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OUR COMPREHENSIVE JOURNAL ON LAM RESEARCH, PATIENT ADVOCACY, EDUCATION AND AWARENESS PROVIDED BY THE LAM FOUNDATION SUMMER 2015 FDA Approved Therapy for LAM in Less Than a (20 Year) DecadeBY FRANK MCCORMACK, MD, LAM FOUNDATION SCIENTIFIC DIRECTOR The FDA-approved sirolimus for use the approved product label for sirolimus, even in the absence of an in patients with LAM on May 28, 2015, application from the manufacturer for this change.
almost exactly 20 years after The LAM With help from Gene Sullivan, MD, a LAM Foundation Board Foundation was founded. The informal member and former Deputy Director of the Division of Pulmonary tag line for the Foundation back then was and Allergy Products at the US FDA, we contacted the FDA about ‘an effective treatment in under a decade', this approach. After reviewing the matter, based on optimism from and the Board's tongue-in-cheek position the MILES trial publication that sirolimus might be approvable for was that we could ‘use our own discretion' LAM by a more conventional approach, the FDA decided that the to decide when the decade started. I am still not sure when the most efficient path would be for Pfizer to submit an application, start date was, but I think we can assign the end date for the first rather than relying on the Citizen Petition procedure. The FDA effective treatment for LAM as May 28, 2015. then actively encouraged Pfizer to apply in May 2012. An atypical The FDA effort started a few months before the MILES trial regulatory filing pathway highlighting a collaborative approach with was published in The New England Journal of Medicine in April the MILES team was judged to be acceptable by the FDA, in which 2011. We had contacted Pfizer to ask if they would consider pursu- the MILES data sets would be directly submitted to the IND ap-ing an FDA indication for LAM based on the MILES trial result plication that I had submitted for the MILES Trial, and Pfizer would that sirolimus stabilized lung function. After about three months of be permitted to cross-reference the data. Under these conditions, internal deliberations, Pfizer replied in June 2011 that they would Pfizer agreed to pursue an indication for sirolimus in LAM. With not approach the FDA about changing the sirolimus label, in part the help of Gene Sullivan, and the pro bono assistance of a skilled because the product was already commercially available and the legal advisor, Frank Sasinowski, of the DC law firm Hyman, Phelps resource demand of a submission would be significant against a and McNamara, the LAM Foundation successfully filed for Orphan limited market potential and expiring patent for sirolimus. Pfizer (as Drug Designation for sirolimus in LAM (granted October 31, 2012) its predecessor, Wyeth) had already contributed greatly to the LAM and transferred it to Pfizer to assist with waiver of a large filing fee effort by supplying sirolimus and financial support in part for the ( $1 million) that is typically required of companies. MILES trial, and under the circumstances their response was not Upon an initial review of the MILES data sets, the FDA ex- unexpected. At the Summit for Drug Discovery in Tuberous Sclerosis pressed optimism that MILES might well be sufficient to support meeting in July 2011, however, one of the panelists mentioned an approval. The randomized and double-blind trial design, rigorously alternative route to FDA approval, called the Citizen's Petition. A maintained despite the complexities of central drug level monitoring Citizen Petition is a procedure by which a person or persons can and dose adjustments, helped to make the case for efficacy. The petition the government to request that it take certain actions. In FDA further offered that an Advisory Committee, extensive post this case, the proposal was to petition the government to change marketing studies, additional audits, or an Integrated Safety Sum- CONTINUES ON NEXT PAGE › LYMPHANGIOLEIOMYOMATOSIS (LAM) IS A PROGRESSIVE LUNG DISEASE THAT AFFECTS PRIMARILY WOMEN.
mary would not likely be required, as long as the FDA review of company. LAM patients in China, Russia, Singapore, Korea and the full data sets confirmed the summary results. The Cincin- other countries are still struggling to obtain sirolimus, however, nati MILES team, the Data Center in Florida and dozens of and there is more work to do. people at Pfizer worked for two years on the 2562 page MILES We owe a lot of people wine. LAM basic and clinical re- Clinical Study Report (CSR) that was required for filing. The searchers for providing the scientific basis for MILES; MILES FDA reviewed 3 dataset submissions, and granted Breakthrough investigators, nurses, coordinators and patients for making the Therapy Designation for sirolimus for the treatment of LAM trial a success; Jeff Krischer, Karalyn Hadley, Marisa Couluris on December 12, 2014, accelerating the review process and and Hye-Seung Lee and the entire team at the Rare Diseases providing access to powerful FDA resources for assistance with Data Center for assistance with trial design and operations, trial design and regulatory approval. Pfizer submitted the final expert data analyses and seemingly endless responses to FDA, MILES datasets, the Clinical Study Report and the supplemental Pfizer and ‘Japanese FDA' queries; The NIH Rare Diseases New Drug Application (sNDA) to the FDA on Christmas Eve, Consortium, Bruce Trapnell and all MILES funders; Sheri Selk 2014. Less than six months later, with little activity and few and the Cincinnati Children's Translational Research Trials Of-queries, the FDA granted approval. fice staff for 6 years of invaluable MILES trial support; Gene This stunning outcome exemplifies the remarkable progress Sullivan for sage advice about trial design and conduct from that can be made when industry, a clinical investigative team, beginning to end; Matthew Hodgson, Jeannie Bailey and Leslie a patient advocacy group and a regulator put financial consid- Korbee for their stellar work as Project Managers for MILES; erations and bureaucratic protocol aside to do what is right for Leslie also for the pro bono, unfailingly eager and capable as-patients. The courage and sacrifice of the women who enrolled, sistance she has provided to the LAM community for 8 years; considered enrolling, attempted to enroll, wished they could Susan McMahan for her outstanding leadership as the MILES- have enrolled, or cheered from the sidelines in the MILES trial trialwide coordinator; Frank Sasinowski and Gene Sullivan for made the FDA decision possible. In essence, MILES subjects all the advice, meetings and document drafting during FDA donated 10-20% of their lung function to get an answer for all interactions; Tammy Roads and her coordinators for work on LAM patients and for all time; bringing us to this place. There MILES and two years of uncompensated weekend and evening is no question who the heroes are in this story. work on the MILES CSR; Eli Katz and Brenda Cooperstone who were early champions at Wyeth and Pfizer for the LAM ef-fort; Sandi See Tai, Dan Levy, and Debi Tran at Pfizer for many months of biweekly CSR conference calls and tireless work on MILES subjects donated 10-20% of their lung this project; Bob Abraham of Pfizer for his pioneering work on function to get an answer for all LAM patients and mTOR and his ongoing encouragement; and, last but not least, for all time; bringing us to this place. There is no Sue Byrnes, Tom Laurenzi, Laura Lentz, Sue Sherman and the question who the heroes are in this story. LAM Foundation Board, donors and staff who provide critical support to the MILES trial, greatly facilitated the FDA approval process and brought the patient voice to every conference table. Sirolimus is the first drug approved for the treatment of Speaking of the FDA—although the agency is not often LAM, and one of only a very few drugs approved for a diffuse publicly thanked, I can tell you that Dr. Badrul Chowdhury and parenchymal lung disease. What will FDA approval mean for his team in the Division of Pulmonary, Allergy and Rheumatol-LAM patients? First and foremost, FDA approval is the ulti- ogy Products bent over backwards for LAM. They proactively mate endorsement that the ratio of benefit to risk of a therapy encouraged Pfizer to seek an indication, pressured us all to hurry is favorable. Physicians will therefore prescribe the drug with with the completion of the CSR and sNDA filing, and guided us greater confidence. Insurers will be more inclined to provide through the shortest regulatory path possible. This has been the coverage. And finally, the FDA ruling has the potential to fa- LAM story from the beginning; in the end people are people, cilitate approvals in other countries where patients have had and whether affected or unaffected; self employed, a member difficulty obtaining the drug. The loss of access to sirolimus for of a multinational company or an official in a federal agency; Japanese patients after MILES has been a primary motivator for good people everywhere go out of their way to help when they me personally. As it turned out, Dr. Inoue and Nakata righted encounter an eminently worthy cause. that wrong about a year ago, when they obtained Japanese gov-ernment approval for sirolimus in LAM through submission of MILES data to the Japanese Ministry, launching of their own safety study, and enlistment of the help of a pharmaceutical Staying Strong TogetherBY SUSAN E. SHERMAN, EXECUTIVE DIRECTOR "Thanks for all the troops in the trenches who gave so much for others for [an approved treatment]. Thank you for all the women who will benefit from your ceaseless endeavors. Thank you for all your strength and perseverance. You have shown to the world what can be done. You are a shining example of courage. You are my heroines!!" Phillip Steele, Family member of a LAM patient This expression of gratitude is one of hundreds of comments face of many academic and clinical priorities, and for a strong and posted on social media and sent via email in response to the confident woman to publically share a personal story of illness FDA approval of Rapamune for the treatment of LAM. For me and fear. And yet, this ingenuity turns family heartache to the it is a sincere, instantaneous and heartfelt expression of what accomplishment of raising thousands of dollars to power LAM we are all feeling. Who could have asked for a more exciting research; turns intellectual curiosity into research projects or development in this, the LAM Foundation's 20th year? When active clinical trials and transforms women with LAM who share added to the growth and achievements of the Foundation during their story from victim to victor. From its inception in a suburban its first two decades, this accomplishment underscores the sense basement in Cincinnati, to being highlighted in the New England that the LAM community was, and continues to be, exceptional. Journal of Medicine and receiving recognition from the National Looking forward, the logical question is, how do we sustain Institutes of Health, The LAM Foundation has built a culture of momentum so that we reach our final goal of a cure, as soon as ingenuity and an expectation of results. possible? The answer is by instilling a renewed sense of urgency into the fundamentals that have defined the LAM community COMPASSIONfrom the beginning: collaboration, ingenuity, and compassion. Finally, as we look forward, the LAM success story will only come to its desired conclusion of a cure, if we remain grounded in the compassion that first inspired Frank McCormack, MD, First, let's consider collaboration. The LAM Foundation has Sue Byrnes and early supporters of the Foundation to take action. shown that encouraging collaboration between scientists, patients, Compassion fuels ingenuity and creates a fertile environment clinicians and families has accelerated both research outcomes for sharing and achieving together. It inspires our LAM Clinic and quality of life for women with LAM. Looking forward, we Directors to intervene to help patients beyond providing routine know that providing even more ways for the entire LAM care, answering emails and helping them through the challenges community to share information will keep progress toward a of having a rare disease. Compassion for each other leads women cure on track. This includes producing research conferences with LAM to volunteer for clinical trials, not for their own ben-and LAMposium, recruiting young scientists, connecting LAM efit, but to help the next generation affected by LAM – as was clinicians and patients and partnering with organizations such the case with the MILES trial. Our nearly 35 LAM Liaisons as the National Institutes of Health. We will also form stronger volunteer countless hours to help women diagnosed with LAM, ties with other rare disease organizations such as the Rare Lung offering hope, education and a shoulder to cry on. They do this Disease Consortium to assure that the LAM community interests in addition to being career women, moms, wives and daughters, and LAM research are a priority. not to mention managing their own LAM diagnosis. Compassion is the heart of the LAM community. What will it take to find better treatments and ulti- The LAM community, led by The LAM Foundation, has "ingenuity" mately a cure for LAM? More collaboration. More ingenu-as its middle name. The endless spirit of volunteerism, scientific ity. Endless compassion. Ask yourself, what can I do? In curiosity, creative fundraising and altruism are why significant the pages of this edition of Journeys you will find inspira-advancements have arrived in 20 short years. It takes unfiltered tion and many opportunities to help propel us forward to grit for a family to create a fundraiser out of heartbreak; for a our next chapter in the LAM success story. Ideas for taking scientist to conceptualize and apply for one more grant in the action include: CONTINUES ON NEXT PAGE › • Supporting the dollar for dollar matching program that will • Invent a new fundraiser – something inspired by your help bring more women to LAMposium in 2016 through the passion. Here's what others have done: Wine & Beer Tasting, LAM Family Network (LFN). Call The LAM Foundation Crawfish Boil, Movie Madness 5K, Afternoon Tea, Laps for at 877.CURE.LAM (877.287.3526) or send an email to LAM, Golf Outings, Letter Writing Campaigns.
