Feasibility Study of [11C]Acetate Positron Emission Tomography (PET) as an Indicator of Early Response to Rapamycin in Lymphangioleiomyomatosis (LAM) Patients
Phase: PHASE1
Conditions: Lymphangioleiomyomatosis, Tuberous Sclerosis Complex
Sponsor: Brigham and Women's Hospital

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[11C]Acetate Positron Emission Tomography (PET) in patients with 
Lymphangioleiomyomatosis (LAM) and Tuberous Sclerosis Complex (TSC). 
 
NCT05467397 
 
 
5/29/2024 
 
Principal Investigator:  
Carmen Priolo, M.D., Ph.D. 
 
Associate Investigators:  
Elizabeth Henske, MD 
 
 
 
    
Souheil El-Chemaly, MD 
 
 
 
    
 
 
 
 
 
Research Contact:   
Carmen Priolo, M.D., Ph.D. 
 
 
Duration of study:   
6 months 
 
Number and type of subjects: 8 or 16 adult female subjects diagnosed with an angiomyolipoma 
 
Ionizing radiation:   
Yes 
 
Project uses IND/IDE:  
IND no. 146871 
 
Multi-Institutional Project: No 
 
Participating Institutions:  Brigham and Women’s Hospital, Boston, MA;  
Massachusetts General Hospital, Boston, MA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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I. 
Background and Significance 
a. Historical Background: Lymphangioleiomyomatosis (LAM) is a rare, multisystem 
disease of women, consisting of a diffuse proliferation of smooth muscle actin-positive 
cells (LAM cells), which harbor inactivating mutations in either the TSC1 or TSC2 tumor 
suppressor gene. These inactivating mutations result in constitutive activation of 
mammalian/mechanistic TOR (target of rapamycin) complex 1 (mTORC1) (2-5), which 
integrates growth factor and nutrient signaling to stimulate cell growth and metabolism (6-
10). Pulmonary LAM is characterized by associated progressive cystic destruction of the 
lung parenchyma, recurrent pneumothorax, and chylous pleural effusions. Extrapulmonary 
proliferative lesions of LAM include renal angiomyolipomas and lymphangiomyomas. 
LAM can occur as a sporadic disorder where LAM cells harbor somatic inactivating 
mutations of the TSC1 or TSC2 gene, or in women with Tuberous Sclerosis Complex 
(TSC). TSC is an autosomal dominant disease characterized by neurologic manifestations 
and hamartomas of the brain, skin, heart, and kidneys (11). Up to 80% of women with TSC 
have radiologic evidence of cystic lung degeneration (11, 12). 
 
b. Previous pre-clinical or clinical studies leading up to and supporting the proposed 
research: Preclinical work was conducted in the laboratory of Dr. Priolo and published in 
part in Clinical Cancer Research (1). The Priolo lab was able to show that lipogenic 
pathways can be detected in preclinical models of TSC and LAM in vivo using microPET-
based metabolic imaging 
 
c. Rationale behind the proposed research and potential benefits to patients and/or 
society: Rapamycin is an FKBP12-dependent allosteric inhibitor of mTORC1 approved by 
the FDA for the treatment of LAM and TSC-associated renal angiomyolipomas. Clinical 
trials of TSC and LAM have shown that 12 month-treatment with rapamycin induces 
response of renal angiomyolipomas and stabilization of pulmonary function and clinical 
benefit is seen after 3 months for both LAM and renal angiomyolipomas (13-15). However, 
lung function decline and tumor growth resume when treatment is interrupted. In addition, 
magnitude of clinical response to rapamycin varies across patients.  For instance, in the 
EXIST-2 trial (double-blind, placebo-controlled, phase 3 trial) the response rate was 42%, 
with the primary efficacy endpoint being the proportion of patients with confirmed 
angiomyolipoma response of at least a 50% reduction in total volume of target 
angiomyolipomas relative to baseline (14). 
This clinical evidence highlights the critical need for sensitive and specific biomarkers of 
response to therapy and/or disease progression, including biomarkers of tumor metabolic 
activity. Currently, elevated levels of vascular endothelial growth factor-D (VEGF-D) in the 
blood of LAM patients represent the only biomarker with diagnostic role in LAM (16, 17) 
and potentially a role as a biomarker of therapeutic response to mTORC1 inhibitors (18). 
However, not all LAM patients have clinically significant blood VEGF-D levels. 
Metabolic imaging biomarkers of disease activity are not currently available for TSC/LAM. 
[18F]fluorodeoxyglucose (FDG)- PET has shown utility to identify malignant neoplasms 
including malignant perivascular epitheliod cell tumors (PEComas), primary lung cancers, 
and lymphomas, in patients with TSC and/or LAM. However, TSC and LAM lesions (renal 
angiomyolipomas, pulmonary LAM, lymphangiomyomas) did not show abnormal FDG 

