Ultra-low dose chest CT with silver filter and deep learning reconstruction significantly reduces radiation dose and retains quantitative information in the investigation and monitoring of lymphangioleiomyomatosis (LAM).

PURPOSE: Frequent CT scans to quantify lung involvement in cystic lung disease increases radiation exposure. Beam shaping energy filters can optimize imaging properties at lower radiation dosages. The aim of this study is to investigate whether use of SilverBeam filter and deep learning reconstruction algorithm allows for reduced radiation dose chest CT scanning in patients with lymphangioleiomyomatosis (LAM). MATERIAL AND METHODS: In a single-center prospective study, 60 consecutive patients with LAM underwent chest CT at standard and ultra-low radiation doses. Standard dose scan was performed with standard copper filter and ultra-low dose scan was performed with SilverBeam filter. Scans were reconstructed using a soft tissue kernel with deep learning reconstruction (AiCE) technique and using a soft tissue kernel with hybrid iterative reconstruction (AIDR3D). Cyst scores were quantified by semi-automated software. Signal-to-noise ratio (SNR) was calculated for each reconstruction. Data were analyzed by linear correlation, paired t-test, and Bland-Altman plots. RESULTS: Patients averaged 49.4 years and 100% were female with mean BMI 26.6 ± 6.1 kg/m2. Cyst score measured by AiCE reconstruction with SilverBeam filter correlated well with that of AIDR3D reconstruction with standard filter, with a 1.5% difference, and allowed for an 85.5% median radiation dosage reduction (0.33 mSv vs. 2.27 mSv, respectively, p < 0.001). Compared to standard filter with AIDR3D, SNR for SilverBeam AiCE images was slightly lower (3.2 vs. 3.1, respectively, p = 0.005). CONCLUSION: SilverBeam filter with deep learning reconstruction reduces radiation dosage of chest CT, while maintaining accuracy of cyst quantification as well as image quality in cystic lung disease. CLINICAL RELEVANCE STATEMENT: Radiation dosage from chest CT can be significantly reduced without sacrificing image quality by using silver filter in combination with a deep learning reconstructive algorithm. KEY POINTS: • Deep learning reconstruction in chest CT had no significant effect on cyst quantification when compared to conventional hybrid iterative reconstruction. • SilverBeam filter reduced radiation dosage by 85.5% compared to standard dose chest CT. • SilverBeam filter in coordination with deep learning reconstruction maintained image quality and diagnostic accuracy for cyst quantification when compared to standard dose CT with hybrid iterative reconstruction.

Computer grading of lung disease severity in patients with lymphangioleiomyomatosis referred for transplantation.

OBJECTIVES: Lymphangioleiomyomatosis (LAM) patients with severe lung disease may be considered for lung transplantation. Clinical, physiologic, and quality of life data are usually employed for referral. The aim of this study was to determine whether computed tomographic measurement of lung volume occupied by cysts (cyst score) complemented clinical and physiologic data in supporting referral for transplantation. METHODS: Forty-one patients were studied. Pre-referral clinical data, pulmonary function tests, exercise testing, and high-resolution computed tomography (HRCT) scans were obtained. From HRCT, a computer-aided diagnostic program was employed to calculate cyst scores. These data were compared to those of 41 age-matched LAM patients not referred for lung transplantation. RESULTS: Cyst score, and % predicted FEV1 and DLCO were respectively, 48.1 ± 9.4%, 36.5 ± 9.1%, and 35.0 ± 10.7%. For the control group, cyst score, FEV1, and DLCO were respectively, 14.8 ± 8.3%, 77.2 ± 20.3%, and 66.7 ± 19.3%. Cyst score values showed a normal distribution. However, the frequency distribution of FEV1 was skewed to the right while the distribution of DLCO was bimodal. Correlations between cyst score and FEV1 and DLCO for the study group were respectively, r = - 0.319 and r = - 0.421. CONCLUSIONS: LAM patients referred for lung transplantation had nearly 50% of lungs occupied by cysts. Correlations between cyst score and FEV1 or DLCO were weak; as shown previously, DLCO was better related to cyst number while FEV1 had a better association with cyst size. Given its normal distribution, cyst score measurements may assist in evaluation of pre-transplant severity of lung disease before referral for transplantation.

