Epidemiology of patients with lymphangioleiomyomatosis: A descriptive study using the national database of health insurance claims and specific health checkups of Japan.

BACKGROUND: Using patient registries or limited regional hospitalization data may result in underestimation of the incidence and prevalence of rare diseases. Therefore, we used the national administrative database to estimate the incidence and prevalence of lymphangioleiomyomatosis over six years (2014-2019) and describe changes in clinical practice and mortality. METHODS: We extracted data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between January 2013 and December 2020. This database covers ≥99% of the population. We used the diagnostic code for lymphangioleiomyomatosis to estimate the incidence and prevalence from 2014 to 2019. Additionally, we examined the demographic characteristics, treatments, comorbidities, and mortality of the patients. RESULTS: In women, the incidence and prevalence of lymphangioleiomyomatosis in 2019 were approximately 3 per 1,000,000 person-years and 28.7 per 1,000,000 persons, respectively. While, in men, the incidence and prevalence of lymphangioleiomyomatosis were <0.2 per 1,000,000 person-years and 0.8 per 1,000,000 persons, respectively. From 2014 to 2019, the proportion of prescriptions of sirolimus and everolimus increased, while the use of home oxygen therapy, chest drainage, comorbid pneumothorax, and bloody phlegm decreased. The mortality rate remained stable at approximately 1%. CONCLUSIONS: The incidence and prevalence of lymphangioleiomyomatosis were higher in women than those reported previously. Although the incidence did not change during the 6-year period, the prevalence gradually increased. Moreover, lymphangioleiomyomatosis was observed to be rare in men. The practice of treating patients with lymphangioleiomyomatosis changed across the six years while mortality remained low, at approximately 1%.

[Diffuse cystic lung disease]. / Cystische Lungenerkrankungen.

INTRODUCTION: Diffuse cystic lung disease (DCLD) represents a heterogeneous group of conditions, typically characterized by the presence of multiple thin-walled, predominantly round parenchymal lucencies. The increased accessibility of computed tomography (CT) underscores the growing relevance of a relatively rare group of diseases as more clinicians are confronted with the presence of multiple lung cysts on the chest CT scan. Although the etiology of these conditions is very diverse, the focus of the differential diagnosis revolves around four primary causative factors - Lymphangioleiomyomatosis (LAM), Pulmonary Langerhanscell histiocytosis (PLCH), Birt-Hogg-Dubé (BHD) and lymphoid interstitial pneumonia (LIP). Achieving an accurate diagnosis poses a challenge and typically necessitates lung biopsies; however, it is crucial for ensuring proper management.

[Genetic diffuse cystic lung disease in adults]. / Maladies kystiques pulmonaires de l'adulte d'origine génétique.

Multiple cystic lung diseases comprise a wide range of various diseases, some of them of genetic origin. Lymphangioleiomyomatosis (LAM) is a disease occurring almost exclusively in women, sporadically or in association with tuberous sclerosis complex (TSC). Patients with LAM present with lymphatic complications, renal angiomyolipomas and cystic lung disease responsible for spontaneous pneumothoraces and progressive respiratory insufficiency. TSC and LAM have been ascribed to mutations in TSC1 or TSC2 genes. Patients with TSC are variably affected by cutaneous, cognitive and neuropsychiatric manifestations, epilepsy, cerebral and renal tumors, usually of benign nature. Birt-Hogg-Dubé syndrome is caused by mutations in FLCN encoding folliculin. This syndrome includes lung cysts of basal predominance, cutaneous fibrofolliculomas and various renal tumors. The main complications are spontaneous pneumothoraces and renal tumors requiring systematic screening. The mammalian target of rapamycin (mTOR) pathway is involved in the pathophysiology of TSC, sporadic LAM and Birt-Hogg-Dubé syndrome. MTOR inhibitors are used in LAM and in TSC while Birt-Hogg-Dubé syndrome does not progress towards chronic respiratory failure. Future challenges in these often under-recognized diseases include the need to reduce the delay to diagnosis, and to develop potentially curative treatments. In France, physicians can seek help from the network of reference centers for the diagnosis and management of rare pulmonary diseases.

French recommendations for the diagnosis and management of lymphangioleiomyomatosis.

BACKGROUND: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France. METHODS: Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases. RESULTS: Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications. CONCLUSION: These recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis.