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uptake, likely due to aberrant trafficking of glucose transporters (19-21). LAM patients 
would benefit from a metabolic imaging biomarker in multiple ways. First, a sensitive a 
specific imaging biomarker would help answer outstanding questions regarding personalized 
dosage and length of treatment for rapamycin and its analogs (rapalogs). Second, biomarkers 
of disease progression and therapeutic response would streamline the design, cost and 
duration of LAM/TSC clinical trials. Third, a metabolic imaging 
biomarker and circulating VEGF-D could be used as complementary diagnostics to enhance 
clinical decision making. 
Forth, PET is a technique already widely used in the clinics, therefore there will be no need 
to generate Intellectual Property or secure additional funding to commercialize any product 
of our study.  
  
 
II. 
Specific aims 
 
The proposed study aims to quantitatively and non-invasively assess metabolic activity of renal 
angiomyolipomas as an early biomarker of response to rapamycin and rapalogs and to 
implement modeling of LAM lung metabolic activity in LAM and TSC patients using 
[11C]acetate positron emission tomography (PET) imaging.     
These milestones will be achieved in the following Specific Aim: 
Specific Aim 1. Test feasibility of [11C]acetate PET to quantify metabolic activity of LAM 
or TSC patient lesions before and after treatment with rapamycin or rapalogs. We plan to 
enroll eight women with LAM or TSC who have renal angiomyolipomas and are rapamycin-
naive. Our preliminary studies reveal that incorporation of acetate in TSC2-deficient cells is 
strongly suppressed by rapamycin. In addition, our proof of concept preclinical studies with 
the acetate derivative fluoroacetate showed rapid uptake of this tracer by TSC2-deficient 
tumors, including tumors generated with LAM patient renal angiomyolipoma-derived cells, 
using dynamic PET.  
 
In the proposed study, dynamic [11C]acetate PET/CT will be used to monitor metabolic activity 
over time and to extract blood and tissue density components in renal (angiomyolipomas) and 
lung lesions in LAM or TSC patients. Patients enrolled who are either on treatment with 
Rapamycin or a rapalog or not will receive 1 scan each and patients who are about to start 
therapy with rapamycin or rapalogs, will receive 2 scans, one at baseline and one after 3 months 
of therapy 
 
We expect to achieve the following outcomes: 
1. Implement quantitative modeling to detect [11C]acetate uptake in renal angiomyolipoma 
and pulmonary LAM. 
2. Test[11C]acetate PET as a biomarker of rapamycin activity in TSC2-deficient 
proliferative lesions.  
Both outcomes will provide standardized uptake value (SUV) as a measure of metabolic 
activity of different LAM/TSC lesions in patients.   
 
Our success will be measured as the ability to non-invasively detect and quantify metabolic 
activity of proliferative lesions in LAM or TSC patients. Importantly, enhanced uptake of 
[11C]acetate has been reported in 10 patients with renal angiomyolipomas, showing 

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significantly higher SUV in the tumors compared to normal kidney. SUV was not affected by 
fat content (1). This published report supports the clinical feasibility of our proposed study. 
 
