PET/MRI in Cervical Cancer: Associations Between Imaging Biomarkers and Tumor Stage, Disease Progression, and Overall Survival.

BACKGROUND: Positron emission tomography (PET)/MRI biomarkers have been shown to have prognostic significance in patients with cervical cancer. Their associations with progression-free survival (PFS) and overall survival (OS) merit further investigation. PURPOSE: To evaluate the association between PET/MRI biomarkers and tumor stage, PFS, and OS in patients with cervical cancer. STUDY TYPE: Prospective cohort study. POPULATION: In all, 54 patients with newly diagnosed cervical cancer and measurable tumors (>1 cm) were included in the image analysis. FIELD STRENGTH/SEQUENCE: 3.0T integrated PET/MRI including diffusion-weighted echo-planar imaging (b = 50 and 1000 s/mm2 ) and [18F]fluorodeoxyglucose PET. ASSESSMENT: Two radiologists measured the minimum and mean apparent diffusion coefficient (ADCmin and ADCmean ), maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumors. STATISTICAL TESTS: A Mann-Whitney U-test was used to evaluate the association between the imaging biomarkers and tumor stage. A Cox proportional hazards model was used to assess the relationships between the imaging biomarkers and survival. RESULTS: In advanced tumors (T ≥ 1b2, M1, stage ≥ IB3), ADCmin was significantly lower and MTV, TLG, MTV/ADCmin , and TLG/ADCmin were significantly higher (P values between <0.001 and 0.036). In N1 tumors, ADCmin was significantly lower and MTV and MTV/ADCmin were significantly higher (P values between 0.005 and 0.016). In survival analysis, SUVmax was an independent predictor of PFS (hazard ratio [HR] = 4.57, P < 0.05), and ADCmin was an independent predictor of OS (HR = 0.02, P < 0.05). In subgroup analysis of patients with different stages, MTV/ADCmin was a predictor of PFS in stage I disease (P = 0.003), ADCmin (P = 0.038), and MTV (P = 0.020) in stage II, SUVmax (P = 0.006), and TLG (P = 0.006) in stage IV; and ADCmin was a predictor of OS in stage III disease (P = 0.008). DATA CONCLUSION: PET/MRI biomarkers of cervical cancer are associated with tumor stage and survival. SUVmax and ADCmin are independent predictors of PFS and OS, respectively. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: 3.

Synthesis and analysis of 4-(3-fluoropropyl)-glutamic acid stereoisomers to determine the stereochemical purity of (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) for clinical use.

(4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is a positron emission tomography (PET) imaging agent for measuring the system xC- transporter activity. It has been used for the detection of various cancers and metastasis in clinical trials. [18F]FSPG is also a promising diagnostic tool for evaluation of multiple sclerosis, drug resistance in chemotherapy, inflammatory brain diseases, and infectious lesions. Due to the very short half-life (110 min) of 18F nuclide, [18F]FSPG needs to be produced on a daily basis; therefore, fast and efficient synthesis and analytical methods for quality control must be established to assure the quality and safety of [18F]FSPG for clinical use. To manufacture cGMP-compliant [18F]FSPG, all four nonradioactive stereoisomers of FSPG were prepared as reference standards for analysis. (2S,4S)-1 and (2R,4R)-1 were synthesized starting from protected L- and D-glutamate derivatives in three steps, whereas (2S,4R)-1 and (2R,4S)-1 were prepared in three steps from protected (S)- and (R)-pyroglutamates. A chiral HPLC method for simultaneous determination of four FSPG stereoisomers was developed by using a 3-cm Chirex 3126 column and a MeCN/CuSO4(aq) mobile phase. In this method, (2R,4S)-1, (2S,4S)-1, (2R,4R)-1, and (2S,4R)-1 were eluted in sequence with sufficient resolution in less than 25 min without derivatization. Scale-up synthesis of intermediates for the production of [18F]FSPG in high optical purity was achieved via stereo-selective synthesis or resolution by recrystallization. The enantiomeric excess of intermediates was determined by HPLC using a Chiralcel OD column and monitored at 220 nm. The nonradioactive precursor with >98% ee can be readily distributed to other facilities for the production of [18F]FSPG. Based on the above accomplishments, cGMP-compliant [18F]FSPG met the acceptance criteria in specifications and was successfully manufactured for human use. It has been routinely prepared and used in several pancreatic ductal adenocarcinoma metastasis-related clinical trials.