Ultra-Small Lung Cysts Impair Diffusion Without Obstructing Air Flow in Lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare lung disease found primarily in women of childbearing age, characterized by the formation of air-filled cysts, which may be associated with reductions in lung function. An experimental, regional ultra-high resolution CT scan identified an additional volume of cysts relative to standard chest CT imaging, which consisted primarily of ultra-small cysts. RESEARCH QUESTION: What is the impact of these ultra-small cysts on the pulmonary function of patients with LAM? STUDY DESIGN AND METHODS: A group of 103 patients with LAM received pulmonary function tests and a CT examination in the same visit. Cyst score, the percentage lung volume occupied by cysts, was measured by using commercial software approved by the US Food and Drug Administration. The association between cyst scores and pulmonary function tests of diffusing capacity of the lungs for carbon monoxide (Dlco) (% predicted), FEV1 (% predicted), and FEV1/FVC (% predicted) was assessed with statistical analysis adjusted for demographic variables. The distributions of average cyst size and ultra-small cyst fraction among the patients were evaluated. RESULTS: The additional cyst volume identified by the experimental, higher resolution scan consisted of cysts of 2.2 ± 0.8 mm diameter on average and are thus labeled the "ultra-small cyst fraction." It accounted for 27.9 ± 19.0% of the total cyst volume among the patients. The resulting adjusted, whole-lung cyst scores better explained the variance of Dlco (P < .001 adjusted for multiple comparisons) but not FEV1 and FEV1/FVC (P = 1.00). The ultra-small cyst fraction contributed to the reduction in Dlco (P < .001) but not to FEV1 and FEV1/FVC (P = .760 and .575, respectively). The ultra-small cyst fraction and average cyst size were correlated with cyst burden, FEV1, and FEV1/FVC but less with Dlco. INTERPRETATION: The ultra-small cysts primarily contributed to the reduction in Dlco, with minimal effects on FEV1 and FEV1/FVC. Patients with lower cyst burden and better FEV1 and FEV1/FVC tended to have smaller average cyst size and higher ultra-small cyst fraction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT00001465; URL: www.clinicaltrials.gov.

Choice of Laboratory Tissue Homogenizers Matters When Recovering Nucleic Acid From Medically Important Ticks.

Ticks can vector and transmit many pathogens and pose a serious human health threat throughout the world. After collection, many diagnostic laboratories must mechanically disrupt tick specimens for diagnostic testing and research purposes, but few studies have evaluated how well-commercial tissue homogenizers perform this task. We evaluated four commercially available tissue homogenizers: The Bead Ruptor 24 Elite, the Bullet Blender Storm, the gentleMACS Dissociator, and the Precellys 24. We quantitatively compared maceration level, nucleic acid quality, quantity, amplification, and DNA shearing to determine which machines performed the best. The Bead Ruptor 24 Elite had the highest overall score when disrupting a single, uninfected adult Amblyomma americanum (Linnaeus) (Ixodida: Ixodidae) and performed well in follow-on tests including disrupting individual juvenile samples and detecting pathogens from infected samples.

Clinical CT underestimation of the percentage volume occupied by cysts in patients with lymphangioleiomyomatosis.

PURPOSE: To evaluate the accuracy of cyst score measurements by standard high-resolution helical volume chest CT (HRCT) in patients with lymphangioleiomyomatosis (LAM), using a short z-length ultra-high resolution re-scan (UH re-scan) as the reference. In cystic lung diseases, cyst score is derived from CT scans and defined as the percentage of the total lung parenchymal volume occupied by cysts, a biomarker which measures the severity of the disease. METHODS: In a prospective study of 73 LAM patients, each patient received the standard HRCT chest scan and a short z-length UH re-scan. Cyst scores were acquired from both scans using a standard FDA-approved scoring software on the CT scanner. RESULTS: The limited UH re-scan resolved small cysts that were not resolved in the HRCT. The HRCT-derived cyst scores were on average 59.6% of the reference values from the UH re-scan (p = 4.7e-25). The amount of under-estimation by HRCT varied from patient to patient, with an inter-quartile range of 29.8% and standard deviation of 20.7%. The overall trend was more pronounced underestimation for patients with lower cyst scores. For patients whose reference cyst scores were below 15 (n = 29), the HRCT cyst scores were 46.9 ± 21.6% of reference values (p = 7.4e-12), while for the rest of the patients (n = 44) the HRCT cyst scores were 68.0 ± 15.3% of reference values (p = 1.2E-19). Reconstructing the HRCT images to the resolution of the UH re-scan further widened the spread of the discrepancy between HRCT and reference values due to increased image noise, and did not provide accurate cyst scores. CONCLUSION: Cyst scores derived from standard high-resolution helical volume chest CT significantly underestimates the percentage lung volume occupied by cysts. This inaccuracy needs to be taken into consideration when cyst score is used as part of the CT assessment of the patient's condition.

