Breast implant-associated anaplastic large cell lymphoma - From diagnosis to treatment.

Breast lymphomas comprise a rare group of malignant breast tumors. Among these, a new entity has emerged as a potentially under-diagnosed disease. Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) most often manifests as a late periprosthetic effusion between 1 and 10 years after the implantation of silicone or saline-filled breast prostheses. BI-ALCL is an anaplastic lymphoma kinase-negative T-cell lymphoma that has a distinctively different clinical course than other breast lymphomas or ALCLs. Diagnosis is based on aspiration of the effusion around the implant and CD30 positivity of the sample. Every periprosthetic effusion after breast augmentation or reconstruction using implants should be considered as potential BI-ALCL until proven otherwise. The majority of cases at diagnosis are in the in situ stage, i.e., confined to the lumen around the prosthesis. Most patients have an excellent prognosis when complete removal of the capsule and prosthesis with negative margins is achieved surgically. Some patients, however, develop infiltrative disease with a potentially life-threatening clinical course. Treatment planning regarding the extent of surgery and role of adjuvant therapy, especially in advanced cases, requires further investigation.

Effects of smoking cessation and nicotine substitution on systemic eicosanoid production in man.

This study investigated the effects of smoking cessation with and without nicotine substitution on the excretion of major urinary metabolites of thromboxane A2 and prostacyclin, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha, respectively, as well as on the excretion of leukotriene E4 in man. Urine samples were obtained from 20 healthy non-smoking controls and from 60 healthy smoking volunteers before, and 3, 7 and 14 days after smoking cessation. Fifteen smokers quit smoking without nicotine substitution, 15 used nicotine chewing gum and 30 used nicotine patches as a substitution therapy. Urinary thiocyanate as well as cotinine and trans-3'-hydroxycotinine excretions were used as compliance and nicotine substitution indicators. 11-Dehydrothromboxane B2, 2,3-dinor-6-ketoprostaglandin F1alpha and leukotriene E4 excretion was about two, three and five times higher in smokers than in controls, respectively. Three days after smoking cessation without nicotine substitution, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha levels were lowered to 75% (P<0.01) and 80% (P<0.05) of the initial values, and after 14 days to 50% (P<0.01) and 60% (P<0.05), respectively. In 3 days leukotriene E4 excretion was dropped to 70% of the initial value (P<0.05), but no further decrease was observed during the study. In individuals using nicotine chewing gum or nicotine patches no significant changes were observed in the analytes during the 2-week follow-up. The increased systemic eicosanoid synthesis observed in smokers may be involved in the harmful cardiovascular effects of smoking. The fact that eicosanoid production remains at pre-cessation level in volunteers who quit smoking but use nicotine substitution may be involved in the risk of cardiovascular complications reported during nicotine replacement therapy.

Clinical pharmacology of eicosanoids, nicotine induced changes in man.

Smoking is an important risk factor for respiratory and cardiovascular diseases. The role of numerous chemical, partly uncharacterised compounds existing in tobacco smoke is not known. (-)-Nicotine, its stereoisomer (+)-nicotine and main metabolite cotinine are biologically active compounds influencing e.g. catecholamine and eicosanoid systems. The precise mechanisms are not well known. The purpose of the present study consisting of a PhD thesis (11) and five original papers was to investigate the in vitro effects of nicotine isomers and cotinine on eicosanoid production in polymorphonuclear leukocytes, platelets and whole blood in vitro, and to clarify the effects of smoking without and with nicotine substitution on eicosanoid production in vivo and ex vivo. It was found that all the tested compounds modulated blood cell eicosanoid synthesis. Nicotine isomers and cotinine increased PGE2 but decreased TXB2, LTB4 and LTE4 synthesis in vitro. Eicosanoid synthesis in vivo and ex vivo was higher in smokers (n = 60) than in non-smoking controls (n = 20). This may contribute to the harmful cardiovascular effects of smoking. Cessation of smoking without, but not with, nicotine substitution reduced eicosanoid synthesis measured ex vivo as whole blood production or in vivo as urinary excretion of eicosanoid metabolites after 3, 7 and 14 days. Thus long-term nicotine substitution diminishes the beneficial effects of smoking cessation.