III. 
Subject Selection 
a. Inclusion/Exclusion Criteria: LAM or TSC patients, aged 18 yrs and over presenting with 
at least one renal angiomyolipoma (at least 1 cm in each diameter) confirmed by CT, MRI, 
or ultrasound and have not received any prior treatment with Rapamycin or rapalogs or 
candidates for initiating treatment with rapalogs or who have been on rapamycin or 
rapalogs for a minimum of 3 months and maximum of 5 years will be eligible for the study. 
Patients with LAM and AML who are currently on rapalogs for < 3 months and > 5 year 
and patients who have participated in other research studies in the past 12 months that have 
involved radiation exposure, which is more than 50 mSv/year, would not be eligible for this 
study.  
b. Source of subjects and recruitment methods: 
Patients are referred to our clinic at the LAM center at Brigham and Women’s hospital by 
local pulmonologists as well as the LAM foundation for their clinical care. All clinic 
patients found to have an angiomyolipoma and other potential participants referred to us by 
physicians who care for LAM or TSC patients at various institutions and by the LAM 
foundation or the Tuberous Sclerosis Alliance could be approached for participation in the 
study. Care will be taken to allow potential subjects to feel free from tension and subtle 
coercion. The physician investigators will advise potential subjects that a study is being 
done, and briefly describe the study to ascertain interest prior to identifying themselves as 
being involved. Investigators will emphasize that participation is voluntary and that not 
participating will not jeopardize their future care at Brigham and Women’s hospital or any 
other Partners institution.  
The study investigators will also contact providers outside of these institutions who may be 
caring for patients with LAM or TSC to notify them of the clinical trial design, inclusion 
and exclusion criteria. This contact will be in the form of a letter to referring physicians. 
Such physicians will be provided with contact information of key personnel in the trial in 
order to refer potential subjects for participation.  
 
IV. 
Subject Enrollment 
The primary specialist or heath care provider, usually a physician, who is known to the 
potential subject and has firsthand knowledge of the patient’s medical history must (1) give 
approval for his/her patient to be contacted for research purposes (2) initially introduce the 
study to the patient and (3) obtain the patient’s permission to be contacted by study staff. A 
nurse or study coordinator will review the informed consent with the subject to avoid the 
possibility of coercion or bias since subjects will be recruited from Investigator’s own 
practice. Subjects will be reminded that refusal to participate in this trial will not change 
the quality of care that she will receive at BWH. Study participation is voluntary and the 
subject will be advised that she can withdraw at any time.  
The subject will be given the opportunity to take the consent home to consider 
participation. The subject will be asked to read the informed consent form prior to the 
physician or study coordinator asking the subject any questions concerning their health. 
Written, informed consent will be obtained after one of the investigators has reviewed the 
protocol verbally in detail with the subject. The physician will inform the subject that she 

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has the alternative not to participate in the study. Subjects will receive a signed copy of the 
consent form for their records. After all questions are answered, and only after the consent 
form is signed by the patient and one of the MDs listed on the application will study 
screening commence. Subjects unable to give consent will not be approached. 
 
In cases where the subject is unable to travel to the MGB site for the consent visit, the 
investigator would call the subject on the phone or over video where details of the study 
will be discussed. All questions will be answered and the consent form would be sent to the 
subject electronically along with contact information for the study team.  The subject 
would then review the consent and there would be an additional call to answer if any 
remaining questions. Once, all questions are answered, the subject would sign and date 
(including time) the consent form agreeing to their participation in the research and return 
the signed (handwritten or digital) and dated consent form electronically. The investigator 
would sign and date (including time) the consent form signed and dated by subject. MGB 
IRB requirements for digital signatures will be followed when the subjects would prefer to 
use digital signatures while signing the consent form. 
 
V. 
Study Procedures 
Patients who are eligible would be consented to the study by a physician investigator at 
Partners. Each subject would then be scheduled and would undergo 2 PET scans over a 
period of 4 months at the Gordon Center for Medical Imaging at Massachusetts General 
Hospital as part of the study.  
Patients would have up to 3 study visits- the first visit would be for consent (lasting about 1 
hour) and 2nd and the 3rd visits would be for the PET/CT (lasting about 3 hours each). The 
PET/CT appointments may need to be rescheduled depending on the patient’s convenience 
and the availability of time slots. 
On the day of the PET scan, if the subject is premenopausal, we would be conducting a 
STAT quantitative serum hCG test before the scan. Then, a low dose x-ray CT scan will be 
performed for anatomical localization and for attenuation correction of PET images. An 
intravenous (IV) catheter would be placed on one arm for the radiotracer (contrast) infusion. 
An intraarterial catheter would be placed on the arm opposite of the IV line for blood draws 
that would occur at first every 15 seconds and gradually reduce to 10 minute intervals by the 
end of the scan. The total volume of blood would be less than 150 ml (10 tablespoons). The 
PET scan would take about 20 to 60 minutes. 
Drug to be use: C-11 Acetate is the tracer used in this study.  
Data to be collected: PET and CT images as well as concentration of the radiotracer 
metabolites in the blood of the patients will be collected  
Since [11C]acetate is not a proven early biomarker of rapamycin response, the PET scan data 
obtained in this study will not be used to adjust the dose of rapamycin that a study participant 
is given. 
Study staff may need to access patient’s medical records in Epic to locate the lesion and 
know the pulmonary function before and/or after the study scan appointment as well as to 
compare the PET/CT images obtained for the study to other imaging tests obtained for 
clinical purposes. 
 
