Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01).

BACKGROUND: Brain metastases (BM) occur in up to 40% of non-small-cell lung cancer (NSCLC) patients. This trial assessed the safety and efficacy of pemetrexed-cisplatin in this population. PATIENTS AND METHODS: Chemonaive NSCLC patients with BM ineligible for (radio)surgery, performance status (PS) of 0 to 2, were eligible for up to six cycles of cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) every 3 weeks. Whole -brain radiotherapy was given in case of disease progression or at chemotherapy completion. Primary end point was objective response rate (RR) on BM. Secondary end points included extracerebral and overall RR, safety profile and survival. RESULTS: Forty-three patients were enrolled. Initial characteristics were mean age 60.4 years; males 29; PS: 0 in 37.2%, 1 in 60.5% and 2 in 22.3% of patients; adenocarcinoma in 36 patients, large cell in 4 patients (nonsquamous, 93%) and squamous carcinoma in 3 patients. Functional classification of neurological status was stage I/II 86.0%, III 2.3% and IV 11.6%. Grade 3-4 hematological toxic effects were neutropenia, 11 patients (febrile neutropenia, 1 patient), and anemia, 6 patients. Non-hematological toxic effects were grade 2 urinary infection, one patient; grade 3 pneumonia, two patients; and grade 3 hypoacousia, one patient. Cerebral, extracerebral and overall RR by intent to treat analysis were 41.9%, 34.9% and 34.9%, respectively. Median survival time and time to progression were 7.4 and 4.0 months, respectively. CONCLUSION: Pemetrexed-cisplatin is an effective and well-tolerated regimen as first-line therapy for NSCLC patients with BM who always suffer a poor prognosis.

[VENISE: Non-invasive ventilation during mechanical ventilation weaning in chronic respiratory failure patients. A prospective randomised controlled and multicenter trial]. / VENISE: VEntilation Non Invasive au cours du SEvrage de la ventilation mécanique des patients insuffisants respiratoires chroniques. Une étude prospective contrôlée randomisée multicentrique.

INTRODUCTION: The clinical efficacy of non-invasive ventilation (NIV) has now been demonstrated in the management of acute-on-chronic respiratory failure (ACRF) in various etiologies. Endotracheal mechanical ventilation (ETMV) can lead to numerous complications and weaning difficulties increasing the risk of prolonged ETMV, morbidity and mortality as well as excess cost of intensive care. Therefore, it could be useful to consider NIV for delivering effective ventilatory support to reduce the length of ETMV in ACRF patients who are still not capable of maintaining spontaneous breathing. From the interesting but discordant results of two recent randomised controlled trials, a working group from the Société de Réanimation de Langue Française (SRLF) decided to perform a new prospective randomised controlled multicenter trial. The aim of the study will be to assess the usefulness of NIV as an extubation and weaning technique in ventilated ACRF patients. METHODS: The methodology used will compare three parallel weaning strategies in ACRF patients considered difficult to wean: invasive conventional weaning (group A), extubation relayed by nasal oxygentherapy (group B), and extubation relayed by NIV (group C). Based on the main end-point defined as the weaning success rate, 208 patients from 17 investigator centers are planned to be included. Results of the study will also allow to assess the respective impact of the three weaning strategies on the length of ETMV and weaning, the mechanical ventilation-related morbidity, the patients lengths of stay and mortality. EXPECTED RESULTS: Results of the VENISE trial should permit to improve the management of the difficult to wean ACRF patients and thus contribute to more precisely define the place of NIV in the weaning and prevention of re-intubation strategies in these patients.

The fibroproliferative response of arterial smooth muscle cells to balloon catheter injury is associated with increased hyaluronidase production and hyaluronan degradation.

