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      Treatment effect of mTOR-inhibition on tissue composition of renal angiomyolipomas in tuberous sclerosis complex (TSC)

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          Abstract

          Purpose

          Tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML) have a high lifetime risk of acute bleeding. MTOR-inhibitors are a promising novel treatment for TSC-AML, however adequate response to therapy can be difficult to assess. Early changes in MRI signal may serve as a novel early indicator for a satisfactory response to mTOR-inhibitor therapy of AML.

          Materials and methods

          Thirty-eight patients with the definite diagnosis of tuberous sclerosis receiving everolimus therapy and n = 19 patients without specific therapy were included. 1.5 Tesla MRI was performed including sequences with a selective fat suppression. Patients were investigated prior to the initiation of therapy (baseline) and after <3 months (n = 21 patients), 3 to 6 months (n = 32) and 18 to 24 months (n = 28). Signal and size changes of renal AMLs were assessed at all different timepoints. Signal-to-noise-ratio (SNR), contrast-to-noise-ratio (CNR) and size of angiomyolipomas were evaluated.

          Results

          Signal changes in 273 AMLs were evaluated. A significant and strong decrease of the CNR of AMLs following the initiation of therapy was measured in the fat-suppressed MR sequence at all time points, compared to the baseline: From 7.41±6.98 to 3.84±6.25 (p ≤ 0.05p = 0.002), 3.36±6.93 (p<0.0001), and 2.50±6.68 (p<0.0001) after less than 3 months, 3–6 months or 18–24 months of everolimus treatment, respectively. Also, a significant, however less pronounced, reduction of angiomyolipoma size in the different groups was measured (from baseline 2022.2±2657.7 mm2 to 1854.4±1670.9 mm2 (p = 0.009), 1875.5±3190.1 mm2 (p<0.001), and 1365.8 ± 1628.8 mm2 (p<0.0001) after less than 3 months, 3–6 months or 18–24 months of everolimus treatment, respectively). No significant changes in CNR (p>0.05) and size (p>0.05) were measured in the control group.

          Conclusion

          mTOR inhibitor therapy in TSC patients results in an early and pronounced fatty transformation of AMLs on MRI. Fatty transformation could represent a novel early indicator of response to therapy in this patient collective.

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          Most cited references10

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          mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor.

          Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK). Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK. RAD001 inhibited proliferation in vitro (IC50 values 1 micromol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values>10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001. VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.
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            Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

            Background Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Conclusions Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. Trial Registration Clinicaltrials.gov NCT00126672
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              Angiomyolipoma: imaging findings in lesions with minimal fat.

              To investigate a method of diagnosing angiomyolipoma that contains minimal fat. In six cases of angiomyolipoma with minimal fat, the attenuation on contrast material-enhanced and unenhanced computed tomographic (CT) images, the echogenicity on sonograms, the signal intensity on T2-weighted magnetic resonance (MR) images, and the gross configuration of the lesion were retrospectively analyzed. In 100 cases of renal cell carcinoma, the same parameters were analyzed, and results were compared with those of angiomyolipoma. When compared with the surrounding renal parenchyma, all six angiomyolipomas showed homogeneously high attenuation on unenhanced CT images, homogeneous enhancement on contrast-enhanced CT images, and homogeneous isoechogenicity on sonograms. Of the five angiomyolipomas examined with MR imaging, four were hypointense and one was isointense on T2-weighted images. All six angiomyolipomas protruded from the renal margin. None of the 100 renal cell carcinomas showed homogeneously high attenuation on unenhanced CT images, homogeneous enhancement on contrast-enhanced CT images, or homogeneous isoechogenicity on sonograms. In the kidney, homogeneously high attenuation on unenhanced CT images, homogeneous enhancement on contrast-enhanced CT images, and homogeneous isoechogenicity on sonograms are suggestive of angiomyolipoma that contains abundant muscle and minimal fat.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curation
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curation
                Role: ConceptualizationRole: Data curationRole: Investigation
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: ValidationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 December 2017
                2017
                : 12
                : 12
                : e0189132
                Affiliations
                [1 ] Department of Nephrology and Medical Intensive Care, Charité, Berlin, Germany
                [2 ] Department of Radiology, Charité, Berlin, Germany
                [3 ] King’s College London, Division of Imaging Sciences, London, United Kingdom
                National Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors of this manuscript have the following competing interests: SB has received honoraria and travel grants from Bristol-Myers Squibb, Novartis, Roche, Pfizer, and Alexion Astellas; KB has received research funds and/or honoraria from Alexion, Astellas, Bristol-Myers Squibb, Chiesi, Fresenius, Genentech, Hexal, Novartis, Otsuka, Pfizer, Roche, Siemens, and Veloxis Pharma; LV, LA, GD, BH and MRM declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; all authors declare no other relationships or activities that could appear to have influenced the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-3845-211X
                Article
                PONE-D-17-27665
                10.1371/journal.pone.0189132
                5726644
                29232371
                64c6f3c9-6d47-44f1-8667-1e493e8cc939
                © 2017 Brakemeier et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 July 2017
                : 20 November 2017
                Page count
                Figures: 4, Tables: 3, Pages: 12
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Biology and Life Sciences
                Biochemistry
                Lipids
                Fats
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Vascular Medicine
                Hemorrhage
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signal Inhibition
                Biology and Life Sciences
                Anatomy
                Renal System
                Medicine and Health Sciences
                Anatomy
                Renal System
                Medicine and Health Sciences
                Clinical Genetics
                Genetic Diseases
                Tuberous Sclerosis
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Mechanisms of Signal Transduction
                Signal Initiation
                Custom metadata
                According to the Charité ethics committee, we are not allowed to share anonymized MRI imaging series. Researchers interested in the original MRI images may contact the Charité ethics committee via ethikkommission@ 123456charite.de for more information. All other data are included within the paper.

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