VI. 
Biostatistical Analysis: 

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We will enroll 8 patients. Assuming a standard deviation of 16% (based on our preclinical in 
vivo imaging data) for the SUV change between baseline and post-rapamycin/ post-rapalog 
treatment, a group of 8 patients will allow us to reach 80% power to detect at least a 
decrease of 7% in [11C]acetate uptake by PET imaging (compared to 11% increase without 
treatment), using a two-sided one sample t-test at alpha=0.05 level. In fact, we expect to find 
a greater decrease than 7% in the proposed study, and we will have higher power to detect 
this greater decrease. 
Alternative statistical approach. Assuming a standard deviation of 0.53 (based on prior study 
(1)) for both a rapamycin/rapalog-naïve and a rapamycin/rapalog-treated group, n= 6 
patients per group will allow us to reach 80% power to detect a difference of at least 25% in 
SUVmax between the two groups using a two-sided two sample t-test at alpha=0.05 level. 
This statistical approach will allow us to analyze imaging data obtained from two 
independent groups of patients receiving a single PET scan rather than one group of patients 
receiving two PET scans each (baseline and after treatment). 
 
VII. 
Risks and Discomforts 
The combined radiation exposure from the PET/CT scan in this study will be not more than 
9.4 mSv (4.7 mSv per scan). This amount of radiation is equivalent to 3.75 years of normal 
background radiation (3.1 mSv exposure = 1 yr background). This level of exposure is 
considered small and there is no evidence that it represents a major health risk. 
Placement of the i.v. catheter may be associated with minor discomfort along with some 
bruising or swelling at the insertion site. Placement of the intra-arteria catheter could lead to 
swelling and redness at the sites of line placement, as well as temporary loss of pulse at the 
wrist. This area may have a bruise or feel uncomfortable for 2-3 days after the catheter is 
removed.  
Inserting an arterial line (A-line) can hurt more than having a regular i.v. or having blood 
drawn with a needle.  The A-line will be placed with local anesthesia (i.e., lidocaine), which 
may cause an allergic reaction.  Even if the wrist area is first numbed, the insertion may still 
hurt. Once the A-line is in place, it usually does not hurt. Even after the catheter is removed, 
the site of insertion may feel tender or may have a bruise for 2 to 3 days.  
The maximum volume of blood drawn at any scan would be 150cc, which is significantly 
less than the volume drawn for a blood donation (i.e., ~470cc).  
It is possible that incidental abnormal findings may be discovered during a subject’s 
participation in this study. Discovery of incidental findings may prompt study anxiety and 
follow-up testing. 
 
VIII. Potential Benefits: 
Individual subjects enrolled in the study would not benefit directly from the study. In the 
future, from information obtained in this study, LAM and TSC patients would benefit from 
a metabolic imaging biomarker in multiple ways. First, a sensitive and specific imaging 
biomarker would help answer outstanding questions regarding personalized dosage and 
length of treatment for rapamycin and its analogs (rapalogs). Second, biomarkers of disease 
progression and therapeutic response would streamline the design, cost and duration of 
LAM/TSC clinical trials. Third, a metabolic imaging biomarker and circulating VEGF-D 
could be used as complementary diagnostics to enhance clinical decision making. 
 

