cluster of differentiation 10 [CD10], B-cell lymphoma 6 [BCL-6], B-cell lymphoma 2 [BCL-2], multiple myeloma oncogene 1 [MUM1], Epstein-Barr virus [EBV] protein, and Ki67), location of lesions, tumor size, multiplicity of lesions, involvement of deep brain structures, and cystic or necrotic appearance of lesions.Of the 104 patients with PCNSL, 14 patients (13.5%) showed PCNSL with low FDG uptake on PET. Among various clinicopathological factors, MUM1 negativity was the only factor associated with low FDG uptake PCNSL by univariate (P = .002) and multivariate analysis (P = .007).This study suggests that the different clinicopathological characteristics between patients with high uptake and low uptake of PCNSL on FDG PET is closely associated with lack of MUM1, a protein known to be a crucial regulator of B-cell development and tumorigenesis.

Prognostic Factors of Quantitative Lymphoscintigraphic Findings in Patients with Breast Cancer-Related Lymphedema.

Background: To evaluate the usefulness of quantitative findings of pretherapy lymphoscintigraphy in predicting the effects of complex decongestive therapy (CDT) in patients with upper extremity lymphedema after breast cancer treatment. Methods and Results: We retrospectively analyzed patients with unilateral breast cancer-related lymphedema (BCRL) who underwent pretherapy lymphoscintigraphy and completed 2 weeks of CDT. A total of 18 patients with unilateral BCRL clinical stage II underwent 30-minute sessions of CDT five times per week for 2 weeks. The quantitative asymmetry index (QAI) of the upper extremity, axillary lymph node (LN) uptake, and axillary plus supraclavicular LN uptake from lymphoscintigraphy were calculated. The volume of lymphedema was calculated by percentage excess volume (PEV) at initial and posttreatment. The CDT response was assessed using percentage reduction in excess volume (PREV). Correlation analyses were conducted using Kendall tau rank correlation. There was positive correlation between upper extremity QAI at 2 hours and initial PEV. Negative correlations were found between axillary LN QAI at 1, 2 hours, and initial PEV, and between axillary plus supraclavicular LN QAI at 1, 2 hours, and initial PEV. The PREV showed a positive correlation with axillary LN QAI at 2 hours after injection (tau-b = 0.354, p = 0.041). Conclusion: Quantitative findings of pretherapy lymphoscintigraphy have potential value for use in predicting the response to CDT in patients with upper extremity lymphedema after breast cancer treatment. Using QAIs from lymphoscintigraphy, we could estimate the excess volume of lymphedema.

Regorafenib-Induced Hypothyroidism as a Predictive Marker for Improved Survival in Metastatic or Unresectable Colorectal Cancer Refractory to Standard Therapies: A Prospective Single-Center Study.

BACKGROUND: Tyrosine kinase inhibitor-induced hypothyroidism is associated with favorable survival in patients with various cancers. OBJECTIVE: We aimed to investigate the incidence of regorafenib-induced hypothyroidism and assess its prognostic value in patients with metastatic or unresectable colorectal cancer (CRC) receiving regorafenib. PATIENTS AND METHODS: This study included 68 patients treated at Asan Medical Center (Seoul, Republic of Korea) between 2014 and 2016 with metastatic or unresectable CRC refractory to standard therapies. Regorafenib (160 mg/day on days 1-21 followed by a 7-day break) was administered. RESULTS: The median patient age was 58 (range 26-72) years; 61.8% of patients were male. Among the 68 patients, 50 (73.5%) showed hypothyroidism; 39 (57.4%) had subclinical and 11 (16.2%) had symptomatic hypothyroidism. Overall, the objective response rate (ORR) and disease control rate (DCR) were 7.4% and 70.6%, respectively; both were significantly higher in patients with symptomatic or subclinical hypothyroidism than in euthyroid patients (ORR 27.3% vs. 5.1% vs. 0.0%, P = 0.001; DCR 100% vs. 76.9% vs. 38.9%, P = 0.001). Median progression-free survival (PFS) and overall survival (OS) were longer in patients with symptomatic hypothyroidism than in those with subclinical hypothyroidism (median PFS 9.1 vs. 3.8 months, P = 0.018; median OS: 19.2 vs. 9.4 months, P = 0.012) or with euthyroid status (median PFS 9.1 vs. 1.8 months, P < 0.001; median OS 19.2 vs. 4.7 months, P = 0.001). Symptomatic hypothyroidism was a significant protective factor for PFS (hazard ratio (HR) = 0.37, P = 0.006) and OS (HR = 0.35, P = 0.007); no other adverse events were associated with survival. CONCLUSIONS: Regorafenib-induced hypothyroidism frequently occurs in patients with metastatic CRC receiving regorafenib and is associated with improved survival. Thyroid function status should be actively monitored in CRC patients receiving regorafenib.