Hyaluronan (HA) is a glycosaminoglycan found in greatest amounts in the extra-cellular matrix of loose connective tissue. HA has been shown to be closely involved in arterial smooth muscle cell (ASMC) proliferation and migration. No studies have examined the degradation of HA in the vessel wall during proliferation of ASMC. The aim of our study was to determine whether HA degradation was modulated in the injured rat aorta with a catheter balloon. To evaluate HA degradation we quantified the activity of the enzyme which degrades HA (hyaluronidase) and determined HA molecular mass in the aorta. Aorta was analyzed in sham operated aorta (D0) and 14 (D14) days after injury. Intima-media wet weight and DNA content, a parameters reflecting ASMC response to injury, were significantly increased at D14 (+35.5 and +40.8%). HA increased at D14 (+87%) and was mainly expressed in the neointima. Hyaluronidase activity also increased in the aorta at D14 (+25.5%). In the normal aorta, HA was mainly present in a high molecular mass form (2000 kDa). Two low molecular mass HA were also detected (29 and <20 kDa). At D14, the form of 2000 kDa was dramatically increased in comparison to that in normal aorta. In addition, the injured aorta contained a large number of low molecular mass form of HA. To know whether hyaluronidase production in the injured aorta was associated with appearance of new isoforms, we determined the molecular mass of this enzyme. Only one form of hyaluronidase (78 kDa) was present in both groups (D0 and D14). In conclusion, the proliferative response of ASMC to injury in the rat was found to be associated with increased HA degradation.

Increased hyaluronan and hyaluronidase production and hyaluronan degradation in injured aorta of insulin-resistant rats.

Diabetic patients have a greater incidence of restenosis, which has been shown to be related to exaggerated intimal hyperplasia. Hyaluronan (HA) has been shown to be closely involved in arterial smooth muscle cell proliferation and migration, which provoke intimal hyperplasia after balloon catheter injury. Our aim was to determine the effect of fructose feeding, which produces certain characteristics of non-insulin-dependent diabetes (ie, insulin resistance, hyperinsulinemia, and hypertriglyceridemia), on production of HA and hyaluronidase and degradation of HA in rat aorta. Treated rats received fructose (25% in tap water) 12 weeks before balloon catheter injury and 14 days afterward. Fructose-fed rats had hyperinsulinemia and hypertriglyceridemia. Injury increased intima-media wet weight (7.5%) and DNA content (20%) in control rats. This increase was significantly greater in fructose-fed rats (22% for wet weight and 34% for DNA content) and was associated with greater HA and hyaluronidase production (123% and 41%, respectively) than in control rats (49% and 7%, respectively). Determination of HA molecular mass showed that balloon catheter injury increased the number of HA fragments in the aorta of control rats. Normal aorta of fructose-fed rats contained more HA fragments than that of control rats. Injury to the aorta of fructose-fed rats increased HA fragments and induced the appearance of a very-high-molecular-mass (>2000 kDa) HA. In conclusion, fructose treatment, which induced hyperinsulinemia and hypertriglyceridemia, increased HA and hyaluronidase production and HA degradation in injured aorta. This finding suggests that HA, which has been shown to play a crucial role in proliferation and migration of arterial smooth muscle cells, may be involved in the promotional effect of long-term fructose feeding on arterial wall reaction to injury.

Effects of diabetes and insulin treatment of diabetic rats on hyaluronan and hyaluronectin production in injured aorta.