Amrinone, a phosphodiesterase III inhibitor, and arachidonic acid metabolism in humans.

Amrinone-a phosphodiesterase III inhibitor-is used in the treatment of acute heart failure. In addition to its hemodynamic effects, amrinone has been shown to inhibit thromboxane synthesis in vitro. We investigated the effects of amrinone on thromboxane, prostaglandin, and leukotriene synthesis in humans. Eight healthy male volunteers took part in this single-blind study in which either amrinone (a 1.5-mg/kg bolus in 30 min and after that 10 microg/kg/min for 1 h 30 min) or placebo (0.9% NaCl) were infused. Amrinone infusion increased systolic blood pressure but had no significant effect on diastolic blood pressure or heart rate. Amrinone did not modulate thromboxane B2 synthesis stimulated by either spontaneous clotting or calcium-ionophore A23187 in whole blood. Amrinone had no effects on prostaglandin E2 or leukotriene E4 production in A23187-stimulated whole blood, nor did it affect urinary excretion of 11-dehydrothromboxane B2 or 2,3-dinor-6-keto-prostaglandin F1alpha, the index metabolites of thromboxane A2 and prostacyclin productions, respectively. We conclude that amrinone has no effects on eicosanoid production in humans at the dose level used in this study, and that the hemodynamic effects noticed are not mediated via cyclooxygenase or lipoxygenase products of arachidonic acid metabolism.

Modulation of arachidonic acid metabolism by phenols: relation to their structure and antioxidant/prooxidant properties.

The effects of substituted catechols (3-methylcatechol, 4-methylcatechol, 4-nitrocatechol, and guaiacol) and trihydroxybenzenes (pyrogallol, propyl gallate, 1,2,4-trihydroxybenzene, and 1,3,5-trihydroxybenzene) on the synthesis of prostaglandin (PG)E2 and leukotriene (LT)B4 were tested in human A23187-stimulated polymorphonuclear leukocytes. The effects were related to their peroxyl-radical-scavenging (antioxidant), superoxide-scavenging (antioxidant), and superoxide-generating (prooxidant) properties. In general, compounds with hydroxyl groups in the ortho position increased PGE2/LTB4 ratio, and compounds with hydroxyl groups in the meta position decreased PGE2/LTB4 ratio. Catechols, which have hydroxyl groups in the ortho position, were the most potent peroxyl radical and superoxide anion scavengers. Trihydroxybenzenes (pyrogallol, 1,2,4-trihydroxybenzene, and 1,3,5-trihydroxybenzene) generated superoxide, whereas dihydroxybenzenes did not. Thus, the positions and number of hydroxyl groups seem to be the most important properties determining the action of phenolic compounds on PGE2/LTB4 ratio and their antioxidant/prooxidant activities.

Catechol estrogens as inhibitors of leukotriene synthesis.

Estrogens have a beneficial effect on atherosclerosis and osteoporosis after menopause, but their exact mechanism of action is still unknown. The aim of the present study was to investigate the effects of estradiol and its metabolites catechol estrogens on arachidonic acid metabolism in vitro. Estradiol had no effect on arachidonic acid metabolism up to 33 microM in A23187-stimulated human whole blood. All catechol estrogens (2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol and 4-hydroxyestrone) had similar kinds of actions on arachidonic acid metabolism, being over ten times more potent inhibitors of leukotriene synthesis (IC50 values 0.044-0.16 microM) than thromboxane (IC50 values 0.99-2.1 microM) and prostaglandin E2 synthesis (IC50 values 0.84-5.5 microM). It is suggested that some of the protective actions of estrogens--e.g., on atherosclerosis and osteoporosis--may be related to the inhibition of leukotriene synthesis by catechol estrogens.

Nitric oxide as a regulator of prostacyclin synthesis in cultured rat heart endothelial cells.