Prospective comparison of (4S)-4-(3-18F-fluoropropyl)-L-glutamate versus 18F-fluorodeoxyglucose PET/CT for detecting metastases from pancreatic ductal adenocarcinoma: a proof-of-concept study.

PURPOSE: (4S)-4-(3-18F-Fluoropropyl)-L-glutamate (FSPG) positron emission tomography (PET) reflects system xC- transporter (xCT) expression. FSPG PET has been used to detect brain, lung, breast and liver cancer with only modest success. There is no report on the use of FSPG PET in pancreatic ductal adenocarcinoma (PDAC), presumably because of normal xCT expression in the pancreas. Nonetheless, the tissue-specific expression of xCT in the pancreas suggests that FSPG PET may be ideal for identifying metastasized PDAC. METHODS: The performance of FSPG in detecting PDAC metastases was compared with that of 18F-fluorodeoxyglucose (FDG) in small-animal PET studies in seven PDAC tumour-bearing mice and in prospective PET/computed tomography (CT) studies in 23 patients with tissue-confirmed PDAC of stage III or stage IV. All PET/CT results were correlated with the results of histopathology or contrast-enhanced CT (ceCT) performed 3 and 6 months later. RESULTS: In the rodent model, FSPG PET consistently found more PDAC metastases earlier than FDG PET. FSPG PET showed a trend for a higher sensitivity, specificity and diagnostic accuracy than FDG PET in detecting PDAC metastases in a patient-based analysis: 95.0%, 100.0% and 95.7%, and 90.0%, 66.7% and 90.0%, respectively. In a lesion-based analysis, FSPG PET identified significantly more PDAC metastases, especially in the liver, than FDG PET (109 vs. 95; P = 0.0001, 95% CI 4.9-14.6). The tumour-to-background ratios for FSPG and FDG uptake on positive scans were similar (FSPG 4.2 ± 4.3, FDG 3.6 ± 3.0; P = 0.44, 95% CI -1.11 to 0.48), despite a lower tumour maximum standardized uptake value in FSPG-avid lesions (FSPG 4.2 + 2.3, FDG 7.7 + 5.7; P = 0.002, 95% CI 0.70-4.10). Because of the lower physiological activity of FSPG in the liver, FSPG PET images of the liver are more easy to interpret than FDG PET images, and therefore the use of FSPG improves the detection of liver metastasis. CONCLUSION: FSPG PET is superior to FDG PET in detecting metastasized PDAC, especially in the liver.

Amyloid-PET burden and regional distribution in cerebral amyloid angiopathy: a systematic review and meta-analysis of biomarker performance.

