Computed Tomography Findings as Determinants of Local and Systemic Inflammation Biomarkers in Interstitial Lung Diseases: A Retrospective Registry-Based Descriptive Study

Purpose

To evaluate the association of peripheral blood (PBL) and broncho-alveolar lavage (BAL) biomarkers with inflammatory versus fibrotic high-resolution computed tomography (HRCT) findings in interstitial lung disease (ILD) patients.

Methods

HRCT findings of 127 consecutive ILD-board patients were semi-quantitatively evaluated: reticulation/honeycombing (RET), traction bronchiectasis (TBR) and emphysema (EMP) were classified as non-inflammatory/fibrotic; consolidations (CON), ground glass opacities (GGO), parenchymal nodules (NDL) and mosaic attenuation (MOS) as active inflammatory. Each HRCT finding was assessed in six distinct lung regions, resulting scores were graded as minimal (0–1 regions involved), medium (2–4) or extensive (5–6). Associations of routinely assessed PBL/BAL biomarkers with these HRCT scores were evaluated using Spearman correlation coefficients and graphical presentation; significance was tested by applying Kruskal–Wallis tests.

Results

Blood neutrophil, lymphocyte and eosinophil fraction, neutrophil to lymphocyte ratio (NLR) and BAL lymphocyte fraction consistently showed opposite correlations with inflammatory versus non-inflammatory/fibrotic HRCT finding scores. Blood lymphocyte fraction significantly differed by graded GGO (p = 0.032) and CON (p = 0.027) extent, eosinophil fraction by TBR (p = 0.006) and NLR by CON (p = 0.009). C-reactive protein was significantly related to GGO (p = 0.023) and CON (p = 0.004), BAL lymphocyte fraction to GGO (p = 0.017) extent.

Conclusion

Blood lymphocyte and eosinophil fraction, NLR, CRP and BAL lymphocyte fraction may aid to differentiate inflammatory from non-inflammatory/fibrotic ILD patterns.

Trial registration

This evaluation was based on data from the ILD registry of Kepler University Hospital Linz, as approved by the ethics committee of the Federal State of Upper-Austria (EK Number. I-26-17).

     

Effects of telithromycin in in vitro and in vivo models of lipopolysaccharide-induced airway inflammation

BACKGROUND: The ketolide antibiotic telithromycin (TEL) exerts immunomodulatory and antiinflammatory effects in vitro and in a mouse model of septic shock. We studied the antiinflammatory activity of TEL in in vitro and in vivo models of airway inflammation induced by lipopolysaccharide (LPS). METHODS: We measured the effects of TEL on the response of RAW 264.7 macrophages to LPS and of murine lung epithelial (MLE)-12 cells to supernatants of LPS-stimulated RAW 264.7 macrophages. Macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-alpha production, nuclear factor (NF)-kappaB activation, and apoptosis were determined. Acute airway inflammation was induced in untreated and TEL-treated BALB/c mice by nebulization with LPS. Total number of leukocytes, macrophages, and neutrophils, the protein concentration, and nitrite and cytokine levels were determined in the BAL fluid. RESULTS: TEL inhibited in a dose-dependent manner the production of MIP-2 and TNF-alpha by LPS-stimulated RAW 264.7 macrophages, and the production of MIP-2 by MLE-12 epithelial cells to supernatants of LPS-stimulated RAW 264.7 macrophages. NF-kappaB activation was inhibited and apoptosis was increased in both cell lines by TEL. The LPS-induced influx of neutrophils in BAL fluid was decreased by TEL pretreatment. TEL also reduced protein, nitrite, MIP-2, and TNF-alpha levels in the BAL fluid of LPS-nebulized animals. CONCLUSIONS: We have provided evidence that TEL exerts potent antiinflammatory effects in LPS-induced airways injury. We propose that TEL acts in the early phase of inflammation by reducing the release of inflammatory mediators through NF-kappaB inhibition, and in the later phase through enhancement of inflammatory cell apoptosis.     

Concurrent DNA Copy‐Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Somatic mosaicism for DNA copy‐number alterations (SMC‐CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC‐CNAs can undergo clonal expansion, it has been proposed that SMC‐CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array‐based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC‐CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC‐CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC‐CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co‐occurrence of gross SMC‐CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.     