Value of the Filtration Fraction Assessed by Dynamic 99mTc-Diethylenetriaminepentaacetic Acid Renal Scintigraphy After Angiotensin-Converting Enzyme Inhibition for the Diagnosis of Renovascular Hypertension.

PURPOSE: This study aimed to determine the diagnostic value of the relative filtration fraction (RFF) assessed by dynamic 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) renal scintigraphy after angiotensin-converting enzyme (ACE) inhibition for renovascular hypertension (RVHT) diagnosis. METHODS: 99mTc-DTPA captopril renal scintigraphy performed in adolescents or adults (≥ 10 years) with suspected RVHT was retrospectively reviewed. The RFF of the affected kidney was qualitatively assessed as the relative glomerular filtration rate during the 2 to 3-min period compared with the relative perfusion during the first 60 s (qualitative RFF) and scored from 1 (definitely same) to 5 (definitely decreased). The quantitative RFF of the affected kidney was obtained by dividing the percentage of glomerular filtration rate by the percentage of renal perfusion. RESULTS: Overall, 173 patients (high probability, n = 15; and low probability, n = 158) were included based on conventional captopril renal scintigraphic criteria. An abnormal qualitative RFF was observed in 12 patients with high probability, and the diagnostic sensitivity was 80.0% (95% CI, 51.9-95.7). The RFF was normal in 152 patients with low probability, and the diagnostic specificity was 96.2% (95% CI, 91.9-98.6). The RFF was lower in patients with high probability than in those with low probability (0.79 ± 0.15 vs. 1.02 ± 0.11, P < 0.0001). CONCLUSIONS: The RFF assessed by dynamic 99mTc-DTPA renal scintigraphy after ACE inhibition can detect patients with high probability for RVHT. The RFF after ACE inhibition might be a useful diagnostic criterion especially when baseline scintigraphy is not available for evaluating ACE inhibition-induced changes.

Radiation dosimetry of [18F]GP1 for imaging activated glycoprotein IIb/IIIa receptors with positron emission tomography in patients with acute thromboembolism.

PURPOSE: 4-(3S)-3-[5-(2-[18F]-fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]-piperidin-3-yl}carbonyl)amino]propanoic acid ([18F]GP1) is a radiotracer developed for targeted imaging of activated platelet glycoprotein IIb/IIIa receptors with positron emission tomography/computed tomography (PET/CT) in acute thromboembolism. We evaluated here radiation dosimetry of [18F]GP1 in humans. PROCEDURES: We studied 30 subjects (10 with deep vein thrombosis, 10 with pulmonary embolism, and 10 with arterial thromboembolism) who had signs or symptoms of acute thromboembolism, and were confirmed to have thromboembolic foci by imaging studies. Dynamic whole-body PET/CT images were acquired for up to 140 min after injection of 250 MBq of [18F]GP1. Radiation absorbed dose and effective dose were calculated using the OLINDA/EXM software. RESULTS: [18F]GP1 PET images showed high initial uptake of the tracer in the heart, spleen, kidney, and liver. [18F]GP1 activity was cleared by hepatobiliary and urinary excretion. The organ receiving the highest radiation absorbed dose (mGy/MBq) was the urinary bladder (0.0884 ±â€¯0.0458), followed by upper large intestine (0.0498 ±â€¯0.0189), small intestine (0.0454 ±â€¯0.0166), and kidneys (0.0350 ±â€¯0.0231). The effective dose (mSv/MBq) was 0.0212 ±â€¯0.0027 (ICRP 103). ED was not significantly different between the three disease groups (p = 0.94). A 45-minute voiding reduced the urinary bladder wall radiation dose to 0.0495 ±â€¯0.0140 mGy/MBq, and effective dose (ICRP 103) to 0.0186 ±â€¯0.0030. CONCLUSIONS: [18F]GP1 has favorable radiation dosimetry profile for clinical PET/CT imaging. The ED is comparable to commonly used 18F PET tracers.