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IX. 
Monitoring and Quality Assurance 
This study will not be monitored by an independent DSMB.  
All unanticipated problems including adverse events will be reported to the Partners Human 
Research Committee (PHRC) in accordance with the accepted guidelines. A 24-hour/7-day 
telephone number will be provided for contacting the licensed physician investigator for this 
purpose.  
The research staff will monitor all subjects during their study involvement for evidence of 
any adverse events. 
X. 
References 
 
1. Verwer…Priolo, CCR, 2018 
Ho CL, Chen S, Ho KM, Chan WK, Leung YL, Cheng KC, 
Wong KN, Cheung MK, Wong KK. Dual-tracer PET/CT in renal angiomyolipoma and subtypes 
of renal cell carcinoma. Clin Nucl Med. 2012;37(11):1075-82. doi: 
10.1097/RLU.0b013e318266cde2. PubMed PMID: 22996247. 
2. 
McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest. 2008;133(2):507-
16. Epub 2008/02/07. doi: 133/2/507 [pii] 
10.1378/chest.07-0898. PubMed PMID: 18252917. 
3. 
Hayashi T, Kumasaka T, Mitani K, Terao Y, Watanabe M, Oide T, Nakatani Y, 
Hebisawa A, Konno R, Takahashi K, Yao T, Seyama K. Prevalence of uterine and adnexal 
involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients. 
Am J Surg Pathol. 2011;35(12):1776-85. Epub 2011/10/25. doi: 
10.1097/PAS.0b013e318235edbd. PubMed PMID: 22020043. 
4. 
Henske EP, McCormack FX. Lymphangioleiomyomatosis - a wolf in sheep's clothing. J 
Clin Invest. 2012;122(11):3807-16. Epub 2012/11/02. doi: 10.1172/JCI58709 
58709 [pii]. PubMed PMID: 23114603; PMCID: 3484429. 
5. 
Kumasaka T, Seyama K, Mitani K, Sato T, Souma S, Kondo T, Hayashi S, Minami M, 
Uekusa T, Fukuchi Y, Suda K. Lymphangiogenesis in lymphangioleiomyomatosis: its 
implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol. 
2004;28(8):1007-16. Epub 2004/07/15. doi: 00000478-200408000-00004 [pii]. PubMed PMID: 
15252306. 
6. 
Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma 
Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, 
Manning BD. Activation of a metabolic gene regulatory network downstream of mTOR complex 
1. Mol Cell. 2010;39(2):171-83. Epub 2010/07/31. doi: S1097-2765(10)00463-6 [pii] 
10.1016/j.molcel.2010.06.022. PubMed PMID: 20670887; PMCID: 2946786. 
7. 
Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H, Yoon SO, Cantley LC, 
Blenis J. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing 
of metabolic demand with supply. Mol Cell. 2010;38(4):487-99. Epub 2010/06/02. doi: S1097-
2765(10)00369-2 [pii] 
10.1016/j.molcel.2010.05.007. PubMed PMID: 20513425; PMCID: 2896794. 
8. 
Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey 
JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, 
Blenis J. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by 
repressing SIRT4. Cell. 2013;153(4):840-54. Epub 2013/05/15. doi: 10.1016/j.cell.2013.04.023 
S0092-8674(13)00465-0 [pii]. PubMed PMID: 23663782; PMCID: 3684628. 