info@thelamfoundation.org, see article on page 20.
Whatever you do, stay involved, stay energized, inspire others. • Attend a regional educational meeting, contact your local You are part of a movement that saves lives. We will stay strong, government representative or jump on Facebook and offer together. Let's find a breakthrough therapy for LAM, faster. advice and support.
• Consider joining the 20 20 20 Campaign to tell more people about LAM and raise critical research funds.
MIDAS TrialBY TAMMY ROADS, CCRC, RESEARCH ASSOCIATE, CLINICAL TRIALS MANAGER, UNIVERSITY OF CINCINNATI Enrollment for the MIDAS Trial launched in March at LAM- Q: If go to the NIH, can I participate in this study?
posium. Within these few short months, the Rare Lung A: Yes Disease Consortium at Cincinnati Children's Hospital Medical Center has signed up 100 women with LAM for this extremely Here are some additional thoughts: important and primarily observational study. • There are no additional visits required to participate (we will As with any research study, patients have a lot of questions. gather your data from your yearly LAM Clinic visit). The only They want to make certain they qualify and most importantly additional information we ask you to provide is a completed make certain they understand what is being asked, and that it questionnaire and completion of home diaries.
will fit with their lifestyle.
• Although there may not be direct benefit, this study provides So I thought I would put together some information and important information to researchers into the progression of answer some of the frequently asked questions from women with LAM and how long term use of sirolimus effects progression.
LAM who are interested in enrolling in MIDAS.
When women with LAM call or email me to enroll, I will email The Multicenter International Durability and Safety of a copy of the consent for them to review. If they are interested, I Sirolimus in LAM or MIDAS Study is being funded by the Rare mail them a packet of information, including the consent, HIPAA Lung Disease Consortium. The study is a long term prospective authorization, diaries, and questionnaires. Once they receive this or observational registry of women with LAM, who are taking packet we schedule a time that I can call to discuss the protocol or considering taking mTOR inhibitor therapy such as sirolimus in detail and to review the consent. After I have answered all or everolimus. The goal of the study is to refine the treatment questions, if they choose to participate, I ask that they sign both of patients with LAM by determining if long term suppressive copies of the consent and HIPAA document and have them return therapy with sirolimus or everoliumus is safe and can prevent that to me. We go over the questionnaires and diaries (when to progression to more advanced stages of LAM.
complete, when to return them). I also ask that they contact me Here are some of the most common questions discussed before they visit a LAM Clinic so I can request records.
with women with LAM, when they call my office: ALL WOMEN WITH A DIAGNOSIS OF LAM CAN Q: Do I need to be taking sirolimus?
ENROLL IN THIS STUDY. A: You do NOT need to be on sirolimus or everolimus We gratefully acknowledge all of the women who have volunteered Q: Will I need to travel to Cincinnati?
to support clinical trials for LAM in the past. These women have A: No, you do not need to travel to Cincinnati. Even if your LAM advanced the treatment of this disease and the continued hope Clinic does not become an official Rare Lung Disease (RLD) for a cure.
study site, you can still participate. With your permission we will collect your data from your LAM Clinic after your yearly visit.
For more information to enroll contact:
Tammy Roads, CCRC

Q: What other sites will be opening or is my LAM Clinic Research Associate, Clinical Trials Manager
going to be a site?

University of Cincinnati / 513.558.2148 /
A: We plan to open up 30 RLD sites across the U.S. Please go Email: Tammy.roads@uc.edu
to the LAM Foundation website to see the complete list of sites.
LAM Foundation Biomarker Innovation Summit:A Model for Engagement and Action Sometimes slogans like "Stronger Together" are a rallying cry November 2014: More than 50 biomarker and LAM scientists
to motivate people to action. Other times a slogan serves to gathered in Atlanta, GA, surrounded by the questions the LAM provide a quick vision of who we are. This story is about our patients prioritized in the survey. With the needs of LAM patients slogan in action. Is there truth to our claim that we are, in fact, in mind, these scientists participated in a series of presentations Stronger Together? Read this story about the LAM Biomarker and small group discussions focused on the four types of biomark-Innovation Summit and you be the judge. What does Stronger ers: diagnostic, predictive, prognostic and surrogate. From there, Together really mean? new ideas emerged in the areas of imaging, validating diagnostic In 2013, The LAM Foundation Board of Directors, a approaches, composite scoring and new ways to analyze historical passionate group of volunteers and leaders wrote a new strategic data and tissue samples.
plan that included the following goal: "Focusing investment on the development of biomarkers that can be used to make the diagnosis of LAM, and to predict disease progression and treatment response." In pursuit of that goal, the Foundation took the following steps to turn goals into action: January 2014: John Adler, in memory
of his wife Vi Adler, provided a major gift to support the planning of the LAM Biomarker Innovation Summit. Industry partners Novartis, Pfizer and Insmed offer December 2014: Biomarker Innovation Grant (BIG) was
sponsorship funds to support meeting. launched, 14 LAM scientists and clinicians sent in letters of intent in search of grant money to begin their LAM biomarker pilot projects. March 2014: At LAMposium in Chicago, a preliminary meet-
ing of interested scientists gathered to consider current LAM February 2015: Final grant submissions were received and peer-
biomarker research and next best steps to accelerate the discovery reviewed by The LAM Foundation Scientific Advisory Board (all
of new biomarkers.
volunteer board) who discussed and prioritized most promising projects. April 2014: The LAM Biomarker Summit Planning Commit-
tee was formed and met regularly for six months to organize the March 2015: LAM Foundation Board of Directors considered
meeting. It included Frank McCormack, MD, Lisa Young, MD, recommendations from the Scientific Advisory Board and six
Lisa Henske, MD, Greg Downey, MD, Laura Lentz, Board Chair, projects were approved and funded.
Pat Venters, Board Vice Chair, Sue Sherman, Executive Director
The first ever LAM Foundation Biomarker Innovation Grants and Judy Sheridan, Grants and Research Manager. (BIG) were awarded at the Friday Night Awards Banquet at LAMposium. Congratulations to Brian Bartholmai, MD, Elizabeth Summer 2014: Women with LAM participated in a LAM Henske, MD, Simon Johnson, MD, David Kwiatkowski, MD,
Foundation Survey to guide priorities for scientists to consider PhD, Carmen Priolo, PhD, and Raymond Yeung, MD.
at the Summit.
More than 60 international biomarker and LAM scientists September 2016: Projected final reports on outcomes of BIG
are invited to attend the first LAM Biomarker Innovation Sum- projects. mit in Atlanta, GA. LAM Foundation staff coordinated meeting details and logistics.
Collaboration = Funded research and new discovery. This is A Biomarker Summit Fundraising campaign was launched the equation and meaning behind STRONGER TOGETHER! and the LAM community raised an additional $140,000 to support pilot research projects generated at the Summit.
Ask the Doctor: Advice for Using Estrogen to Treat Bladder Infections for Women with LAMANSWER PROVIDED BY: LISA LARKIN, MD, ASSOCIATE PROFESSOR OF OBSTETRICS AND GYNECOLOGY, DIRECTOR OF VISION MIDLIFE WOMEN'S HEALTH AND PRIMARY CARE, UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE sorbed (which it is not). It is still a small amount; I predict that Dr. Larkin is a woman's health physi- cian and expert in menopause and you would do fine with decreasing to 1 gram of cream 2 times helping women manage hormone issues. per week. Vagifem tabs are even lower in estrogen–the standard She offers her expert advice to women prescription is one 10ug tab 2 times per week which equates to with LAM related to these women's health 1mg estradiol per year, the equivalent of one birth control pill a questions. YEAR. The Estring is 2 mg of Estradiol per 90 days or 8mg per YEAR (8 birth control pills). Dear Dr. Larkin:
I am a woman with LAM and have ex- 2. When a patient uses vaginal estrogen, the first few DAYS to
perienced multiple bladder infections. 1-2 weeks there might be a MINIMAL increase in serum es- The prescribed treatment includes vaginal estrogen (Estrace, 2 tradiol levels. There is a little more absorption when the vagina grams, 2x/week). I asked my urologist if he could do a blood test is very atrophic (a tree will soak up tons of water very quickly for estrogen before I started and then while using the cream to if the ground has been very dry for a long time) but as soon as see how much estrogen was getting into the blood. He said the the vagina is well estrogenized, the absorption is MINIMAL. In tests were too inexact. He was unfamiliar with LAM.
fact there are several studies that document that serum estradiol You must have lots of LAM patients–older women with levels do not change, and remain in the post-menopausal range bladder infections. I asked for the smallest amount of estrogen with vaginal estrogen use.
possible. The 2 grams seems like a lot. Is there something better from the point of view of LAM that I could be using? The Estrace 3. It IS possible to measure serum estradiol levels before and after (plus lots of water) seems to be doing the trick.
vaginal estrogen use- this is commonly done to reassure breast cancer patients that their levels do not change. I think it is very reasonable to do this. A suggestion would be to only measure the estradiol level before use and then wait about 4 weeks before measuring the level again (the estradiol needs to use it regularly Reply: Dear Wary of Estrogen:
for those 4 weeks to estrogenize the vagina).
