A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer

Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions. Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms. Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor

Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis.

BACKGROUND:Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects multiple organs, including the lungs, pancreas, liver and intestine. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) locus lead to defective proteins and reduced Cl- secretion and Na+ hyperabsorption in the affected organs. In addition, patients suffering from CF display chronic inflammation that contributes to the pathogenesis of CF. Recent work suggests that CF patients have a reduced capacity to biosynthesize specialized pro-resolving lipid mediators (SPMs), which contributes to the development and duration of the unwanted inflammation. Alterations in the metabolism of arachidonic acid (AA) and docosahexaenoic acid (DHA) to specialized pro-resolving mediators (SPMs), like lipoxins (LXs), maresins (MaRs), protectins (PDs) and resolvins (Rvs), may play a major role on clinical impact of airway inflammation in CF. METHODS:In this study, our aims were to detect and quantitate Resolvin D1 (RvD1) in sputum and plasma from patients with CF and compare levels of RvD1 with biomarkers of inflammation and lung function. We studied 27 CF patients aged 6 to 55 years (median 16 years) in a prospective approach. RESULTS:DHA can be found in the plasma of our CF patients in the milligram range and is decreased in comparison to a healthy control group. The DHA-derived pro-resolving mediator Resolvin D1 (RvD1) was also present in the plasma (286.4 ± 50 pg/ mL, mean ± SEM) and sputum (30.0 ± 2.6 pg/ mL, mean ± SEM) samples from our patients with CF and showed a positive correlation with sputum inflammatory markers. The plasma concentrations of RvD1 were ten times higher than sputum concentrations. Interestingly, sputum RvD1/ IL-8 levels showed a positive correlation with FEV1 (rs = 0.3962, p< 0.05). CONCLUSIONS:SPMs, like RvD1, are well known to down-regulate inflammatory pathways. Our study shows that the bioactive lipid mediator RvD1, derived from DHA, was present in sputum and plasma of CF patients and may serve as a representative peripheral biomarker of the lung resolution program for CF patients

Prevalence and Clinical Significance of Staphylococcus aureus Small-Colony Variants in Cystic Fibrosis Lung Disease

Small-colony variants (SCVs) of Staphylococcus aureus can be isolated from the chronically infected airways of patients suffering from cystic fibrosis (CF). These slow-growing morphological variants have been associated with persistent and antibiotic-resistant infections, such as osteomyelitis and device-related infections, but no information is available to date regarding the clinical significance of this special phenotype in CF lung disease. We therefore investigated the prevalence of S. aureus SCVs in CF lung disease in a 12-month prospective study and correlated the microbiological culture results with the patients' clinical data. A total of 252 patients were screened for the presence of SCVs. The prevalence rate was determined to be 17% (95% confidence interval, 10 to 25%) among S. aureus carriers. S. aureus isolates with the SCV phenotype showed significantly higher antibiotic resistance rates than those with the normal phenotype. Patients positive for SCVs were significantly older (P = 0.0099), more commonly cocolonized with Pseudomonas aeruginosa (P = 0.0454), and showed signs of more advanced disease, such as lower forced expiratory volume in 1 s (P = 0.0148) than patients harboring S. aureus with a solely normal phenotype. The logistic regression model determined lower weight (P = 0.016), advanced age (P = 0.000), and prior use of trimethoprim-sulfamethoxazole (P = 0.002) as independent risk factors for S. aureus SCV positivity. The clinical status of CF patients is known to be affected by multiple parameters. Nonetheless, the independent risk factors determined here point to the impact of S. aureus SCVs on chronic and persistent infections in advanced CF lung disease

Connexin 37 and Connexin 43 genotypes in correlation to cytokines in induced sputum and blood in cystic fibrosis (CF)