Phenotypic distinctions between mosaic forms of tuberous sclerosis complex.

PURPOSE: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. METHODS: Next-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2. Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records. RESULTS: The median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24 years, n = 7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10 years, n = 12), and germline TSC patients (10 findings, 4 years, n = 29). Cutaneous and internal organ involvement positively correlated in mosaic (R = 0.62, p = 0.005), but not germline (R = -0.24, p = 0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0-19%) positively correlated with the number of major features (R = 0.55, p = 0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC. CONCLUSION: The phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.

Expanding the phenotype of COPA syndrome: a kindred with typical and atypical features.

BACKGROUND: Copa syndrome is a rare autosomal dominant disorder with abnormal intracellular vesicle trafficking. The objective of this work is to expand the knowledge about this disorder by delineating phenotypic features of an unreported COPA family. METHODS AND RESULTS: A heterozygous missense variant (c.698 G>A, p.Arg233His) in COPA was identified in four members of a three-generation kindred with lung, autoimmune and malignant disease of unknown aetiology. Ages of onset were 56, 26, 16 and 1 year, with earlier age of onset in successive generations. Presenting symptoms were cough and dyspnoea. Findings included small lung cysts, follicular bronchiolitis, interstitial lung disease, neuroendocrine cell hyperplasia, rheumatoid arthritis, avascular necrosis and select abnormal autoimmune serologies. Neither alveolar haemorrhage nor glomerular disease were present. Features not previously associated with Copa syndrome included neuromyelitis optica, pulmonary carcinoid tumour, clear cell renal carcinoma, renal cysts, hepatic cysts, nephrolithiasis, pyelonephritis and meningitis. Longitudinal evaluations demonstrated slow progression of lung disease and extrapulmonary cysts. CONCLUSIONS: Worsening severity with successive generations may be observed in Copa syndrome. Extrapulmonary cysts, malignancies, autoimmune neurological disorders and infections are clinical features that may be associated with Copa syndrome. Further studies are indicated to fully define the phenotypic spectrum of this disorder.

Chest CT Scan at Radiation Dose of a Posteroanterior and Lateral Chest Radiograph Series: A Proof of Principle in Lymphangioleiomyomatosis.

BACKGROUND: Given the rising utilization of medical imaging and the risks of radiation, there is increased interest in reducing radiation exposure. The objective of this study was to evaluate, as a proof of principle, CT scans performed at radiation doses equivalent to that of a posteroanterior and lateral chest radiograph series in the cystic lung disease lymphangioleiomyomatosis (LAM). METHODS: From November 2016 to May 2018, 105 consecutive subjects with LAM received chest CT scans at standard and ultra-low radiation doses. Standard and ultra-low-dose images, respectively, were reconstructed with routine iterative and newer model-based iterative reconstruction. LAM severity can be quantified as cyst score (percentage of lung occupied by cysts), an ideal benchmark for validating CT scans performed at a reduced dose compared with a standard dose. Cyst scores were quantified using semi-automated software and evaluated by linear correlation and Bland-Altman analysis. RESULTS: Overall, ultra-low-dose CT scans represented a 96% dose reduction, with a median dose equivalent to 1 vs 22 posteroanterior and lateral chest radiograph series (0.14 mSv; 5th-95th percentile, 0.10-0.20 vs standard dose 3.4 mSv; 5th-95th percentile, 1.5-7.4; P < .0001). The mean difference in cyst scores between ultra-low- and standard-dose CT scans was 1.1% ± 2.0%, with a relative difference in cyst score of 11%. Linear correlation coefficient was excellent at 0.97 (P < .0001). CONCLUSIONS: In LAM chest CT scan at substantial radiation reduction to doses equivalent to that of a posteroanterior and lateral chest radiograph series provides cyst score quantification similar to that of standard-dose CT scan. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT00001465 and NCT00001532; URL: www.clinicaltrials.gov.