INTRODUCTION: We performed a meta-analysis to synthesise current evidence on amyloid-positron emission tomography (PET) burden and presumed preferential occipital distribution in sporadic cerebral amyloid angiopathy (CAA). METHODS: In a PubMed systematic search, we identified case-control studies with extractable data on global and occipital-to-global amyloid-PET uptake in symptomatic patients with CAA (per Boston criteria) versus control groups (healthy participants or patients with non-CAA deep intracerebral haemorrhage) and patients with Alzheimer's disease. To circumvent PET studies' methodological variation, we generated and used 'fold change', that is, ratio of mean amyloid uptake (global and occipital-to-global) of CAA relative to comparison groups. Amyloid-PET uptake biomarker performance was then quantified by random-effects meta-analysis on the ratios of the means. A ratio >1 indicates that amyloid-PET uptake (global or occipital/global) is higher in CAA than comparison groups, and a ratio <1 indicates the reverse. RESULTS: Seven studies, including 106 patients with CAA (>90% with probable CAA) and 138 controls (96 healthy elderly, 42 deep intracerebral haemorrhage controls) and 72 patients with Alzheimer's disease, were included. Global amyloid-PET ratio between patients with CAA and controls was above 1, with an average effect size of 1.18 (95% CI 1.08 to 1.28; p<0.0001). Occipital-to-global amyloid-PET uptake ratio did not differ between patients with CAA versus patients with deep intracerebral haemorrhage or healthy controls. By contrast, occipital-to-global amyloid-PET uptake ratio was above 1 in patients with CAA versus those with Alzheimer's disease, with an average ratio of 1.10 (95% CI 1.03 to 1.19; p=0.009) and high statistical heterogeneity. CONCLUSIONS: Our analysis provides exploratory actionable data on the overall effect sizes and strength of amyloid-PET burden and distribution in patients with CAA, useful for future larger studies.

PET/MRI for evaluating subclinical inflammation of ulcerative colitis.

PURPOSE: To explore the utility of integrated positron emission tomography (PET) / magnetic resonance imaging (MRI) for evaluating subclinical inflammation in patients with ulcerative colitis (UC). MATERIALS AND METHODS: This prospective study was approved by the Institutional Review Board and informed consent was obtained. Between November 2015 and April 2016, 19 consecutive patients with UC in clinical remission were enrolled. These patients underwent 18F-fluorodeoxyglucose PET/MRI (3T) and colonoscopy. Serum high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FC) levels were also obtained. The findings of colonoscopy were graded using the Mayo endoscopic subscore. Quantitative (minimum apparent diffusion coefficient [ADCmin ] and maximum standardized uptake value [SUVmax ]), semiquantitative, and qualitative parameters of PET/MRI were evaluated and correlated with colonoscopic findings. RESULTS: In per-segment analysis, ADCmin was significantly lower and SUVmax and ratio of SUVmax to ADCmin were significantly higher in the colonic segments with active inflammation (Mayo endoscopic subscore ≥2) (P < 0.05). Qualitative MRI score, PET activity grade, and PET/MRI score were also significantly higher in the colonic segments with active inflammation (P < 0.05). Among these parameters, the ratio of SUVmax to ADCmin exhibited the highest area under the receiver operating characteristic curve (AUC) (0.763). In per-patient analysis, the AUC of PET activity grade was 0.778, higher than those of hs-CRP (0.589) and FC (0.722). Using a combined index of FC and PET, an even higher AUC (0.867) was achieved. CONCLUSION: PET/MRI is a potentially useful tool in identifying subclinical inflammation in patients with UC. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:737-745.

Comparison of biventricular ejection fractions using cadmium-zinc-telluride SPECT and planar equilibrium radionuclide angiography.

BACKGROUND: We compared biventricular ejection fractions (EFs) from gated blood-pool single-photon emission computed tomography (SPECT) using a cadmium-zinc-telluride camera (CZT-SPECT) with planar equilibrium radionuclide angiography (ERNA) using a NaI gamma camera (NaI-planar). We also evaluated whether imaging time can be reduced without compromising image quality using the CZT camera. METHODS: Forty-eight patients underwent NaI-planar and CZT-SPECT on the same day. CZT-SPECT datasets were re-projected at an LAO orientation similar to ERNA acquisition, forming CZT-repro planar datasets. The resulting biventricular volumetric measurements and EFs were compared. RESULTS: LVEF calculated from CZT-SPECT and CZT-repro correlated better with NaI-planar (r = 0.93 and 0.99, respectively) than RVEF (r = 0.76 and 0.82, respectively). Excellent intra-class correlation and low bias in intra-observer comparisons were observed for the biventricular EFs derived from three datasets. A wider limit of agreement in CZT-SPECT-derived LVEFs, lower correlation and significant bias for NaI-planar, and CZT-repro-derived RVEFs was found in the inter-observer analyses. Nonetheless, the imaging time can be reduced to 4 minutes without increasing variability in EFs using the CZT camera (P = NS). CONCLUSIONS: LVEFs calculated from CZT-SPECT and CZT-repro correlated well with NaI-planar. CZT camera may reduce imaging time while preserving image quality in the assessment of biventricular EFs.

