American Thoracic Society Conference 2016 Information

Thank you for joining us this year at the American Thoracic Society conference. Below are articles that you may find interesting and helpful when you are working with LAM patients. If you would like to continue to receive the most up-to-date information about LAM research and what's happening at The LAM Foundation, please register with us and join our mailing list. If you have any further questions, please contact The LAM Foundation at info@thelamfoundation.org or by phone at (513) 777-6889.


Eight LAM Articles That Led To An Effective Treatment

Identification of the genes that cause tuberous sclerosis
1: European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993 Dec 31;75(7):1305-15. PubMed PMID: 8269512.

2: van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S,Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997 Aug 8;277(5327):805-8. PubMed PMID: 9242607.

Discovery of the function of LAM genes
3: Ito N, Rubin GM. gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell. 1999 Feb 19;96(4):529-39. Erratum in: Cell 2001 May 4;105(3):415. PubMed PMID: 10052455.

Discovery that tuberous sclerosis mutations cause LAM
4: Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EP. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am J Hum Genet. 1998 Apr;62(4):810-5. PubMed PMID: 9529362; PubMed Central PMCID: PMC1377043.

5: Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6085-90. PubMed PMID: 10823953; PubMed Central PMCID: PMC18562.

Discovery that mTOR is activated in LAM tissues
6: Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM, Panettieri RA Jr, Krymskaya VP.Tuberin regulates p70 S6 kinase activation and ribosomal protein S6phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem. 2002 Aug 23;277(34):30958-67. Epub2002 Jun 3. PubMed PMID: 12045200.

Demonstration that mTOR inhibitors have promise in tuberous sclerosis models.
7: Kenerson H, Dundon TA, Yeung RS. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res. 2005 Jan;57(1):67-75. Epub 2004 Nov 19. PubMed PMID: 15557109.

Identification of sirolimus is an effective therapy for LAM
8: McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L,Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16. PubMed PMID: 21410393; PubMed Central PMCID: PMC3118601.


The Ten Most Exciting Papers Since ATS 2015

Pulmonary rehabilitation is beneficial in LAM
1: Araujo MS, Baldi BG, Freitas CS, Albuquerque AL, Marques da Silva CC, Kairalla RA, Carvalho CR, Carvalho CR. Pulmonary rehabilitation in lymphangioleiomyomatosis: a controlled clinical trial. Eur Respir J. 2016 May;47(5):1452-60. doi: 10.1183/13993003.01683-2015. Epub 2016 Feb 25. PubMed PMID: 26917604.

Uterine TSC2 KO mouse model of LAM
2: Prizant H, Taya M, Lerman I, Light A, Sen A, Mitra S, Foster T, Hammes SR. Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model. Endocr Relat Cancer. 2016 Feb 15. pii: ERC-15-0505. [Epub ahead of print] PubMed PMID: 26880751.

mTOR drives production of purines for DNA and ATP generation
3: Ben-Sahra I, Hoxhaj G, Ricoult SJ, Asara JM, Manning BD. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science. 2016 Feb 12;351(6274):728-33. doi: 10.1126/science.aad0489. PubMed PMID: 26912861; PubMed Central PMCID: PMC4786372.

Deep sequencing of LAM lesions
4: Fujita A, Ando K, Kobayashi E, Mitani K, Okudera K, Nakashima M, Miyatake S, Tsurusaki Y, Saitsu H, Seyama K, Miyake N, Matsumoto N. Detection of low-prevalence somatic TSC2 mutations in sporadic pulmonary lymphangioleiomyomatosis tissues by deep sequencing. Hum Genet. 2016 Jan;135(1):61-8. doi: 10.1007/s00439-015-1611-0. Epub 2015 Nov 12. PubMed PMID: 26563443.