Pseudoneutropenia in lymphangioleiomyomatosis (LAM) patients receiving sirolimus: evaluation in a 100 patient cohort.

In lymphangioleiomyomatosis patients receiving sirolimus treatment, transient leukopenia in the morning may be due to circadian rhythm, with leukocyte counts recovering later in the day, indicating that a decrease in drug dose may not be warranted http://ow.ly/jPFz30iysgV.

Rates of change in FEV1 and DLCO as potential indicators for mTOR inhibitor therapy in premenopausal lymphangioleiomyomatosis patients.

The value of rates of change in forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) to predict disease progression, and initiation of mTOR (mechanistic target of rapamycin) inhibitor therapy has not been evaluated.In 84 premenopausal lymphangioleiomyomatosis patients, individual rates of change in FEV1 and DLCO and their 95% confidence intervals were used to derive subsequent lowest values of FEV1 and DLCO that would prompt initiation of sirolimus therapy. These treatment criteria were compared with a criterion based on FEV1 or DLCO ≤70% predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated.27 and 35 patients who experienced greater than expected rates of change in FEV1 and DLCO, respectively, would have been excluded from therapy based on an FEV1 or DLCO >70% pred. 25 of the 84 patients were eventually treated, but only when FEV1 or DLCO were ≤70% pred. Applying such treatment criteria to 12 patients undergoing sirolimus therapy would have delayed treatment for many years.Premenopausal females in whom FEV1 or DLCO are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV1 or DLCO falls to ≤70% pred.

Mounier-Kuhn Syndrome Mimicking Lymphangioleiomyomatosis.

We present the case of a man with Mounier-Kuhn syndrome (MKS), or tracheobronchomegaly, who was referred to the National Institutes of Health Clinical Research Center because of a potential diagnosis of lymphangioleiomyomatosis (LAM), a rare condition in men. The patient was evaluated using ongoing protocols and provided written informed consent. The case demonstrates the presence of chronic inflammation surrounding the dilated airways and histologic changes of the lung parenchyma with emphysematouslike disruption in areas adjacent to the dilated airways. This finding suggests that damage to the lung parenchyma is an ongoing phenomenon in MKS. Moreover, our analysis of CT images indicates similar abnormalities in areas remote from the dilated airways. Finally, because of increased anatomic dead space, calculation of lung diffusion capacity by the single-breath method yielded abnormally low values that required making a correction for the large anatomic dead space, which can be measured by the single-breath nitrogen washout test.

Long-Term Effect of Sirolimus on Serum Vascular Endothelial Growth Factor D Levels in Patients With Lymphangioleiomyomatosis.

BACKGROUND: Sirolimus reduces serum levels of vascular endothelial growth factor D (VEGF-D); the size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas; and stabilizes lung function in patients with lymphangioleiomyomatosis (LAM). METHODS: To determine whether reductions in VEGF-D levels are sustained over time, as well as parallel changes in lung function and lymphatic disease, we evaluated 25 patients with LAM and measured VEGF-D levels, lung function, and extent of lymphatic disease before and during sirolimus therapy. RESULTS: Treatment with sirolimus stabilized FEV1 and diffusion capacity for carbon monoxide (Dlco) over a period of 4.5 ± 1.6 years, caused resolution of lymphatic disease, and reduced the size of angiomyolipomas and VEGF-D levels (3,720 ± 3,020 pg/mL to 945 ± 591 pg/mL; P < .0001). Yearly changes in FEV1 % predicted and Dlco % predicted were reduced from -7.4% ± 1.4% to -0.3% ± 0.5% (P < .001) and -6.4% ± 0.9% to -0.4% ± 0.5% (P < .001), respectively. Lower VEGF-D levels correlated with sirolimus therapy (P < .001), but no significant relationship was observed between reduction in VEGF-D levels and FEV1 and Dlco during sirolimus therapy. The magnitude of VEGF-D decline was not related to the effect on lung function. Patients with lymphatic disease had higher serum VEGF-D levels, a greater reduction in VEGF-D levels, and better long-term sustained improvement in lung function during sirolimus therapy than did those without lymphatic disease. CONCLUSIONS: Sirolimus therapy stabilizes lung function over many years of therapy while producing a sustained reduction in VEGF-D levels in patients with elevated levels preceding therapy. An association was not demonstrated between the magnitude of VEGF-D decline and the beneficial effect of sirolimus on lung function. Persistent improvement in lung function was observed in patients with lymphatic disease.

Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: Results of a Phase I Clinical Trial.

BACKGROUND: Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function. METHODS: This 48-week, two-center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100-200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks. RESULTS: Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400-mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV1 and FVC remained stable at 48 weeks, but the 6-min walk distance showed a decrease toward baseline. CONCLUSIONS: The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov.

HIV Testing Among Internet-Using MSM in the United States: Systematic Review.

Regular HIV testing enables early identification and treatment of HIV among at-risk men who have sex with men (MSM). Characterizing HIV testing needs for Internet-using MSM informs development of Internet-facilitated testing interventions. In this systematic review we analyze HIV testing patterns among Internet-using MSM in the United States who report, through participation in an online study or survey, their HIV status as negative or unknown and identify demographic or behavioral risk factors associated with testing. We systematically searched multiple electronic databases for relevant English-language articles published between January 1, 2005 and December 16, 2014. Using meta-analysis, we summarized the proportion of Internet-using MSM who had ever tested for HIV and the proportion who tested in the 12 months preceding participation in the online study or survey. We also identified factors predictive of these outcomes using meta-regression and narrative synthesis. Thirty-two studies that enrolled 83,186 MSM met our inclusion criteria. Among the studies reporting data for each outcome, 85 % (95 % CI 82-87 %) of participants had ever tested, and 58 % (95 % CI 53-63 %) had tested in the year preceding enrollment in the study, among those for whom those data were reported. Age over 30 years, at least a college education, use of drugs, and self-identification as being homosexual or gay were associated with ever having tested for HIV. A large majority of Internet-using MSM indicated they had been tested for HIV at some point in the past. A smaller proportion-but still a majority-reported they had been tested within the year preceding study or survey participation. MSM who self-identify as heterosexual or bisexual, are younger, or who use drugs (including non-injection drugs) may be less likely to have ever tested for HIV. The overall findings of our systematic review are encouraging; however, a subpopulation of MSM may benefit from targeted outreach. These findings indicate unmet needs for HIV testing among Internet-using MSM and identify subpopulations that might benefit from targeted outreach, such as provision of HIV self-testing kits.

Incidence of Pneumothorax in Patients With Lymphangioleiomyomatosis Undergoing Pulmonary Function and Exercise Testing.

Because pneumothorax is frequent in lymphangioleiomyomatosis, patients have expressed concerns regarding the risk of pneumothorax associated with pulmonary function or exercise testing. Indeed, pneumothorax has been reported in patients with lung disease after both of these tests. The aim of this study was to determine the incidence of pneumothorax in patients with lymphangioleiomyomatosis during admissions to the National Institutes of Health Clinical Research Center between 1995 and 2015. Medical records were reviewed to identify patients who had a pneumothorax during their stay at the National Institutes of Health. A total of 691 patients underwent 4,523 pulmonary function tests and 1,900 exercise tests. Three patients developed pneumothorax after pulmonary function tests and/or exercise tests. The incidence of pneumothorax associated with lung function testing was 0.14 to 0.29 of 100 patients or 0.02 to 0.04 of 100 tests. The incidence of pneumothorax in patients undergoing exercise testing was 0.14 to 0.28 of 100 patients or 0.05 to 0.10 of 100 tests. The risk of pneumothorax associated with pulmonary function or exercise testing in patients with lymphangioleiomyomatosis is low.

Effects of glucose and insulin on secretion of amyloid-ß by human adipose tissue cells.

