[89Zr]-immuno-PET prediction of response to rituximab treatment in patients with therapy refractory interstitial pneumonitis: a phase 2 trial.

INTRODUCTION: Immune-mediated interstitial pneumonitis may be treated with anti-CD20 therapy after failure of conventional therapies. However, clinical response is variable. It was hypothesized that autoreactive CD20-positive cells may play an important role in this variability. This prospective study aims to elucidate if imaging of CD20-positive cells in the lungs allows prediction of the response to anti-CD20 treatment. METHODS: Twenty-one patients with immune-mediated interstitial lung disease (ILD) with deteriorated pulmonary function received a dose of 1000 mg rituximab on day 1 and day 14 spiked with a tracer dose of radiolabeled [89Zr]-rituximab. PET/CT was performed on days 3 and 6. Standardized uptake values (SUV) were calculated as a measure for pulmonary CD20 expression. Based on pulmonary function tests (PFT), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), prior to and 6 months after treatment, patients were classified as responder (stable disease or improvement) or non-responder. RESULTS: Fifteen patients (71%) were classified as responder. Pulmonary [89Zr]-rituximab PET SUVmean was significantly correlated with the change in FVC and DLCO (K = 0.49 and 0.56, respectively) when using target-to-background ratios, but not when using SUVmean alone. [89Zr]-rituximab SUVmean was significantly higher in responders than in non-responders (0.35 SD 0.09 vs. 0.23 SD 0.06; P = 0.02). CONCLUSION: Rituximab treatment was effective in the majority of patients. As a higher pulmonary uptake of [89Zr]-rituximab correlated with improvement of PFT and treatment outcome, [89Zr]-rituximab PET imaging may serve as a potential predictive biomarker for anti-CD20 therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02251964.

The usefulness of repeated CMR and FDG PET/CT in the diagnosis of patients with initial possible cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis (CS) diagnosis is usually based on advanced imaging techniques and multidisciplinary evaluation. Diagnosis is classified as definite, probable, possible or unlikely. If diagnostic confidence remains uncertain, cardiac imaging can be repeated. The objective is to evaluate the usefulness of repeated cardiac magnetic resonance imaging (CMR) and fluorodeoxyglucose positron emission tomography (FDG PET/CT) for CS diagnosis in patients with an initial "possible" CS diagnosis. METHODS: We performed a retrospective cohort study in 35 patients diagnosed with possible CS by our multidisciplinary team (MDT), who received repeated CMR and FDG PET/CT within 12 months after diagnosis. Imaging modalities were scored on abnormalities suggestive for CS and classified as CMR+/PET+, CMR+/PET-, CMR-/PET+ and CMR-/PET-. Primary endpoint was final MDT diagnosis of CS. RESULTS: After re-evaluation, nine patients (25.7%) were reclassified as probable CS and 16 patients (45.7%) as unlikely CS. Two patients started immunosuppressive treatment after re-evaluation. At baseline, eleven patients (31.4%) showed late gadolinium enhancement (LGE) on CMR (CMR+) and 26 (74.3%) patients showed myocardial FDG-uptake (PET+). At re-evaluation, nine patients (25.7%) showed LGE (CMR+), while 16 patients (45.7%) showed myocardial FDG-uptake (PET+). When considering both imaging modalities together, 82.6% of patients with CMR-/PET+ at baseline were reclassified as possible or unlikely CS, while 36.4% of patients with CMR+ at baseline were reclassified as probable CS. Three patients with initial CMR-/PET+ showed LGE at re-evaluation. CONCLUSION: Repeated CMR and FDG PET/CT may be useful in establishing or rejecting CS diagnosis, when initial diagnosis is uncertain. However, clinical relevance has to be further determined.

Effectiveness and safety of infliximab in cardiac Sarcoidosis.