The effects of nitric oxide (NO) and its second messenger cyclic guanosine monophosphate (cGMT) on prostacyclin (PGI2) synthesis were studied in cultured rat heart endothelial cells using three different non-enzymatic nitric oxide releasing substances as well as inhibitors of nitric oxide synthase and of soluble guanylate cyclase. Production of prostacyclin, measured as 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), was stimulated up to 1.7 fold in endothelial cells treated with the NO donors SIN-1 (3-morpholino sydnonimine), GEA 3162 (3-aryl-substituted oxatriazole imine) and GEA 3175 (3-aryl-substituted oxatriazole sulfonyl), chloride). In each case the synthesis of cGMP increase as much as 40-100 fold. An inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), decreased the basal production of 6-keto-PGF1 alpha in non-stimulated endothelial cells, an effect that could be reversed by the NO donors SIN-1, GEA 3162 and GEA 3175. cGMP formation in the L-NAME treated endothelial cells was unaltered. The guanylate cyclase inhibitors, methylene blue (100 mumol/l) and LY83583 (100 mumol/l), caused a 1.5-10 fold increase in 6-keto-PGF1 alpha production while NO-donor-stimulated endothelial cGMP production was decreased by 10 to 90%. However, when SIN-1 was used as a stimulant, LY83583 had no significant effect on the production of cGMP. These findings support the hypothesis that NO stimulates prostacyclin production directly by activating cyclooxygenase. The results also suggest that NO could have an indirect effect on prostacyclin production via cGMP.

Percutaneous transluminal angioplasty increases thromboxane A2 production in claudicants.

Percutaneous transluminal angioplasty is an acute, local stimulus to platelets which activation is regarded as an important factor for a later restenosis. The balance between the production of prostacyclin and thromboxane A2 is of (patho)physiological importance due to their opposite actions on vascular tone and platelet reactivity. In this study we investigated the influence of percutaneous transluminal angioplasty of the peripheral arteries on prostacyclin and thromboxane A2 productions in vivo by measuring the excretions of their urinary index metabolites, 2,3-dinor-6-ketoprostaglandin F1 alpha and 11-dehydrothromboxane B2, respectively, in 10 patients. We found a twofold increase in thromboxane A2, but no significant change in prostacyclin, production after peripheral transluminal angioplasty which shifted prostacyclin/thromboxane A2 balance to the direction of thromboxane A2 formation. This gives theoretical support to the use of thromboxane A2 synthase inhibitors and receptor antagonists as well as prostacyclin analogues in combination with peripheral percutaneous transluminal angioplasty to prevent thrombosis and restenosis.

Theophylline infusion modulates prostaglandin and leukotriene production in man.

Although theophylline has been used in the treatment of asthma for decades, it is not a first line choice any more. It is a well-known bronchodilator, but was recently discovered also to be an anti-inflammatory, immunomodulatory and bronchoprotective agent. Therefore we wanted to establish the role of theophylline on prostaglandin and leukotriene production, which plays a part in the pathogenesis of asthma. Theophylline was infused (bolus 5 mg/kg in 15 min and infusion 0.4 mg/kg/h for 1 h 45 min) into healthy volunteers. Thromboxane B2, prostaglandin E2 and leukotriene E4 were measured from the A23187-stimulated whole blood samples and stable metabolites of thromboxane A2; prostacyclin and leukotriene E4 were measured from urine. Theophylline increased prostaglandin E2 production and decreased leukotriene E4 production ex vivo in whole blood, thus increasing the prostanoid/leukotriene ratio. It did not change thromboxane B2 production stimulated by either spontaneous clotting or A23187 in the whole blood. Theophylline had hardly any effect on in vivo thromboxane, prostacyclin and leukotriene E4 production measured as urinary metabolites, 11-dehydro-thromboxane B2, 2,3-dinor-6-keto-prostaglandin F1alpha and leukotriene E4, respectively. Serum theophylline concentrations were at the lower level of normal therapeutic range during the infusion. The increase in PGE2 and the decrease in LTE4 synthesis ex vivo may offer a new explanation for the mode of antiasthmatic action of theophylline. It is notable that this phenomenon occurs at low serum theophylline concentrations. These results confirm the idea that theophylline has an anti-inflammatory and bronchoprotective action and support the use of theophylline as a therapeutic agent in asthmatic patients.

Prostacyclin and thromboxane A2 synthesis are increased in acute lower limb ischaemia.

