Plasma IL-23 and IL-5 as surrogate markers of lesion metabolic activity in patients with hepatic alveolar echinococcosis.
ABSTRACT: Fluorodeoxyglucose (FDG) uptake by alveolar echinococcosis (AE) liver lesions is a signal of their metabolic activity and of disease progression. In order to find a surrogate marker for this status, we investigated whether parameters of the peripheral and/or periparasitic immune responses were associated with metabolic activity in a prospective case-control study of 30 AE patients and 22 healthy controls. Levels of 18 cytokines and chemokines, representative of innate and adaptive immune responses, were assessed in plasma and peripheral cells of two groups of patients with (MAAE) and without (MIAE) metabolically active lesions, and in the liver of MAAE patients. Mixed cytokine profile was observed in the peripheral blood of AE patients, with a predominance of Th2, Th17 and Treg responses. Among the detected markers only plasma IL-5 and IL-23, more elevated in MAAE patients, were found discriminant. Discrimination between MAAE and MIAE patients obtained by using IL-23 was improved when IL-5 was used in combination. The combination of elevated levels of IL-5 and IL-23 is significantly associated with FDG uptake at PET scan. It offers a new tool for the follow-up of AE patients which could substitute to FDG-PET whenever non-available to assess disease progression.
Project description:To compare the rate of abnormal brain metabolism by FDG-PET/CT to other paraclinical findings and to describe brain metabolism patterns in autoimmune encephalitis (AE).A retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with AE, per consensus criteria, treated at a single tertiary center over 123 months. Z-score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections with comparison to age group-matched controls. Brain region mean Z-scores with magnitudes ?2.00 were interpreted as significant. Comparisons were made to rates of abnormal initial brain MRI, abnormal initial EEG, and presence of intrathecal inflammation.Sixty-one patients with AE (32 seropositive) underwent brain FDG-PET/CT at median 4 weeks of symptoms (interquartile range [IQR] 9 weeks) and median 4 days from MRI (IQR 8.5 days). FDG-PET/CT was abnormal in 52 (85%) patients, with 42 (69%) demonstrating only hypometabolism. Isolated hypermetabolism was demonstrated in 2 (3%) patients. Both hypermetabolic and hypometabolic brain regions were noted in 8 (13%) patients. Nine (15%) patients had normal FDG-PET/CT studies. CSF inflammation was evident in 34/55 (62%) patients, whereas initial EEG (17/56, 30%) and MRI (23/57, 40%) were abnormal in fewer. Detection of 2 or more of these paraclinical findings was in weak agreement with abnormal brain FDG-PET/CT (? = 0.16, p = 0.02).FDG-PET/CT was more often abnormal than initial EEG, MRI, and CSF studies in neurology inpatients with AE, with brain region hypometabolism the most frequently observed.
Project description:BACKGROUND/AIMS:Benzimidazoles are efficacious for treating non-resectable alveolar echinococcosis (AE), but their long-term parasitocidal (curative) effect is disputed. In this study, we prospectively analyzed the potential parasitocidal effect of benzimidazoles and whether normalization of FDG-PET/CT scans and anti-Emll/3-10-antibody levels could act as reliable "in vivo" parameters of AE-inactivation permitting to abrogate chemotherapy with a low risk for AE-recurrence. METHOD:This prospective study included 34 patients with non-resectable AE subdivided into group A (n = 11), followed-up after diagnosis and begin of chemotherapy at months 6, 12 and 24, and group B (n = 23) with a medium duration of chemotherapy of 10 (range 2-25) years. All patients were assessed by FDG-PET/CT examinations and anti-EmII/3-10 serology. Chemotherapy was abrogated in patients with normalization of FDG-PET/CT and serum anti-EmII/3-10 levels. These patients were closely followed-up for AE recurrence. Endpoint (parasitocidal efficacy) was defined by the absence of AE-recurrence >24 months after stopping treatment. RESULTS:Normalization of FDG-PET/CT scan and anti-EmII/3-10 levels occurred in 11 of 34 patients (32%). After abrogation of chemotherapy in these 11 patients, there was no evidence of AE-recurrence within a median of 70.5 (range 16-82) months. However, the patients' immunocompetence appears pivotal for the described long-term parasitocidal effect of benzimidazoles. CONCLUSIONS:The combination of negative FDG-PET/CT-scans and anti-EmII/3-10 antibody levels seem to be reliable parameters for assessing in vivo AE-larval inactivity after long-term benzimidazole chemotherapy. TRIAL REGISTRATION:clinicaltrials.gov: NCT00658294.