OBJECTIVE: Obesity and type 2 diabetes mellitus are risk factors for developing Alzheimer disease. Overlapping patterns of metabolic dysfunction may be common molecular links between these complex diseases. Amyloid-ß (Aß) precursor protein and associated ß- and γ-secretases are expressed in adipose tissue. Aß precursor protein is up-regulated with obesity and correlated to insulin resistance. Aß may be secreted by adipose tissue, its production may be regulated through metabolic pathways, and Aß may exert effects on adipose tissue insulin receptor signaling. METHODS: Human stromal-vascular cells and differentiated adipocytes were cultured with different combinations of glucose and insulin and then assayed for Aß in conditioned media. Aß was measured in vivo using adipose tissue microdialysis. RESULTS: Aß secretion was increased by glucose and insulin in vitro. Adipose tissue microdialysates contained Aß. Adipocytes treated with Aß had decreased expression of insulin receptor substrate-2 and reduced Akt-1 phosphorylation. CONCLUSIONS: Aß was made by adipose tissue cells in vitro at concentrations similar to in vivo measurements. Regulation of Aß production by glucose and insulin and effects of Aß on the insulin receptor pathway suggest similar cellular mechanisms may exist between neuronal dysfunction in Alzheimer disease and adipose dysfunction in type 2 diabetes.

Effect of fasting on the size of lymphangioleiomyomas in patients with lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomas occur in 38% of patients with sporadic lymphangioleiomyomatosis (LAM) and may cause pain and increased abdominal girth, mimicking the presence of a malignancy. Lymphatic involvement in LAM is closely associated with elevated serum levels of vascular endothelium growth factor-D (VEGF-D). Because lymphangioleiomyomas undergo diurnal variation in volume, we hypothesized that daytime ingestion of food, by increasing chyle formation and lymphatic flow, is the cause of an increase in lymphangioleiomyoma volume. METHODS: Subjects had abdominopelvic sonograms and blood drawn for measurement of serum VEGF-D levels under nonfasting (day 1) and fasting (day 2) conditions. The size of the lymphangioleiomyomas was determined by a radiologist who was blinded to the subjects' status. The Wilcoxon signed rank test was used to determine whether the nonfasting tumor size was different from the fasting tumor size. RESULTS: Thirty-five women were studied (aged 45.2 ± 8.5 years; FEV1, 82% ± 25%; diffusing capacity of the lung for carbon monoxide, 64% ± 25% predicted). Images suitable for volume measurements were obtained in 30 subjects. Fasting decreased the tumor size by 20.7 ± 39.3 cm3 (24% ± 40%, P < .001). Fasting VEGF-D levels (10,650 ± 900 pg/mL) were not significantly different from nonfasting values (12,100 ± 800 pg/mL, P = .56). CONCLUSIONS: Lymphangioleiomyoma volume decreased during the fasting state. Conversely, a combination of food intake and decreased chyle flow through lymphatics partially obstructed by LAM cells may account for increases in lymphangioleiomyoma size. Imaging studies performed under fasting conditions may help in determining whether an abdominal tumor is a result of LAM or malignancy.

Retrospective review of combined sirolimus and simvastatin therapy in lymphangioleiomyomatosis.

BACKGROUND: Combined simvastatin and sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM. METHODS: To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus sirolimus (n = 14), sirolimus alone (n = 44), or simvastatin alone (n = 20). RESULTS: Sirolimus-related adverse events in the simvastatin plus sirolimus and sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus sirolimus therapy, FEV1 and diffusing capacity of the lung for carbon monoxide (Dlco) yearly rates of change were, respectively, -1.4 ± 0.2 and -1.8 ± 0.2% predicted. After simvastatin plus sirolimus therapy, these rates changed to +1.2 ± 0.5 (P = .635) and +0.3 ± 0.4% predicted (P = .412), respectively. In 44 patients treated with sirolimus alone, FEV1 and Dlco rates of change were -1.7 ± 0.1 and -2.2 ± 0.1% predicted before treatment and +1.7 ± 0.3 and +0.7 ± 0.3% predicted after treatment (P < .001). CONCLUSIONS: Therapy with sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of sirolimus.