You are wise to pay attention to your estrogen levels. Here are 4. A recommended regimen for this patient would be an ESTRING some points that may help you: in the vagina every 90 days) and then a tiny pea size amount of estradiol placed directly on the urethra at bedtime a few times 1. The dose you have been prescribed is correct. One gram (1 gm) per week. The cream is perfectly reasonable, but the ESTRING of CREAM is only 0.1 mg of estradiol. It is the cream VEHICLE delivers the estrogen slowly over 90 days and there is no peak or that is being measured. The cream is still very low dose. Using trough. Oncologists like it the best of the 3 options adding the drop 2 gms of cream two times per week mean you are using 0.4 mg of cream will help to prevent the UTI's you need to estrogenize of estradiol per week, or about 20 mg of estradiol per year. That the tip of the urethra (to allow for the mucous barrier to return) is equivalent to 20 birth control pills IF all of the cream was ab- and the ring does not get estrogen to the urethra.
Causes of Chylothorax in LAM: It is Not (Always) What you Think.
BY MAXIM ITKIN, MD, PHILADELPHIA VA MEDICAL CENTER AND FRANK MCCORMACK, MD, LAM FOUNDATION SCIENTIFIC DIRECTOR The lymphatic tree is a one-way circulatory the flow of the lymph, lymphatic leaks, and abnormal perfusion patterns.
system, which returns tissue fluid to the Using these imaging techniques over the last few years, we have blood circulation, transports immune cells to learned that there are three anatomic origins for non-traumatic chylothorax:lymph nodes and assists with absorption of 1. Chylous ascities (chyle leaks into the abdomen) dietary fat and other nutrients. The lymphatic 2. Occlusion of the thoracic duct circulation begins as a lacy network of tiny 3. Leakage from the retroperitoneal lymphatic masses channels at the tips of fingers and toes, and (extra-pulmonary LAM) proceeds to larger and larger vessels analogous In cases in which chylothorax arises from chylous ascites (chyle to small creeks becoming streams and finally leaks into the abdomen) chyle migrates into the chest through tiny holes a river that flows toward the abdomen. Once in the diaphragm. The existence of the communications between the in the abdomen, nutrients are dumped into abdominal cavity and chest through the holes in the diaphragm has the flow for transport into our blood stream. The fats from our foods are been known for many years. Negative pressures in the chest during packaged into small particles called chylomicrons, which give chyle its normal breathing cause chyle to be suctioned from the abdomen into characteristic white color. Chyle originates in cells that line the small the pleural cavity. bowel and is transported through intestinal lymphatic vessels in the bowel When lymphatic channels are blocked by LAM cells or masses, the wall and support structures, and is then transported into the cisternae lymphatic system bypasses the blockage by development of a system of chyli and thoracic duct. The thoracic duct transports chyle through collateral lymphatic vessels. If one of these collateral vessels courses near the chest cavity to the great veins in the neck. If the lymphatic system the lining of organs in the chest or abdomen, it can rupture and cause becomes blocked at any point with LAM cells, chyle can "reflux" or flow a chylous leak into a potential space such as the peritoneal, pleural, or backwards into other areas. Leakage of the chyle into the chest cavity pericardial cavities.
results in a pleural effusion, (which just means fluid in the chest,) called Retroperitoneal lymphatic masses are often present in patients chylothorax, which occurs in about a third of patients with LAM. Leakage with LAM. Chyle leaking from these masses can migrate through tissue of chyle into the abdomen (chylous ascites) or pericardium, the walled planes and spaces in the abdomen and chest and appear as chylothorax.
sac containing the heart, (chylopericardium) are complications of LAM. The key for successful treatment of non-traumatic chylothorax is Conventional wisdom once held that the injury or obstruction of an understanding the source of the specific chyle leak. Interruption of the lymphatic channels above the diaphragm (the thoracic duct) is the the flow in the thoracic duct below the leak by surgery or percutaneuos primary cause of chylothorax. For that reason, interventional therapies embolization can cure chylothorax. However, that same strategy can were directed toward the interruption of the flow in the thoracic duct by make chylous leaks worse in patients with weeping retroperitoneal surgical thoracic duct ligation (tying of the thoracic duct) or obliteration masses or chylous ascities. of pleural cavity by pleurodesis (a procedure that adheres the outside of The preferred treatment of chylothorax originating in abdominal the lung to the inside of the chest cavity). Because recent advances in LAM masses is the injection of agents that close off lymphatic channels the imaging of the lymphatic tree have revealed that chylothorax from with glue or scar. Due to complex structure and interconnected nature sub-diaphragmatic causes occurs with some frequency in LAM, alterna- of these masses, the main challenge to effective treatment is locating tive approaches to this problem are required. the leak. The "trial and error" treatment approach can take many hours The key to understanding of the pathophysiology of body fluid and several sessions to complete.
flow disorders is imaging. Until recently the imaging of the lymphatic Interventional or surgical treatment of chylous ascites remains a system lagged behind the imaging of the vascular systems, primarily significant treatment challenge due to difficulty in visualization of the because of difficulties introducing contrast material into the lymphatic intestinal lymphatic ducts and the leaks. In essence, the dye injected vasculature. Conventional pedal lymphangiogram, in which contrast is into the river to find the leak does not course upstream into the feeding used to produce an X-ray image of the lymph vessels and nodes, and tributaries that are draining the leaking masses, so it is difficult to "see" lymphoscintigraphy in which a radioactive material is used for the same the source of the leak. purpose, are outdated methods that lack sufficient spatial resolution and Over the years, we have developed an algorithm to diagnose and robustness for imaging the entire lymphatic system. treat non-traumatic chylous effusions. We first perform non-contrast The recent development of improved technology for imaging of the and contrast enhanced MRI in order to identify presence of chylous lymphatic system and image-guided interventions have provided an op- ascities, to visualize the thoracic duct and lymphatic malformations, and portunity to better understand and address the causes of non-traumatic to determine the patterns of the lymphatic flow. These studies can be chylothorax. A widely available, non-invasive procedure called non-contrast completed at the referring institution for patients that require consulta-MRI lymphangiogram utilizes heavy T2 weighted MRI (an MRI view tion or who are being considered for a future lymphatic intervention. We that almost any scanner can produce, like changing your camera setting then perform intranodal lymphangiography in order to confirm the MR from color to black and white) sequences to allow visualization of the findings and direct the treatment. In cases of occlusion of the thoracic thoracic duct and abnormal lymphatic structures such as extra-pulmonary duct or thoracic duct leak, thoracic duct embolization can cure chylo-LAM. Contrast enhanced MR lymphangiogram is a new technique in thorax. If thoracic duct flow is normal, thoracic duct occlusion should which contrast material (gadolinium) is injected into the groin lymph be avoided. Often, the simple introduction on an oil-based contrast nodes during MR imaging. This technique allows dynamic imaging of agent can facilitate closure of the leak.
The future development of new lymphatic imaging agents may If you would like more information about the imaging technique provide us with deeper insight into anatomy, physiology, and flow dynam- discussed in this article, please contact: Maxim Itkin, MDics in the lymphatic system. Hopefully, these new insights will trigger Philadelphia VA Medical Center University and further research and understanding of this vital yet overlooked "human Woodland Avenue Philadelphia, PA 19104plumbing" system.