Lymphangioleiomyomatosis and Other Cystic Lung Diseases.

Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤2 mm) from cavities and characterize their distribution as focal or multifocal versus diffuse. Focal cavitary lesions are often caused by inflammatory, infectious, or neoplastic processes in contrast to diffuse cystic lung diseases. An algorithmic approach to diffuse cystic lung disease can help narrow the differential diagnosis, and additional testing such as skin biopsy, serum biomarkers, and genetic testing can be confirmatory. An accurate diagnosis is essential for the management and disease surveillance of extrapulmonary complications.

Prophylactic renal artery embolization before pregnancy in patients with lymphangioleiomyomatosis and renal angiomyolipoma.

OBJECTIVE: Pregnant patients with lymphangioleiomyomatosis (LAM) and renal angiomyolipomas (AMLs) require care for both renal AMLs and pulmonary dysfunction because AMLs can grow and rupture during pregnancy, potentially causing hemorrhagic shock and fetal death. This study examined whether prophylactic transcatheter arterial embolization (TAE) could prevent the pregnancy-associated growth and rupture of renal AMLs in patients with LAM. METHODS: This retrospective study included five women with 14 renal AMLs (initial diameter, ≥2 cm) first encountered between September 2010 and August 2015 who subsequently became pregnant. Seven tumors in five patients were embolized, and seven tumors in two patients were not treated. Changes in the volume of each tumor were evaluated. RESULTS: Untreated tumors were much more likely to grow than embolized tumors both during pregnancy (100% vs. 0%) and at the first follow-up visit after delivery (100% vs. 14%). One untreated hypervascular tumor grew rapidly during pregnancy to 409% of the pretreatment volume. No tumor ruptured. CONCLUSIONS: Prophylactic pre-pregnancy TAE decreased the growth and bleeding of renal AMLs during pregnancy in patients with LAM. TAE can be recommended for hypervascular tumors before pregnancy regardless of the size of the aneurysm.

YouTube-videos for patient education in lymphangioleiomyomatosis?

BACKGROUND: The Internet is commonly used by patients to acquire health information. To date, no studies have evaluated the quality of information available on YouTube regarding lymphangioleiomyomatosis (LAM). Our aim was to determine the quality and content of YouTube videos regarding LAM and to compare the information provided with current knowledge and guidelines about the disease. METHODS: The first 200 video hits on YouTube in English for the search term "lymphangioleiomyomatosis" were recorded. All videos suitable for patient education on LAM were included. Video quality was analyzed independently by two investigators utilizing the Health on the Net (HONcode) score, which assesses whether websites provide understandable, accessible, and trustworthy health information; the DISCERN score, which evaluates the quality of information about treatment decisions; and a newly developed LAM-related content score (LRCS) with 31 guideline elements. RESULTS: The search identified 64 eligible videos. The "engagement rate" of 0.3 was low, with a median number of views of 408 (range 42-73,943), a median of 4 likes (range 0-2082), and the majority (53%) receiving a low HONcode score (≤ 2) and only 10% of videos achieving a high score (> 5). The median DISCERN score was 28 (range 15-61, maximum possible score 80), indicating poor video quality and reliability. The median LRCS was 8 (range 0-29, maximum possible score 31) and videos frequently failed to provide sources of information. CONCLUSIONS: Online resources could contribute to the limited and often inaccurate information available to patients with LAM, with only a few YouTube videos providing high-quality patient-relevant information.

Sarcoma de Kaposi tipo linfangiomatoso: comunicación de un caso / 9 LYMPHANGIOMATOUS KAPOSI'S SARCOMA: CASE REPORT

El sarcoma de Kaposi linfangiomatoso es una variante clínica rara del sarcoma de Kaposi. Tiene la característica de presentarse como cavidades con contenido líquido que muchas veces se confunden con enfermedades ampollares de la piel. Presentamos un paciente masculino con antecedente de infección por VIH asociado a sarcoma de Kaposi clásico, diseminado a nivel pulmonar, gastrointestinal y cutáneo. Tras dos ciclos de quimioterapia mejoró el compromiso sistémico, pero comenzó con ampollas en ambos muslos, por lo que junto con estudios clínicos y estudios complementarios se llegó al diagnóstico de sarcoma de Kaposi linfangiomatoso.