Prostacyclin (PGI2) and thromboxane A2 (TXA2) play an important role in the pathophysiology of various cardiovascular diseases. The balance between PGI2 and TXA2 regulates the interaction between platelets and the vessel wall in vivo. In this study we measured PGI2 and TXA2 synthesis by analysing their urinary index metabolites 2,3-dinor-6-keto-PGF1 alpha and 11-dehydro-TXB2, respectively, in acute (10 patients) and chronic (10 patients) lower limb ischaemia. Both PGI2 and TXA2 synthesis were increased about two-fold in patients with acute lower limb ischaemia compared to chronic lower limb ischaemia. However, the PGI2/TXA2 ratio was more or less the same in acute and chronic lower limb ischaemia. In patients with acute lower limb ischaemia caused by thrombotic occlusion, PGI2 and TXA2 formation were about two times higher than in patients with acute lower limb ischaemia caused by embolic occlusion. Elevation of PGI2 and TXA2 synthesis in acute lower limb ischaemia may reflect increased platelet-vascular wall interactions without changing the PGI2/TXA2 ratio.

Effects of noradrenaline and dopamine infusions on arachidonic acid metabolism in man.

We infused noradrenaline (0.025 micrograms/kg/min for 60 min, n=7) and dopamine (3.0 micrograms/kg/min for 60 min, n=6) into healthy male volunteers to study the effects of these catecholamines on in vivo thromboxane A2, prostacyclin and leukotriene E4 production measured as urinary excretions of 11-dehydro-thromboxane (TX) B2, 2,3-dinor-6-keto-prostaglandin (PG) F1alpha and leukotriene (LT) E4, respectively. Plasma noradrenaline and dopamine concentrations were 2.9+/-0.3 and 233+/-17 nmol/l at the endo fo the noradrenaline and dopamine infusions, respectively. Noradrenaline decreased thromboxane production and increased leukotriene production almost two fold. It had hardly any effect on prostacyclin production. Dopamine had no significant effects on any of the variables, however, it had a tendency to increase prostacyclin and leukotriene production. The results indicate that noradrenaline is a more important modulator of arachidonic acid metabolism than dopamine in vivo.

Noradrenaline and dopamine infusions modulate arachidonic acid cyclooxygenase and 5-lipoxygenase pathways ex vivo in man.

We have previously demonstrated that adrenaline infusion increases the thromboxane/leukotriene (TX/LT) ratio in whole blood in healthy volunteers. The aim of the present study was to see whether other catecholamines--noradrenaline and dopamine--are also capable of modulating arachidonic acid (AA) metabolism in man. Low doses of noradrenaline (0.025 microgram/kg/min) and dopamine (3.0 micrograms/kg/min), which did not change hemodynamics, were infused for 60 min into healthy male volunteers. Both dopamine and noradrenaline decreased TX synthesis stimulated by spontaneous clotting, but no remarkable effect was seen when calcium ionophore A23187 was used as a stimulus. Dopamine but not noradrenaline increased prostaglandin E2 (PGE2) synthesis in A23187-stimulated whole blood. They both marginally decreased LTB4 formation in A23187-stimulated whole blood. The findings indicate that not only adrenaline but also noradrenaline and dopamine modulate AA metabolism in man.

Smoking cessation and nicotine substitution modulate eicosanoid synthesis ex vivo in man.

The effects of smoking cessation with and without nicotine substitution on prostaglandin E2, leukotriene B4, leukotriene E4, and thromboxane B2 synthesis ex vivo in man were investigated. Blood samples were obtained from 20 healthy non-smoking controls and from 30 healthy smoking volunteers before and 3, 7 and 14 days after smoking cessation. Half of the smokers used nicotine chewing gum as a substitution therapy. Urinary cotinine and trans-3'-hydroxycotinine as well as thiocyanate excretions were used as indicators for the use of nicotine chewing gum and smoking, respectively. Prostaglandin E2, leukotriene E4, and thromboxane B2 were measured from whole blood after calcium ionophore A23187 stimulation by direct radioimmunoassay and leukotriene B4 by RP-HPLC. Prostaglandin E2 and thromboxane B2 syntheses were about three times and leukotriene B4 and E4 syntheses four times higher in smokers than in controls. Three days after smoking cessation without nicotine substitution, levels were lowered significantly to about 70%, 80%, 45% and 60% of the initial values; and after 14 days to 55%, 80%, 45% and 50%, respectively. In the nicotine substitution group no significant decreases were seen during the two-week follow-up. The increased level of eicosanoid synthesis detected in smokers in this ex vivo study may contribute to the harmful cardiovascular effects of smoking. Long-term nicotine substitution might diminish the beneficial effects of smoking cessation due to the possible stimulatory effects of nicotine and cotinine on eicosanoid synthesis even in vivo.

