Long-term efficacy and safety of sirolimus therapy in patients with lymphangioleiomyomatosis.

BACKGROUND: Sirolimus has been confirmed to be effective for lymphangioleiomyomatosis (LAM), a rare multisystem neoplastic disease in women. The long-term effects of sirolimus treatment for LAM, however, are largely unknown. We aimed to analyze the long-term efficacy and safety of sirolimus therapy for LAM with 4-year follow-up. METHODS: In total, 142 sporadic LAM patients who took sirolimus for 1-4 years were retrospectively enrolled for this analysis. The variables used for analysis included pulmonary function tests, arterial blood gas analysis, 6-min walking distance (6MWD), St. George's Respiratory Questionnaires (SGRQ) and serum vascular endothelial growth factor-D (VEGF-D) levels before and after the initiation of sirolimus therapy. The rates of change (slope) in those variables were calculated, and adverse events were also analyzed. RESULTS: In total, 122, 83, 60 and 32 patients out of 142 were followed for 1, 2, 3 and 4 years respectively. Sirolimus treatment improved the change rate in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) compared with the data before treatment (FEV1, - 10 ± 15 vs. - 178 ± 36 ml/y, P <  0.001 and FVC, 54 ± 22 vs.-72 ± 68 ml/y, P < 0.05). In comparison to the baseline measurements, significant improvements were observed in FEV1 at the first year; FVC at 1-2 years; arterial oxygen levels, 6MWD, and SGRQ at 1-3 years; and VEGF-D at 1-4 years. Overall, all variables stabilized or improved during the 4 years of observation. Adverse events related to sirolimus were mild. CONCLUSION: Sirolimus therapy is effective at improving or stabilizing pulmonary function, oxygen levels, exercise capacity, and quality of life in patients with LAM for up to 4 years. VEGF-D is maintained at a lower level for 4 years after treatment. Adverse events related to sirolimus were mild.

Diagnostic and Treatment Monitoring Potential of Serum Vascular Endothelial Growth Factor-D in Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease occurring almost exclusively in premenopausal women and characterized by cystic lung destruction, abdominal tumors (renal angiomyolipomas (AML)), and involvement of the axial lymphatics (adenopathy, lymphangioleiomyomas). Serum vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic factor, has been recently considered as a novel marker for LAM. Herein we report the diagnostic and differential diagnostic value of serum VEGF-D in LAM patients and evaluate the change of serum VEGF-D levels before and after treatment with sirolimus. The study group included 66 patients with LAM (47 definite LAM and 19 probable LAM based on European Respiratory Society guidelines), 14 patients with other polycystic lung diseases, and 20 healthy female controls. Serum VEGF-D levels were quantified by enzyme-linked immunoassay (ELISA). Serum VEGF-D levels were significantly increased in definite LAM patients compared with healthy controls (3890.3±373.3 pg/ml vs. 413.3±33.2 pg/ml, p<0.05). The optimal cutoff point for LAM diagnosis was 692.5 pg/ml with sensitivity of 97.9% and specificity of 100%. In probable LAM patients, serum VEGF-D levels were all greater than 692.5 pg/ml. Serum VEGF-D levels were significantly increased in definite LAM patients who had chylothorax compared with those without chylothorax (5153.9±598.3 pg/ml vs. 2869.8±372.8 pg/ml, p<0.05). But serum VEGF-D levels in LAM patients with/without pneumothorax, AML, and lymphangioleiomyomas were not significantly changed. Serum VEGF-D levels in definite LAM patients and patients with other cystic lung diseases were 3890.3±373.3 pg/ml and 412.6±27.5 pg/ml, respectively (p <0.05). We determined an optimal cutoff value of 688.5pg/ml, resulting in sensitivity of 97.9% and specificity of 100%. Following a median of 12-month treatment with sirolimus, serum VEGF-D levels decreased from 3135.0±909.4 pg/ml to 1731.8±621.2 pg/ml and symptoms improved. Our study found that serum VEGF-D levels were significantly higher in LAM patients compared with healthy controls and patients with other polycystic lung diseases and that the levels were further increased when complicated by chylothorax. Serum VEGF-D levels may be useful for diagnosis and differential diagnosis with high specificity and sensitivity as well as for following treatment response with sirolimus.

Correlation of serum vascular endothelial growth factor-D concentration with clinical presentation and course of lymphangioleiomyomatosis.