8 
 
9. 
Parkhitko AA, Priolo C, Coloff JL, Yun J, Wu JJ, Mizumura K, Xu W, Malinowska IA, 
Yu J, Kwiatkowski DJ, Locasale JW, Asara JM, Choi AM, Finkel T, Henske EP. Autophagy-
dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-
aminonicotinamide. Mol Cancer Res. 2014;12(1):48-57. Epub 2013/12/04. doi: 10.1158/1541-
7786.MCR-13-0258-T 
1541-7786.MCR-13-0258-T [pii]. PubMed PMID: 24296756; PMCID: 4030750. 
10. 
Priolo C, Ricoult SJ, Khabibullin D, Filippakis H, Yu J, Manning BD, Clish C, Henske 
EP. Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in 
Lymphangioleiomyomatosis. Am J Respir Cell Mol Biol. 2015;53(1):33-41. Epub 2015/03/18. 
doi: 10.1165/rcmb.2014-0379RC. PubMed PMID: 25780943. 
11. 
Henske EP, Jozwiak S, Kingswood JC, Sampson JR, Thiele EA. Tuberous sclerosis 
complex. Nat Rev Dis Primers. 2016;2:16035. Epub 2016/05/27. doi: 10.1038/nrdp.2016.35 
nrdp201635 [pii]. PubMed PMID: 27226234. 
12. 
Cudzilo CJ, Szczesniak RD, Brody AS, Rattan MS, Krueger DA, Bissler JJ, Franz DN, 
McCormack FX, Young LR. Lymphangioleiomyomatosis screening in women with tuberous 
sclerosis. Chest. 2013;144(2):578-85. Epub 2013/03/30. doi: 10.1378/chest.12-2813 
1672803 [pii]. PubMed PMID: 23539171. 
13. 
McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, 
Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP, 3rd, Goldberg HJ, Young LR, 
Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-
DaSilva AM, Lee HS, Krischer JP, Trapnell BC. Efficacy and safety of sirolimus in 
lymphangioleiomyomatosis. N Engl J Med. 2011;364(17):1595-606. Epub 2011/03/18. doi: 
10.1056/NEJMoa1100391. PubMed PMID: 21410393; PMCID: 3118601. 
14. 
Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, 
Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah 
G, Lincy J, Lebwohl D, Budde K. Everolimus for angiomyolipoma associated with tuberous 
sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, 
randomized, double-blind, placebo-controlled trial. Lancet. 2013;381(9869):817-24. Epub 
2013/01/15. doi: S0140-6736(12)61767-X [pii] 
10.1016/S0140-6736(12)61767-X. PubMed PMID: 23312829. 
15. 
Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst 
VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. Sirolimus for angiomyolipoma in 
tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358(2):140-51. 
Epub 2008/01/11. doi: 358/2/140 [pii] 
10.1056/NEJMoa063564. PubMed PMID: 18184959. 
16. 
Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for 
lymphangioleiomyomatosis. N Engl J Med. 2008;358(2):199-200. Epub 2008/01/11. doi: 
10.1056/NEJMc0707517 
358/2/199 [pii]. PubMed PMID: 18184970; PMCID: 3804557. 
17. 
Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, Linehan WM, 
Hajjar F, Kinder BW, Trapnell BC, Bissler JJ, Franz DN, McCormack FX. Serum vascular 
endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other 
diseases. Chest. 2010;138(3):674-81. Epub 2010/04/13. doi: 10.1378/chest.10-0573 
chest.10-0573 [pii]. PubMed PMID: 20382711; PMCID: 2940071. 
18. 
Young L, Lee HS, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, 
Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP, 3rd, Goldberg HJ, Downey GP, 

9 
 
Swigris JJ, Taveira-DaSilva AM, Krischer JP, Trapnell BC, McCormack FX, Group MT. Serum 
VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment 
response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis 
Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013;1(6):445-52. doi: 10.1016/S2213-
2600(13)70090-0. PubMed PMID: 24159565; PMCID: PMC3804556. 
19. 
Young LR, Franz DN, Nagarkatte P, Fletcher CD, Wikenheiser-Brokamp KA, Galsky 
MD, Corbridge TC, Lam AP, Gelfand MJ, McCormack FX. Utility of [18F]2-fluoro-2-
deoxyglucose-PET in sporadic and tuberous sclerosis-associated lymphangioleiomyomatosis. 
Chest. 2009;136(3):926-33. Epub 2009/04/08. doi: chest.09-0336 [pii] 
10.1378/chest.09-0336. PubMed PMID: 19349386; PMCID: 3198490. 
20. 
Mukherjee A, Karunanithi S, Singla S, Bal C, Das CJ, Kumar R. (18)F-FDG PET/CT in 
detection of sarcomatous degeneration of renal angiomyolipoma in setting of tuberous sclerosis. 
Indian J Nucl Med. 2014;29(4):280-1. doi: 10.4103/0972-3919.142650. PubMed PMID: 
25400377; PMCID: PMC4228601. 
21. 
Jiang X, Kenerson H, Aicher L, Miyaoka R, Eary J, Bissler J, Yeung RS. The tuberous 
sclerosis complex regulates trafficking of glucose transporters and glucose uptake. Am J Pathol. 
2008;172(6):1748-56. doi: 10.2353/ajpath.2008.070958. PubMed PMID: 18511518; PMCID: 
PMC2408433.