Low Dose or Not Low Dose, That is the Question– But What is the Answer?BY BRIAN BARTHOLMAI, MD, ASSOCIATE PROFESSOR OF RADIOLOGY, DIVISION CHAIR FOR RADIOLOGY INFORMATICS, MAYO CLINIC, ROCHESTER, MINNESOTA Advances in CT technology in the last few years have allowed for For both the initial diagnosis of pulmonary disease and the monitoring of changes over improved image quality at lower dose. A ‘low dose' chest CT can be time radiologic imaging is key. Chest radiog- performed with 5-10 times less radiation than 10 years ago, around 1-2 raphy (x-ray) is a low-cost and low radiation mSv. For lung nodule detection, a next-generation CT scanner administers dose tool that provides a highly useful overview a mere 0.06-mSv, nearly equivalent to a radiograph. [4] of the chest. However, radiography provides The key questions for patients with LAM are most commonly: When images with numerous overlapping structures. is a chest x-ray or CT scan is needed? Should the CT scan be routine or Often, radiography cannot demonstrate subtle low-dose technique? The answer depends on the individual and reason changes or differentiate pathological changes for the test. Obviously, for both cost considerations and radiation risk, definitively. Computed tomography (CT) also no procedure should be performed that is not medically necessary. It is uses x-rays, but this technology makes numerous high-resolution ‘slices' essential to keep in mind that the risk of death from diagnostic medi- that can be less than 1mm thick and show small blood vessels, airways, cal radiation remains much less than other common activities such as lung tissue and changes due to disease in exquisite detail. The bright- driving a car or walking across a street. [5] ness values of the CT pixels represent the density of materials such as In general, for characterization of disease at baseline, detection of air, fat, water, calcium and metal that be measured, tracked over time subtle or very small abnormalities and or evaluation of potentially life- and may be helpful in predicting prognosis. [1] threating problems such as blood clots in the pulmonary vessels, a scan One of the drawbacks of radiography and CT is the potential risk from radiation. Some radiation, measured in milliSieverts (mSv), is obtained with the highest quality imaging at regular dose is reasonable. unavoidable. Average annual background exposure is around 3mSv. The For monitoring of known disease such as changes in pulmonary cysts, radiation for a two-view chest x-ray is extremely low, about .05 mSv, fibrosis or some types of infection, low dose technique should allow while a chest CT scan is around 5-7 mSv. [2] sufficient quality to answer the diagnostic question. In particular, for Extremely high doses of radiation can cause immediate tissue repeated evaluation of chronic pulmonary diseases such as LAM that damage, such as with radiation therapy, but the direct effects of radia- commonly affect young patients that can live for decades, a low dose tion are not typically evident. Increases in cancer for people exposed to technique chest CT scan is probably prudent. For some questions, a radiation following Hiroshima and Nagasaki demonstrates that radia- chest x-ray may provide a sufficient answer. When a test is needed to tion can cause genetic damage. However, a 2006 National Research answer an important medical question, the dose for that exam and the Council report [3], notes that "At doses of 100 mSv or less, statistical overall dose a patient receives over their lifetime should be as low as limitations make it difficult to evaluate cancer risk in humans." For reasonably achievable. What is ‘reasonable' must be decided by thoughtful medical imaging, the general rule is that radiation exposure should be consideration by the patient and the physician as partners in managing as low as reasonably achievable. The imaging team, including medical risk for each individual situation. physicists, work to keep the dose as low as possible, without reducing the effectiveness of the study. [1] M. T. R. S. K. R. Maldonado F and D. P. H. T. B. B. R. R. R. J. Raghunath S, "Automated Quantification of Radiologic Patterns Predicts Survival in Patients with Idiopathic Pulmonary Fibrosis," Eur Respir J., 2013. [2] H. C. M. C. Leng S, "Use of Ionizing Radiation in Screening Examinations for Coronary Artery Calcium and Cancers of the Lung, Colon, and Breast," Seminars in Roentgenology, pp. 148-160, 2014. [3] Committee to Assess Health Risks from Exposure to Low Level of Ionizing Radiation, National Re- search Council, "Health risks from exposure to low levels of ionizing radiation: BEIR VII Phase 2.," Washington, DC: National Academies Press, 2006. [4] M. F. S. B. e. a. Gordic S, "Ultralow-dose chest computed tomography for pulmonary nodule detection: First performance evaluation of single energy scanning with spectral shaping.," Invest Radiol , vol. 49, pp. 465-473, 2014. [5] C. J. A. A. e. a. Gerber TC, "Ionizing radiation in cardiac imaging: a science advisory from the American Heart Association Committee on Cardiac Imaging of the Council on Clinical Cardiology and Committee on Cardiovascular Imaging and Intervention of the Council on Cardiovascular Radiology and Intervention.," Circulation, p. 1056–1065, 2009. [6] D. X. C. J. L. S. Y. L. M. C. Wang J, "Radiation dose reduction to the breast in thoracic CT: Comparison of bismuth shielding, organ-based tube current modulation, and use of a globally decreased tube current.," Med. Phys., vol. 38, pp. 6084-6092, 2011. The International LAM Research Conference: Basic Science OverviewBY VERA KRYMSKAYA PHD, MBA, ASSOCIATE PROFESSOR OF MEDICINE, PERELMAN SCHOOL OF MEDICINE,UNIVERSITY OF PENNSYLVANIA There were fi ve general basic science themes covered:1. Advancing mTORC1 signaling2. Lymphatics and infl ammation in LAM3. Hormonal regulation in LAM4. Lung destruction in LAM5. LAM cell of origin ADVANCING MTORC1 SIGNALING Brendan Manning, PhD (Harvard University's School of Public Health and the Dana-Farber/Harvard Cancer Center) studies how the mTOR signaling network coordinates nutrient availability with metabolic responses and how dysregulation of this network contributes to cancer and other diseases, including TSC and LAM. Dr. Manning's presentation was focused on defi ning the role of TSC complex in the suppression of LAM. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) has the ability to sense and integrate growth signals in various forms, including intracellular nutrients and energy, growth factors, and cellular stresses. Multi-site phosphorylation of the TSC2 protein, within a complex with TSC1 and TBC1D7, downstream of distinct signaling pathways appears to account for much of mTORC1's signal-integrating capacity. Through unbiased genomic and metabolomic approaches, he has found that, in addition to its established role in promoting protein synthesis, mTORC1 stimulates changes in specifi c metabolic pathways to promote anabolic cell growth and proliferation.
Kun-Liang Guan, PhD (University of California, San Diego) studies signaling mechanisms of cell growth, organ size control and tumorigenesis, particularly focusing on the mTOR and Hippo pathways. He presented on mTOR signaling in nutrient signaling and autophagy regulation. The AMP activated kinase (AMPK) and the mechanistic target of rapamycin (mTOR) are key intracellular signaling molecules that are regulated by nutrient status. AMPK is activated whereas mTORC1 is inhibited by nutrient limitation. They display opposite effects on cellular metabolism and growth. AMPK promotes autophagy while mTORC1 inhibits autophagy. Investigation of the mechanism of mTOR regulation by amino acids demonstrated that different amino acids use different mechanisms to activate mTOR. Leucine and glutamine act through Rag GTPases and Arf1 GTPase, respectively, to activate mTOR. Dr. Guan's study showed that AMPK and mTORC1 regulate the autophagy initiating protein kinase ULK1 and the autophagy machinery VPS34, which is a lipid kinase critically important for intracellular vesicle traffi cking and autophago-some formation. Further, his study revealed a molecular link from nutrient status, to intracellular nutrient sensor/integrator and eventually the regulation of autophagy.
John Blenis, PhD (Weill Cornell Medical College) is focused on defi ning critical signal transduction mechanisms and how altered cellular signaling promotes carcinogenesis. Dr. Blenis presented on mTORC1/S6K1 control of tumor metabolism. The mTOR Complex 1 (mTORC1) signaling pathway has evolved to sense and respond to cellular energy status, nutrient availability and surrounding oxygen concentrations. In addition, mTORC1 can be further activated by mitogen- and hormone-activated AGC kinases including Akt and RSK, and suppressed by mTORC1 and/or S6K1 via a variety of negative feedback loops. The integration of these multiple inputs control the strength and duration of downstream signaling, which is important in differentially regulating a variety of mTORC1-dependent processes. He has investigated the mTORC1 phosphoproteome and metabolome using mass spectrometry-based analysis. These studies have identifi ed many novel targets that are revealing new connections between mTORC1, S6 kinase and various links to gene expression, mRNA metabolism, protein production and cell metabolism; biological processes critical to the control of cell growth. He discussed the characterization of new molecular targets and biological processes and also provided evidence that targeting nutrient metabolism in cancer cells with activated mTORC1 may provide an important therapeutic opportunity.
Marina Holz, PhD (Yeshiva University and the Albert Einstein College of Medicine) presented that resveratrol in combination with rapamycin reduces TSC2-null xenograft tumor growth. Dr. Holz's study demonstrated that the addition of resveratrol to rapamycin treatment may be a promising option for selective and targeted therapy for diseases with TSC2 loss and mTORC1 hyperactivation.
CONTINUES ON NEXT PAGE › LYMPHATICS AND INFLAMMATION IN LAM Melody A. Swartz, PhD (University of Chicago) is trained as a bioengineer and she uses quantitative approaches in cell biology and physiology, including biotransport and biomechanics, to investigate the role of the lymphatic system in immunity and pathophysiology, particularly in cancer metastasis. Dr. Swartz presented on deciphering the complex roles of lymphatic vessels in modulating immunity. In tissues, interstitial fl uid fl ow is mechanically coupled to lymphatic drainage, and both are often increased in infl ammation as well as in the tumor microenvironment. It has long been assumed that local lymph formation is driven primarily by pressure gradients generated by downstream lymphatic pump function, but she found that vesicular transendothelial transport also contributes signifi cantly to lymph formation and is actively regulated by the lymphatic endothelium according to infl ammatory stimuli, allowing fi ne-tuning of the transport of antigens, cells, and chemokines to the local lymph node.
But why does lymphatic transport need to be actively regulated, if its primary function is to merely drain excess fl uid from the interstitium to prevent swelling? In exploring this question, she is fi nding lymphatic transport to play fundamental roles in fi ne-tuning immune responses and regulating the presentation of abundant self-antigens for deletion of autoreactive T cells. At the same time, infl ammatory lymphangiogenesis coupled with increased interstitial fl ow drives fi broblast activation and stromal changes that promote matrix alignment and stiffening as well as, simultaneously, immune suppression. In the tumor microenvironment, these factors synergize to promote escape from host immunity, which is presumably necessary for metastasis. Together, her fi ndings help to defi ne new immunomodulatory roles for lymphatic vessels in infl ammation and cancer.
Caroline Le Poole, PhD (Loyola University Medical Center) presented on modeling LAM therapy by chimeric antigen receptor (CAR)-transduced T cells in mice. Dr. Le Poole's study identifi ed GD3 as a surface molecule up-regulated on LAM cells. Up-regulation may be a direct consequence of mTOR dysregulation in TSC mutant cells. This also holds true for cell line LAM10224, derived from a patient with mild disease whose diagnosis of LAM was confi rmed by HMB45 immunostaining of lung biopsy tissue. GD3 thus offers a potential target for immunotherapy. In vitro and in vivo data suggest that the treatment potential of CAR transduced T cells can well be assessed in human LAM cell challenged SCID/ beige mice. If proven effective and safe in repeat experiments, adoptive transfer of CAR transduced T cells may be readily translatable to the treatment of human LAM.
Elena Atochina-Vasserman, PhD, MD (University of Pennsylvania) presented on how pharmacological targeting of VEGFR signaling inhibits TSC2-null lesion growth in the lung. LAM severity correlates with the degree of lymphatic vessel density in the lung and up-regulation of serum VEGF-D, a predictor of the LAM prognosis and potential response to treatment. The VEGF-D activates VEGFR2/3, which has not been targeted therapeutically in LAM. FDA-approved axitinib is a small-molecule inhibitor of VEGFR1, VEGFR2/3. Dr. Atochina-Vasserman's data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib has a potential benefi cial effect in decreasing VEGF-D levels, lymphangiogenesis, infl ammatory lung response, and Tsc2-null lesion growth, and suggests a potential therapeutic benefi t of targeting of VEGFR signaling for treatment of LAM.
HORMONAL REGULATION IN LAM Yang Sun, PhD (Harvard Medical School and Brigham and Women's Hospital) presented that Pg and E2 synergistically promote the lung me-tastasis of TSC2-defi cient cells in a preclinical model. His data indicate that estradiol and progesterone synergistically increases the metastatic potential of TSC2-defi cient LAM patient-derived cells in vitro and lung metastasis in vivo. Thus, targeting both of estradiol and progesterone-mediated signaling events may have therapeutic benefi t for LAM and possibly other hormonally dependent cancers.
LUNG DESTRUCTION IN LAM Jeanine D'Armiento, MD, PhD (Columbia University Medical Center) presented her recent fi ndings leading to insight into lung physiology and pathology through understanding the mechanisms altering lung injury and repair and translating these fi ndings into practical clinical solutions.
