S-EPMC2826700 - CT of sclerotic bone lesions: imaging features differentiating tuberous sclerosis complex with lymphangioleiomyomatosis from sporadic lymphangioleiomymatosis. - OmicsDI

Unknown

Dataset Information

CT of sclerotic bone lesions: imaging features differentiating tuberous sclerosis complex with lymphangioleiomyomatosis from sporadic lymphangioleiomymatosis.

ABSTRACT: PURPOSE: To determine if sclerotic bone lesions evident at body computed tomography (CT) are of value as a diagnostic criterion of tuberous sclerosis complex (TSC) and in the differentiation of TSC with lymphangioleiomyomatosis (LAM) from sporadic LAM. MATERIALS AND METHODS: Informed consent was signed by all patients in this HIPAA-compliant study approved by the institutional review board. Retrospective analysis was performed of the body CT studies of 472 patients: 365 with sporadic LAM, 82 with TSC/LAM, and 25 with TSC. The images were reviewed by using a picture archiving and communication system workstation with bone settings (window width, 1500 HU; window level, 300 HU) and fit-to-screen option. CT image characteristics assessed included shape, size, and distribution of sclerotic bone lesions with subsequent calculation of differences in the frequency of these lesions. RESULTS: Most commonly the sclerotic bone lesions were round, measured 0.3 cm (range, 0.2-3.2), and were distributed throughout the spine. The frequencies differed among the three patient groups Four or more sclerotic bone lesions were detected in all 25 (100%) of those with TSC, with a sensitivity of .89 (72 of 82) and specificity of .97 (355 of 367) in the differentiation of sporadic LAM from TSC/LAM (P < .01). CONCLUSION: The number of sclerotic bone lesions at body CT is of potential value in the diagnosis of TSC and in the differentiation of patients with sporadic LAM from those with TSC/LAM. (c) RSNA, 2010.

SUBMITTER: Avila NA

PROVIDER: S-EPMC2826700 | biostudies-other | 2010 Mar

REPOSITORIES: biostudies-other

Similar Datasets

Project description:IntroductionThe EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase.MethodsFor patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015).ResultsOf the 112 patients who received ≥1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm3) from baseline was -70.56 (-88.30; -49.64) at time of everolimus discontinuation (n = 11), and -50.55 (-79.40; -23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage.ConclusionsAngiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth.Trial registrationClinicalTrials.gov NCT00790400.

Project description:Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Project description:Tuberous sclerosis syndrome (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting multiple organs, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). LAM is a female-predominant interstitial lung disease characterized by the progressive cyst formation and respiratory failure, which is also seen in sporadic patients without TSC. Mutations in TSC1 or TSC2 cause TSC, result in hyperactivation of mammalian target of rapamycin (mTOR), and are also seen in LAM cells in sporadic LAM. We recently reported that prostaglandin biosynthesis and cyclooxygenase-2 were deregulated in TSC and LAM. Phospholipase A2 (PLA2) is the rate-limiting enzyme that catalyzes the conversion of plasma membrane phospholipids into prostaglandins. In this study, we identified upregulation of adipocyte AdPLA2 (PLA2G16) in LAM nodule cells using publicly available expression data. We showed that the levels of AdPLA2 transcript and protein were higher in LAM lungs compared with control lungs. We then showed that TSC2 negatively regulates the expression of AdPLA2, and loss of TSC2 is associated with elevated production of prostaglandin E2 (PGE2) and prostacyclin (PGI2) in cell culture models. Mouse model studies also showed increased expression of AdPLA2 in xenograft tumors, estrogen-induced lung metastatic lesions of Tsc2 null leiomyoma-derived cells, and spontaneous renal cystadenomas from Tsc2+/- mice. Importantly, rapamycin treatment did not affect the expression of AdPLA2 and the production of PGE2 by TSC2-deficient mouse embryonic fibroblast (Tsc2-/-MEFs), rat uterine leiomyoma-derived ELT3 cells, and LAM patient-associated renal angiomyolipoma-derived "mesenchymal" cells. Furthermore, methyl arachidonyl fluorophosphate (MAFP), a potent irreversible PLA2 inhibitor, selectively suppressed the growth and induced apoptosis of TSC2-deficient LAM patient-derived cells relative to TSC2-addback cells. Our findings suggest that AdPLA2 plays an important role in promoting tumorigenesis and disease progression by modulating the production of prostaglandins and may serve as a potential therapeutic target in TSC and LAM.