BACKGROUND: Increased serum vascular endothelial growth factor D (VEGF-D) concentration has been accepted as a diagnostic marker in lymphangioleiomyomatosis (LAM). The study was performed to evaluate the correlation of VEGF-D with clinical presentation and course of LAM. MATERIAL: The study group comprised of 48 women with LAM (27 with sLAM, 9 with sLAM and lymphangioma (sLAM-LYM) and 12 patients with TSC/LAM). Patients were assessed at the time of VEGF-D examination, and pulmonary function parameters were compared with those, obtained one year before. VEGF-D serum concentration was measured by ELISA method. RESULTS: Patients with TSC/LAM and sLAM-LYM displayed higher concentrations of VEGF-D than patients with sLAM (2682 ± 1347 pg/mL and 2223 ± 1184 pg/mL vs.1281 ± 791 pg/mL; p = 0.0002, p = 0.009) respectively. Patients with sLAM and VEGF-D concentration <800 pg/mL (sLAM-L) had better lung function as assessed by FEV1 (2.38 ± 0.88 L vs. 1.75 ± 0.8 L; p < 0.015) and DL,CO (5.8 ± 2.25 vs. 3.93 ± 1.74 mL/min/mmHg; p < 0.028), had higher blood oxygenation, then those with VEGF-D >800 pg/mL (sLAM-H). Significant yearly increase of TLC (390 ± 700 mL; p < 0.021) and RV (340 ± 790 mL; p < 0.03), and decrease of distance in 6MWT (-30 ± 50 m; p = 0.04) were observed in sLAM-H group. Lung function parameters remained constant in sLAM-L patients. Patients with sLAM-H displayed higher yearly decline of FVC (120 vs. 50 mL; p = 0.035) and increase of TLC (390 vs. -80 mL; p = 0.038) and RV (340 vs. 90 mL; p = 0.045) than sLAM-L patients. Negative correlations between VEGF-D concentration and DL,CO, PaO2, PaCO2, and positive with HRCT grading, and desaturation in 6MWT were noticed in sLAM patients without lymphangioma. CONCLUSIONS: Serum VEGF-D is the useful biomarker of LAM extension, and might also prove predictive towards therapeutic decision.

[Influence of prolonged treatment with octreotide on GH, IGF I, insulin, ACTH, cortisol, T3, T4 and TSH secretion in a case of congenital chylothorax]. / Influenza del trattamento prolungato con octreotide sulla secrezione di GH, IGFI, insulina, ACTH, cortisolo, T3, T4 e TSH in un caso di chilotorace congenito.

Congenital chylothorax is a rare condition characterized by the accumulation of lymph fluid in the pleural space that causes respiratory and circulatory dysfunctions, immune deficiencies, hypoalbuminemia, electrolyte imbalance and alterations of the coagulation. Mortality rates are elevated and can rise to 50%. Therapy consists in conservative treatment based on thoracic drainage combined with total parenteral nutrition or use of low-fat high-protein diet supplemented with medium chain triglycerides. In case of failure surgical intervention may be considered. During the last years some authors have experienced the use of octreotide with doubtful results. In no case the drug impact on insulin, GH and cortisol secretion in neonatal age has been investigated and only in one case the effect on thyroid hormones has been assessed. We report the case of a 36-week baby with congenital chylothorax treated with octreotide for 42 days. The drug was well tolerated but hormonal level measurements showed a deep depression of insulin secretion unaccompanied by alterations of glucose levels. Levels of GH and TSH showed only a transitory decrease. ACTH and cortisol remained normal. At 5 months, the measurements of hormonal levels did not show significant alterations. It is not possible to determine if such a drug played an essential role in the solution of the pleural effusion, but it is important to emphasize that a prolonged treatment with octreotide has not caused, in our case, persistent hormonal alterations.

Accumulation of CD8+CD45RA+CD62L+ T cells in acute chylothorax in neonates.

BACKGROUND: Acute chylothorax in neonates is a rare disease but results in significant loss of lymphatic cells. OBJECTIVES: The purpose of the study was to determine whether acute chylothorax in neonates results in quantitative changes of lymphocyte subpopulations in peripheral blood and chyle. METHODS: 6 neonates who had acute chylothorax after thoracic surgery due to transposition of the great arteries were prospectively enrolled in the study. Peripheral blood mononuclear cells (PBMC) and chylous fluid mononuclear cells (CFMC) including CD45RA+ and CD45RO+ T cells and the expression of the lymphocyte homing marker CD62L were investigated by fluorescence-activated cell sorting. RESULTS: In chyle, CD3+CD45RA+ T cells were significantly increased compared to peripheral blood (PMBC: median 65.8% of CD3+; range 32.3-76.9% vs. CFMC: 90.3%; 68.6-94.4%) (p = 0.02). In chyle, changes of percentages of the CD45RA+ were limited to CD8-expressing T cells (CD8+CD45RA+: PBMC: 77.3%; 69.3-85.6% vs. CFMC: 93.2%; 86.3-98.5%) (p = 0.02). The CD8+CD45RA+ were mainly CD62L+ (PBMC: 59.4%; 31.6-62.0% vs. CFMC: 87.8%; 62.7-90.7%) (p = 0.02). CONCLUSIONS: The study gives evidence that acute chylothorax in neonates results in immunophenotypic alterations and accumulation of certain T-cell subpopulations in the pleural cavity. Although limited by small numbers of patients due to the rare manifestation of the disease, we were able to demonstrate an abundance of CD8+CD45RA+ T cells expressing CD62L in the chyle compared to peripheral blood. However, whether CD62L expression may contribute to the accumulation of CD8+CD45RA+ T cells in chyle and whether quantitative changes of these specific cells are of clinical relevance has to be determined.

