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Background: The long-term outcomes of adult pulmonary Langerhans cell histiocytosis (PLCH), particularly survival, are largely unknown. Two earlier retrospective studies reported a high rate of mortality, which contrasts with our clinical experience., Methods: To address this issue, all patients with newly diagnosed PLCH referred to the French national reference centre for histiocytoses between 2004 and 2018 were eligible for inclusion. The primary outcome was survival, which was defined as the time from inclusion to lung transplantation or death from any cause. Secondary outcomes included the cumulative incidences of chronic respiratory failure (CRF), pulmonary hypertension (PH), malignant diseases and extrapulmonary involvement in initially isolated PLCH. Survival was estimated using the Kaplan-Meier method., Results: 206 patients (mean age 39±13 years, 60% female, 95% current smokers) were prospectively followed for a median duration of 5.1 years (IQR 3.2-7.6 years). Of these, 12 patients (6%) died. The estimated rate of survival at 10 years was 93% (95% CI 89-97%). The cumulative incidences of CRF and/or PH were <5% at both 5 and 10 years, and 58% of these patients died. 27 malignancies were observed in 23 patients. The estimated standardised incidence ratio of lung carcinoma was 17.0 (95% CI 7.45-38.7) compared to an age- and sex-matched French population. Eight (5.1%) of the 157 patients with isolated PLCH developed extrapulmonary involvement., Conclusion: The long-term prognosis of PLCH is significantly more favourable than has previously been reported. Patients must be closely monitored after diagnosis to detect severe complications early., Competing Interests: Conflict of interest: A. Benattia has nothing to disclose. Conflict of interest: E. Bugnet has nothing to disclose. Conflict of interest: A. Walter-Petrich has nothing to disclose. Conflict of interest: C. de Margerie-Mellon has nothing to disclose. Conflict of interest: V. Meignin has nothing to disclose. Conflict of interest: A. Seguin-Givelet reports personal fees for lectures from Medtronic and AstraZeneca, outside the submitted work. Conflict of interest: G. Lorillon reports travel grants from Vitalaire, outside the submitted work. Conflict of interest: S. Chevret has nothing to disclose. Conflict of interest: A. Tazi reports personal fees for lectures from Chiesi and BMS, and travel grants from Vitalaire, AstraZeneca, Boehringer Ingelheim and Teva, outside the submitted work., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.) more...

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplastic disease driven by activating mutations in the mitogen-activating protein kinase signalling pathway, including the BRAF V600E mutation and BRAF deletions ( BRAF del). Next-generation sequencing and whole exome sequencing (WES) are valuable and powerful approaches for BRAF del identification, but these techniques are costly and time consuming. Pyrosequencing is an alternative method that has the potential to rapidly and reliably identify gene deletions. We developed a custom pyrosequencing assay to detect the exon-12 BRAF del in 18 biopsies from adult patients with LCH, which were all genotyped in parallel using Sanger sequencing and WES. A BRAF del was detected in 7/18 (39%), 6/18 (33%) and 3/18 (17%) LCH lesions using WES, pyrosequencing and Sanger, respectively, with good concordance between the WES and pyrosequencing results (Kappa-coefficient=0.88). Therefore, our pyrosequencing assay is reliable and useful for detecting BRAF del, particularly in BRAF V600E -negative LCH lesions, for which targeted treatment is indicated., Competing Interests: Competing interests: GL declares travel accommodations from Vitalaire and Chiesi. SM declares advisory roles for Roche and Biocartis. AT declares speaker fees from Chiesi and travel accommodations from Boehringer Ingelheim, Astrazeneca, and Vitalaire., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Background: The prevalence of psychological symptoms and the co-occurrence of substance abuse disorders in adult patients with Langerhans cell histiocytosis (LCH) has not been previously explored. We aimed to use validated scales to evaluate depression and anxiety symptoms experienced by adult LCH patients., Methods: In this cross-sectional study, all consecutive adult LCH patients seen at our national reference center between January 2012 and January 2013 were asked to complete the following instruments: the Hospital Anxiety and Depression scale (HADS); Barratt Impulsiveness Scale, Version 10 (BIS-10); and Cannabis Use Disorders Identification Test (CUDIT). Self-reported scores on these scales were used to determine the point prevalence of clinically significant psychological symptoms and substance use disorders in LCH patients. Patient profiles in terms of psychological features were assessed by principal component analysis including the HADS and BIS-10 instruments values, followed by hierarchical clustering. Fisher exact tests and Wilcoxon tests were used to examine the associations between disease-related parameters and high levels of anxiety and impulsivity., Results: Seventy-one adult LCH patients, mainly with pulmonary LCH (PLCH), completed the evaluations. Clinically significant anxiety and depression symptoms were reported by 22 (31%) and 4 (6%) subjects, respectively. Impulsivity was detected in 14% (10/71) of the patients. Seventeen percent (12/71) of the patients used cannabis on a regular basis, with 50% of these individuals (6/12) exhibiting scores consistent with cannabis use disorder. Three derived clusters of patients were identified in the principal component analysis; these patient clusters differed in successful weaning from tobacco at the time of evaluation (p = 0.03). In univariate analyses, isolated PLCH and the use of psychotropic treatments were statistically associated with clinically significant anxiety symptoms., Conclusions: High levels of anxiety and impulsivity are common in adult patients with LCH. The consequences of these symptoms for the management of LCH patients warrant further evaluation., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following updated competing interests: G. Lorillon reports travel accomodation from Chiesi and VitalAire; A Tazi reports personal fees from Chiesi, travel accomodation from VitalAire, Astrazeneca, and Boehringer Ingelheim, outside the submitted work. All other authors have declared that no competing interest exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials. more...

