A Study on the Psychological Profile and Coping With the Disease in Patients With Lymphangioleiomyomatosis.

Introduction: Lymphangioleiomyomatosis (LAM) is a rare disease that affects women almost exclusively. We aimed to determine the psychological profile in patients with LAM, and their potential association with sociodemographic and clinical features, and to know their role in coping with the disease. Material and methods: Cross-sectional and descriptive study in collaboration with the Spanish Association of LAM (AELAM). The variables measured were: socio-demographic, psychological (anxiety, depression, demoralization, spirituality, resilience, social support), clinical (treatment) and health-related quality of life. Results: We studied 87 LAM patients, with a mean (SD) age of 47.7 (7.7) years, and time since diagnose was 10.1 (5.4) years. 75.9% of patients were receiving sirolimus or everolimus, and oxygen therapy was required in 34.5% of patients. Anxiety was found in 46% of patients, depression in 55%, while only 2% presented demoralization and 14% deficit in spirituality. Social support and resilience were adequate. The "non-severe" group (without oxygen therapy) presented worse results in anxiety. A structural equation model to explore association between variables, showed very adequate fit indices: χ2(14) = 29.743 (p = .074); CFI = .983; TLI = .967; SRMR = .058; RMSEA = .075[.000-.128]. The model identifies resilience, spirituality and social support as "protective factors" from anxiety, depression, and demoralization. Conclusions: This study performed on a large series of women with LAM describes their psychological profile, in addition to showing how they cope with the disease. We have found that other psychological constructs, such as perceived social support and resilience, are protective factors. Early psychological evaluation and intervention is necessary to reduce comorbidities and prevent mental health problems in women with LAM.

Introducción: La linfangioleiomiomatosis (LAM) es una enfermedad rara que afecta casi exclusivamente a las mujeres. Nuestro objetivo fue determinar el perfil psicológico en los pacientes con LAM, y su potencial asociación con características sociodemográficas y clínicas, y conocer su papel en el afrontamiento de la enfermedad. Material y métodos: Estudio transversal y descriptivo en colaboración con la Asociación Española de LAM (AELAM). Las variables medidas fueron: sociodemográficas, psicológicas (ansiedad, depresión, desmoralización, espiritualidad, resiliencia, apoyo social), clínicas (tratamiento) y calidad de vida relacionada con la salud. Resultados: Se estudiaron 87 pacientes con LAM, con una edad media (DE) de 47,7 ± 7,7 años y un tiempo desde el diagnóstico de 10,1 ± 5,4 años. El 75,9% de los pacientes estaban recibiendo sirolimus o everolimus, y el 34,5% de los pacientes requirió oxigenoterapia. La ansiedad se encontró en el 46% de los pacientes, la depresión en el 55%, mientras que solo el 2% presentó desmoralización y el 14% déficit en la espiritualidad. El apoyo social y la resiliencia fueron adecuados. El grupo «no grave¼ (sin oxigenoterapia) presentó peores resultados en ansiedad. Un modelo de ecuaciones estructurales para explorar asociación entre variables, mostró índices de ajuste muy adecuados: χ2(14) = 29,743 (p = 0,074); CFI = 0,983; TLI = 0,967; SRMR = 0,058; RMSEA = 0,075 (0,000-0,128). El modelo identifica la resiliencia, la espiritualidad y el apoyo social como «factores protectores¼ contra la ansiedad, la depresión y la desmoralización. Conclusiones: Este estudio realizado en una amplia serie de mujeres con LAM describe su perfil psicológico, además de mostrar cómo afrontan la enfermedad. Hemos descubierto que otros constructos psicológicos, como el apoyo social percibido y la resiliencia, son factores protectores. La evaluación e intervención psicológica temprana es necesaria para reducir las comorbilidades y prevenir problemas de salud mental en mujeres con LAM.

Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function.

INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare low-grade metastasising disease characterised by cystic lung destruction. The genetic basis of LAM remains incompletely determined, and the disease cell-of-origin is uncertain. We analysed the possibility of a shared genetic basis between LAM and cancer, and LAM and pulmonary function. METHODS: The results of genome-wide association studies of LAM, 17 cancer types and spirometry measures (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio and peak expiratory flow (PEF)) were analysed for genetic correlations, shared genetic variants and causality. Genomic and transcriptomic data were examined, and immunodetection assays were performed to evaluate pleiotropic genes. RESULTS: There were no significant overall genetic correlations between LAM and cancer, but LAM correlated negatively with FVC and PEF, and a trend in the same direction was observed for FEV1. 22 shared genetic variants were uncovered between LAM and pulmonary function, while seven shared variants were identified between LAM and cancer. The LAM-pulmonary function shared genetics identified four pleiotropic genes previously recognised in LAM single-cell transcriptomes: ADAM12, BNC2, NR2F2 and SP5. We had previously associated NR2F2 variants with LAM, and we identified its functional partner NR3C1 as another pleotropic factor. NR3C1 expression was confirmed in LAM lung lesions. Another candidate pleiotropic factor, CNTN2, was found more abundant in plasma of LAM patients than that of healthy women. CONCLUSIONS: This study suggests the existence of a common genetic aetiology between LAM and pulmonary function.

Heterogeneity and Cancer-Related Features in Lymphangioleiomyomatosis Cells and Tissue.

Lymphangioleiomyomatosis (LAM) is a rare, low-grade metastasizing disease characterized by cystic lung destruction. LAM can exhibit extensive heterogeneity at the molecular, cellular, and tissue levels. However, the molecular similarities and differences among LAM cells and tissue, and their connection to cancer features are not fully understood. By integrating complementary gene and protein LAM signatures, and single-cell and bulk tissue transcriptome profiles, we show sources of disease heterogeneity, and how they correspond to cancer molecular portraits. Subsets of LAM diseased cells differ with respect to gene expression profiles related to hormones, metabolism, proliferation, and stemness. Phenotypic diseased cell differences are identified by evaluating lumican (LUM) proteoglycan and YB1 transcription factor expression in LAM lung lesions. The RUNX1 and IRF1 transcription factors are predicted to regulate LAM cell signatures, and both regulators are expressed in LAM lung lesions, with differences between spindle-like and epithelioid LAM cells. The cancer single-cell transcriptome profiles most similar to those of LAM cells include a breast cancer mesenchymal cell model and lines derived from pleural mesotheliomas. Heterogeneity is also found in LAM lung tissue, where it is mainly determined by immune system factors. Variable expression of the multifunctional innate immunity protein LCN2 is linked to disease heterogeneity. This protein is found to be more abundant in blood plasma from LAM patients than from healthy women. IMPLICATIONS: This study identifies LAM molecular and cellular features, master regulators, cancer similarities, and potential causes of disease heterogeneity.

Upconverting Carbon Nanodots from Ethylenediaminetetraacetic Acid (EDTA) as Near-Infrared Activated Phototheranostic Agents.

This work describes the synthesis of nitrogen-doped carbon nanodots (CNDs) synthesized from ethylenediaminetetraacetic acid (EDTA) as a precursor and their application as luminescent agents with a dual-mode theranostic role as near-infrared (NIR) triggered imaging and photodynamic therapy agents. Interestingly, these fluorescent CNDs are more rapidly and selectively internalized by tumor cells and exhibit very limited cytotoxicity until remotely activated with a NIR illumination source. These CNDs are excellent candidates for phototheranostic purposes, for example, simultaneous imaging and therapy can be carried out on cancer cells by using their luminescent properties and the in situ generation of reactive oxidative species (ROS) upon excitation in the NIR range. In the presence of CNDs, NIR remote activation induces the in vitro killing of U251MG cells. Through the use of flow imaging cytometry, we have been able to successfully map and quantify the different types of cell deaths induced by the presence of intracellular superoxide anions (. O2 - ) and hydrogen peroxide (H2 O2 ) ROS generated in situ upon NIR irradiation.