Targeting the VEGF axis is effective in LAM mouse models
5: Atochina-Vasserman EN, Abramova E, James ML, Rue R, Liu AY, Ersumo NT, Guo CJ, Gow AJ, Krymskaya VP. Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis. Am J Physiol Lung Cell Mol Physiol. 2015 Dec 15;309(12):L1447-54. doi: 10.1152/ajplung.00262.2015. Epub 2015 Oct 2. PubMed PMID: 26432869; PubMed Central PMCID: PMC4683311

Aromatase is expressed in LAM tissues
6: Adachi K, Miki Y, Saito R, Hata S, Yamauchi M, Mikami Y, Okada Y, Seyama K, Kondo T, Sasano H. Intracrine steroid production and mammalian target of rapamycin pathways in pulmonary lymphangioleiomyomatosis. Hum Pathol. 2015 Nov;46(11):1685-93. doi: 10.1016/j.humpath.2015.02.019. Epub 2015 Jul 21. PubMed PMID: 26298231.

Development of a new LAM specific quality of life tool
7: Walker TD, Desserich J, Albright K, Wamboldt FS, Belkin A, Fier K, Swigris JJ. Development of ATAQ-LAM: a tool to assess quality of life in Lymphangioleiomyomatosis. Health Qual Life Outcomes. 2015 Jul 30;13:112. doi: 10.1186/s12955-015-0294-5. PubMed PMID: 26220448; PubMed Central PMCID: PMC4518581.

New LAM Biomarkers
8: Ruiz de Garibay G, Herranz C, Llorente A, Boni J, Serra-Musach J, Mateo F, Aguilar H, Gómez-Baldó L, Petit A, Vidal A, Climent F, Hernández-Losa J, Cordero Á, González-Suárez E, Sánchez-Mut JV, Esteller M, Llatjós R, Varela M, López JI, García N, Extremera AI, Gumà A, Ortega R, Plà MJ, Fernández A, Pernas S, Falo C, Morilla I, Campos M, Gil M, Román A, Molina-Molina M, Ussetti P, Laporta R, Valenzuela C, Ancochea J, Xaubet A, Casanova Á, Pujana MA. Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness. PLoS One. 2015 Jul 13;10(7):e0132546. doi: 10.1371/journal.pone.0132546. eCollection 2015. PubMed PMID: 26167915; PubMed Central PMCID: PMC4500593.

Everolimus treatment for LAM
9: Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, Cheng Y, Khindri S, Kovarik JM, Ma S, McCormack FX, Henske EP. Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. Eur Respir J. 2015 Sep;46(3):783-94. doi: 10.1183/09031936.00210714. Epub 2015 Jun 25. PubMed PMID: 26113676.

Increased lysoPC in LAM
10: Priolo C, Ricoult SJ, Khabibullin D, Filippakis H, Yu J, Manning BD, Clish C, Henske EP. Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol. 2015 Jul;53(1):33-41. doi: 10.1165/rcmb.2014-0379RC. PubMed PMID: 25780943; PubMed Central PMCID: PMC4566115.


Articles That Are Most Important For LAM Patients

Sirolimus is an effective treatment that slows lung function decline
1: McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF,Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L,Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety ofsirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16. PubMed PMID: 21410393; PubMed Central PMCID: PMC3118601.

Everolimus appears to be an effective treatment too
2: Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, Cheng Y, Khindri S, Kovarik JM, Ma S, McCormack FX, Henske EP. Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. Eur Respir J. 2015 Sep;46(3):783-94. doi: 10.1183/09031936.00210714. Epub 2015 Jun 25. PubMed PMID: 26113676.

Lower dose sirolimus may work as well as higher doses
3: Ando K, Kurihara M, Kataoka H, Ueyama M, Togo S, Sato T, Doi T, Iwakami S, Takahashi K, Seyama K, Mikami M. Efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis. Respir Investig. 2013 Sep;51(3):175-83. doi: 10.1016/j.resinv.2013.03.002. Epub 2013 May 30. PubMed PMID: 23978644.

Doxycycline does not appear to work for LAM
4: Chang WY, Cane JL, Kumaran M, Lewis S, Tattersfield AE, Johnson SR. A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis. Eur Respir J. 2014 Apr;43(4):1114-23. doi: 10.1183/09031936.00167413. Epub 2013 Dec 5. PubMed PMID: 24311763.