Recent collaborative studies between her group and Dr. Paul Eklington (Southampton, UK) have shown that in tuberculosis the expression of MMP-1 is critical for the development of cystic lesions. Animals that do not express MMP-1 do not develop destructive cystic lesions. Investi-gators have shown that the proliferating smooth muscle cells in Lymphangiomyomatosis secrete a variety of proteases. Her group investigated whether the LAM cell expressed collagenolytic enzymes, hypothesized to be necessary for cyst formation. Interestingly, LAM cells express two collagenolytic enzymes, MMP-1 and MMP-14, which are not found in the healthy lung. Given the known importance of collagenolytic enzymes in cyst formation of other lung diseases it is likely that these enzymes are contributing to the destructive lung lesions seen in LAM. Based upon these fi ndings in disease, inhaled inhibitors of the collagenolytic metalloproteinases are actively being developed in her laboratory with anticipa-tion that delivery of such compounds will protect the lung from destructive injury in the chronic disease state.
Victoria Stepanova, PhD (University of Pennsylvania) presented on urokinase type plasminogen activator (uPA) in the pathogenesis of LAM. Her data implicate uPA as a novel mediator through which TSC2-null tumors destroy lung parenchyma, identify new approaches to regulate expression of uPA in TSC-compromised cells, and position uPA as an attractive target for potential combinational therapy to enhance the ef-fectiveness of rapamycin monotherapy in LAM patients.
LAM CELL OF ORIGIN Maya E. Kumar, PhD (Stanford University School of Medicine) presented on defi ning a mesenchymal progenitor niche at single cell resolu-tion. Most vertebrate organs are composed of epithelium surrounded by support and stromal tissues formed from mesenchyme cells, which are not generally thought to form organized progenitor pools. She described the use of clonal cell labeling with multicolor reporters to characterize individual mesenchymal progenitors in the developing mouse lung. Through such single cell labeling, she observed a diversity of mesenchymal progenitor populations with different locations, movements, and lineage boundaries. Airway smooth muscle (ASM) progenitors map exclusively to mesenchyme ahead of budding airways. Progenitors recruited from these tip pools differentiate into ASM around airway stalks; fl anking stalk mesenchyme can be induced to form an ASM niche by a lateral bud or by an airway tip plus focal Wnt signal. Thus, mesenchymal progenitors can be organized into localized and carefully controlled domains that rival epithelial progenitor niches in regulatory sophistication.
Debbie Clements, PhD (University of Nottingham, UK) presented on recruitment of fi broblasts in pulmonary LAM. She demonstrated CXCR4- dependent recruitment of fi broblasts by TSC2-/-cells, and identifi ed proteases which may be activated via the interaction between these cell types. Dr. Clements will use her established 3D models of LAM to further investigate the regulation of proteolytic activity in these co-cultures.
Magdalena Karbowniczek, MD, PhD (Texas Tech University Health Science Center) presented on rheb mediated reprogramming of neuronal progenitors suggests neural crest origin of angiomyolipoma and leads to phenotype spreading. Her study suggests that AML cells are predestinated NC-derived neurons lacking capability to achieve terminal differentiation as a result of Notch/Rheb/miR34.
The International LAM Research Conference: Clinical Science OverviewBY JEFF SWIGRIS DO, MS, LAM CLINIC ASSOCIATE DIRECTOR, NATIONAL JEWISH HEALTH, DENVER Four general clinical themes were covered during the scientifi c sessions:1. Imaging LAM2. Patient contributions to advancing knowledge in LAM: from cells to perceptions3. Biomarkers for LAM4. LAM pathogenesis Joel Moss, MD, PhD (National Institutes of Health (NIH)) kicked off the scientifi c meeting with a talk focusing on two topics: 1) heterogeneity among patients with LAM; and 2) quantifying LAM-related fi ndings on high-resolution computed tomography (HRCT). Dr. Moss discussed the variability LAM cells possess in their morphology, surface receptor expression, and genetics and how this variability likely plays a large role in phenotypic heterogeneity—how LAM manifests in a particular patient and whether/how well it responds to rapamycin (or rapamycin analogs). Dr. Moss spent the second half of his talk discussing recent work from his lab on HRCT, and how he and his co-investigators are using HRCT to quantify cyst burden, pneumothorax and subtle parenchymal abnormalities adjacent to cysts. Most interesting, microscopically, in LAM, the peri-cystic parenchyma is emphysematous; this is a fi nding that is impossible to appreciate when viewing the HRCT with the naked eye but can be captured with sophisticated software-directed texture analysis of the HRCT. This software, developed by Dr. Moss and his NIH collaborators, CONTINUES ON NEXT PAGE › allows quantifi cation of these metrics while exposing patients to a fraction (10% or less) of the radiation they would be exposed to if undergoing a "standard" HRCT. Dr. Moss's lab is now working to make this software available at LAM centers outside the NIH and to better understand what these quantifi ed metrics can teach us about how a patient's LAM will behave over time.
Maxim Itkin, MD (University of Pennsylvania) talked about imaging and treating leaks in the lymphatic duct. Dr. Itkin described how he injects contrast into inguinal lymph nodes and then uses MR imaging to follow the contrast as it navigates its way up the thoracic duct. This technol-ogy produces clear images of tortuous lymphatic ducts and branches; aberrant vessels; refl ux of lymph fl uid into the lungs; leakage of lymph into the thorax, pericardium or peritoneum and other lymphatic-related, extrapulmonary manifestations of LAM. His talk included incredible video clips of lymphatic leaks identifi ed on chest imaging and how he intervenes to correct them. He described his technique of using "coil and glue" to embolize the lymphatic duct and sclerotherapy to permanently close off leaking and non-leaking collateral lymphatic vessels. Dr. Itkin's pioneering work has helped make such percutaneous techniques the gold standard in treatment of chylous leaks.
P TIENT CONTRIBUTIONS TO TIENT CONTRIBUTIONS TO ANCING KNOWLEDGE IN LAM: FROM CELLS TO PERCEPTIONS Yuen-Yi (Moony) Tseng, PhD (The Broad Institute) gave a talk on building next-generation patient derived models to elucidate LAM pathogenesis. Dr. Tseng described the ambitious goals of her team to generate fully-characterized, completely genotyped cell models for many tumor types, including LAM and angiomyolipoma (AML). She described the process they use to collect samples, develop single cell suspensions, grow cells in a "cell nursery" and then conduct verifi cation studies to assess the purity of the model before banking. She aims to use these techniques to fully develop a "cell line factory" to serve the scientifi c community. Dr. Tseng painted a picture of the future in which a physician could collect a biospecimen from a patient and send it to the "factory" where the cell would be grown and immortalized, allowing for testing of various thera- peutic agents on it. At present, she has 8 LAM and 21 AML samples at various stages in the "factory".
Kristen Holm, PhD, MPH (National Jewish Health, Denver) delivered a talk on patient-reported attitudes and beliefs about supplemental oxygen. Dr. Holm presented her work on developing instruments aimed at capturing chronic obstructive pulmonary disease (COPD) patients' attitudes and beliefs around supplemental oxygen (O2). Specifi cally, she seeks to determine how decisional balance (a weighing of the pros and cons), teamwork standards (is O2 use viewed by patients and their partners using a "team" approach or a "patient-only" therapy), and health-related social controls (e.g., nagging by a loved one) affect oxygen adherence among patients with COPD. Although her work is in patients with COPD, not LAM, she drew on a subset of her data (from the young females in her cohort) to shed light on some of the attitudes and beliefs that LAM patients who need O2 might have. She noted that young females in her study were less likely than other patients to be adherent with using O2; and young females were less likely to perceive "pros" of using O2, and are more likely to perceive "cons" of using oxygen. Thus, she concluded that when it comes to encouraging patients with LAM to adhere to O2, it likely will be more effective to focus on the anticipated benefi ts—rather than the potential downsides (e.g., social stigma) of O2.
Jeffrey Swigris, DO, MS (National Jewish Health, Denver) discussed health-related quality of life (HRQL) in LAM. He described how, on aver-age, patients with LAM have impaired HRQL in various domains, including those in the physical health and emotional well-being domains. He discussed his lab's ongoing efforts to develop a LAM-specifi c instrument to assess HRQL called ATAQ-LAM (A Tool to Assess Quality of Life in LAM). His goal is to have ATAQ-LAM be included as an endpoint in future trials of novel therapy for LAM.
BIOMARKERS FOR LAM Kuniaki Seyama, MD, PhD (Juntendo University School of Medicine, Japan) talked about circulating endothelial growth factors in LAM. He began by reviewing the vascular endothelial growth factor (VEGF) family and then showed data on how VEGF-D levels in patients with LAM are markedly higher, VEGF-C levels in patients with LAM are somewhat higher and VEGF-A levels in patients with LAM are no different from normal controls. He reviewed how VEGF-D levels in chyle are two times greater than levels in the blood in patients with LAM. Dr. Seyama showed some data to suggest that LAM cells produce VEGF-D. He showed how treatment with sirolimus decreases VEGF-D but not VEGF-C levels. He capped off his talk by showing how, in 10 LAM patients, pregnancy did not change FEV1 slope. Lisa Young, MD (Vanderbilt University Medical Center) spoke on VEGF-D as a biomarker in LAM. Vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that plays a key role in tumor metastasis and is now regarded as a serum biomarker in LAM. Specifi cally, serum VEGF-D levels are elevated in most (but not all) patients with LAM, and levels correlate with certain measures of disease severity. Why serum VEGF-D levels are normal in a signifi cant minority of women with LAM is not clear. She reviewed diagnostic test performance characteristics of VEGF-D and its utility as a prognostic marker. She sees potential for VEGF-D as a surrogate outcome measure of treatment response. Dr. Young reminded the audience that although data on VEGF-D in LAM continue to grow, there remain many unanswered questions about LAM pathogenesis and the role of VEGF-D. In 2011, serum VEGF-D quantitation became available as a clinical test in the United States.