Functionalization of α-hydroxyphosphonates as a convenient route to N-tosyl-α-aminophosphonates

Direct conversion of the α-hydroxyl group by para-toluenesulfonamide to yield α-(N-tosyl)aminophosphonates is reported. α-Aminophosphonates 23a,b–37a,b were obtained from the corresponding α-hydroxyphosphonates 6a,b–21a,b in the presence of K₂CO₃, via the retro-Abramov reaction of the appropriate aldehydes, 1–5. The subsequent formation of imines with simultaneous addition of diethyl phosphite provided access to the α-sulfonamide phosphonates 23a,b–37a,b with better diastereoselectivity than in the case of the Pudovik reaction. The mechanism for this transformation is proposed herein. When Cbz N-protected aziridine 9a,b and phenylalanine analogue 12a,b were exploited, intramolecular substitution was observed, leading to the corresponding epoxide 38 as the sole product, or oxazolidin-2-one 39 as a minor product. Analogous substitution was not observed in the case of proline 18a,b and serine 21a,b derivatives.

The reaction mechanism and diastereoselectivity of the direct transformation of α-hydroxyphosphonates 6a,b–21a,b by para-toluenesulfonamide, yielding α-(N-tosyl)aminophosphonates 23a,b–37a,b under K₂CO₃ conditions are presented.     

Incidental findings in multislice computed tomography prior to transcatheter aortic valve implantation: frequency,clinical relevance and outcome

Multislice computed tomography (MSCT) has emerged as the mainstay in patients planned for transcatheter aortic valve implantation (TAVI). Incidental findings (IF) in MSCT are common. However, the exact incidence, clinical relevance and further consequences of IF are unclear and it is controversial whether IF adversely affect patients’ outcome. We analyzed MSCT data of 1050 patients screened for TAVI between January 2011 and December 2014. Median follow-up of patients was 20 months. In total, 3194 IF were identified, which were classified into clinically non-relevant IF (2872, 90%) and clinically relevant IF (322, 10%). In 25% of patients (258/1050) at least one clinically relevant IF was present. Age (80?±?7 vs. 80?±?7 years; p?=?0.198) and EuroSCORE II (3.6% [2.1–5.7] vs. 3.6% [2.1–5.9]; p?=?0.874) was similar between patients with and without a clinically relevant IF. TAVI was performed less frequently in patients with a clinically relevant IF (76% vs. 85%; p?<?0.001), with more patients receiving surgical aortic valve replacement in that group (14% vs. 11%; p?=?0.042), possibly due to the high rate of incidental aneurysms of the ascending aorta (n?=?48). If TAVI was performed mortality did not differ (30-days: 4% vs. 3%; p?=?0.339, 1-year: 11% vs. 14%; p?=?0.226) between patients with and without a clinically relevant IF. Our study is the largest study to analyze prevalence, clinical relevance and therapeutic consequences of IF during screening for TAVI. IF in pre-procedural MSCT are common and clinically relevant in one-quarter of patients. However, these findings had no impact on overall mortality.     

Superb Micro-vascular Imaging (SMI): a Doppler ultrasound technique with potential to identify,classify, and follow up endoleaks in patients after Endovascular Aneurysm Repair (EVAR)

Purpose

The aim of the study was to assess the effectiveness of Superb Micro-vascular Imaging (SMI) as an alternative to Contrast-Enhanced Ultrasound (CEUS) and Computed Tomography Angiography (CTA) for endoleak detection and classification in patients followed up after endovascular abdominal aortic aneurysm repair (EVAR).

Materials and methods

From May 2015 to January 2017, 30 patients underwent post-EVAR follow-up with Color Doppler Ultrasound (CDUS), CEUS, SMI, and CTA examinations. Aneurysmal sac diameter and graft patency were evaluated; endoleaks were identified and classified. Sensitivity, specificity, and accuracy values were calculated for each of the four diagnostic methods of endoleak detection. A percentage of agreement and Cohen’s Kappa coefficient were calculated for comparison of methods in terms of endoleak identification.

Results

CTA revealed fifteen endoleaks (50%): three type Ia, nine type II, and three type III. The sensitivity of CDUS, CEUS, and SMI relative to CTA was 27%, 100%, and 100%, respectively. Specificity was 93%, 93%, and 93%, respectively. Accuracy was 60%, 97%, and 97%, respectively. There were no differences between SMI and CEUS in terms of sensitivity, specificity, or accuracy (100%, 93%, and 97%). We do not observe statistically significant differences between CTA, CEUS, and SMI concerning endoleak identification ability. The weakest method in endoleak identification was CDUS.

Conclusions

The analysis showed that SMI is effective, repeatable, and comparable with the CEUS modality in identification endoleaks after EVAR; it may be considered as a potential tool to monitor patients after EVAR implantation, especially those with renal insufficiency or with an allergy to any contrast media.