BACKGROUND: Immunosuppressive therapy in active cardiac sarcoidosis (CS) might prevent potential life-threatening complications. Infliximab (IFX) is a tumor necrosis factor alpha monoclonal antibody proven to be effective in refractory extracardiac sarcoidosis. It is sparsely used in CS, because of its association with worsening heart failure in prior studies. The goal of this study is to assess the effectiveness and safety of IFX in CS. METHODS AND RESULTS: A retrospective, single center cohort study was performed in sarcoidosis patients treated with IFX based on a cardiac indication between January 2016 and March 2019. Patients received IFX intravenously at a dose of 5 mg/kg at week 0, 2, and subsequently every 4 weeks. After every six months, treatment response was evaluated within the multidisciplinary team using FDG-PET/CT, transthoracic echocardiography, biomarkers and device interrogation reports. Responder analysis definitions were based on; dosage of immunosuppressive drugs, improvement in functional class, left ventricular ejection fraction (LVEF) and SUVmax. Twenty-two patients were included (mean age 51.0 SD10.0 years, male 68.2%) with a mean follow-up of 18.9 months (6 to 44 months) of whom 18 (82%) were classified as responders. Median SUVmax on FDG-PET/CT decreased from SUVmax 5.2 [3.7-8.4] to 2.3 [1.4-2.3], p = 0.015. The target-to-background ratio decreased from 3.2 [2.1-5.1] to 1.0 [0.7-2.4], p = 0.002. The median left ventricular (LV) ejection fraction increased from 45.0% [34.0-60.0] to 55.0% [41.0-60.0], p = 0.02. The majority of patients (73%) experienced no side effects and no patients had worsening of heart failure. CONCLUSION: In this pilot study, patients with refractory CS treated with infliximab, on top of standard of care, had a reduction in inflammation on FDG-PET/CT and an improvement in LV function, without serious adverse events.

Incidental colonic focal FDG uptake on PET/CT: can the maximum standardized uptake value (SUVmax) guide us in the timing of colonoscopy?

PURPOSE: In patients undergoing (18)F-FDG PET/CT, incidental colonic focal lesions can be indicative of inflammatory, premalignant or malignant lesions. The maximum standardized uptake value (SUVmax) of these lesions, representing the FDG uptake intensity, might be helpful in differentiating malignant from benign lesions, and thereby be helpful in determining the urgency of colonoscopy. The aim of our study was to assess the incidence and underlying pathology of incidental PET-positive colonic lesions in a large cohort of patients, and to determine the usefulness of the SUVmax in differentiating benign from malignant pathology. METHODS: The electronic records of all patients who underwent FDG PET/CT from January 2010 to March 2013 in our hospital were retrospectively reviewed. The main indications for PET/CT were: characterization of an indeterminate mass on radiological imaging, suspicion or staging of malignancy, and suspicion of inflammation. In patients with incidental focal FDG uptake in the large bowel, data regarding subsequent colonoscopy were retrieved, if performed within 120 days. The final diagnosis was defined using colonoscopy findings, combined with additional histopathological assessment of the lesion, if applicable. RESULTS: Of 7,318 patients analysed, 359 (5 %) had 404 foci of unexpected colonic FDG uptake. In 242 of these 404 lesions (60 %), colonoscopy follow-up data were available. Final diagnoses were: adenocarcinoma in 25 (10 %), adenoma in 90 (37 %), and benign in 127 (53 %). The median [IQR] SUVmax was significantly higher in adenocarcinoma (16.6 [12 - 20.8]) than in benign lesions (8.2 [5.9 - 10.1]; p < 0.0001), non-advanced adenoma (8.3 [6.1 - 10.5]; p < 0.0001) and advanced adenoma (9.7 [7.2 - 12.6]; p < 0.001). The receiver operating characteristic curve of SUVmax for malignant versus nonmalignant lesions had an area under the curve of 0.868 (SD ± 0.038), the optimal cut-off value being 11.4 (sensitivity 80 %, specificity 82 %, positive predictive value 34 %, negative predictive value 98 %). CONCLUSION: In these patients with incidental colonic focal activity undergoing PET/CT (the largest series published to date), malignancies had significantly higher SUVmax values than all other types of lesions. However, SUVmax could not distinguish between benign lesions and adenomas. In conclusion, all incidental findings in the colon should be further evaluated and lesions with SUVmax ≥11.4 should be evaluated without delay.

Earlobe sarcoidosis.

BACKGROUND: Infliximab, a TNF-alpha blocking agent, is an upcoming therapeutic option for cases of refractory sarcoidosis. In pulmonary sarcoidosis, changes imaged by 18F-FDG-PET during infliximab treatment in sarcoidosis patients correlate with signs of clinical improvement. DESIGN: Case-report. RESULTS AND CONCLUSIONS: A patient with severe earlobe sarcoidosis, treated with infliximab, is presented. This case shows that even relatively small extrapulmonary localisations of sarcoidosis can be visualised by 18F-FDG-PET, and that a decrease of FDG-uptake correlates well with clinical improvement on infliximab treatment.

18F-FDG PET as a predictor of pulmonary function in sarcoidosis.