Vera Krymskaya, PhD, MBA, (University of Pennsylvania) gave a talk on VEGF-D, lymphangiogenesis, and airspace enlargement. Clinical evidence demonstrates that LAM severity correlates with the degree of lymphatic vessel density and with serum levels of the pro-lymphangiogenic vascular endothelial growth factor D (VEGF-D). Although, LAM disease has been linked to up=regulation VEGF-D, and therapy with sirolimus leads to reductions in serum VEGF-D, it is unclear whether upregulation of VEGF-D plays a protective or pathogenic role in LAM. Dr. Krymskaya offered up excessive lymphatic vessel sprouting as a process contributing to—or driving—lung remodeling processes that underlie airspace enlargement and lung destruction. She reminded the audience that three very important key questions remain to be answered in this arena: 1) what is the mechanism of VEGF-D up-regulation in LAM, 2) do abnormal lymphatics contribute to cyst formation characteristic of LAM, and 3) can VEGF-D signaling and neo-lymphangiogenesis be targeted therapeutically? Cheryl Walker, PhD (MD Anderson) gave a talk on how the combination of a person's genes and the environment in which they have lived (or things to which they have been exposed) can determine whether and when a disease might occur later in life. This gene-environment interaction (G by E; or G x E) infl uences (and in certain cases, inappropriately modifi es) the "reading," "writing" and "erasing" of our epigenome and creates a specifi c genetic program for an individual. Dr. Walker highlighted that, amazingly, exposures that occur perhaps very early on in development can dictate survival/disease susceptibility in adult life. She went on to explain how these fi ndings are applicable to TSC gene-related diseases, like LAM: (from her abstract) the penetrance of a TSC2 gene defect is profoundly affected by exposures to endocrine disrupting chemicals (EDCs) during development. In the uterus, this reprogramming causes estrogen responsive genes to become hyper-responsive to hormones, exaggerates the effects of normal levels of ovarian hormones on this tissue, and dramatically increases the penetrance of a TSC2 defect. Very little is known about the contribution of environmental exposures to TSC-linked diseases, and these studies point to the importance of both the epigenome and the environment as determinants of penetrance, and perhaps severity, of diseases such as LAM that occur in TSC patients Jane Yu, PhD (Brigham and Women's Hospital) gave a talk on the dysregulation of prostaglandin metabolism and action in LAM progression. Prostaglandin (PGE2) biosynthesis is upregulated in TSC2-defi cient, LAM patient-derived cells and in women with pulmonary LAM. Dr. Yu and members of her lab aimed to identify the cellular impact of PGE2 and its receptors (EP1-4). Expres-sion of the PGE2 receptor, EP3, was upregulated in TSC2-defi cient LAM patient-derived cells compared to TSC2-addback cells, and she found abundant accumulation of EP3 in LAM lung lesions compared to adjacent normal tissues. Importantly, a specifi c EP3 antagonist, L-798106, suppresses the growth of TSC2-defi cient cells in a dose-dependent manner. In vivo, L-798106 treat-ment resulted in a reduction of lung colonization of TSC2-null ELT3 cells using non-invasive bioluminescent imaging. Dr. Yu's innovative work raises the question of whether targeting the prostaglandin pathway—with agents like aspirin or celecoxib—could yield a viable therapeutic option for patients with LAM.
Guillermo Oliver, PhD (St. Jude's Children's Hospital) spoke on the lymphatic vasculature in health and disease. He reminded the audience that most lymphatic vessels do not contain smooth muscle and that large—but not small—lymphatic vessels are surrounded by pericytes. Lymph vessel cell progenitors actually start their lives in the walls of veins and migrate from the vein wall to form lymphatic vessels. Prox1 is a specifi c lymphatic endothelial cell marker, and if this signal is removed, lymph vessel cells will migrate back to blood vessel walls. Interestingly, Prox1 heterozygote mice (most die at birth with chylous ascites and/or chylothorax, but some live) develop late onset obesity. Dr. Oliver described how vascular endothelial cells are heterogeneous—they express different surface markers in different organs, within different regions in the same organ, and within the same organ at different stages of development. Emerging data from his lab suggest the same is true for lymphatic endothelial cells. He reminded the audience that lymphatics play a signifi cant role in immune function, infl ammation and metabolism—leaky lymphatics promote visceral adiposity. Before closing, he commented on how further study of Schlemm's Canal, a hybrid lymph/blood vessel in the eye, may hold the key to better understanding and treating glaucoma. CONTINUES ON NEXT PAGE › Lisa Henske, MD (Brigham and Women's Hospital) closed the scientifi c session with a talk on the role of microRNA in LAM pathogenesis and therapy. MicroRNAs (or miRs) are recently discovered, non-coding RNA fragments that can fi ne-tune gene expression by silencing messenger RNA by destabilizing or destroying it. Small changes in miR levels, even as little as 1.2-fold, can have large downstream effects, since a single miR can regulate dozens of genes. Selected miRs, termed "oncomiRs" appear to promote cell survival, growth, proliferation, migration, and invasion in benign and malignant diseases. The role of miRNA in TSC and TSC therapeutic responses represents a key knowledge gap. Dr. Henske's lab has discovered that many miRs are regulated by mTORC1 and that several miRs are up-regulated in the presence of rapamycin. She discovered that miR-21 (microRNA-21) is the miR most elevated in response to rapamycin. She calls miR-21 and the other rapamcyin-dependent microRNA "RapaMiRs." Dr. Henske postulated that miRs could play a role directing the effects of rapamycin on cell growth and survival in LAM, and ongoing work in her lab seeks to determine if miRs could serve as biomarkers of rapamycin response.
LAMposium 2015This year's International LAM Research Conference and with LAM who want to attend LAMposium but otherwise could LAMposium is being described as an exceptional, unique not afford to. Read more about the LAM Family Network (LFN) and inspiring conference. Nearly 120 women with LAM - from on page 20.
8 different countries gathered for a second year in Chicago, IL, and 17 of these patients attended for the very fi rst time. Also in attendance were 120 family members and friends along with 108 scientists and clinicians. If you look at these numbers closely, you will see the ratio of patient to scientist/clinician is 1:1; remarkable for a rare disease conference.
Here are some of the fabulous highlights from the conference: LAM Liaison, Shar- FIRST TIME ATTENDEE ORIENTATION lene Dunn Brells orga-nized the inaugural Breath Cheerleader and LAM Liaison, of Hope Remembrance Marla Hamlin did a lovely job of get- Room, a quiet place to ting women with LAM, who are new refl ect and share memories to the conference, up to speed on of the courageous and everything LAMposium. "Marla was a beautiful LAM women warm, welcoming speaker, perfect for who have passed before us. this audience. I counted 25 signifi cant Sharlene's inspiration for bits of information delivered effi ciently this room was the memory and effectively. Bravo!" said a LAM of her friend Patricia Marie patient attendee.
STRONGER TOGETHER: OPENING CELEBRATION "A good way to create a ‘sisterhood link' with audience Congratulations to Andrea Byrnes, who inspired her Mom, participation", was a quote offered about our Stronger Together: Sue Byrnes, to create The LAM Foundation! Andrea was pre- Opening Celebration. LAM Foundation Executive Director, Sue sented with this year's LAM Quilt.
Sherman and LAMposium Medical Advisor, Dr. George Pappas, Thank you to Stacey Wheelus for assembling the 2015 LAM welcomed everyone by offering highlights for the weekend, giv- Quilt. Stacy and 35 women lent their "hands" to the beautifully ing Foundation news and community updates. The introduction hand sewn quilt. of all women with LAM in the room gave everyone a chance to Money donated to the quilt will go to the LAM Family "put a face with a name".
Network (LFN) which supplements travel expenses for women LAM LIAISON MEETING RED CARPET PHOTOS Everyone can be a star in front of our Red Carpet Banner. The Foundation now has a branded banner available for photos. We are not certain how many photos were posted, but the Red Carpet Banner was "the place to be and be seen" on Facebook, Twitter, Instagram and other social media outlets. DISTINGUISHED FUNDRAISING AWARD WINNER REBECCA NISSLY Our LAM Liaisons, from across the country, had an op- portunity to get together for a working lunch. The Liaisons At the Friday Night Awards Banquet, participated in a communication and an advocacy presentation Rebecca Nissly was recognized with to help in their efforts to raise LAM awareness. Jackie Reau, a the Distinguished Fundraising Award PR Consultant, worked with the Liaisons on building awareness for initiating a $100,000 donation and enticing media attention for LAM. Christina Hamilton, The from Metamucil's, "Do More Than LAM Foundation Advocacy Board Chair, talked with the Liaisons You Think" campaign. 22,000 votes about how to focus their LAM story with local, state and federal were cast, and Rebecca‘s winning government offi cials. essay about The LAM Foundation Our LAM Liaisons work within their regions to gather received more votes than the seven women with LAM, family and friends for educational and social other charity organizations. Women with LAM, families and meetings. We hope you get a chance to join a regional meeting. friends around the world cast the winning votes.
We would like to welcome some new LAM Liaisons to the group. Region 15, Texas, New Mexico and parts of Oklahoma A landslide victory for Rebecca and for LAM Research!now have LAM Liaisons; please welcome Maria Teniente and Frances Saldivar. Region 9; Indiana, Kentucky, Ohio, and West LAM LEADER AWARDSVirginia now have an additional LAM Liaison, Melaney Parrish. Welcome back Carmen Iglesias to Region 13 our Great Plains 2014 offered an extraordinary list of LAM Leader candidates Region that covers Iowa, Kansas, Missouri and Nebraska. Wel- including women with LAM who put together regional and com- come Reina Endo who will work with Sharlene Brells Dunn in munity fundraisers; women with LAM who quietly changed the Region 18 which covers Alaska, Oregon and Washington. And lives of others through their compassion and empathy, and those fi nally, Elena Perez Blair is going to start a new region, Region who selfl essly volunteered for clinical trials and made their annual 21 in Puerto Rico. Thank you for being a part of this great group trips to the NIH. Every year –women with LAM have pursued hope, faced LAM with courage and cared for their sisters and families. Because of this, all women with LAM received this OXYGEN REFILL CENTER year's LAM Leader Award.
A special Thanks goes to Lincare Respi-ratory Specialists who donated their time and O2 to our conference. For two days, women on oxygen therapy could talk with the Lincare specialists about new technologies in O2 therapy. They could also refi ll their oxygen tanks and re-charge their oxygen equip-ment. For some women, this meant they did not need to go back to their hotel rooms to refi ll their tanks. International LAM Research Conference Over 108 physicians and scientists attended two days of Research grants for 2014 LAM studies were presented to:
exceptional presentations and research updates at The International LAM Research Conference. Debbie Clements, PhD, from Nottingham University for her
A significant moment for one professional was, "Hearing the Pilot Award study, Investigating the Cross Talk Between LAM patients share their experience during the scientific sessions." Cells and Recruited Stromal Fibroblasts.
Women with LAM inspire scientists and clinicians as they work Lisa Young, MD, from Vanderbilt University for her three year
to find better treatments, diagnostics and ultimately, a cure. study on Lymphangiogenesis and Estrogenic Milieu and LAM Biomarkers.
International LAM Research Conference Highlights: Khalid Almoosa, MD, from University of Texas Health Center
for his one year special project, Does Variability of Care Exist
Among LAM Specialty Clinics.