Correction: Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

[This corrects the article DOI: 10.1371/journal.pone.0132546.].

In-vitro toxicity of carbon nanotube/polylysine colloids to colon cancer cells.

Single-walled carbon nanotubes (SWCNTs) are thoroughly purified and dispersed in an aqueous solution of high molecular weight poly-L-lysine (pLlys). Human intestinal epithelial Caco-2/TC7 cells are incubated with the SWCNT dispersions in pLlys, and their effects on cell viability are studied by image flow cytometry. No significant changes are observed in the cell culture wells up to pLlys concentrations of 10 µg ml-1. However, high mortality is detected at pLlys concentrations of 100 µg ml-1. The presence of oxygen-free SWCNTs does not modify the effects of pLlys on cell cultures at any of the tested concentrations (≤1 µg ml-1). In addition, SWCNTs having an 8 wt.% of surface oxygen are tested with identical results. Thus, purified SWCNTs, even bearing oxygen functional groups, act as inert particles in the cell culture medium. This result supports the applicability of SWCNTs as carriers in pharmacological formulations against digestive tract diseases.

Understanding the priorities for women diagnosed with lymphangioleiomyomatosis: a patient perspective.

Lymphangioleiomyomatosis (LAM) is a rare lung disease that almost exclusively affects women and develops in about one in 400 000 adult females. The European Lung Foundation worked closely with one of the patient organisations within its network, the European LAM Federation, to raise awareness of LAM at the 2014 European Respiratory Society International Congress in Munich, Germany. In addition, an invitation-only workshop with 45 individuals from 13 countries was held to discuss the priorities for women in Europe living with the disease. The need for ongoing collaboration to improve knowledge of this rare lung condition with healthcare professionals across Europe was highlighted.

Study of breast cancer incidence in patients of lymphangioleiomyomatosis.

Molecular evidence has linked the pathophysiology of lymphangioleiomyomatosis (LAM) to that of metastatic breast cancer. Following on this observation, we assessed the association between LAM and subsequent breast cancer. An epidemiological study was carried out using three LAM country cohorts, from Japan, Spain, and the United Kingdom. The number of incident breast cancer cases observed in these cohorts was compared with the number expected on the basis of the country-specific incidence rates for the period 2000-2014. Immunohistochemical studies and exome sequence analysis were performed in two and one tumors, respectively. All cohorts revealed breast cancer standardized incidence ratios (SIRs) ≥ 2.25. The combined analysis of all cases or restricted to pre-menopausal age groups revealed significantly higher incidence of breast cancer: SIR = 2.81, 95 % confidence interval (CI) = 1.32-5.57, P = 0.009; and SIR = 4.88, 95 % CI = 2.29-9.99, P = 0.0007, respectively. Immunohistochemical analyses showed positivity for known markers of lung metastatic potential. This study suggests the existence of increased breast cancer risk among LAM patients. Prospective studies may be warranted to corroborate this result, which may be particularly relevant for pre-menopausal women with LAM.

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Lymphangioleiomyomatosis treatment with sirolimus.

Lymphangioleiomyomatosis (LAM) is a rare lung disease, that predominantly affects young females and generally progresses to respiratory failure. There is not sufficient evidence to support the routine use of any treatment in LAM. The only treatment for severe LAM is currently lung transplantation. Activation of mammalian target of rapamycin (mTOR) signalling pathway has been observed in LAM. LAM is often associated with angiomyolipoma in the kidneys. mTOR inhibitor sirolimus reduces angymiolipoma volumes. Some reports have shown improvement in lung function with sirolimus in LAM. We report 3 women with LAM, with a rapid decline in lung function and symptoms and who were treated with sirolimus.

[Predictive factors for survival in patients with idiopathic pulmonary fibrosis]. / Factores predictivos de supervivencia en pacientes con fibrosis pulmonar idiopática.