Background: Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed., Methods: Among 1482 children (< 15 years) registered in the French LCH registry (1994-2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure., Results: The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease. First-line vinblastine-corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine: n = 7; etoposide-aracytine: n = 3; targeted therapy n = 2). A total of 6 children (35%) died (repeated pneumothorax: n = 3; diffuse micronodular lung infiltration in the context of multisystem disease: n = 2; following lung transplantation: n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging., Conclusions: Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy. more...

Compared to control lung tissues from smokers, MCPyV DNA is rarely detected in PLCH lesions and is not associated with alterations of the MAPK pathway. A viral trigger in PLCH pathogenesis remains elusive. https://bit.ly/2xKmkIo., Competing Interests: Conflict of interest: F. Jouenne has nothing to disclose. Conflict of interest: J. Le Goff has nothing to disclose. Conflict of interest: E. Bugnet has nothing to disclose. Conflict of interest: M. Salmona has nothing to disclose. Conflict of interest: V. Meignin has nothing to disclose. Conflict of interest: G. Lorillon reports support for travel and accommodation from Vitalaire and Chiesi outside the submitted work. Conflict of interest: A. Sadoux has nothing to disclose. Conflict of interest: J. Cherot has nothing to disclose. Conflict of interest: C. Lebbé reports honoraria from, and consultancy, and serving on a speakers bureau and an advisory board for Amgen; grants and honoraria from, and consultancy, and serving on a speakers bureau and an advisory board for BMS; grants and honoraria from, and consultancy, and service in an advisory role and on an advisory board for, and travel and accomodation for meetings from MSD; grants and honoraria, and consultancy, and service in a speakers bureau, in an advisory role and on an advisory board for Roche and Novartis; consultancy for and honoraria from Pierre Fabre; consultancy for Sanofi and Merck Serono; and honoraria from Pfizer and Incyte, all outside the submitted work. Conflict of interest: S. Mourah reports consulting for Novartis and Roche outside the submitted work. Conflict of interest: A. Tazi reports personal fees from Bristol-Myers Squibb for speaking at a conference, and travel and accommodation support from Boehringer Ingelheim, Teva, Vitalaire and AstraZeneca, all outside the submitted work., (Copyright ©ERS 2020.) more...

The clinical significance of the BRAF V600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome.Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAF V600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.MAPK pathway alterations were detected in 59 out of 69 cases (86%) ( BRAF V600E mutation: 36%, BRAF N486&#95;P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRAS Q61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAF V600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAF V600E status did not influence the risk of LCH progression over time.Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAF V600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH., Competing Interests: Conflict of interest: F. Jouenne has nothing to disclose. Conflict of interest: S. Chevret has nothing to disclose. Conflict of interest: E. Bugnet has nothing to disclose. Conflict of interest: E. Clappier has nothing to disclose. Conflict of interest: G. Lorillon reports travel/accommodation from Vitalaire and Chiesi, outside the submitted work. Conflict of interest: V. Meignin has nothing to disclose. Conflict of interest: A. Sadoux has nothing to disclose. Conflict of interest: S. Cohen has nothing to disclose. Conflict of interest: A. Haziot has nothing to disclose. Conflict of interest: A. How-Kit has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: C. Lebbé reports personal fees for consultancy, lectures and advisory board work from Amgen, grants and personal fees for consultancy, lectures, advisory board work and travel to meetings from BMS, grants and personal fees for consultancy, advisory board work and travel to meetings from MSD, grants and personal fees for consultancy, lectures and advisory board work from Roche and Novartis, personal fees for consultancy from Pierre Fabre, Sanofi and Merck Serono, and personal fees from Pfizer and Incyte, outside the submitted work. Conflict of interest: D. Gossot reports personal fees from Delacroix-Chevalier (instrument manufacturer), outside the submitted work. Conflict of interest: S. Mourah reports consultancy for Novartis and Roche, outside the submitted work. Conflict of interest: A. Tazi reports personal fees for lectures from BMS and travel/accommodation fees from Boehringer Ingelheim, Teva, Vitalaire and AstraZeneca, outside the submitted work., (Copyright ©ERS 2020.) more...

