Successful treatment of a patient with chyluria due to lymphangioleiomyomatosis using sirolimus

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.) 2008 Massachusetts Medical Society

Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease of women. LAM is caused by mutations in the tuberous sclerosis genes, resulting in activation of the mTOR complex 1 signaling network. Over the past 11 years, there has been remarkable progress in the understanding of LAM and rapid translation of this knowledge to an effective therapy. LAM pathogenic mechanisms mirror those of many forms of human cancer, including mutation, metabolic reprogramming, inappropriate growth and survival, metastasis via blood and lymphatic circulation, infiltration/invasion, sex steroid sensitivity, and local and remote tissue destruction. However, the smooth muscle cell that metastasizes, infiltrates, and destroys the lung in LAM arises from an unknown source and has an innocent histological appearance, with little evidence of proliferation. Thus, LAM is as an elegant, monogenic model of neoplasia, defying categorization as either benign or malignant.

Postoperative chylous ascites is a rare complication of retroperitoneal and mediastinal surgery that represents a difficult management problem due to the serious mechanical, nutritional and immunological consequences of the constant loss of protein and lymphocytes. We reviewed the topic of postoperative chylous ascites with special emphasis on the relevant diagnostic and imaging modalities. We propose a novel management algorithm. We performed a MEDLINE search of the literature on chylous ascites using chyloperitoneum as the subject heading and chylous ascites as an additional key word. The search yielded 651 articles. We focused on 102 series, collective reviews and mainly case reports related to the issue of postoperative chylous ascites. We propose a novel algorithm based on a step-up approach aimed at promoting decreased lymph production and flow as well as maintaining nutritional balance. The management algorithm integrates repeat palliative paracentesis, dietary measures, total parenteral nutrition therapy, peritoneovenous shunting and surgical closure of the lymphoperitoneal fistula. Due to the remarkable effectiveness of somatostatin therapy for the closure of lymphatic fistula somatostatin therapy should be attempted with or without total parenteral nutrition early in the course of treatment of chylous ascites before any invasive steps are taken. Various management modalities may be used successfully to treat chylous ascites. Therefore, treatment should be individualized and adjusted to the severity of lymphatic leakage and its consequences. The outcome mostly depends on the underlying pathological condition. Thus, in the absence of malignant or congenital underlying pathology the prognosis in cases of postoperative chylous ascites is good with the majority responding to conservative measures.