Experiences in the treatment of refractory chylothorax associated with lymphoproliferative disorders.

BACKGROUND: Chylothorax is a rare condition which can be associated with malignant lymphoproliferative disorders (LPDs). We retrospectively analyzed the results of the conservative treatment of 10 patients with persistent non-traumatic malignant chylothorax. RESULTS: Conservative treatment lead to a decline of chylothorax after mean of 66 days and consisted of the treatment of the underlying disease and of simultaneous long-term supportive care (drainage of the thoracic cavity, dietary measures and nutrition management). In most cases (80%), chylothorax disappeared only after a successful therapeutic response of the underlying disease. Low-dose radiotherapy had very good effects in two patients. CONCLUSION: Conservative treatment of malignant chylothorax can be considered a suitable method. Based on our results, successful treatment of the lymphoproliferative disorder seems to be a very important factor for the disappearance of chylothorax.

Levels of miRNA and Hormones in Thoracic Duct Lymph in Rats with Experimental Breast Cancer Induced by N-Methyl-N-Nitrosourea.

We studied hormone levels in the thoracic duct lymph and expression of miRNA involved in the pathogenesis of breast cancer induced in rats by intramammary injection of N-methyl-Nnitrosourea. The correlations between miRNA expression and hormone levels depended on the type of treatment.

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis.

OBJECTIVE: Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF. APPROACH AND RESULTS: TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice. CONCLUSIONS: ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature.

The effect of photodynamic therapy on cisterna chyli patency in rats.

OBJECTIVE: To radiographically and histologically evaluate the effects of photodynamic therapy on the cisterna chyli in rats. STUDY DESIGN: Experimental study. ANIMALS: Adult male Sprague-Dawley rats (n = 60). METHODS: Cecal lymph nodes were injected with the photodynamic compound verteporfin. A 690 nm, 500 mW diode laser was then directed at the area of the cisterna chyli for either 0, 1.5, or 3 minutes. Cisterna chyli patency was evaluated using lymphography, and histologic changes were evaluated on postoperative Days 1, 3, 5, 7, and 14. RESULTS: Histologically, minimal to marked injury to the cisternal and/or pericisternal tissues was present in all treated rats at all time periods. Radiographically, 8/20 cisternae were occluded in the 1.5-minute treatment group (including 1/4 on Day 1, 2/4 on Day 3, 3/4 on Day 5, 0/4 on Day 7, and 2/4 on Day 14), and 9/20 cisternae were occluded in the 3-minute treatment group (including 0/4 on Day 1, 1/4 on Day 3, 3/4 on Day 5, 3/4 on Day 7, and 2/4 on Day 14). There was minimal to no histologic evidence of tissue injury in control rats. All control cisternae were radiographically open. CONCLUSIONS: Further investigations into the timing of laser application and light dose, or alternative photodynamic agents are required to limit injury to adjacent tissues and to improve the effectiveness of cisternal photoablation.

Erlotinib and radiation therapy for elderly patients with esophageal cancer - clinical and correlative results from a prospective multicenter phase 2 trial.

PURPOSE: Elderly patients with esophageal cancer who are not candidates for chemoradiation may benefit from targeted agents; hence erlotinib combined with radiotherapy was evaluated in this trial. MATERIALS AND METHODS: Patients >65 years with carcinoma of the thoracic esophagus or gastroesophageal junction who were not eligible for platinum-based treatment received erlotinib daily for 1 year starting on day 1 of radiotherapy [50.4 Gy days 1-28 (Mon-Fri) at 1.8 Gy per fraction]. Response was assessed by endoscopy and computed tomography. The primary endpoint was overall survival (OS), and secondary endpoints were complete response, progression-free survival (PFS) and toxicity. RESULTS: The ECOG performance status in the 17 study patients was 0,1 and 2 in 2, 12 and 3 patients, respectively; 1, 5, 7 and 4 patients were in stage I, II, III and IV, respectively; adenocarcinoma was noted in 16 patients and squamous cell carcinoma in 1; there were 3 current, 12 past and 2 never smokers. Median OS was 7.3 months (95% confidence interval, CI: 3.8-22.3) with 14 deaths. There were 2 mucosal complete responses, 1 residual carcinoma in situ and 3 partial endoscopic responses in 9 patients who had endoscopy after radiotherapy. Estimated PFS was 4.5 months (95% CI: 2.4-7.3). Progression was distant (n = 3), locoregional (n = 6), unknown (n = 5) and too early (n = 3). Estimated 1-year survival was 29% (95% CI: 11-51%), 5 patients lived >12 months. Treatment-related toxicities of grade 3-4 occurred in 5 patients. Patients with epidermal growth factor receptor amplification and never smokers had the longest OS (22.3 and 16.6 months, respectively). CONCLUSIONS: Erlotinib with radiotherapy is tolerable and warrants further biomarker-driven evaluation in this population.

Black-tea polyphenols decrease micellar solubility of cholesterol in vitro and intestinal absorption of cholesterol in rats.

Administration of black-tea polyphenols (BTP) simultaneously reduced lymphatic recovery of both (3)H-cholesterol and (14)C-trioleoylglycerol in rats that were cannulated in the thoracic duct. BTP decreased the in vitro micellar solubility of cholesterol in a dose-dependent manner. When purified theaflavins, which are components of BTP, were used, theaflavin-monogallates (TFMGs), theaflavin-3-gallate (TF3G), and theaflavin-3'-gallate (TF3'G) were effective in eliminating cholesterol from bile salt micelles in vitro. Theaflavin (TF) and theaflavin-3,3'-digallate (TFDG) had no effect on the micellar solubility of cholesterol. The concentration of bile acid in the micelles was not influenced by the addition of any BTPs or theaflavins. These results suggest that the reduction of micellar cholesterol by BTP could be important to reducing cholesterol absorption.