Aims: We have provided evidence in former studies that cytokines (IL-8, TNF alpha, LBP, TGFß) measured in blood correlate negatively with lung function in deltaF508 homozygous patients. GAP junction proteins might be of importance for the influx of blood cells into the lung. Our aim was to assess the relationship between connexin genotypes and cytokines (IL-8, TNF-alpha, LBP, TGFß) in induced sputum and serum, and lung disease. Methods: 36 patients homozygous for deltaF508 (median age 18 y, m/f 16/20, FEV1(%) 77) were examined. Sequence analysis was performed for genes encoding GAP junction protein alpha 1 (GJA1/connexin 43) and gap junction protein alpha 4 (GJA4/connexin 37). Cytokines were assessed in serum and induced sputum (IS) by chemiluminescence (DPC Biermann, Bad Homburg, Germany) as well as leukocyte counts. Results: DNA analysis was performed in 35 patients. Whereas GJA1 showed only one rare heterozygous synonymous SNP (rs138386744) in one patient, four common SNPs were detected in GJA4. Two were synonymous changes, but the third variant (rs41266431) predicts an amino acid substitution (GTA → valine, ATA → isoleucine) as well as the fourth SNP (rs1764391: CCC→proline, TCC→serine). For rs41266431 patients with homozygosity for the G variant had higher IL-8 levels (median: 13.3/8.0 pg/ml, p=0.07) in serum as well as leukocytes in sputum (median: 2050/421 /µl p=0.041) than those showing heterozygosity (G/A). In individuals > 30 years lung function (FEV1 41.3/84.83 % predicted, p=0.07) was worse. Conclusion: SNP rs41266431 seems a promising candidate for further investigations, suggesting GJA4 a potential disease modifying gene

Correlation of sputum RvD1/ IL-8 ratio with FEV₁.

<p>Correlation of sputum RvD1/ IL-8 ratio with FEV₁ [%]. Red dots represent <i>Ps</i>. <i>a</i>. positive patients. The Spearman correlation coefficient (r_s) and the associated p- value is given for each analysis.</p

Transforming Growth Factor ß1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis

Background: High TGFβ1-producing variants cause severe clinical disease in F508del homozygous patients. Lately, we showed that a single nucleotide polymorphism (SNP), rs41266431, in the GJA4 gene modifies the disease severity of cystic fibrosis (CF). Our aim was to investigate whether the clinical phenotype associated with GJA4 variants was independent of TGFβ1 variants. Methods: Homozygous F508del patients (n = 115, mean age 27.2 years, m/f (65/50)) were included in this study. A deep sequence analysis was performed for GJA4 and TGBβ1, and disease severity was assessed over 3 years using lung function tests (LFTs), body mass index, diabetes mellitus, colonization with Pseudomonas aeruginosa, survival to end-stage lung disease (ESLD), as well as distinct inflammatory biomarkers. Results: The analyses revealed that one SNP (rs41266431) in GJA4 may be clinically relevant. Carriers homozygous for the G variant (n = 84; 73%) presented with worse LFTs (forced vital capacity (FVC) % predicted: mean 80/86.6, p < 0.035) and a lower survival to ESLD (p < 0.029). For the TGBβ1 variant: 509 carriers of the C variant (CT + CC genotype, n = 105, 91.3%) had better LFTs (Forced expiratory flow at 75% of the FVC (FEF75% predicted: median 40/29.5, p < 0.015), although a similar outcome to ESLD. A gene–gene interaction was not observed between TGBβ1 and GJA4 variants for any clinical measure. Conclusions: GJA4 variants are independent of TGBβ1 variants. Both variants had an impact on the LFTs, although only GJA4 variants were associated with an improved outcome for ESLD. Clinical Trial Registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020

Patient characteristics.

<p>Patient characteristics.</p

Levels of RvD1 in plasma and sputum from CF patients.

<p>Levels of (a) plasma and sputum RvD1 from CF patients and (b) correlation of plasma and sputum RvD1 levels. Values are represented as Mean ± SEM. The Spearman correlation coefficient (r_s) and the associated p- value is given for each analysis.</p

Correlation of pro-inflammatory sputum and serum biomarkers with sputum RvD1 levels.

<p>Correlation of (a) sputum PMNs, (b) serum IgG, (c) sputum IL-1β and (d) sputum IL-8 with sputum RvD1 levels from CF patients. Red dots represent <i>Ps</i>. <i>a</i>. positive patients. The Spearman correlation coefficient (r_s) and the associated p- value is given for each analysis.</p

Baseline pulmonary function data of CF patients and healthy controls and correlation of pulmonary function in CF to sputum neutrophils.

<p>Comparison of mean (a) FEV₁ [%] and (c) MEF 25 [%] in CF patients and healthy controls. Correlation of (b) FEV₁ [%] and (d) MEF25 [%] in CF patients with percentage of sputum neutrophils. Red dots represent <i>Ps</i>. <i>a</i>. positive patients. Values are represented as Mean ± SEM. The Spearman correlation coefficient (r_s) and the associated p-value is given for each analysis. ** p< 0.01.</p