Project description:PurposeTo describe carpet lesions (laterally spreading tumors ≥ 3 cm) detected at computed tomographic (CT) colonography, including their clinical, imaging, and pathologic features.Materials and methodsThe imaging reports for 9152 consecutive adults undergoing initial CT colonography at a tertiary center were reviewed in this HIPAA-compliant, institutional review board-approved retrospective study to identify all potential carpet lesions detected at CT colonography. Carpet lesions were defined as morphologically flat, laterally spreading tumors 3 cm or larger. For those patients with neoplastic carpet lesions, CT colonography studies were analyzed to determine maximal lesion width and height, oral contrast material coating, segmental location, and computer-aided detection (CAD) findings. Demographic data and details of clinical treatment in these patients were reviewed.ResultsEighteen carpet lesions in 18 patients (0.2%; mean age, 67.1 years; eight men, 10 women) were identified and were subsequently confirmed at colonoscopy and pathologic examination among 20 potential flat masses (≥3 cm) prospectively identified at CT colonography (there were two nonneoplastic rectal false-positive findings). No additional neoplastic carpet lesions were found in the cohort undergoing colonoscopy after CT colonography and/or surgery (there were no false-negatives). Mean lesion width was 46.5 mm (range, 30-80 mm); mean lesion height was 7.9 mm (range, 4-14 mm). Surface retention of oral contrast material was noted in all 18 cases. All but two lesions were located in the distal rectosigmoid or proximal right colon. At CAD, 17 (94.4%) lesions were detected (mean, 6.2 CAD marks per lesion). Sixteen lesions (88.9%) demonstrated advanced histologic features, including a villous component (n = 11), high-grade dysplasia (n = 4), and invasive cancer (n = 5). Sixteen patients (88.9%) required surgical treatment for complete excision.ConclusionCT colonography can effectively depict carpet lesions. Common features in this series included older patient age, rectal or cecal location, surface coating with oral contrast material, multiple CAD hits, advanced yet typically benign histologic features, and surgical treatment.

Project description:BackgroundLymphangioleiomyomatosis (LAM), a destructive lung disease that affects primarily women, is caused by loss-of-function mutations in TSC1 or TSC2, leading to hyperactivation of mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Rapamycin (sirolimus) treatment suppresses mTORC1 but also induces autophagy, which promotes the survival of TSC2-deficient cells. Based on the hypothesis that simultaneous inhibition of mTORC1 and autophagy would limit the availability of critical nutrients and inhibit LAM cells, we conducted a phase 1 clinical trial of sirolimus and hydroxychloroquine for LAM. Here, we report the analyses of plasma metabolomic profiles from the clinical trial.MethodsWe analyzed the plasma metabolome in samples obtained before, during, and after 6 months of treatment with sirolimus and hydroxychloroquine, using univariate statistical models and machine learning approaches. Metabolites and metabolic pathways were validated in TSC2-deficient cells derived from patients with LAM. Single-cell RNA-Seq was employed to assess metabolic enzymes in an early-passage culture from an LAM lung.ResultsMetabolomic profiling revealed changes in polyamine metabolism during treatment, with 5'-methylthioadenosine and arginine among the most highly upregulated metabolites. Similar findings were observed in TSC2-deficient cells derived from patients with LAM. Single-cell transcriptomic profiling of primary LAM cultured cells revealed that mTORC1 inhibition upregulated key enzymes in the polyamine metabolism pathway, including adenosylmethionine decarboxylase 1.ConclusionsOur data demonstrate that polyamine metabolic pathways are targeted by the combination of rapamycin and hydroxychloroquine, leading to upregulation of 5'-methylthioadenosine and arginine in the plasma of patients with LAM and in TSC2-deficient cells derived from a patient with LAM upon treatment with this drug combination.Trial registryClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov. Partners Human Research Committee, protocol No. 2012P000669.