Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response.

Gain-of-function mutations in stimulator of interferon gene 1 (STING1) result in STING-associated vasculopathy with onset in infancy (SAVI), a severe autoinflammatory disease. Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, which have roles in the onset and severity of SAVI and remain to be elucidated. To this end, we performed a multi-omics comparative analysis of peripheral blood mononuclear cells (PBMCs) and plasma from SAVI patients and healthy controls, combined with a dataset of healthy PBMCs treated with IFN-ß. Our data reveal a subset of disease-associated monocyte, expressing elevated CCL3, CCL4, and IL-6, as well as a strong integrated stress response, which we suggest is the result of direct PERK activation by STING. Cell-to-cell communication inference indicates that these monocytes lead to T cell early activation, resulting in their senescence and apoptosis. Last, we propose a transcriptomic signature of STING activation, independent of type I IFN response.

Diagnostic accuracy of 18F-FDG PET/CT for assessing response to radiofrequency ablation treatment in lung metastases: a multicentre prospective study.

PURPOSE: To assess diagnostic accuracy of (18)F-FDG PET/CT at 3 months for the detection of local recurrence after radiofrequency ablation (RFA) of lung metastases. METHODS: The PET/CT scan at 3 months was compared with a baseline PET/CT scan from a maximum of 2 months before RFA, with the reference standard as recurrence diagnosed by CT during a 12-month follow-up. Local recurrence was diagnosed on the PET/CT scan if lesional uptake was greater than the mediastinal background. Maximum standardized uptake values (SUVmax) were recorded. ROC curve analysis for SUVmax was performed. Overall survival (OS) and time to local relapse were computed from the date of RFA using the Kaplan-Meier method (www.clinicaltrials.gov: NCT 00382252). RESULTS: Between 2005 and 2009, 89 patients (mean age 65 years) underwent RFA for 115 lung metastases (mean size 16.2 ± 6.9 mm). The median SUVmax before RFA was 5.8 ± 4. PET/CT at 3 months and the reference standard were available in 77 patients and 100 lesions. Accuracy was 66.00% (95% CI 55.85-75.18%), sensitivity 90.91% (95 % CI 58.72-99.77 %), specificity 62.92% (95% CI 52.03-72.93%), PPV 23.26% (95% CI 11.76-38.63%), and NPV 98.25% (95% CI 90.61-99.96%). One-year OS was 94.2% (95% CI 86.6-97.5%) and the probability of being free of local recurrence 1 year after RFA was 84.6% (95% CI 75.0-90.8%). CONCLUSION: The specificity of PET/CT at 3 months is low because of persistent inflammation, especially when the lesion is close to the pleura. This technique is useful for its negative predictive value, but positive findings need to be confirmed by histology before new treatment is planned.

Sites of left and right ventricular lead implantation and response to cardiac resynchronization therapy observations from the REVERSE trial.

OBJECTIVES: The objective of this study is to ascertain the effects of the left (LV) and right (RV) ventricular lead tip position in response to cardiac resynchronization therapy (CRT). BACKGROUND: The REVERSE randomized trial examined the effects of CRT in patients with asymptomatic or mildly symptomatic heart failure (HF). METHODS: We analysed data collected from the active group (CRT-ON) of REVERSE in whom the precise locations of the LV and RV ventricular lead tips were determined from postoperative chest roentgenograms as part of a prespecified sub-study. LV position was classified as lateral or non-lateral, and apical or non-apical. RV position was classified as apical or non-apical. Echocardiographic LV end-systolic volume index (LVESVi), QRS duration, and clinical outcomes at 12-24 months of follow-up were evaluated with respect to the lead tip position. The primary trial endpoint was the proportion of patients with a worsened HF clinical composite response, scored as improved, unchanged, or worsened. RESULTS: Totally 346 patients included in this analysis were followed for a median of 12.6 months (interquartile range: 11.9-23.9 months). The proportion of worsened HF clinical composite response did not correlate with lead position, whereas a significantly greater decrease in the powered secondary endpoint of LVESVi was observed with the non-apical vs. the apical LV lead positions. CRT-paced QRS duration was significantly shorter than at baseline in patients with lateral vs. non-lateral LV position, as well non-apical vs. apical LV position. The incidence of composite endpoint of death and first hospitalization for HF was lower in the LV lateral than in the non-lateral (HR 0.44; 95% CI 0.19-0.99; P= 0.04), and in the LV non-apical than in the apical group (HR 0.27; 95% CI 0.11-0.63; P= 0.001). No significant differences were observed between RV apical and non-apical positions of the lead tip. CONCLUSIONS: A more favourable outcome of CRT with regard to LV reverse remodelling and the composite of time to death or first HF hospitalization was observed when the LV lead tip was implanted in the lateral wall, away from the apex, while the position of the RV lead tip was indifferent. The long-term change in QRS duration was significantly associated with the position of the LV lead tip. ClinicalTrials.gov Identifier: NCT00271154.

¹³¹I-labeled lipiodol-induced interstitial pneumonia: a series of 15 cases.

BACKGROUND: The drug (131)I-labeled lipiodol is used as internal radiotherapy for unresectable hepatocellular carcinoma. Although the drug was considered safe during preapproval studies, we observed several cases of interstitial pneumonia following its administration. METHODS: Cases were retrospectively identified through the drug safety unit database of Rennes University Hospital. RESULTS: From 1994 to 2009, interstitial pneumonia developed in 15 patients following (131)I-labeled lipiodol administration, with an estimated prevalence of 15.5 cases (95% CI, 7.7-23.2) per 1,000 treated patients. Mean age of the patients was 60 ± 8 years, and the male to female ratio was 6.5:1. All patients had cirrhosis, mainly related to long-term alcohol intoxication (n = 12). Most (n = 10) cases occurred after the second (131)I-labeled lipiodol injection. The median delay between last (131)I-labeled lipiodol administration and first respiratory symptoms was 30 days (interquartile range, 16.5-45 days). All patients presented with shortness of breath. Physical examination mostly revealed fever (n = 11) and bilateral crackles (n = 12). Chest CT scan showed bilateral ground-glass opacities (n = 8) with septal thickening, retraction, or both (n = 8). BAL (n = 7) was remarkable for increased neutrophils (n = 4) or CD8(+) T cell count (n = 3). Despite corticosteroids, 12 (80%) patients died, mostly of untractable respiratory failure (n = 9). Median delay between last (131)I-labeled lipiodol injection and death was 63 days (interquartile range, 34-129 days). CONCLUSIONS: Interstitial pneumonia may be a serious and not uncommon complication of (131)I-labeled lipiodol administration.

[Pulmonary alveolar phospholipoproteinosis]. / Lipoprotéinose alvéolaire pulmonaire.

Pulmonary alveolar phospholipoproteinosis is a rare lung disease of unknown cause characterized by surfactant plugging of the alveoli. At the present time, surgical lung biopsy, long considered as the gold standard, is not necessary for positive diagnosis of pulmonary alveolar phospholipoproteinosis when computed tomography anomalies and analysis of bronchial lavage fluids present a typical pattern. Treatment requires abundant lavage, but the demonstration of anti-GM-CSF antibodies in primary forms opens new therapeutic perspectives.