The present study was conducted to determine the effect of diabetes with and without insulin treatment on the production of hyaluronen (HA) and distribution of hyaluronectin (HN) in the rat aorta 14 days after injury with a catheter balloon. Injury increased intima-media wet weight (+11%) and DNA content (+37.5%). This increase was slightly enhanced in untreated diabetic rats (+14.7% for wet weight and +48.9% for DNA content) and was significantly greater in diabetic rats treated with insulin (+28.9% for wet weight and +54% for DNA content). HA content increase in the injured aorta of nondiabetic rats (+43.6%) was similar in untreated diabetic (+44.7%) and more pronounced in diabetic rats treated with insulin (+91.3%). HA was markedly expressed in the neointima of nondiabetic rats, particularly near the lumen of the aorta. In untreated diabetic rats, HA was present throughout the neointima and not mainly close to the lumen. HA staining in the neointima of diabetic rats treated with insulin was similar to that in nondiabetic rats. HN was strongly expressed throughout the neointima of all groups. Injury enhanced the production of a high molecular mass HN (>400 kDa); this was not observed either in untreated or in insulin-treated diabetic rats. In conclusion, insulin treatment promoted the proliferative response of aorta to injury and this was associated mainly with increased HA production. This finding suggests that HA, which has been shown to play a crucial role in smooth muscle cell proliferation and migration, may be involved in the promoting effect of insulin treatment on arterial wall reaction to injury.

[Role of hyaluronic acid in the arterial response to angioplasty]. / Rôle de l'acide hyaluronique dans la réponse artérielle à l'angioplastie.

Angioplasty has become enormously popular since its introduction in 1979 for the treatment of arterial stenosis at coronary or other sites. The success rate is currently around 95%. Unfortunately, restenosis occurs in 30 to 40% of cases within six months of the procedure. Restenosis is the result of a number of events that are triggered by the angioplasty. These events involve both blood components (platelets, leukocytes, and plasma constituents) and arterial wall components (smooth muscle cells [SMCs], endothelial cells, and the extracellular matrix). Hyaluronate is a high-molecular-weight glycosaminoglycane found in the extracellular matrix of arterial SMCs and endothelial cells. Hyaluronate and its receptors (CD44 and RHAMM or receptor for HA-mediated motility) contribute actively to leukocyte adhesion and infiltration at experimental angioplasty sites. Studies of cell cultures have shown that leukocyte adhesion and migration are inhibited by substances (antibodies, peptides, high levels of hyaluronate) that prevent hyaluronate from binding to CD44 and RHAMM. Hyaluronate expression by arterial SMCs is modulated by the angioplasty-produced arterial lesion. The SMCs that migrate and divide actively at the arterial lesion site are those that express hyaluronate, CD44, and RHAMM. Hyaluronate both stimulates SMC migration via an effect on RHAMM and enhances SMC division via an effect on CD44. In animal studies, administration of high levels of hyaluronate to saturate hyaluronate receptors on leukocytes and SMCs was followed by inhibition of leukocyte infiltration into the damaged arterial wall and by a significant reduction in the arterial neointima. Hyaluronate, a compound with an excellent safety profile, may offer hope for the prevention of restenosis after angioplasty.

Effect of aging on neointima formation and hyaluronan, hyaluronidase and hyaluronectin production in injured rat aorta.

Few studies have examined the effect of aging on arterial wall response to injury, and the results are discordant. Moreover, the effect of aging on hyaluronan synthesis in injured vessels is unknown. The aim of this present study was to determine the effect of aging on neointima formation and hyaluronan (HA), hyaluronidase and hyaluronectin production in injured rat aorta. Aorta was analysed in sham-operated rats (group D0) and 14 (D14) and 28 (D28) days after injury using biochemical and immunohistochemical techniques. Uninjured aorta of old rats was more thickened than that of young rats; it showed a decreased number of arterial smooth muscle cells (ASMC) and was characterized by HA accumulation in the intima and increased hyaluronidase activity. Intima-media wet weight was significantly increased in young rats at D14 and D28 but remained unchanged in old rats. DNA content was significantly enhanced at D14 in both young and old rats. DNA decreased slightly in young rats at D28 but significantly in old rats to return to control level. HA content and hyaluronidase activity in the intima-media were markedly increased in young rats at D14 (+148% and +116% respectively) but slightly in old rats (+23% and +15% respectively). Both HA and hyaluronidase activity continued to increase at D28, but remained more produced in young rats. The immunohistochemical analysis showed the formation of a thickened neointima in young rats, which was associated with strong expression of HA and HN. Neointima of old rats was reduced; it also showed strong expression of HA and HN but their distributions were different from those observed in neointima of young rats. In conclusion, aorta of old rats showed an increased amount of HA in the intima and elevated activity of hyaluronidase. Injury induced formation of a significant neointima in young rats but not in old rats. This was correlated with more HA and hyaluronidase production in injured aorta of young rats. As HA is considered to increase extracellular matrix space and to promote ASMC proliferation and migration, our findings suggest that HA may be implicated in intima thickening with age and after injury.

