Characteristics of the investigated TSC patient cohort.

<p>Characteristics of the investigated TSC patient cohort.</p

Signal changes in magnetic resonance imaging with selective fat suppression in TSC patients following the initiation of mTOR inhibitor therapy.

<p>Patients were investigated at baseline and after 0–3 months, 3–6 months and 18–24 months of mTOR inhibitor therapy. Additionally, a control collective of TSC patients without mTOR inhibitor therapy was investigated. A pronounced and significant reduction of the mean contrast to noise ratio (CNR) was already observed in the early group within the first three months. In the control group, no reduction of the mean CNR value was observed. Error bars indicate the standard deviation. P-values generated from linear mixed model statistical analysis (* p<0.01, *** p<0.0001); CNR: Contrast to noise ratio.</p

Size changes in magnetic resonance imaging in TSC patients following the initiation of mTOR inhibitor therapy.

<p>Patients were investigated at baseline and after 0–3 months, 3–6 months and 18–24 months of mTOR inhibitor therapy. Additionally, a control collective of TSC patients without mTOR inhibitor therapy was investigated. A significant (p ≤ 0.05) reduction of the size of angiomyolipomas (in mm²) was already observed in the early group within the first three months. In the control group, no reduction of the size was observed. Error bars indicate the standard deviation. P-values generated from linear mixed model statistical analysis (* p<0.01, ** p<0.001, *** p<0.0001).</p

Fatty transformation of angiomyolipoma in TSC patients after initiation of mTOR inhibitor therapy.

<p><b>A</b>: Example of a large AML at the central part of the right kidney in a 33 year-old female TSC patient. <b>A1</b>: At baseline a heterogeneous AML with a mixed-signal on the T2 fat saturated MR sequence (solid arrows) could be visualized. Slow flowing blood in a small vessel (dotted arrows) appears hyperintense on the fat saturated sequence. The unaffected “healthy” kidney tissue is also visualized with a hyperintense signal (*). <b>A2</b>: 2.5 months following the initiation of the mTOR inhibitor therapy a reduction in the overall signal of the AML on the T2 fat saturated sequence can be visualized. The vessel, which was visible at baseline (A1: dotted line) cannot be delineated anymore. Additionally, a reduction of size of the AML can be visualized. This case represents a good example of how difficult it can be to clearly quantify a size reduction in a heterogenous AML following the initiation of mTOR therapy. <b>B</b>: Example of a AML at the caudal part of the right kidney in a 45 year-old male TSC patient. <b>B1</b>: At baseline a heterogeneous relatively bright angiomyolipoma could be visualized on the T2 fat saturated sequence (arrows). The unaffected “healthy” kidney tissue is visualized with a homogenous hyperintense signal on the T2 fat saturated sequence (*). <b>B2</b>: 3 to 6 months following the initiation of the mTOR inhibitor therapy, a clear reduction in the signal on the T2 fat saturated sequence as well as in the size of the angiomyolipoma is visualized. The signal of the healthy kidney tissue does not change following the initiation of the therapy (*). MRI: Magnetic Resonance Imaging. Fatsat: Fat saturated. Scale bar: 1.5 cm.</p

Best percentage reduction of contrast to noise ratio as well as size of angiomyolipomas in each individual patient reported at any time point.

<p>In all analyzed patients a reduction in CNR could be observed whereas 2 patients did not show a size reduction of AML under everolimus treatment. AML size is given in mm², results are sorted by value.</p

Trough levels and dosing of everolimus.

<p>Trough levels and dosing of everolimus.</p

Median GFR (A) and creatinine (B) over time.

<p>Medians are connected by lines, means are displayed as dots. Boxes are drawn from P25 to P75. Whiskers extend from P10 to P90. # indicates values that lie outside [P10, P90]. *Baseline assessment is the last performed before start of everolimus. Post-baseline laboratory assessments performed at unplanned schedule or more than 28 days after discontinuation of everolimus are not presented. Only results from central laboratory are included. Abbreviations: BL = baseline; GFR = glomerular filtration rate; P = percentile.</p

Pulmonary function tests in patients with LAM over time.

<p>Pulmonary function tests in patients with LAM over time.</p

CONSORT flow diagram of patient disposition in the double-blind followed by open-label periods.

<p>^aPatients with angiomyolipoma progression were unblinded at the end of the double-blind phase, and patients who were on placebo were allowed to cross over to open-label everolimus.</p

Time to renal angiomyolipoma progression.

<p>Time to renal angiomyolipoma progression.</p