Search of Unknown Fever Focus Using PET in Critically Ill Children With Complicated Underlying Diseases.

OBJECTIVES: PET/CT with F-fluorodeoxyglucose can be used to image cellular metabolism and has been used for evaluating fever of unknown origin in adults. However, there are limited studies about the role of F-fluorodeoxyglucose PET/CT in evaluation of fever of unknown origin in critically ill children, especially those presenting with complicated underlying diseases under treatment. Here, we report our preliminary experience using F-fluorodeoxyglucose PET/CT in this specific group of patients. DESIGN: Retrospective observational study. SETTING: PICUs of a university hospital. PATIENTS: Nineteen critically ill children (mean age, 5.7 yr old) with complicated underlying diseases requiring intensive care support underwent F-fluorodeoxyglucose PET/CT to evaluate fever of unknown origin. The median hospitalized stay was 34 days (range, 15-235 d) and fever of at least 7 days (mean, 21.6 d; range, 7-52 d). The PET scan was advocated after all routine microbiology, and conventional imaging showed negative or inconclusive results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The F-fluorodeoxyglucose PET/CT findings (blinded to the final clinical diagnosis) were compared with final histopathology, culture, serology results, or follow-up imaging. A final diagnosis was made in 16 patients (84.2%). F-fluorodeoxyglucose PET/CT accurately localized the source of fever in 14 patients, confers to a sensitivity of 87.5% (14 of 16; 95% CI, 0.604-0.978). A false-positive scan in a patient led to subsequent unnecessary investigations. Two false-negative F-fluorodeoxyglucose PET/CT images were later attributed to relapse of underlying disease in the bone marrow and renal abscesses, respectively. In the other two patients where F-fluorodeoxyglucose PET/CT also showed negative findings, fever subsided shortly thereafter without treatment. CONCLUSIONS: Our preliminary experience suggests that F-fluorodeoxyglucose PET/CT may be clinically beneficial in evaluating fever of unknown origin in children with complicated underlying diseases mandating intensive support in ICUs if usual investigative methods are unsuccessful. Further large prospective studies are needed to validate these findings.

Usefulness of PET/CT for the differentiation and characterization of periampullary lesions.

PURPOSE: At present, there is no ideal imaging modality for the diagnosis of periampullary lesions. We prospectively evaluated the preoperative diagnostic usefulness of PET/CT for differentiating malignant from benign periampullary lesions. METHODS: A total of 62 patients aged 27-86 years with periampullary lesions scheduled for surgical resection were consecutively recruited. Dual-phase (18)F-FDG PET/CT was performed in all patients. An additional 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) scan was performed in 21 patients (33.9%). The relationship of visual interpretation, SUV, and lesion to background ratio (LBR) with surgical histopathology diagnosis was evaluated. RESULTS: There were 36 patients with malignancies, 15 with benign neoplasms, and 11 with benign non-neoplasms. Using visual analysis, FDG PET/CT had good sensitivity (86.1%; 31/36), lower specificity (57.7%; 15/26), and fair accuracy (74.2%; 46/62). Regional lymph node metastases were identified in 7 of 11 patients by FDG PET/CT and only in 1 patient by abdominal CT. On the other hand, hepatic metastasis was detected in 1 patient by FDG PET/CT. Dual-phase FDG (P < 0.001) and FLT (P < 0.05) SUV(max) and LBR were significantly higher in malignant than in benign lesions, and in malignant neoplasms than in benign neoplasms. Although average FLT SUV(max) was significantly lower than the average FDG SUV(max) (P < 0.001), the specificity and accuracy of the former were significantly better. CONCLUSION: FDG PET/CT may help identify patients with periampullary malignancy. FDG SUV(max) and LBR appear to aid in the differential diagnosis and add diagnostic confidence. In addition, higher specificity and diagnostic accuracy may be achieved by additional FLT PET/CT.