Andrey Parkhitko, PhD, from Harvard Medical School for
his 3 year Fellowship Award on A Cross-Species Approach to
the Discovery of Genes Accelerating TSC/LAM Tumor Growth.
Raymond Yeung, MD, from University of Washington for his
one year Pilot Award on Serum Metabolites in LAM.
The first-ever LAM Foundation Biomarker Innovation
Grants (BIG) were awarded to:
David Kwiatkowski, MD, PhD
Carmen Priolo, MD, PhD
Congratulations to Drs. Inoue and Nakata, who were pre-
sented with the LAM Foundation Scientific Advancement Award Elizabeth Henske, MD
(LFSAA). For the past 20 years, they have worked tirelessly for Brian Bartholmai, MD
LAM patients in Japan. They brought the MILES trial to Japan Simon Johnson, Professor of Respiratory Medicine
and led the effort to obtain Japanese FDA approval for sirolimus. Raymond Yeung, MD
These grants were awarded as a result of the LAM Biomarker Innovation Summit held in November 2014. The LAM com-munity and The LAM Foundation awarded at total of $185,000 in grants to these six recipients MDBR Grant Awardees
Congratulations go out to Million Dollar Bike Ride Grant Awardees, Vera Krymskaya, PhD, from University of Penn-
sylvania and Aris Astreinidis, PhD, from Texas Tech Health
Sciences Center. LAM Foundation Donors met the UPenn
matching funds challenge, for a total raised of $120,000 for the
2014 Million Dollar Bike Ride. Drs. Krymskaya and Astreinidis
both received $60,000 for their LAM pilot studies.
This year, all nine LFSAA recipients were present. Seated left Poster Awards went to:
to right: Frank McCormack, MD; Elizabeth Henske, MD;
Vera Krymskaya, PhD; Simon Johnson, Professor of Re- Debbie Clements, PhD,
best basic science poster award
spiratory Medicine
Yang Sun, PhD, best translational science poster
Standing left to right: Yoshikazu Inoue, MD, PhD; Koh
Mariana Sponholz Araujo, MD, best clinical science poster
Nakata, MD, PhD; David Kwaitkowski, MD, PhD; Joel
Congratulations and Thank You to all the scientists and cli- Moss, MD, PhD; Kuniaki Seyama, MD, PhD
nicians who could join us at the conference, we are Stronger Together. Stronger Together The LAM Foundation is celebrating its 20th Anniversary and JOINT SESSION: WOMEN'S HEALTH FORUM adopted the theme, "Stronger Together". When Sue Byrnes created The LAM Foundation in 1995, she knew that hope starts Hormones and the LAM with a conversation. Because of her courage and perseverance, patient is a topic of interest for today we are a global community of women with LAM, their professionals and women with families, scientists, clinicians, and external partners who have LAM alike. This was the topic of a joint session panel discus- come to be…Stronger Together.
sion, Women's Health Forum: Stronger Together was evident at this year's International LAM Hormones and LAM Across Research Conference, LAMposium and Breath of Hope Gala. a Lifetime. LAM Foundation Board Member, Geraldine Finlay, MD, moderated a panel of Take a look at the numbers:
experts including MeiLan Han, MD, MS, University of Michigan; • Over 350 women with LAM, family, friends, scientists and Kathleen Hoeger, MD, MPH, University of Rochester Medical clinicians attended Center; Lisa Larkin, MD, University of Cincinnati Medical • 16 countries were represented Center; and Steven Hammes, MD, PhD, University of Rochester Medical Center.
• 118 LAM patients attended along with 120 family and friends • 17 LAM patients attended the conference for the very first time BREATH OF HOPE GALA PLANTINIUM ANNIVERSARY CELBRATION • 108 physicians and scientists attended and were inspired to help move LAM research forward faster It was the most successful year ever for the Breath of Hope • An astounding 1: 1 Patient to Scientist-Clinician ratio Gala Platinum Anniversary • More than $210,000 was raised for LAM Research at the Celebration. The Silent Auc- Breath of Hope Gala. 100% of which will directly fund LAM tion cocktail party was a hit for everyone. The paparazzi did • 285 direct story links to medical and news websites who not arrive, but that did not stop everyone from taking a turn at shared the inspiration of the International LAM Research the Red Carpet Banner.
Conference and LAMposium story and our partnership with A lovely dinner was served and the program was filled with Loyola University Health Center; resulting in… many emotional highlights.
• 59,667,276 media impressions We celebrated 20 years of progress and pursuing a There were some new events added to this year's confer- cure with three stories that ence. Thursday evening women with LAM, family and friends demonstrate the real impact of attended the annual social. It was also a great opportunity for what Sue Byrnes and Dr. Frank first time attendees to make new McCormack created when they connections and place a friendly started The LAM Foundation. face with those they met online.
Brian Kleps, emeritus board The conference moved into member, shared his story of participating in early letter writing full gear later that evening as campaigns and fundraising in memory of his wife, whom he lost Jeffrey Swigris, DO, MS, from to LAM before the Foundation was created. National Jewish Health, gave Shelby and Zack Garner the Conference Kick-Off presentation. His presentation, "Incor- shared their experiences of fear and uncertainty which turned to porating Patient- Centered Outcomes into LAM Research", was hope and optimism when Shelby well received. Newly diagnosed and first time attendee, Melaney responded well to treatment Parrish took the time to share her story with everyone. Her vision -- an outcome from the ground- of raising LAM awareness in her West Virginia hometown and breaking MILES Trial that was across the US inspired the audience.
supported by the Foundation Combined breakfasts and lunches, throughout the weekend and women with LAM during prompted conversations about exciting new LAM research and our second decade. new connections were made while sharing a meal.
CONTINUES ON NEXT PAGE › Frances Saldivar gave The rose ceremony ended with Dr. Clark Baxter playing the a beautiful and motivating bagpipes in tribute to the 242 women who lost their battle presentation, about how she with LAM. Their memories and friendship lives on in our has channeled her grief over the mind-bending diagnosis of hearts. LAM into action and a vision Funding for LAM research was accelerated as the Emcee for for a bright future for herself, the night, Sherry Truhlar, entertained with an extremely gener- and all women and families ous Fund – A – Cure auction. Once the audience's paddles were affected by the disease.
exhausted, applause for raising over $210,000 for LAM research erupted from the room.
More than 100 women with LAM came to the dance fl oor to accept a rose and have their picture taken; they then donated their roses back to a nearby Chicago nursing home. Roses were distributed by LAM Clinic Directors, Robert Kotloff, MD, George Pappas, MD, Steve Ruoss, MD and Joel Moss, MD, PhD, from the NIH.
And of course the night would not be complete without the party going into the late evening as the celebration continued with dancing and casino games. When asked what was the most signifi cant moment expe- rienced at the LAMposium and the Breath of Hope Gala, one attendee said, "There were so many moments; it is hard to identify one. My husband attended with me and we are amazed at the collaboration and enthusiasm shown by everyone." Save the Date!
2016 International LAM Research Conference and LAMposium at the Cincinnati Marriott at Rivercenter Covington, Kentucky September 22 – 25, 2016
Thank you to our Loyal Sponsors for Their Support
Platinum Feather Sponsor:
Andrew and Kim Romanosky In honor of Barbara Laurenzi Supported in part by NIH Research Grant R13HL093774-08 funded by the Offi ce of Rare Disease Research, National Center for Advancing Translational Sciences and The National Heart, Lung, and Blood Institute.
Francis & Peggy McCormack, Sr. In honor of Dr. Frank McCormack John Adler In Memory of Vi Adler In memory of Melinda Wehland Jack & Ann Struthers Ed Plocharczyk In memory of Jean Togikawa The LAM Foundation appreciates
Coleen Murphy In support of travel your generous gifts and is proud
your generous gifts and is proud
to have you
ve you as our partners in the
as our par
tners in the
ght to cure LAM.
In support of transportation and logistics CONTINUES ON NEXT PAGE › Announcing The LAM Foundation's 20 20 20 Campaign!The 20 20 20 Campaign is a fundraising drive of The LAM We are taking steps to create a world without LAM. Join us today! Foundation which brings together families, friends, and communities to heighten awareness of LAM – a progressive lung Visit www.thelamfoundation.org and click on the 20 20 20 icon disease – and to fund a breakthrough therapy for LAM…faster. for details to:As recognition of the Foundation's 20th anniversary, friends, fami- • Launch your 20 20 20 Campaign.
lies, and co-workers are inspiring 20 people in their communities • Support a 20 20 20 Campaign.
• Make your personal donation to the 20 20 20 Campaign.
to join them in giving $20 a month for 20 months. During this 20 month period, we will seek local, state, regional, and national attention for The 20 20 20 Campaign and the LAM Foundation. The initial sign-up for this fi rst-ever 20 20 20 Campaign began on June 1, 2015 and continues through September 30, 2015. Through the 20 20 20 Campaign, we will • Heighten awareness of LAM across larger community circles • Identify and provide support for more women with LAM• Fund a breakthrough therapy for LAM…faster! You Can Bring More Women to LAMposium with $1:$1 Match If you are inclined to support women with LAM in their search for education, expert clinical advice, clinical trial opportunities and the empathy and support of the LAM Community, please consider donating to LFN between now and October 31, 2015. Traveling to the conference can be a remarkable experience for women who are newly diagnosed with LAM or who have never attended. Many women have never met someone else who has LAM and may not have access to LAM clinicians. By giving to the LFN Travel Fund you are giving these women a chance to enerous donations to the LAM Family Network (LFN) make connect and engage in communit it possible for women with LAM to travel to the International LAM Research Conference, LAMposium and Breath of Hope You can give three different ways: Gala. This year, just over $11,000 in travel grants were awarded to 21 women with LAM who would not have attended without 1) Online at thelamfoundation.org by clicking on the DONATE NOW button and choosing LAM Family Network (LFN) in the LFN support. Grants are awarded based on fi nancial need and previous conference attendance. The LFN Fund is generously supported each year by donors 2) Use the Journeys donation envelope attached; indicate LFN and proceeds from the LAM Quilt Project. For the fi rst time
MATCH on the Occasion Line. ever, an anonymous donor has offered a dollar for dollar 3) Mail a check to The LAM Foundation and indicate LFN
match, up to $10,000 to replenish the LFN Fund. That
MATCH. Or call The LAM Foundation at 877.CURE.LAM gives us the opportunity to raise $20,000 to bring more women (877.287.3526) or send an email to info@thelamfoundation.orgto the 2016 LAMposium in Cincinnati.