Human thoracic duct in vitro: diameter-tension properties, spontaneous and evoked contractile activity.

The current study characterizes the mechanical properties of the human thoracic duct and demonstrates a role for adrenoceptors, thromboxane, and endothelin receptors in human lymph vessel function. With ethical permission and informed consent, portions of the thoracic duct (2-5 cm) were resected and retrieved at T(7)-T(9) during esophageal and cardia cancer surgery. Ring segments (2 mm long) were mounted in a myograph for isometric tension (N/m) measurement. The diameter-tension relationship was established using ducts from 10 individuals. Peak active tension of 6.24 +/- 0.75 N/m was observed with a corresponding passive tension of 3.11 +/- 0.67 N/m and average internal diameter of 2.21 mm. The equivalent active and passive transmural pressures by LaPlace's law were 47.3 +/- 4.7 and 20.6 +/- 3.2 mmHg, respectively. Subsequently, pharmacology was performed on rings from 15 ducts that were normalized by stretching them until an equivalent pressure of 21 mmHg was calculable from the wall tension. At low concentrations, norepinephrine, endothelin-1, and the thromboxane-A(2) analog U-46619 evoked phasic contractions (analogous to lymphatic pumping), whereas at higher contractions they induced tonic activity (maximum tension values of 4.46 +/- 0.63, 5.90 +/- 1.4, and 6.78 +/- 1.4 N/m, respectively). Spontaneous activity was observed in 44% of ducts while 51% of all the segments produced phasic contractions after agonist application. Acetylcholine and bradykinin relaxed norepinephrine preconstrictions by approximately 20% and approximately 40%, respectively. These results demonstrate that the human thoracic duct can develop wall tensions that permit contractility to be maintained across a wide range of transmural pressures and that isolated ducts contract in response to important vasoactive agents.

Effects of VEGF on Ca(2+)-transient in cultured lymphatic endothelial cells and mechanical activity of isolated lymph vessels.

We investigated the effects of vascular endothelial growth factor (VEGF(165)) on [Ca(2+)](i)-transient in cultured lymphatic endothelial cells (LEC) and mechanical activity of isolated dog thoracic ducts. VEGF (0.1-10 ng/ml) caused a dose-dependent increase of the [Ca(2+)](i) in LEC. Pretreatment with 10(-5) M genistein or 5x10(-6) M herbimycin A produced a significant reduction of the VEGF-induced [Ca(2+)](i)-transient. In the presence of 10(-6) M thapsigargin, VEGF caused no significant effect on the [Ca(2+)](i)-transient. Pretreatment with Ca(2+)-free solution containing 0.1 mM EGTA produced no significant effect on the peak increase of [Ca(2+)](i) induced by 0.1 or 10 ng/ml VEGF, but significantly depressed the sustained part of [Ca(2+)](i) observed at the higher concentration of VEGF. The VEGF (0.1-10 ng/ml) caused a significant dilation of the isolated lymph vessels with intact endothelium, which were precontracted with U46,619. The 10 ng/ml VEGF-induced dilation was significantly reduced by 3 x 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME). The action of L-NAME was inhibited by the simultaneous application of 10(-3) M L-arginine. Mechanical rubbing of the endothelium also caused significant inhibition of the VEGF-induced dilation. The findings suggest that VEGF(165) may activate the receptor-related tyrosine kinase and cause the release of Ca(2+) from the inositol 1,4, 5-triphosphate-sensitive intracellular Ca(2+) stores in LEC. VEGF(165) also produces endothelium-dependent nitric oxide-mediated dilation of the precontracted isolated lymph vessels.

Effects of vasoconstrictive and vasodilative agents on lymphatic smooth muscles in isolated canine thoracic ducts.

A study was made of the isometric responses of isolated canine thoracic ducts to several physiological vasoactive substances. Contractions of the lymphatic smooth muscles were induced by epinephrine, norepinephrine, 5-hydroxytryptamine, histamine (HIS) and prostaglandin F2 alpha in a dose-dependent manner. The decreasing order of potency in the contractile responses was as follows: epinephrine greater than norepinephrine greater than 5-hydroxytryptamine much greater than HIS not equal to prostaglandin F2 alpha. There were no significant regional differences in the responses to vasoconstrictive agents. Phenylephrine, xylazine and clonidine caused a dose-dependent contraction in the lymphatic preparations. Prazosin (10(-8) to 10(-7) M) inhibited the phenylephrine-induced vasoconstriction in a competitive manner. Xylazine-induced responses were inhibited competitively by yohimbine (10(-8) to 10(-7) M). These results suggest that both alpha-1 and alpha-2 adrenoceptors are located on the lymphatic smooth muscles of canine thoracic ducts. On the other hand, acetylcholine, isoproterenol, HIS, adenosine and ATP caused dose-dependent relaxations in canine thoracic ducts precontracted by 10(-5) M norepinephrine. The decreasing order of potency in the relaxant responses was as follows: acetylcholine much greater than isoproterenol much greater than adenosine not equal to HIS not equal to ATP. There were no significant regional differences in the relaxant responses to the agents. Procaterol, salbutamol, dobutamine and denopamine caused a dose-dependent relaxation of isolated canine thoracic ducts. Propranolol (10(-9) to 10(-8) M) inhibited procaterol- and dobutamine-induced vasorelaxations in a competitive manner. Metoprolol (10(-8) to 10(-7) M) inhibited only the dobutamine-induced vasorelaxation, but did not significantly influence the procaterol-induced response.(ABSTRACT TRUNCATED AT 250 WORDS)