3'-Deoxy-3'-18F-Fluorothymidine and 18F-Fluorodeoxyglucose positron emission tomography for the early prediction of response to Regorafenib in patients with metastatic colorectal cancer refractory to all standard therapies.

PURPOSE: The purpose of this study was to evaluate the value of 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early prediction of standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving Regorafenib. METHODS: Sixty-eight patients with mCRC refractory to standard cytotoxic chemotherapy were enrolled and received Regorafenib (160 mg/day on days 1-21, following a 7-day break). Standard anatomical response was evaluated every 8 weeks. Both scans were performed before and on day 21 of Regorafenib. RESULTS: Of the 61 patients included in per-protocol analysis, complete response was not observed, but partial response was observed in 8.2% (n = 5), stable disease in 67.2% (n = 41), and progressive disease in 24.6% (n = 15). The objective response rate was 8.2% and disease control rate 75.4%. Five responders (8.2%) and 13 non-responders (21.3%) met the CT and 18F-FLT PET/CT criteria (maximum standardized uptake value decrease ≥ 10.6% for responders). Forty-three (70.5%) exhibited discordant responses on CT and 18F-FLT PET/CT (McNemar test, P < 0.001). At a median follow-up of 8.9 months, median progression-free survival (PFS) and median overall survival (OS) were 3.6 months (95% confidence interval [CI], 3.34-3.80 months) and 8.5 months (95% CI, 6.95-10.10 months), respectively. Comparison of PFS and OS according to 18F-FLT PET/CT response revealed slightly longer PFS (P = 0.015) in responders, but the correlation with OS was not significant. The PET Response Criteria in Solid Tumours (PERCIST) of 18F-FDG PET/CT revealed differences in PFS and OS between partial metabolic response (PMR) and non-PMR (P = 0.048 and P = 0.014, respectively), and between progressive metabolic disease (PMD) and non-PMD (P = 0.189 and P = 0.007, respectively). CONCLUSIONS: Survival outcome was significantly associated with PERCIST using 18F-FDG PET/CT but the change of 18F-FLT uptake was only slightly associated with PFS. 18F-FDG PET/CT can be used as imaging biomarker to predict clinical outcomes early in patients with mCRC receiving Regorafenib.

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.

A phase 1, first-in-human study of 18F-GP1 positron emission tomography for imaging acute arterial thrombosis.

BACKGROUND: 18F-GP1 is a novel positron emission tomography (PET) tracer that targets glycoprotein IIb/IIIa receptors on activated platelets. The study objective was to explore the feasibility of directly imaging acute arterial thrombosis (AAT) with 18F-GP1 PET/computed tomography (PET/CT) and to quantitatively assess 18F-GP1 uptake. Safety, biodistribution, pharmacokinetics and metabolism were also evaluated. METHODS: Adult patients who had signs or symptoms of AAT or had recently undergone arterial intervention or surgery within 14 days prior to 18F-GP1 PET/CT were eligible for inclusion. The AAT focus was demonstrated by conventional imaging within the 5 days prior to 18F-GP1 administration. Whole-body dynamic 18F-GP1 PET/CT images were acquired for up to 140 min after injection of 250 MBq of 18F-GP1. Venous plasma samples were analysed to determine 18F-GP1 clearance and metabolite formation. RESULTS: Among the ten eligible patients assessed, underlying diseases were abdominal aortic aneurysm with endovascular repair (n = 6), bypass surgery and stent placement (n = 1), endarterectomy (n = 1), arterial dissection (n = 1) and acute cerebral infarction (n = 1). 18F-GP1 administration and PET/CT procedures were well tolerated, with no drug-related adverse events. All patients showed high initial 18F-GP1 uptake in the spleen, kidney and blood pool, followed by rapid clearance. Unmetabolised plasma 18F-GP1 levels peaked at 4 min post-injection and decreased over time until 120 min. The overall image quality was sufficient for diagnosis in all patients and AAT foci were detected in all participants. The 18F-GP1 uptake in AAT foci remained constant from 7 min after injection and began to separate from the blood pool after 20 min. The median standardised uptake value of AAT was 5.0 (range 2.4-7.9) at 120 min post-injection. The median ratio of standardised uptake value of AAT foci to the mean blood pool activity was 3.4 (range 2.0-6.3) at 120 min. CONCLUSIONS: 18F-GP1 is a safe and promising novel PET tracer for imaging AAT with a favourable biodistribution and pharmacokinetic profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02864810 , Registered August 3, 2016.