Lymphangiomatous Kaposi's sarcoma is a rare clinical variant of Kaposi's sarcoma. It has the characteristic of appearing as cavities with liquid content that are often confused with blistering skin diseases. We present a male patient with a history of HIV infection associated with classic Kaposi's sarcoma, disseminated to the pulmonary, gastrointestinal and skin levels. After two cycles of chemotherapy, the systemic involvement improved but she began with blisters on both thighs, from which, together with clinical studies and complementary studies, a diagnosis of lymphangiomatous Kaposi's sarcoma was reached.

Lung Diseases Unique to Women.

The differences in the respiratory system between women and men begin in utero. Biologic sex plays a critical role in fetal development, airway anatomy, inhalational exposures, and inhaled particle deposition of the respiratory system, thus leading to differences in risk for disease, as well as clinical manifestations, morbidity, and mortality. In this article, we focus on those respiratory diseases unique to females: lymphangioleiomyomatosis and thoracic endometriosis syndrome.

Linfangioleiomiomatosis. Similitudes y diferencias entre sus dos formas clínicas / Lymphangioleiomyomatosis. Similarities and differences between its two clinical forms

La linfangioleiomiomatosis (LAM) es una enfermedad pulmonar que se caracteriza por la proliferación de células musculares lisas atípicas en el pulmón y por la destrucción del tejido en forma de quistes. Existen dos formas clínicas de LAM, la esporádica (LAM-S) y la asociada a CET (LAM-CET), esta última es cinco veces más frecuente que la LAM-S, puede tener mutación tanto en el gen TSC1 o en el TSC2, mientras que la LAM-S solo en TSC2. La LAM-S es más sintomática, agresiva, presenta mayor ocupación quística, con peores valores en FEV1 y DLCO, menor número de NP (HMNM) y menor número de AML renales que la LAM-CET. No se han descrito diferencias en cuanto a la histología, fisiopatología, tipo de tratamiento o pronóstico

Lymphangioleiomyomatosis (LAM) is a lung disease characterized by the proliferation of atypical smooth muscle cells in the lung and the destruction of tissue in the form of cysts. There are two clinical forms of LAM, sporadic (LAM-S) and associated with TSC (LAM-CET), the latter is five times more frequent than LAM-S, it may have a mutation in both the TSC1 or TSC2 gene, while LAM-S only in TSC2 while LAM-S is more symptomatic and aggressive with greater cystic occupation, worse FEV1 and DLCO values, fewer pulmonary nodules (PN) and fewer renal AML than form LAM-CET. No differences have been described in terms of histology, pathophysiology, type of treatment or prognosis

Description of a multidisciplinary model of care in a French cohort of adult patients with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Due to the various manifestations of TSC and their potential complications, a multidisciplinary care approach is recommended by consensus guidelines. OBJECTIVES: Our study aimed to give a complete description of our TSC adult cohort and to evaluate the multidisciplinary and interdisciplinary management model. METHODS: Data on each adult patient diagnosed with TSC, including disease manifestations, interventions and outcomes, were collected at baseline and updated annually. A multidisciplinary TSC approach with all the recommended explorations was carried out annually. RESULTS: 90 patients were enrolled in Centre Hospitalier Universitaire de Bordeaux, between January 2000 and September 2018. Median age of patients at inclusion was 37 years (range, 27-47) and 20 years old at diagnosis of TSC. Regarding the occurrence of TSC manifestations, 97% of the patients had cutaneous lesions, 89% had neurological manifestations, 83% had renal manifestations and 100% had dental lesions with pits. More than half the patients had sclerotic bone lesions (68%), TSC-associated neuropsychiatric disorders (64%) and lymphangioleiomyomatosis (59%). A TSC multidisciplinary approach was developed including a global follow-up and an evaluation of TSC targeting organs, according to the recommendations. A satisfaction survey revealed global and entire satisfaction of patients with TSC. CONCLUSION: We obtained an accurate description of a cohort of adult patients with TSC. Our multidisciplinary approach model allowed us to provide optimal management of patients with TSC with a high level of patient satisfaction.

Benefits of pulmonary rehabilitation in patients with advanced lymphangioleiomyomatosis (LAM) compared with COPD - a retrospective analysis.

Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung disease with limited therapeutic options. We retrospectively analyzed the effects of a comprehensive 4-week inpatient pulmonary rehabilitation (PR) program in 58 patients with advanced LAM (FEV1: 45 ± 34%predicted, 6-min walk distance (6MWD): 338 ± 167 m). Exercise performance (6MWD: + 49 ± 50 m; p < 0.001) and quality of life (SF-36 physical component: + 2.4 ± 7.8 points; p = 0.049 and mental component: + 5.2 ± 12.1 points; p < 0.001) increased significantly after PR comparable to an COPD cohort. There were no clinical parameters that predicted changes in outcomes following PR. PR seems to be an effective therapeutic option even in patients with advanced LAM. TRIAL REGISTRATION: Clinical-Trials registration number: NCT04184193 ; date of registration: December 3, 2019.

High-intensity exercise improves pulmonary function and exercise tolerance in a patient with TSC-LAM.

INTRODUCTION: While exercise has been shown to improve respiratory symptoms, exercise tolerance, and bone mineral density in many populations, no supervised exercise training interventions have been undertaken in patients with lymphangioleiomyo-matosis (LAM). MATERIAL AND METHODS: One patient with TSC-LAM (tuberous sclerosis complex lymphangioleiomyomatosis) participated in two weekly sessions (50-60 min) of supervised aerobic exercise at 80-85% heart rate max for one year. Treadmill ergometry (VO2peak), spirometry (FEV1, FVC, FEV1/FVC, peak flow), and bone mineral density testing were performed prior to every 3 months. RESULTS: After one year of supervised aerobic exercise training we saw dramatic increases in the patient's VO2max (20%), FEV1 (9.5%), FEV1/FVC (9.1%) and peak flow (47%). CONCLUSIONS: The results from this study indicate that supervised exercise training can improve exercise tolerance and pulmonary function in a patient with lymphangioleiomyomatosis. Further research is needed, including longitudinal studies with larger sample sizes, to determine long-term effects and consistency of these findings. Aerobic exercise may offer a viable alternative or com-pliment to pharmacological interventions in the treatment of lymphangioleiomyomatosis. We show that high-intensity exercise training can markedly and safely improve pulmonary function in a patient with TSC-LAM. While we did not record quality of life or mood states, our patient did report improved self-confidence as well as enhanced mood.

Pregnancy in lymphangioleiomyomatosis: clinical and lung function outcomes in two national cohorts.

Pregnancy in women with lymphangioleiomyomatosis (LAM) has been associated with increased complications and worsening lung function although objective data to advise patients are not available. We assessed lung function and CT scans before and after pregnancy in 16 women with LAM. During the pregnancy, pneumothorax was frequent and mean forced expiratory volume in 1 s (FEV1) fell from 77%±19% prepregnancy to 64%±25% predicted and DLCO from 66±26 to 57±26 (both p<0.01). After pregnancy, rates of FEV1 decline were high and 10 patients required sirolimus. Women with LAM, especially with moderate or advanced disease should be counselled regarding adverse events and loss of lung function during the pregnancy.

Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a slow albeit progressive rare neoplastic disease featured with diffuse thin-walled cysts in lungs and angiomyolipomas in kidneys. LAM affects almost exclusively women and has one of the strongest gender predispositions of any extragenital human disease. Two forms of LAM present clinically, sporadic (S-LAM) and tuberous sclerosis complex-associated (TSC-LAM). TSC is an autosomal dominant genetic multisystems neoplastic disease. A high prevalence of LAM can be detected in adult female TSC patients. Tremendous progress has been made in our understanding and management of this rare disease. Both LAM and TSC are TSC2 or TSC1 mutated diseases that result in overactivation of the mechanistic target of rapamycin (mTOR) pathway. Sirolimus, an mTOR inhibitor, has been approved for LAM treatment in the United States and many other countries. Therapies targeting female sex hormones have shown preclinical efficacy in animal and cell culture-based experiments, but have not been properly investigated clinically. In this review, we summarize current recommendations in the diagnosis and treatment of LAM.

Effects of yoga on exercise capacity in patients with lymphangioleiomyomatosis: a nonrandomized controlled study.