Phenols inhibit prostaglandin E2 synthesis in A23187-stimulated human whole blood and modify the ratio of arachidonic acid metabolites.

We have previously demonstrated that the phenolic compounds catechol, hydroquinone, and phenol increase the prostaglandin (PG) E2/leukotriene (LT) B4 ratio in human polymorphonuclear leukocytes (PMNs), while resorcinol has the opposite effect. However, in human whole blood phenols have a different effect on the thromboxane (TX) B2/LT ratio than in PMNs on the PGE2/LTB4 ratio. To establish whether the discrepancy between the results of our previous studies is due to different indicators of prostaglandin H synthase activity in PMNs (PGE2) and in whole blood (TXB2), we measured the effect of phenols on PGE2 synthesis in whole blood. The phenols only inhibited PGE2 synthesis (IC50 values for resorcinol, catechol, hydroquinone, and phenol of 10 microM, 10 microM, 60 microM and 700 microM, respectively). No significant stimulatory activity was seen as earlier in PMNs. Thus, the effect of phenols on PGE2 synthesis in whole blood is different from that in PMNs, although their order of potency to inhibit PGE2 synthesis is the same.

Effects of NO-donors, SIN-1 and GEA 3175 on prostacyclin and cGMP synthesis in cultured rat endothelial cells.

The aim of the present study was to investigate, whether nitric oxide (NO) modifies prostacyclin synthesis in endothelial cells. Two different NO-donors: SIN-1 (3-morpholino sydnonimine) and GEA 3175 (4-aryl-substituted oxatriazol derivative), and the NO-synthesis inhibitor; L-NAME were used. Endothelial cells were incubated with the tested compounds with or without Ca ionophore A23187 stimulation. SIN-1 (> 33 microM) and GEA 3175 (> 1 microM) increased the endothelial cGMP levels independently of A23187 stimulation. SIN-1 did not influence prostacyclin synthesis. GEA 3175 (> 33 microM) increased prostacyclin synthesis up to 2-fold, when incubated without A23187. GEA 3175 with A23187 induced about 30% inhibition in prostacyclin synthesis. L-NAME decreased unstimulated prostacyclin synthesis and this inhibition was reversed by GEA 3175. Obviously NO is able to modulate prostacyclin synthesis, however, much higher concentrations are needed than those to increase cGMP synthesis.

Panaxynol, a polyacetylene compound isolated from oriental medicines, inhibits mammalian lipoxygenases.

Panaxynol is a polyacetylene compound isolated from commonly used oriental medicines, and its effects on various cyclooxygenases and lipoxygenases were investigated. The compound had only a marginal effect on cyclooxygenase activities (IC50 values >> 100 microM), but inhibited lipoxygenases; 5-lipoxygenase (IC50, 2 microM), two isoforms of 12-lipoxygenase (leukocyte-type, 1 microM; platelet-type, 67 microM) and 15-lipoxygenase (4 microM). Thus, panaxynol inhibited leukocyte-type 12-lipoxygenase much more effectively than platelet-type 12-lipoxygenase. Falcarindiol, an analogue of panaxynol, inhibited these lipoxygenases with higher IC50 values than panaxynol. These compounds could provide a clue to develop a selective inhibitor of one isoform of 12-lipoxygenase.

Effects of Trolox C and SIN-1 on arachidonic acid metabolism and on cyclic GMP formation in leukocytes.