Background: Pneumothorax may recur during pulmonary Langerhans cell histiocytosis (PLCH) patients' follow-up and its management is not standardised. The factors associated with pneumothorax recurrence are unknown., Methods: In this retrospective study, PLCH patients who experienced a pneumothorax and were followed for at least 6 months after the first episode were eligible. The objectives were to describe the treatment of the initial episode and pneumothorax recurrences during follow-up. We also searched for factors associated with pneumothorax recurrence and evaluated the effect on lung function outcome. Time to recurrence was estimated by the Kaplan Meier method and the cumulative hazard of recurrence handling all recurrent events was estimated. Univariate Cox models and Andersen-Gill counting process were used for statistical analyses., Results: Fourty-three patients (median age 26.5 years [interquartile range (IQR), 22.9-35.4]; 26 men, 39 current smokers) were included and followed for median time of 49 months. Chest tube drainage was the main management of the initial pneumothorax, which resolved in 70% of cases. Pneumothorax recurred in 23 (53%) patients, and overall 96 pneumothoraces were observed during the study period. In the subgroup of patients who experienced pneumothorax recurrence, the median number of episodes per patient was 3 [IQR, 2-4]. All but one recurrence occurred within 2 years after the first episode. Thoracic surgery neither delayed the time of occurrence of the first ipsilateral recurrence nor reduced the overall number of recurrences during the study period, although the rate of recurrence was lower after thoracotomy than following video-assisted thoracic surgery (p = 0.03). At the time of the first pneumothorax, the presence of air trapping on lung function testing was associated with increased risk of recurrence (hazard ratio = 5.08; 95% confidence interval [1.18, 21.8]; p = 0.03). Pneumothorax recurrence did not predict subsequent lung function decline (p = 0.058)., Conclusions: Our results show that pneumothorax recurrences occur during an "active" phase of PLCH. In this observational study, the time of occurrence of the first ipsilateral recurrence and the overall number of pneumothorax recurrences were similar after conservative and thoracic surgical treatments. Further studies are needed to determine the best management to reduce the risk of pneumothorax recurrence in PLCH patients. more...

Langerhans cell histiocytosis is a rare histiocytic disorder for which skin involvement and management are poorly described in adults. The aim of this retrospective monocentric study in a national reference centre is to describe the clinical characteristics, quality of life, BRAF mutation status and outcomes of skin involvement in adult patients with Langerhans cell histiocytosis. Twenty-five patients (14 females, mean age 47 years) were included, with a median follow-up of 33 months (range 4-420 months). Patients experienced poor dermatological quality of life despite low body surface involvement. BRAFV600 mutations were detected in 8 of the 18 patients analysed (45%). Eight patients had an associated malignancy. Several treatment options were used and consisted of surgery, topical steroids and carmustine, thalidomide, methotrexate, vinblastine and steroids and cladribine. This study highlights the need to evaluate quality of life and to screen for associated malignancy in adult patients with Langerhans cell histiocytosis. more...