Project description:Purpose: The metabolic patterns of 18F-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG-PET) in autoimmune encephalitis associated with leucine-rich glioma-inactivated 1 antibody (LGI1 AE) are still unclear. We performed a cohort study to investigate the clinical metabolic characteristics and diagnostic value based on 18F-FDG-PET in patients with LGI1 AE. Materials and Methods: A total of 34 patients including 18 patients (53%) in the acute phase and 16 patients (47%) in the chronic phase who were diagnosed with LGI1 AE were retrospectively analyzed from October 2014 to June 2018 at the Department of Neurology in Beijing Tiantan Hospital, the Capital Medical University. The clinical data were collected by searching through electronic medical records. Results: The initial 18F-FDG-PET scan indicated a significant abnormal metabolic pattern in 31 LGI1 AE patients (91%), whereas only 20 patients (59%) showed an abnormal MRI signal (P < 0.05). The 18F-FDG-PET metabolic pattern was reversible after treatment; most of the patients showed an almost normal uptake of 18F-FDG-PET after discharge. Regarding the spatial distribution, the abnormal metabolic pattern in LGI1 AE subjects exhibiting hypermetabolism was specifically located in the basal ganglia (BG) and medial temporal lobe (MTL). BG hypermetabolism was observed in 28 subjects (82%), and 68% of patients showed MTL hypermetabolism. A total of 17 patients (50%) exhibited faciobrachial dystonic seizures (FBDS), and the remaining subjects showed non-FBDS symptoms (50 and 50%). BG-only hypermetabolism was detected in seven subjects in the FBDS subgroup (7/16) but in only one subject in the non-FBDS subgroup (1/15) (44 vs. 7%, P < 0.05). Conclusion: 18F-FDG-PET imaging was more sensitive than MRI in the diagnosis of LGI1 AE. Isolated BG hypermetabolism was more frequently observed in subjects with FBDS, suggesting the potential involvement of the BG.
Project description:Pathogenesis of chronically developing alveolar echinococcosis (AE) is characterized by a continuous, granulomatous, periparasitic infiltration of immune cells surrounding the metacestode of Echinococcus multilocularis (E.multilocularis) in the affected liver. A detailed cytokine and chemokine profile analysis of the periparasitic infiltrate in the liver has, however, not yet been carried out in a comprehensive way all along the whole course of infection in E. multilocularis intermediate hosts. We thus assessed the hepatic gene expression profiles of 18 selected cytokine and chemokine genes using qRT-PCR in the periparasitic immune reaction and the subsequent adjacent, not directly affected, liver tissue of mice from day 2 to day 360 post intra-hepatic injection of metacestode. DNA microarray analysis was also used to get a more complete picture of the transcriptional changes occurring in the liver surrounding the parasitic lesions. Profiles of mRNA expression levels in the hepatic parasitic lesions showed that a mixed Th1/Th2 immune response, characterized by the concomitant presence of IL-12?, IFN-? and IL-4, was established very early in the development of E. multilocularis. Subsequently, the profile extended to a combined tolerogenic profile associating IL-5, IL-10 and TGF-?. IL-17 was permanently expressed in the liver, mostly in the periparasitic infiltrate; this was confirmed by the increased mRNA expression of both IL-17A and IL-17F from a very early stage, with a subsequent decrease of IL-17A after this first initial rise. All measured chemokines were significantly expressed at a given stage of infection; their expression paralleled that of the corresponding Th1, Th2 or Th17 cytokines. In addition to giving a comprehensive insight in the time course of cytokines and chemokines in E. multilocularis lesion, this study contributes to identify new targets for possible immune therapy to minimize E. multilocularis-related pathology and to complement the only parasitostatic effect of benzimidazoles in AE.
