Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.

New approach for quantification of left ventricular function from low-dose gated bloodpool SPECT: Validation and comparison with conventional methods in patients.

BACKGROUND: Planar equilibrium radionuclide angiocardiography (ERNA) has been used as the gold standard for assessment of left ventricular (LV) function for over three decades. However, this imaging modality has recently gained less favor due to growing concerns about radiation exposure. We developed a novel approach that involves integrating short axis slices of gated bloodpool SPECT for quantification of LV function with improved signal-to-noise ratio and reduced radioactive dose while maintaining image quality and quantitative precision. METHODS: Twenty patients referred for ERNA underwent standard in vitro 99mTc-labeling of red blood cells (RBC), and were initially imaged following a low-dose (~ 8 mCi) injection using a dedicated cardiac SPECT camera, and then had planar imaging following a high-dose (~ 25 mCi) injection. Four different quantification methods were utilized to assess the LV function and were compared for quantitative precision and inter-observer reproducibility of the quantitative assessments. RESULTS: The Yale method resulted in the most consistent assessment of LV function compared with the gold standard high-dose ERNA method, along with excellent inter-observer reproducibility. CONCLUSIONS: The new low-dose 99mTc-RBC imaging method provides precise quantification of LV function with a greater than 67% reduction in dose and may potentially improve assessment of regional function.

Quantification of myocardial blood flow (MBF) and reserve (MFR) incorporated with a novel segmentation approach: Assessments of quantitative precision and the lower limit of normal MBF and MFR in patients.

BACKGROUND: Quantification of myocardial blood flow (MBF) and myocardial flow reserve (MFR) has shown diagnostic and prognostic values for the assessment of coronary artery disease (CAD). This study aimed to evaluate in patients a highly automatic Yale-MQ (myocardial blood flow quantification) software incorporated with a novel image segmentation approach for quantification of global and regional MBF and MFR from dynamic 82Rb cardiac positron emission tomography (PET). METHODS: Global and regional MBFs and MFRs were quantified in 80 patients (18 normal and 62 CAD subjects) by two different observers using the Yale-MQ software. Lower limits of normal (LLN) values and intra- and inter-observer variabilities of MBFs and MFRs were calculated for the assessment of quantitative precision. The Yale-MQ was compared with a commercially available software (Corridor 4DM) being used as a reference. RESULTS: The Yale-MQ method provided precise assessments of LLNs of MBF and MFR. The global and regional MBFs and MFR quantified via Yale-MQ were correlated strongly with those via Corridor4DM (R ≥ 0.867). The intra- and inter-observer variabilities of MBFs and MFRs quantified via Yale-MQ were small (≤ 7.7% for MBFs and ≤ 10.0% for MFRs) with excellent correlations (R ≥ 0.980 for MBFs and R ≥ 0.976 for MFRs). CONCLUSIONS: The new Yale-MQ software associated with the automatic processing scheme provides a highly reproducible clinical tool for precise quantification of MBF and MFR in patients with reliable LLN values.

A robust segmentation method with triple-factor non-negative matrix factorization for myocardial blood flow quantification from dynamic 82 Rb positron emission tomography.

PURPOSE: In this work, we proposed a triple-factor non-negative matrix factorization (TNMF) method to semiautomatically segment the regions of interest (ROIs) of the left ventricular (LV) cavity and myocardium to improve the reproducibility of myocardial blood flow (MBF) quantification from dynamic 82 Rb positron emission tomography (PET). METHODS: The proposed TNMF method was evaluated using NCAT phantom simulation with three noise levels. The segmented ROIs, time-activity curves (TACs), and K1 derived from the TNMF method were compared with the ground truth simulated. The TNMF method was further evaluated in two patients each undergone both rest and stress 82 Rb PET studies. The TNMF and manual segmentations were implemented by two different observers, and the interoperator variations of MBF and myocardial flow reserve (MFR) were compared between the two methods. RESULTS: Our simulation results showed that the TNMF method for dynamic PET image segmentation was robust as evidenced by the high Dice similarity coefficient, regardless of high or low count level. The relative bias in K1 estimation was less than 1%. Our patient results also showed that reasonable ROIs for the LV cavity and myocardium could be obtained precisely for patients with and without myocardial perfusion defects. The TACs derived from the TNMF method were highly correlated with those obtained with the manual method (R2  ≥ 0.964). The interoperator variations of MBF and MFR were markedly reduced using the TNMF method. CONCLUSIONS: In conclusion, the TNMF method is highly feasible for semiautomatic segmentation of the LV cavity and myocardium, with the potential to improve the precision of MBF quantification by improving segmentation.