The LAM Foundation would like to thank our many
generous donors for their support.
This list reflects gifts made between July 1, 2014 and December 31, 2014
GIFTS OF $20,000 AND ABOVE MG General Electric Community Donald and Betty Scoralle Tim and Lou Alexander Mitch and Sandra Shaheen The Rothberg Institute GKN Foundation/ Sinter Metals Richard and Joyce Gordon Matthew and Elizabeth Shaughnessy GIFTS OF $10,000 - $19,999 Nishant Gupta, MD Richard and Glenna Shearer Mary and Tom Harbaugh Frank and Louise Steele MG Michael and Lynn Nemser Eugene and Terese Hawkins Steele Family Foundation Heather Joy Memorial Fund Jack and Ann Struthers Quint and Andrea Slattery Hal and Penne Holt Eugene J. Sullivan, MD Insmed Incorporated Justin and Samornchit Tansuwan GIFTS OF $5,000 - $9,999 January and Aaron Butler The Anders Foundation Jean and Stanley Chenoweth The Wade Creek House, LLC.
Aaron and Edith Dichter Mr. & Mrs. Dan Goldstein Don and Madonna Van Brackel Indiana Grand Casino Gerrit and Anneke van den Dool Shirley Lefkowitz Sharon and Eldon Mason Tom and Barbara Laurenzi Richard and Janette Verhey Gerald and Regina Musser Laura and Chris Lentz Susan and Conan Ward David and Kristine Mason MG McMaster-Carr Supply Company GIFTS OF $1,000 - $4,999 Pete and Margaret Williamson Steve and Sylvia Menashe Baiardi Family Charitable MG Microsoft Matching Gifts Program Barbara Yamashiro Jim and Marilyn Young Patti and Burt Aronoff Deborah and Alfred Yudes David and Michelle Zimmermann Robert and Barbara Bovine Kristine Zylstra and The Deboer Family Aubrey and Carol Bush Nuveen Investments Holdings GIFTS OF $500 - $999 CareFusion Foundation Gregory Allen and Martina Bulk Betty and Bob Copple Aquanut Water Shows, Inc.
MG Covidien Employee Matching James and Jacqueline Patton MG Piedmont Natural Gas Foundation Taylor and Julie Bozarth Bill Crispin and Maureen Mahoney Mariele Briones, MD Leslie and LeAnn Cunningham Eden and Douglas Pontz Day Out for the Blind Curt and Leslie Pontz Matthew and Adrienne Carr David and Gloria Eiseman Craig Christensen Aaron and Annette Roberts Irvin and Jacqueline Cohen Fitzgerald Auto Malls William and Lee Anna Combs Eric and Linda Schwarz Richard and Morgan Cook CONTINUES ON NEXT PAGE › Harvey and Helen Cummings Gregory Downey, MD Ed and Tish Davey Lena and Uwe Schmalenbach Mark and Brittan Dubose Robert and Carleen Schuh Alfred and Anne DiPasqua Timothy Shaughnessy Richard and Cathleen Early Tom and Rosalyn Ellis Randall and Katherine Erickson Mike and Laura Elsigian Leslie and Eugene Espinola MG ExxonMobil Foundation Danny and Angela Faught Constance and Mike Farkas Zachary and Joyce Stoumbos Ron Faught Sr.
The M&W Logistics Group, Inc.
Joseph Feeney Jr.
Scott and Kathryn Finke Barrie and Richard Galanti Arvel and Donna Trent James and Elizabeth Graham Truepoint Wealth Counsel, LLC Debbie Washington Tory and Meghan Wierzbicki Eric and Peggy Haupt Heldman Exteriors, Inc.
Robert and Linda Winter Raymond Yeung, MD Michael and Nancy Hagist Peter and Karen Jakes John C. Grimberg Co., Inc.
Mr. & Mrs. Timothy Hanratty GIFTS OF $250 - $499 Lewis and Elizabeth Harper Paul and Jane Hart Nicholas and Joyce Andre Arnold and Phyllis Hayutin Bryan and Diane Kahler Kathy Avezzie-Gonce William and Mary Henson Brian Bartholmai, MD Larry Holbein and Carol Ross and Suzann Klompenberg Sandra and Ronald Martin Carol Jean Blackburn Tony and Susan Isaak Master Plumbing & Mechanical, Inc.
Ivy Rose, Inc.
William and Diane Blumenthal Jane and John Mazzarella Michael Bork and Sheryl Cohen Alex and Patricia Janicijevic MG BP America, Inc.
Moss Construction Jason and Stefanie Brown Nisha and Tony Mossing Herbert and Mildred Bulk Adriane and Aaron Nelson Business Printing Specialists, Inc.
Tim and Kris Cada Marc and Betty Kaplan Rhonda and Kevin Offi cer David and Marsha Kelpe John and Jan Oltman Capitol Federal Foundation Donald and Annette Pacheco Stuart and Mary Carroll MeiLan King Han, MD, MS Cetylite Industries, Inc.
Christopher and Lindsay Pierce Colin and Wendy Chopin Chowchilla Spring Festival Roger and Vickie Lansman Danelle Christensen Russ and Sharon Larson Progressive Printing Solutions Marian Christensen Lea Springs Baptist Church James and Maureen Corry David Leck and Roxane Gelroth Sam and Lynne Reynolds Cary and Lynda Levinson MG Dan and Donna Roche Magic Valley Electric Cooperative Justin Reis, MD and Team Norman and Kim Vandervoort Joseph and Tracey Malick Randy and Lynn Vaneyck Guy and Leslie Marchesseault David and Gwen Pryor William and Joyce Martin Travis and Janice Watkins Rob Jeffrey and Cathy Mason McAllen Evening Lions Club Julie and Paul Roberts Patrick and Maureen Roche Brandon and Eileen Wiedwald Randy and Mary Mercure Sharon Rounds, MD Garth and Laura Will Bill and Betty Moore Saldana Supply Company, LLC.
Don and Karen Wolnik Joyce and Herbert Nakatsu Shelton General Contractors Nancy Kay, Inc.
Southwestern Ohio Football Coaches Association Anthony and Deborah Zoia David and Janet Neff Al and Kim Steele Vincent Stefanelli Gregory and Natalie Otto Harold and Donna Stover Bill and Jill Packer Sheila and Timothy Patton Total Rehabilitation of Harlingen Dick and Kathy Trapp Evan and Lanie Pontz Thanh Hung Truong The LAM Foundation would also like to thank the more than 1,332 donors who contributed $5-$249. We appreciate your support.
The pink feather denotes donors who have included The LAM Foundation in their charitable estate plan. By doing so, they are now members of the Breath of Hope The LAM Foundation has made every Legacy Society. To learn more, please contact The LAM Foundation at info@ effort to be as accurate as possible thelamfoundation.org. If you have made a planned gift to the Foundation, please when creating our list of contributors. let us know so we can recognize your name with a pink feather.
If there is an error in the recognition of your gift, please contact the Foundation at 513.777.6889 or info@ MG The MG denotes companies that offer matching gifts. If your company has a thelamfoundation.org so we may correct matching gift program, please contact your HR Department to find out how to our records. Thank you.
request a matching gift donation to The LAM Foundation.
4015 Executive Park Dr., Ste. 320 Cincinnati, OH 45241 5th Worldwide LAM Awareness Day
The Fifth Annual Worldwide LAM Awareness Day was held offi cially on Monday, June 1, 2015. Thank you to those of you Monday, June 1, 2015
who have and continue to promote awareness, raise funds offl ine, and have set up online fundraising pages. At The LAM Foundation, online WWLAD Campaigns are open and will continue through December 31, 2015.
Worldwide LAM
Lymphangioleiomyomatosis (LAM) is a rare lung disease that occurs almost
exclusively in women. It affects mainly the lungs causing excessive growth of
smooth muscle cel s that progressively destroy lung tissue and diminish lung
function. Although research is ongoing, there is currently no cure for LAM. For
some patients lung transplantation is their only means of survival.
Monday, June 1, 2015 has been designated as the 5th Worldwide LAM
Awareness Day by the WLPC (Worldwide LAM Patient Coalition).
Please see the links below for details of your national organization.
LAM Australia Research Alliance (www.lamaustralia.org.au) Österreichs Selbsthilfegruppe für Lymphangioleiomyomatose (www.
lamaustria.com) ALAMBRA: Associacao LAM Do Brasil (www.alambra.org.br) LAM Canada (www.lamcanada.org) LAM China (www.
lamchina.org) FLAM: France Lymphangioléiomyomatose (www.asso.orpha.net/FLAM/) LAM Selbsthilfe Deutschland e.V. (www.
lam-info.de) LAM Support Ireland (www.lamsupportireland.com) Israel LAM Organization (www.lam-israel.org) LAM Italia (www.
lam-italia.org) J-LAM (www.j-lam.net) Asociación Mexicana de Linfangioleiomiomatosis (http://lammexico.org) LAM Nederland
(www.lam-nederland.nl) New Zealand LAM Trust (www.lam.org.nz) LAM Norway LAM Romania (www.lamromania.ro) AELAM:
Asociación Española de Linfangioleiomiomatosis (www.aelam.org) LAM Academy (www.lamacademy.org) LAM Action (www.
lamaction.org) The LAM Foundation (www.thelamfoundation.org) The Europe LAM Federation (www.europelamfederation.org)

Source: https://www.thelamfoundation.org/Portals/0/Files/Journeys/summer15a.pdf?ver=2016-06-13-083001-080

ayhansahenkvakfi.org.tr

ARTHRITIS & RHEUMATISMVol. 46, No. 5, May 2002, pp 1309–1318DOI 10.1002/art.10262© 2002, American College of Rheumatology A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Adjuvant Methotrexate Treatment for Giant Cell Arteritis Gary S. Hoffman,1 Maria C. Cid,2 David B. Hellmann,3 Loic Guillevin,4 John H. Stone,3 John Schousboe,5 Pascal Cohen,4 Leonard H. Calabrese,1 Howard Dickler,6 Peter A. Merkel,7

bioolmetto.it

Nutrition and Food KiwifruitOverview of Potential Health Benefits Keith Singletary, PhD Kiwifruit belongs to the genus Actinidia (Actinidiaceae) and is derived brought to New Zealand in the early 20th century, where it from a deciduous woody, fruiting vine. It is composed of different was eventually domesticated, renamed, and sold world- species and cultivars that exhibit a variety of characteristics and sen-