Antithrombin activity in children with chylothorax.

OBJECTIVE: To determine whether increased antithrombin loss is present in children with chylothorax after cardiac surgery. METHODS: Plasma and pleural effusion samples of children with chylous and non-chylous pleural effusion were assayed for antithrombin activity. RESULTS: Ten children with chylothorax and five children with non-chylous pleural effusion were investigated. There was statistically significant increase in mean antithrombin activity in chylous samples (32.2+/-11.4%) compared to non-chylous samples (14.4+/-13.9%), and significant decrease in plasma of children with chylothorax (44.6+/-15.4%) compared to children with non-chylous pleural effusion (69.9+/-22.4%). Seven of 10 children with chylous and none of the children without chylous developed thrombosis (p<0.007). CONCLUSIONS: Increased loss of antithrombin is present in children with chylothorax, potentially predisposing these children to an increased risk of thrombosis. Repeated antithrombin substitution should be considered in critically ill children with chylothorax.

Evaluation of cholesterol and triglyceride concentrations in differentiating chylous and nonchylous pleural effusions in dogs and cats.

Serum and pleural fluid cholesterol and triglyceride concentrations and cholesterol/triglyceride ratios were determined in 9 dogs and 9 cats with pleural effusion (8 nonchylous, 10 chylous). The pleural fluid triglyceride concentrations were significantly higher (P less than 0.05) and the pleural cholesterol/triglyceride ratios were significantly lower (P less than 0.05) in chylous effusions than in nonchylous effusions in all animals. There were no differences in serum cholesterol and triglyceride concentrations and serum cholesterol/triglyceride ratios for chylous and nonchylous effusions in either species. There also were no differences in pleural fluid cholesterol concentrations between the 2 groups in the dog or cat. It was concluded that determinations of cholesterol/triglyceride ratios may be an accurate method for helping distinguish chylous from nonchylous effusions in dogs and cats.

Spontaneous chylothorax in newborns.

During a 22-year period, 12 cases of spontaneous chylothorax in newborns were diagnosed at a large pediatric tertiary care center. Seven infants had right-sided effusions; only one effusion occurred on the left. Severe bilateral accumulations occurred in four nonimmune hydropic premature infants. The diagnosis was made by the milky appearance and/or the presence of more than 80% lymphocytes in the pleural fluid. Early diagnosis of the pleural effusion as chyle was associated with a less protracted course than when diagnosis was delayed. The total pleural fluid losses varied from 130 to 3,308 mL. Initial treatment included chest taps and/or drains in all the infants and mechanical ventilation in six. Oral feedings with standard or medium-chain triglyceride formulas were given in five; total parenteral nutrition was administered in seven. The conditions of two infants with copious and persistent drainage improved following surgery. All but one infant survived, and the chylothoraxes never recurred.

Use of 125-I- and 51-Cr-labeled albumin for the measurement of gastrointestinal and total albumin catabolism.

A method for the simultaneous measurement of gastrointestinal protein loss and total albumin turnover entailing the use of a combination of (125)iodine- and (51)chromium-labeled albumin is described. Albumin turnover was calculated by the measurement of albumin-(125)I plasma decay and cumulative urinary excretion, and the results obtained agreed closely with previous studies utilizing albumin-(131)I. Gastrointestinal catabolism was calculated from the rate of fecal excretion of (51)Cr and the specific activity of plasma albumin-(51)Cr, and these data were related to the calculated albumin turnover results. During the period of 6-14 days after administration, the ratio of specific activties of albumin-(125)I and -(51)Cr in plasma and in extravascular spaces or gastric and biliary secretions remained almost identical. Fecal excretion of (51)Cr was also quite stable at this time. In six normal subjects gastrointestinal catabolism accounted for less than 10% of total albumin catabolism. Excessive gastrointestinal protein losses did not contribute to the low serum albumin in three patients with cirrhosis or in two adults with the nephrotic syndrome. Multiple mechanisms leading to hypoalbuminemia were demonstrated in other subjects with a variety of gastrointestinal disorders.