BACKGROUND AND OBJECTIVE: To determine the median survival and determinants of survival in patients with idiopathic pulmonary fibrosis (IPF). PATIENTS AND METHOD: We retrospectively evaluated 29 IPF patients who died in the pneumology department between 2001 and 2006. Data from the time of diagnosis until death were analysed. Determinants of survival including age at diagnosis, gender, history of cigarette smoking, fibrosis-emphysema association, and lung function tests were analysed. RESULTS: The mean age at diagnosis was 69.7, 16 patients were men (55.2%). The median survival time, from the time of diagnosis, was 28.47 months (20.44-36.5 IC95%). There was a significant difference in survival between age groups. The median survival time in patients older than 65 years was 22.40 months and in patients younger than 65 years it was 56.37 months (p<0.001). There was no significant difference in survival when other determinants of survival. were evaluated. CONCLUSION: The median survival of IPF patients is low. It is necessary to continue investigating to find more effective and selective therapeutic strategies.

[Methicillin-resistant Staphylococcus aureus in patients with cystic fibrosis]. / Staphylococcus aureus resistente a meticilina en pacientes adultos con fibrosis quística.

OBJECTIVE: To determine the prevalence of chronic colonization with methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis, describe antibiotic sensitivity of the strains, and compare the patients' clinical characteristics with those of patients infected with methicillin-sensitive S. aureus (MSSA). PATIENTS AND METHODS: Patients with chronic S. aureus colonization were selected from a total of 50 patients with cystic fibrosis. Sputum samples were cultured according to standard microbiological procedures. Patients were considered to have chronic bronchial colonization if the same microorganism was isolated in 3 consecutive sputum samples, separated by an interval of at least 1 month. The following variables were compared between patients with MSSA (17) and MRSA (8): sex, body mass index, presence of pancreatic insufficiency, bacterial colonization, pulmonary function, Brasfield radiological score, Shwachman clinical score, and number of respiratory exacerbations in the previous year. RESULTS: The prevalence of infection by MRSA was 16%. All the MRSA strains were sensitive to vancomycin, teicoplanin, and linezolid. Patients with MRSA were older and had a larger number of respiratory exacerbations than patients with MSSA. CONCLUSIONS: There is a high percentage of colonization by MRSA in adult cystic fibrosis patients. Although the pathogenic role of this microorganism remains unclear, patients with MRSA had more frequent exacerbations and poorer lung function. Thus, infection control is important and patients should be adequately monitored.

[Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease: data from the Spanish patient registry]. / Neumonía intersticial descamativa y bronquiolitis respiratoria asociada a enfermedad pulmonar intersticial: datos del registro español.

Among the idiopathic interstitial lung diseases, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP) make up a subgroup of rare diseases that are clearly smoking related. Few large case series have been published. We describe 19 cases registered in Spain: 12 patients with DIP and 7 with RB-ILD. Clinical and radiologic features are described along with clinical course, treatments applied, and outcomes. With the exception of 2 patients with DIP, all were smokers or ex-smokers. Cough and dyspnea were the most common symptoms at onset in both diseases. The most frequent radiologic findings were ground-glass opacity in DIP and pulmonary nodules in BR-ILD. Most patients were treated with corticosteroids. Outcomes were good in general; only 1 patient, with DIP, died.

[Polymyositis and interstitial lung disease with a favorable response to corticosteroids and methotrexate]. / Polimiositis y afectación pulmonar intersticial con buena respuesta a glucocorticoides y metotrexato.

Polymyositis is a rare collagen disease that can involve the lungs. Between 5% and 30% of patients with polymyositis present interstitial lung disease at diagnosis or during the course of disease. Onset is usually insidious and involves dyspnea and nonproductive cough. Several histopathological findings are associated with polymyositis and the most common is nonspecific interstitial pneumonia. The prognosis of interstitial lung disease associated with polymyositis is better than that of idiopathic pulmonary fibrosis, since most patients respond to treatment with corticosteroids and immunosuppressants. We report the case of a 60-year-old woman with dyspnea and muscle weakness who was diagnosed with polymyositis and interstitial lung disease (radiography indicated possible nonspecific interstitial pneumonia). The patient responded well to prednisone and methotrexate.