The effects of Trolox C (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a vitamin E analogue, (60-900 microM) and SIN-1 (3-morpholino sydnonimine), a nitric oxide donor, (30-3000 microM) on arachidonic acid metabolism and on cyclic GMP formation in calcium ionophore A23187 (calcimycin)-stimulated human polymorphonuclear leukocytes were investigated. Trolox C elicited a dose dependent decrease in leukotriene B4 levels and increase in prostaglandin E2 levels but did not affect cyclic GMP levels. SIN-1 dose dependently inhibited leukotriene B4 and stimulated prostaglandin E2 and cyclic GMP formation. Dibutyryl cyclic GMP did not affect the formation of leukotriene B4 and prostaglandin E2. Trolox C (180 microM), which itself had no effect on cyclic GMP levels, enhanced the effect of SIN-1 (100 microM) on cyclic GMP levels more than 5-fold. The effects of SIN-1 on arachidonic acid metabolism seem to be independent of cyclic GMP and are probably due to nitric oxide. In this experimental model both Trolox C and SIN-1 have similar actions on the prostaglandin/leukotriene ratio, and Trolox C potentiates the SIN-1-induced increase in cyclic GMP levels.

Adrenaline infusion increases systemic prostacyclin production in man.

We have previously shown that adrenaline infusion induces an almost twofold increase in systemic thromboxane synthesis, measured as urinary 11-dehydrothromboxane B2. The purpose of the present study was to investigate whether high levels of adrenaline, found e.g. in heavy physical exercise and myocardial infarction are involved in the regulation of prostacyclin synthesis. To this end the effect of adrenaline infusion (0.1 microgram/kg/min for 45 min and thereafter 0.2 microgram/kg/min for 15 min) on prostacyclin synthesis in healthy male volunteers was investigated. Adrenaline infusion produced an over twofold increase in systemic prostacyclin synthesis, measured as urinary 2,3-dinor-6-keto-prostaglandin F1 alpha. Our study demonstrates that high circulating levels of adrenaline are associated with increased formation of prostacyclin.

Nicotine and cotinine modulate eicosanoid production in human leukocytes and platelet rich plasma.

We investigated the effects of nicotine and cotinine (0.5 nM-0.5 mM) on prostaglandin E2 and leukotriene B4 production in human polymorphonuclear leukocytes and on thromboxane B2 formation in human platelet-rich plasma, stimulated by calcium ionophore A23187. Nicotine and cotinine dose-dependently increased prostaglandin E2 synthesis in polymorphonuclear leukocytes from 25% (0.5 nM) up to nearly four-fold (0.5 mM). In concentrations found in the plasma of smokers, nicotine and cotinine increased prostaglandin E2 production by 33% (50 nM) and 50% (500 nM), respectively. Nicotine and cotinine equipotentially reduced both leukotriene B4 production in polymorphonuclear leukocytes and thromboxane B2 production in platelet rich plasma, the inhibition increasing from 20% (0.5 nM) to 60% (0.5 mM). The stimulation of prostaglandin E2 and inhibition of leukotriene B4 and thromboxane B2 production by nicotine and cotinine may due to the pyridine moiety that these compounds have in common.

Effects of phenols on eicosanoid synthesis in A23187-stimulated human whole blood.

We have previously demonstrated that catecholamines have opposite effects on leukotriene (LT) and prostanoid synthesis. The aim of the present study was to test the effects of phenols (catechol, hydroquinone, phenol and resorcinol) on LTB4, LTE4 and thromboxane (TX)B2 synthesis in A23187-stimulated human whole blood. All tested compounds inhibited LTB4 and LTE4 synthesis. The IC50 values for catechol were 3 microM, 6 microM; for hydroquinone 4 microM, 3 microM; for phenol 285 microM, 226 microM and for resorcinol 180 microM, 902 microM. The compounds did not stimulate TXB2 synthesis but only inhibited it. The IC50 value for catechol was 3 microM, for hydroquinone 7 microM, for phenol 18 microM and for resorcinol 25 microM. Catechol and hydroquinone had hardly any effect on the LT/TX ratio. Phenol and resorcinol even increased the LT/TX ratio. The positions of hydroxyl groups of phenolic compounds are thus important for their actions on the LT/TX ratio.