PURPOSE: Fluor-18 fluorodeoxyglucose (18F-FDG) PET is able to demonstrate sarcoidosis activity. Ongoing pulmonary sarcoidosis activity can be reflected by a decline in pulmonary function tests (PFT). To assess whether diffuse metabolic activity of the lung parenchyma imaged by 18F-FDG PET predicts future pulmonary deterioration, 18F-FDG PET was compared with PFT. METHODS: In this retrospective cohort study, 43 newly diagnosed, sarcoidosis patients were analyzed. Based on 18F-FDG PET, patients were diagnosed with diffuse parenchymal disease activity, without or with immunosuppressive treatment, started after 18F-FDG PET was performed. As a control, sarcoidosis patients with mediastinal/hilar disease activity but without metabolic activity in the lung parenchyma were analyzed, all without treatment. Vital capacity (VC), forced expiratory volume (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO) were analyzed per group at baseline, i.e., at the time 18F-FDG PET was performed, and after one year follow-up. RESULTS: At follow-up, a significant decrease in DLCO was found in untreated patients with diffuse parenchymal activity. No change in VC or FEV1 could be observed. Treated patients with parenchymal activity showed a significant increase in VC, FEV1 and DLCO, while patients without parenchymal activity did not show any change in PFT. CONCLUSIONS: In sarcoidosis, diffuse parenchymal disease imaged by 18F-FDG PET, predicts a future deterioration of DLCO when untreated. Treatment however, improves VC, FEV1 and DLCO significantly suggesting that 18F-FDG PET represents the pulmonary improvement that can be achieved. The absence of metabolic activity in the lung parenchyma justifies a wait-and-see policy.

Imaging the inflammatory activity of sarcoidosis: sensitivity and inter observer agreement of (67)Ga imaging and (18)F-FDG PET.

AIM: The aim of this study was to investigate sensitivity of 67Ga imaging and 18F-FDG PET for sarcoidosis activity and their inter observer variability. METHODS: Thirty-four newly diagnosed, histologically proven sarcoidosis patients were analyzed prospectively. (67)Ga imaging and (18)F-FDG PET were performed, the presence of pulmonary and extra pulmonary lesions was evaluated and inter observer variability of both techniques was assessed. RESULTS: Overall sensitivity to detect active sarcoidosis was 88% for (67)Ga imaging and 97% for (18)F-FDG PET. Although these results were not significantly different, 18F-FDG PET detected more lesions in the mediastinum (P<0.05), hila (P<0.05), lymph nodes (P<0.001) and extra pulmonary regions in general (P<0.001). Inter observer agreement was poor to moderate for (67)Ga imaging (kappa 0.19-0.59) and good to very good for (18)F-FDG PET (kappa 0.65-1.00). CONCLUSION: (18)F-FDG PET is more sensitive than (67)Ga imaging in the assessment of sarcoidosis activity with regard to the mediastinum, hila, lymph nodes and extra pulmonary lesions in general. Furthermore, (18)F-FDG PET demonstrates a very good inter observer agreement in contrast with (67)Ga imaging and (18)F-FDG PET is therefore the nuclear imaging technique of choice in sarcoidosis assessment.

18F-FDG PET in sarcoidosis: an observational study in 12 patients treated with infliximab.

BACKGROUND: 18F-FDG PET is a promising technique in sarcoidosis imaging, although it is not incorporated in routine activity assessment. The purpose of this study was to correlate 18F-FDG PET with standard sarcoidosis activity parameters during infliximab treatment. METHODS: Twelve patients with refractory sarcoidosis were treated with 6 cycles of infliximab. Pre- and post-therapy 18F-FDG PET was visually evaluated and SUVmax was measured. In addition, the effect of infliximab was evaluated by changes in symptoms, angiotensin converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), vital capacity (VC), diffusion capacity of the lung for carbon monoxide (DLCO) and chest radiography. SUVmax and conventional parameters were correlated. RESULTS: Clinical improvement as judged by conventional parameters was seen in all patients, though with a minor response in one. Symptoms improved in 11/12 patients while chest radiographic stages did not change. The decrease in ACE was 39% and in sIL-2R 47% (p<0.01). Improvement of VC and DLCO was 5.4% and 3.3% (p<0.05), respectively. 18F-FDG PET revealed either improvement or normalization in 11/12 (92%) clinically responding patients. The overall decrease in SUVmax was 55% (p<0.01); the patient with a limited response showed a 34% increase. A decrease in SUVmax of the lung parenchyma correlated with an improvement of VC (r=-0.75, p<0.01). No significant correlation between SUVmax and other parameters was found. CONCLUSION: Changes imaged by 18F-FDG PET during infliximab treatment in sarcoidosis patients correlate with signs of clinical improvement to a considerate extent, which supports the hypothesis that 18F-FDG uptake represents disease activity.