Project description:This study sought to relate imaging findings on positron emission tomography (PET) to adverse cardiac events in patients referred for evaluation of known or suspected cardiac sarcoidosis.Although cardiac PET is commonly used to evaluate patients with suspected cardiac sarcoidosis, the relationship between PET findings and clinical outcomes has not been reported.We studied 118 consecutive patients with no history of coronary artery disease, who were referred for PET, using [(18)F]fluorodeoxyglucose (FDG) to assess for inflammation and rubidium-82 to evaluate for perfusion defects (PD), following a high-fat/low-carbohydrate diet to suppress normal myocardial glucose uptake. Blind readings of PET data categorized cardiac findings as normal, positive PD or FDG, positive PD and FDG. Images were also used to identify whether findings of extra-cardiac sarcoidosis were present. Adverse events (AE)-death or sustained ventricular tachycardia (VT)-were ascertained by electronic medical records, defibrillator interrogation, patient questionnaires, and telephone interviews.Among the 118 patients (age 52 ± 11 years; 57% males; mean ejection fraction: 47 ± 16%), 47 (40%) had normal and 71 (60%) had abnormal cardiac PET findings. Over a median follow-up of 1.5 years, there were 31 (26%) adverse events (27 VT and 8 deaths). Cardiac PET findings were predictive of AE, and the presence of both a PD and abnormal FDG (29% of patients) was associated with hazard ratio of 3.9 (p < 0.01) and remained significant after adjusting for left ventricular ejection fraction (LVEF) and clinical criteria. Extra-cardiac FDG uptake (26% of patients) was not associated with AE.The presence of focal PD and FDG uptake on cardiac PET identifies patients at higher risk of death or VT. These findings offer prognostic value beyond Japanese Ministry of Health and Welfare clinical criteria, the presence of extra-cardiac sarcoidosis and LVEF.
Project description:Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. The diagnosis and monitoring of IBD are reliant on endoscopy, which is invasive and does not provide information on specific mediators. Symptom flare in IBD is associated with increased activation of innate immune pathways. Immuno-PET approaches have previously demonstrated the ability to detect colitis; however, a direct comparison of antibodies targeted to innate immune mediators and cells has not been done. We aimed to compare immuno-PET of antibodies to IL-1? and CD11b against standard <sup>18</sup>F-FDG and MRI approaches to detect colonic inflammation. <b>Methods:</b> Colonic concentrations of IL-1? and myeloperoxidase were determined by ELISA, and colonic infiltration by CD11b-positive CD3-negative innate immune cells was determined by flow cytometry and compared between healthy and dextran sodium sulphate-treated colitic mice. PET of <sup>89</sup>Zr-l?-IL-1?, <sup>89</sup>Zr-?-CD11b, and <sup>18</sup>F-FDG was compared by volume-of-interest analysis and with MRI by region-of-interest analysis. Imaging results were confirmed by ex vivo biodistribution analysis. <b>Results:</b> Colonic inflammation was associated with impaired colonic epithelial barrier permeability, increased colonic IL-1? and myeloperoxidase concentrations, and increased CD11b-positive CD3-negative innate immune cell infiltration into the colon. <sup>89</sup>Zr-?-IL-1? and <sup>89</sup>Zr-?-CD11b immuno-PET detected colonic inflammation, as did <sup>18</sup>F-FDG, and all PET tracers were more sensitive than MRI. Although <sup>18</sup>F-FDG volumes of interest correlated with colitis severity and a strong trend was observed with <sup>89</sup>Zr-?-IL-1?, no correlation was observed for <sup>89</sup>Zr-?-CD11b or MRI. <sup>89</sup>Zr-?-IL-1? was distributed mainly to the gastrointestinal tract, whereas <sup>89</sup>Zr-?-CD11b was distributed to more tissue types. <b>Conclusion:</b> Immuno-PET using antibodies directed to innate immune markers detected colonic inflammation, with <sup>89</sup>Zr-?-IL-1? providing a more tissue-specific signal than <sup>89</sup>Zr-?-CD11b. Development of these technologies for human subjects will potentially provide a less invasive approach than endoscopy for diagnosing and monitoring IBD.