OBJECTIVE: To evaluate the effects of yoga on exercise capacity and quality of life in patients with lymphangioleiomyomatosis (LAM), a rare cystic lung disease in women. PATIENTS AND METHODS: This was a nonrandomized, controlled study conducted in Beijing, China (August 27, 2017 - April 26, 2018). Twenty-six participants were allocated to the intervention (yoga) group (n = 13) or control group (n = 13). The yoga intervention involved a 24-week program of yoga class training for 90 min once a week and no fewer than 2 at-home sessions per week (at least 15 min per session). The 6-min walking distance (6MWD), lung function, serum vascular endothelial growth factor-D (VEGF-D) levels, quality of life, and symptoms of anxiety and depression were measured at baseline, 12-week and 24-week follow-up. An incremental cardiopulmonary exercise test was conducted at baseline and the 24-week follow-up. RESULTS: Eleven patients completed the yoga training program. The yoga group exhibited improvements in the following outcomes versus those of the control group: 6MWD (+ 55 ± 29 m vs + 18 ± 49 m, P = 0.04), anaerobic threshold (3.4 ± 2.4 ml/min/kg vs 1.6 ± 1.4 ml/min/kg, P = 0.035) and peak work load (11.7 ± 14.6 W vs 0.2 ± 9.1 W, P = 0.027). There was no significant difference in peak oxygen consumption (VO2peak), lung function, VEGF-D level, and quality of life between the yoga and control groups. No adverse effects were found in the yoga group. CONCLUSION: Yoga is a feasible and safe intervention for pulmonary rehabilitation and potentially improves exercise capacity in patients with LAM. TRIAL REGISTRATION: (Clinical trial registration number at www.chictr.org.cn: ChiCTR-OON-1701274).

Adoptive T-Cell Transfer to Treat Lymphangioleiomyomatosis.

Patients with lymphangioleiomyomatosis (LAM) develop pulmonary cysts associated with neoplastic, smooth muscle-like cells that feature neuroendocrine cell markers. The disease preferentially affects premenopausal women. Existing therapeutics do not cure LAM. As gp100 is a diagnostic marker expressed by LAM lesions, we proposed to target this immunogenic glycoprotein using TCR transgenic T cells. To reproduce the genetic mutations underlying LAM, we cultured Tsc2-/- kidney tumor cells from aged Tsc2 heterozygous mice and generated a stable gp100-expressing cell line by lentiviral transduction. T cells were isolated from major histocompatibility complex-matched TCR transgenic pmel-1 mice to measure cytotoxicity in vitro, and 80% cytotoxicity was observed within 48 hours. Antigen-specific cytotoxicity was likewise observed using pmel-1 TCR-transduced mouse T cells, suggesting that transgenic T cells may likewise be useful to treat LAM in vivo. On intravenous injection, slow-growing gp100+ LAM-like cells formed lung nodules that were readily detectable in severe combined immunodeficient/beige mice. Adoptive transfer of gp100-reactive but not wild-type T cells into mice significantly shrunk established lung tumors, even in the absence of anti-PD-1 therapy. These results demonstrate the treatment potential of adoptively transferred T cells to eliminate pulmonary lesions in LAM.

Immunotherapy for Lymphangioleiomyomatosis and Tuberous Sclerosis: Progress and Future Directions.

Pulmonary lymphangioleiomyomatosis (LAM) is a rare genetic multisystem disease characterized by the nodular proliferation of smooth muscle-like LAM cells, progressive cystic changes of the lung, lymphatic abnormalities, and renal angiomyolipomas (AMLs). LAM can arise sporadically or in women with the autosomal dominant disorder, tuberous sclerosis complex (TSC), in which hamartomatous tumors of brain, heart, skin, kidney, and lung are found. LAM and TSC are caused by mutations in the TSC1 or TSC2 tumor suppressor genes leading to elevated mechanistic/mammalian target of rapamycin complex activity. Recent data indicate that T cells within LAM nodules and renal AMLs exhibit features of T-cell exhaustion, with coinhibitory receptor programmed cell death protein 1 (PD-1) expression on tumor-infiltrating T cells. Treatment of animal models of TSC and LAM with anti-PD-1 antibodies or with the combination of anti-PD-1 and anti-CTLA4 antibodies has led to remarkable results, suppressing TSC2-null tumor growth and inducing tumor rejection. Here we review our current knowledge about the potential for immunotherapy for the treatment of LAM and TSC and highlight critical unknowns and key next steps.