Background: Vinblastine is the standard treatment for children with Langerhans cell histiocytosis (LCH). Whether this treatment could be extended to adults with LCH is questionable. This retrospective multicenter study included 35 adult patients (median age 33 years; 23 men; 80% with multisystem LCH) who were treated with vinblastine + steroids as a first-line chemotherapy and followed for a median time of 83 months. The objectives were to determine the overall response rate (based on the Histiocyte Society criteria), disease reactivation rate, toxicity, permanent consequences, and survival rate corresponding to this treatment. The lung involvement outcome was based on serial lung function tests. The distribution of right-censored end points was estimated by the Kaplan-Meier method. Univariate Cox model with time-fixed and time-varying covariates was used for the predictive analysis of reactivation in the responders. Univariate analyses of risk factors for neurotoxicity were based on nonparametric Wilcoxon rank sum tests and exact Fisher tests., Results: The median duration of the first course of vinblastine was 7.6 months, with a median cumulative dose of 160 mg [IQR 120-212]. Seventy percent of the patients were responders at the end of this treatment. Subsequently, LCH reactivation occurred with a 5-year cumulative incidence of 40%. During the study, 27 reactivations were observed in 17 patients, and half of these episodes were retreated with vinblastine. At the end of the last vinblastine treatment, 70% of the patients were responders. None of the patients with impaired lung function improved. No grade 3-4 peripheral neuropathy was observed. At the final vinblastine treatment, permanent LCH consequences, primarily pituitary stalk involvement, were present in 15 (43%) patients, and all were present at the time of vinblastine initiation. The 10-year survival rate was 86.2% (95CI, 71.8-100%), and the 2 patients who died from LCH had risk organ localizations., Conclusions: Vinblastine is an effective and well-tolerated first-line treatment for adult LCH except in patients with lung involvement and impaired lung function. However, a significant portion of patients experienced LCH reactivation during long-term follow up. As in childhood LCH, the presence of risk organ involvement has a negative impact on patient prognosis. more...

Purpose: The standard evaluation of multisystem Langerhans cell histiocytosis (LCH) includes a clinical evaluation, laboratory tests and a skeleton/skull X-ray survey, with chest high-resolution computed tomography (HRCT) in the case of pulmonary involvement. Preliminary reports suggest that 18 F-fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET-CT) may be useful for evaluating patients with LCH., Methods: Fourteen consecutive adult patients with multisystem LCH were included in this retrospective study, and were evaluated using standard procedures and 18 F-FDG PET-CT. The two sets of findings were compared both at baseline and during follow-up. Serial HRCT and pulmonary function tests were used to evaluate outcome in patients with lung involvement., Results: At the baseline evaluation, PET-CT identified every LCH localization found with the standard evaluation (except a mild cecum infiltration). PET-CT showed additional lesions in seven patients, mostly involving bones, and differentiated inactive from active lesions. Thyroid 18 F-FDG uptake was identified in three cases. No pituitary stalk 18 F-FDG uptake was observed in patients with pituitary LCH. Only 3/12 (25 %) patients with pulmonary LCH displayed moderate pulmonary 18 F-FDG uptake. During follow-up, variations (≥50 % of maximum standardized uptake) in bone 18 F-FDG uptake intensity were correlated with disease state and response to treatment. The absence of lung 18 F-FDG uptake did not preclude lung function improvement after treatment., Conclusions: Except for cases with pulmonary and pituitary involvement, 18 F-FDG PET-CT could replace the standard evaluation for staging of adult patients with multisystem LCH. Serial PET-CT scans are useful for evaluating treatment responses, particularly in cases with bone LCH involvement. more...

The mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH). Mutations of the downstream kinases BRAF and MAP2K1 mediate this activation in a subset of LCH lesions. In this study, we attempted to identify other mutations which may explain the MAPK activation in nonmutated BRAF and MAP2K1 LCH lesions.We analysed 26 pulmonary and 37 nonpulmonary LCH lesions for the presence of BRAF, MAP2K1, NRAS and KRAS mutations. Grossly normal lung tissue from 10 smoker patients was used as control. Patient spontaneous outcomes were concurrently assessed.BRAF(V600E) mutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harboured NRAS(Q61K) (/R) mutations, whereas no NRAS mutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11 NRAS(Q61K) (/R)-mutated pulmonary LCH lesions, BRAF(V600) (E) mutations were also present. Separately genotyping each CD1a-positive area from the same pulmonary LCH lesion demonstrated that these concurrent BRAF and NRAS mutations were carried by different cell clones. NRAS(Q61K) (/R) mutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrent BRAF(V600E) and NRAS(Q61K) (/R) mutations was significantly associated with patient outcome.These findings highlight the importance of NRAS genotyping of pulmonary LCH lesions because the use of BRAF inhibitors in this context may lead to paradoxical disease progression. These patients might benefit from MAPK kinase inhibitor-based treatments., (Copyright ©ERS 2016.) more...