Project description:To determine the LncRNA and mRNA expression profile in periparasitic liver tissues and matched distal-liver tissues, we used LncRNA microarray analysis from Arraystar to examine the expression of LncRNAs and mRNAs in periparasitic liver tissues and matched distal-liver tissues. Overall design: Paired liver tissues from six AE patients surgery were distributed into two experimental groups: periparasitic liver tissue group and matched distal-tissue group, then perform LncRNAs chips by Arraystar Human LncRNAs chip (Arraystar)
Project description:Small series have suggested that Fluorodesoxyglucose Positron-Emission-Tomography with Computed-Tomography (FDG-PET/CT) is feasible to screen for cancer in patients with unprovoked venous thromboembolism (VTE), but without validation in a large population. The aim was to assess diagnostic accuracy indices of FDG-PET/CT for occult cancer diagnosis in patients with unprovoked VTE.We analysed patients from the FDG-PET/CT group of a randomized trial that compared a screening strategy based on FDG-PET/CT with a limited screening strategy for occult malignancy detection in patients with unprovoked VTE. FDG-PET/CT was interpreted as positive for cancer, as negative or as equivocal. Patients were considered as having cancer on the basis of screening results, or of any test performed during a two-years follow-up period. We ran two sets of analysis, considering patients with equivocal FDG-PET/CT as positive, then as negative for malignancy.Between March 2009, and August 2012, 172 patients were included. FDG-PET/CT was interpreted as positive for malignancy in 10 patients (5.8%), as equivocal in 23 patients (13.4%) and as negative in 139 patients (80.8%). Malignancy was diagnosed in 7/10 (70.0%), 2/23 (8.7%) and 1/139 (0.7%) patients, respectively. Grouping positive and equivocal results, sensitivity and specificity were 90% (95%CI 60% to 98%) and 85% (95%CI 79% to 90%), respectively. Grouping negative and equivocal results, sensitivity and specificity were 70% (95%CI 40% to 89%) and 98% (95%CI 95% to 99%), respectively.FDG-PET/CT showed good accuracy for occult cancer screening in patients with unprovoked VTE. Remaining challenges include the need to define specific interpretation criteria in this dedicated population.
Project description:We hypothesised that in esophagogastric junction adenocarcinomas combining molecular predictive biomarkers with FDG-PET would optimise response prediction. Changes in FDG uptake in tumours meaured by PET scans after 14 days of chemotherapy define metabolic responders and non-responders. However while <5% of metabolic non-responders will go onto have a response to the full 9-12 week chemotherapy protocol providing a high negative predictive value for FDG-PET, the positive predictive value of metabolic response is more limited. Only 50% of those patients that have a metabolic response determined by FDG PET at day 14 will go on to subsequently have a response to the full 9-12 week chemotherapy protocol . We used global gene expression profiling to identify molecular biomarkers that when combined with FDG-PET would improve predictive accuracy, in particular we aimed to identify molecular biomarkers that could sub-classify FDG PET defined metabolic responders into those that did and did not subsequently go on to have a radiological response and hence clinical benefit from the full chemotherapy protocol. Patients with stage IB-IV esophagogastric junction adenocarcinomas(n=28) received platinum combination chemotherapy .FDG-PET CT scans were performed at baseline and day 14 and expression profiling (Affymetrix ST1.0 Exon Genechips) on baseline tumour biopsies. 14 patients were classified as FDG-PET metabolic responders and gene expression was analysed in these tumour specimens to determine differences between those that did subsequently go on to have a radiological response (n=10) or did not have a radiological response (n=4) to the full 9-12 week chemotherapy protocol. A tissue microarray(n=154 esophagogastric adenocarcinomas who underwent surgery+/-neoadjuvant chemotherapy)was used with immunohistochemistry for qualification of gene expression profiling results. Radiological response was assessed after 3or4 cycles of chemotherapy by RECISTv1.1.
Project description:BACKGROUND AND OBJECTIVES:This current study assessed the value of S-100B measurement to guide fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning for detecting recurrent disease in stage III melanoma patients. METHODS:This study included 100 stage III melanoma patients in follow-up after curative lymph node dissection. Follow-up visits included physical examination and S-100B monitoring. FDG PET/CT scanning was indicated by clinical symptoms and/or elevated S-100B. RESULTS:Of 100 patients, 13 (13%) had elevated S-100B without clinical symptoms, of whom 7 (54%) showed disease evidence upon FDG PET/CT scanning. Twenty-six patients (26%) had clinical symptoms with normal S-100B and FDG PET/CT revealed metastasis in 20 (77%). Three patients had clinical symptoms and elevated S-100B, and FDG PET/CT revealed metastasis in all three (100%). Overall, FDG PET/CT scanning revealed metastasis in 30 of the 42 patients (71.4%). For seven recurrences, elevated S-100B prompted early detection of asymptomatic disease; 10% of all asymptomatic patients in follow-up, 23% of all patients with recurrent disease. CONCLUSION:S-100B cannot exclude recurrent disease during follow-up of stage III melanoma. However, adding S-100B measurement to standard clinical assessment can guide FDG PET/CT scanning for detecting recurrent melanoma.