Physical exercise enhances adult cortical plasticity in a neonatal rat model of hypoxic-ischemic injury: Evidence from BOLD-fMRI and electrophysiological recordings.

Neuroplasticity is considered essential for recovery from brain injury in developing brains. Recent studies indicate that it is especially effective during early postnatal development and during the critical period. The current study used functional magnetic resonance imaging (fMRI) and local field potential (LFP) electrophysiological recordings in rats that experienced neonatal hypoxic-ischemic (HI) injury during the critical period to demonstrate that physical exercise (PE) can improve cortical plasticity even when performed during adulthood, after the critical period. We investigated to what extent the blood oxygen level-dependent (BOLD)-fMRI responses were increased in the contralesional spared cortex, and how these increases were related to the LFP electrophysiological measurements and the functional outcome. The balance of excitation and inhibition was assessed by measuring excitatory and inhibitory postsynaptic currents in stellate cells in the primary somatosensory (S1) cortex, which was compared with the BOLD-fMRI responses in the contralesional S1 cortex. The ratio of inhibitory postsynaptic current (IPSC) to excitatory postsynaptic current (EPSC) at the thalamocortical (TC) input to the spared S1 cortex was significantly increased by PE, which is consistent with the increased BOLD-fMRI responses and improved functional outcome. Our data clearly demonstrate in an experimental rat model of HI injury during the critical period that PE in adulthood enhances neuroplasticity and suggest that enhanced feed-forward inhibition at the TC input to the S1 cortex might underlie the PE-induced amelioration of the somatosensory deficits caused by the HI injury. In summary, the results of the current study indicate that PE, even if performed beyond the critical period or during adulthood, can be an effective therapy to treat neonatal brain injuries, providing a potential mechanism for the development of a potent rehabilitation strategy to alleviate HI-induced neurological impairments.

Glycoprotein IIb/IIIa receptor imaging with 18F-GP1 positron emission tomography for acute venous thromboembolism: an open-label, non-randomized, first-in-human phase 1 study.

18F-GP1 is a derivative of elarofiban with a high affinity to activated platelet glycoprotein IIb/IIIa (GPIIb/IIIa) and favorable in vivo characteristics for thrombus imaging in preclinical models. We aimed to explore the detection rate of thromboembolic foci with 18F-GP1 positron emission tomography/computed tomography (PET/CT) in patients with acute venous thromboembolism (VTE), and to evaluate the safety, biodistribution, pharmacokinetics, and metabolism of 18F-GP1. Methods: We studied patients who had signs or symptoms of acute deep vein thrombosis (DVT) of the leg or acute pulmonary embolism (PE) within 14 days prior to 18F-GP1 PET/CT, and had thromboembolic foci confirmed by conventional imaging (n = 10 for DVT and n = 10 for PE). Dynamic whole-body PET/CT images were acquired for up to 140 minutes after injection of 250 MBq of 18F-GP1. Results:18F-GP1 PET/CT was well tolerated without any drug-related adverse events, and showed high initial uptake in spleen, kidney, and blood pool, followed by rapid clearance. The overall image quality was excellent and allowed interpretation in all patients. 18F-GP1 PET/CT identified thromboembolic foci in all 20 patients with either DVT or PE. Vessel-level analysis revealed that 18F-GP1 PET/CT detected 89% (68/76) of vessels with DVT, and 60% (146/245) for PE. Importantly, 18F-GP1 PET/CT showed increased uptake in 32 vessels that were not detected by conventional imaging, of which 25 were located in distal veins of the lower extremity in 12 patients. A positive correlation was found between 18F-GP1 uptake and P-selectin-positive circulating platelets (r = 0.656, P = 0.002). Conclusion:18F-GP1 is a promising PET tracer for imaging acute VTE in patients. 18F-GP1 PET/CT may identify thrombi in distal veins of the leg, where conventional imaging has limitations.