Serial measurements of serum alkaline phosphatase for early prediction of osteopaenia in preterm infants.

AIM: Osteopaenia commonly occurs in preterm infants; however, its diagnosis is often delayed when based on radiological findings. The aim of this study was to examine whether serial measurements of bone turnover markers are useful for early prediction of osteopaenia in preterm infants. METHODS: Premature infants of ≤ 34 weeks gestation were enrolled. Serum alkaline phosphatase (ALP), bone form ALP (BALP), calcium and inorganic phosphate were concurrently measured biweekly from 3 weeks post-natal age until 40 weeks post-conceptional age. Radiographic examination of the forearm was performed at term age. Osteopaenia was defined as positive radiographic findings according to Koo's criteria. RESULTS: Of the 46 premature infants completing the follow-up study at term age, 18 showed osteopaenia in radiographic examination. Serum ALP was highly correlated with BALP (R(2) = 0.93, P < 0.001). Infants who had osteopaenia showed a higher level of ALP and BALP after 3 weeks post-natal age than those who had no osteopaenia. ALP concentration exceeding 700 IU/L at 3 weeks post-natal age was predictive of osteopaenia at term age (sensitivity 73% and specificity 73%) and so did for the predictive value of BALP concentration exceeding 95 ug/L (sensitivity 73% and specificity 80%). BALP measures provided no greater benefit of diagnostic performance than ALP in early detection of osteopaenia. Furthermore, premature infants with osteopaenia showed similar levels of calcium and inorganic phosphatase concentration compared with those without. CONCLUSION: Serum ALP concentration exceeding 700 IU/L at 3 weeks post-natal age can predict the risk of osteopaenia in preterm infants.

Correlation of F-18 fluorodeoxyglucose-positron emission tomography maximal standardized uptake value and EGFR mutations in advanced lung adenocarcinoma.

OBJECTIVE: Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are involved in the tumorigenesis and regulation of cell metabolism via Akt signaling. F-18 fluorodeoxyglucose-positron emission tomography ([(18)F]FDG PET), a functional imaging modality, can be used to measure tumor cell metabolism. Thus, in this study, we hypothesize that there exist correlations between EGFR mutation status and [(18)F]FDG uptake of advanced lung adenocarcinoma. METHODS: From May 2004 to April 2008, patients with stage IIIB or IV lung adenocarcinoma who underwent [(18)F]FDG PET and EGFR mutation analysis before receiving any treatment were eligible to participate in this study. The association of EGFR mutation status with patient characteristics and the SUV(MAX) from the [(18)F]FDG PET was evaluated. Multivariate logistic regression analysis was used to analyze predictors of EGFR mutations. RESULTS: Seventy-seven lung adenocarcinoma patients were included in this study. EGFR mutations were identified in 49 (64%) of the patients. The [(18)F]FDG uptake was significantly higher in EGFR-mutant (mean SUV(MAX) = 10.5 +/- 4.7) than wild-type (8.0 +/- 3.3) lung adenocarcinoma patients (P = 0.008). The median SUV(MAX) was 9.5, and patients with an SUV(MAX) >or= 9.5 were more likely to harbor EGFR mutations (P = 0.009). In the multivariate analysis, an SUV(MAX) >or= 9.5 remained a statistically significant predictor of EGFR mutations (P = 0.005). CONCLUSIONS: Among Asian patients with advanced lung adenocarcinoma, those with higher SUV(MAX) on the [(18)F]FDG PET are more likely to carry EGFR mutations.