Background: An important objective on diagnosis of patients with Langerhans cell histiocytosis (LCH) is to determine the extent of disease. However, whether systematic extrathoracic investigation is needed in adult patients with clinically isolated pulmonary LCH (PLCH) has not been evaluated., Methods: In this prospective, multicentre study, 54 consecutive patients with newly diagnosed clinically isolated PLCH were systematically evaluated at inclusion by bone imaging and blood laboratory testing to search for subclinical extrapulmonary LCH involvement. The patients were followed over a 2-year period. At each visit, they were asked about the presence of extrapulmonary manifestations of LCH., Results: In the absence of bone symptoms, the skeletal X-ray survey results were normal for all but two patients who had a localised bone lesion consistent with possible LCH involvement, that remained unchanged over 2 years of follow-up. Whole-body bone scintigraphy did not add information to the plain radiography findings for the detection of asymptomatic bone involvement in isolated PLCH. Conversely, it showed nonspecific focal bone uptake in 18% of the patients, mainly corresponding to post-traumatic or degenerative abnormalities unrelated to LCH. Mild leucocytosis due to neutrophilia was observed in 22% of the patients and was not related to their smoking habits. Three patients had mild isolated lymphocytosis without haematological disease, whereas two patients had mild lymphopaenia. A mild inflammatory biological syndrome was observed in a minority of patients without infection or constitutional symptoms and was not associated with progressive disease. A substantial proportion (24.5%) of the patients had abnormal biological liver test results, including elevated liver enzymes and/or cholestasis, which were not linked to LCH involvement in this cohort., Conclusions: Obtaining a thorough history and performing comprehensive physical examination are essential for staging patients diagnosed with PLCH. In the absence of symptoms or signs suggestive of extrapulmonary LCH involvement, the systematic performing of recommended bone imaging does not appear informative. Although the observed blood laboratory abnormalities were not specifically related to LCH, performing these tests in the diagnostic workup for PLCH is useful because some of these alterations may impact patient management., Trial Registration: ClinicalTrials.gov: No. NCT01225601; URL: www.clinicaltrials.gov. more...

Background: The natural history of pulmonary Langerhans cell histiocytosis (PLCH) has been unclear due to the absence of prospective studies. The rate of patients who experience an early progression of their disease is unknown. Additionally, conflicting effects of smoking cessation on the outcome of PLCH have been reported., Methods: In this prospective, multicentre study, 58 consecutive patients with newly diagnosed PLCH were comprehensively evaluated over a two-year period. Our objectives were to estimate the incidence of early progression of the disease and to evaluate the impact of smoking status on lung function outcomes. Lung function deterioration was defined as a decrease of at least 15% in FEV1 and/or FVC and/or DLCO, compared with baseline values. At each visit, smoking status was recorded based on the patients' self-reports and urinary cotinine measurements that were blinded for the patients. The cumulative incidence of lung function outcomes over time was estimated using the non-parametric Kaplan-Meier method. Multivariate Cox models with time-dependent covariates were used to calculate the hazards ratios of the lung function deterioration associated with smoking status with adjustment for potential confounders., Results: The cumulative incidence of lung function deterioration at 24 months was 38% (22% for FEV1 and DLCO, and 9% for FVC). In the multivariate analysis, smoking status and PaO2 at inclusion were the only factors associated with the risk of lung function deterioration. The patients' smoking statuses markedly changed over time. Only 20% of the patients quit using tobacco for the entire study period. Nevertheless, being a non-smoker was associated with a decreased risk of subsequent lung function deterioration, even after adjustment for baseline predictive factors. By serial lung computed tomography, the extent of cystic lesions increased in only 11% of patients., Conclusions: Serial lung function evaluation on a three- to six-month basis is essential for the follow-up of patients with recently diagnosed PLCH to identify those who experience an early progression of their disease. These patients are highly addicted to tobacco, and robust efforts should be undertaken to include them in smoking cessation programs., Trial Registration: ClinicalTrials.gov: No: NCT01225601 . more...

Low-molar-mass organogelators (LMOG) can turn liquids into thermoreversible gels because they self-assemble into a fibrous network. In contrast, using the same kind of low-molar-mass additives to harden materials, which are already solidlike on their own, has been hardly exploited. We show here that simple dicarboxylic acids are very efficient low-molar-mass organogelators (LMOG) for bitumen. Indeed, they increase the range of temperature where bitumen is a solid. Moreover, the hardness and elastic modulus of bitumen at room temperature are also improved. This concept of improving the mechanical properties of a solid with an LMOG can probably be applied to other materials. more...