Sirolimus is an effective treatment for chylous effusions and lymph node involvement.
5: Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med. 2011 Jun 21;154(12):797-805, W-292-3. doi: 10.7326/0003-4819-154-12-201106210-00007. PubMed PMID: 21690594; PubMed Central PMCID: PMC3176735.

VEGF-D is a diagnostic blood test that can substitute for lung biopsy in some patients
6: Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, Linehan WM,Hajjar F, Kinder BW, Trapnell BC, Bissler JJ, Franz DN, McCormack FX. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest. 2010 Sep;138(3):674-81. doi:10.1378/chest.10-0573. Epub 2010 Apr 9. PubMed PMID: 20382711; PubMed CentralPMCID: PMC2940071.

6a: Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):199-200. doi: 10.1056/NEJMc0707517. PubMed PMID: 18184970; PubMed Central PMCID: PMC3804557

VEGF-D is a blood test that can help with decisions about whether treatment will be effective
7: Young L, Lee HS, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF,Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Downey GP, Swigris JJ, Taveira-DaSilva AM, Krischer JP, Trapnell BC, McCormack FX; MILES Trial Group. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus(MILES) trial. Lancet Respir Med. 2013 Aug;1(6):445-52. PubMed PMID: 24159565; PubMed Central PMCID: PMC3804556.

Air travel is safe in LAM
8: Pollock-BarZiv S, Cohen MM, Downey GP, Johnson SR, Sullivan E, McCormack FX. Air travel in women with lymphangioleiomyomatosis. Thorax. 2007 Feb;62(2):176-80. Epub 2006 Oct 13. PubMed PMID: 17040934; PubMed Central PMCID: PMC2111263. 1: Taveira-DaSilva AM, Burstein D.

8a: Hathaway OM, Fontana JR, Gochuico BR, Avila NA, Moss J. Pneumothorax after air travel in lymphangioleiomyomatosis, idiopathic pulmonary fibrosis, and sarcoidosis. Chest. 2009 Sep;136(3):665-70. doi: 10.1378/chest.08-3034. Epub 2009 Mar 24. PubMed PMID: 19318672; PubMed Central PMCID: PMC2775992.

LAM produces fatigue
9: Cohen MM, Pollock-BarZiv S, Johnson SR. Emerging clinical picture of lymphangioleiomyomatosis. Thorax. 2005 Oct;60(10):875-9. Epub 2005 Ju29. PubMed PMID: 16055626; PubMed Central PMCID: PMC1747203.

Lung transplantation is an effective option for end stage LAM
10: Maurer JR, Ryu J, Beck G, Moss J, Lee JC, Finlay G, Brown K, Chapman J, McMahan J, Olson E, Ruoss S, Sherer S; National Heart, Lung, and Blood Institute LAM Registry Study Group. Lung transplantation in the management of patients with lymphangioleiomyomatosis: baseline data from the NHLBI LAM Registry. J Heart Lung Transplant. 2007 Dec;26(12):1293-9. PubMed PMID: 18096481; PubMed Central PMCID: PMC2276877.

Understanding the priorities for women diagnosed with lymphangioleiomyomatosis: a patient perspective
11:Iris Bassi, Gill Hollis, Vincent Cottin, Sergio Harari, Elma Zwanenburg, Marcel Veltkamp, Alvaro Casanova, Monica Fletcher, Sarah Masefield, Pippa Powell, Jeanette Boyd. DOI: 10.1183/23120541.00102-2015 Published 21 April 2016

Patient Organizations and Research on Rare Diseases
12: Ingelfinger, Julie R., and Jeffrey M. Drazen. 2011The New England Journal of Medicine 364 (17): 1670–71. doi:10.1056/NEJMe1102290.

How Much Would You Give to Save a Dying Bird? Patient Advocacy and Biomedical Research
13: Rosenbaum, Lisa. 2012. The New England Journal of Medicine 367 (18): 1755–59. doi:10.1056/NEJMms1207114.