Hyaluronan and hyaluronectin production in injured rat thoracic aorta.

The aim of our study was to investigate the production of hyaluronan (HA) by the intima-media during the sclerotic response to aortic injury with a catheter balloon in the rat. In addition we analyzed, for the first time in this model, the production of a glycoprotein (hyaluronectin, HN) which binds specifically to HA. HA and HN were analyzed in control (D0), 14 (D14) and 28 (D28) days after injury using biochemical and immunohistochemical techniques. Intima-media DNA content and wet weight increased significantly on D14 and declined on D28 (but remained significantly increased in comparison to controls). HA content (median in D0 = 448 ng) increased significantly on D14 (2P < 0.04) and on D28 (2P < 0.02). HN content (median in D0 = 920 ng) increased significantly on D14 (2P < 0.05) but decreased on D28 to return to the control level. On D0 the amount of HN was about 3 times higher than that of HA (median ratio HA/HN = 0.34). The ratio remained unchanged on D14 but significantly increased on D28 (2P < 0.02). HPLC and Western blotting showed no difference between HN extracted from normal aorta and HN extracted from injured aorta at D14. Different isoforms of HN were present in both cases, ranging from 400 to 45 kDa. The HA increase on D14 and D28 was not related to a change in hyaluronidase activity of aortic tissue. Immunohistochemical analysis showed at D0 a small amount of HA around arterial smooth muscle cells (ASMC) in media, at D14 more HA was localized around and between ASMC in media and neointima but at D28 it was localized mainly near the vessel lumen. HN formed all the time (D0, D14 and D28) a continuous layer localized near the vessel lumen. In vitro studies showed that production of HA and HN was stimulated when ASMC proliferate and HA at high concentrations (1-100 micrograms/ml) reduced, in a dose dependent manner, ASMC growth. In conclusion our results show that both neointima formation in vivo and ASMC proliferation in vitro correlated with increased HA and HN production. This suggests that HA and HN are probably involved in the formation of neointima. On the other hand, the finding that HA continued to increase in the aorta when neointima decreased and that high concentrations of HA reduce ASMC proliferation in culture suggest that HA might be involved in the regression of neointima.

Targeting platelets containing electro-encapsulated iloprost to balloon injured aorta in rats.

Drugs can be electro-encapsulated within platelets and targeted to damaged blood vessels by exploiting the platelet's natural haemostatic properties to adhere to collagen and other vessel wall constituents revealed by injury. A rat aorta balloon angioplasty model has been used to study the effect on platelet deposition of giving iloprost loaded platelets i.v. during the balloon injury. After labelling the circulating platelets with 111-Indium before balloon injury, time course studies showed maximum platelet deposition on the injured aorta occurred at about 1 h post-injury and the deposition remained stable over the next 2-3 h. When iloprost-loaded platelets were given i.v. during injury and the circulating platelet pool labelled with 111-Indium 30 min later, platelet deposition, measured at 2 h postinjury, was substantially and significantly reduced compared with control platelet treatment. Some anti-proliferative effects of iloprost-loaded platelets given i.v. during injury have also been observed. Whereas the incorporation of [3H]-thymidine into aorta intima-media DNA at 3 days post injury was 62-fold higher in balloon injured rats than in control sham operated rats, thymidine incorporation into intima/media of rats which had received iloprost loaded platelets during injury was reduced as compared with rats subjected only to the injury procedure. The reduction was only of near significance, however, but at 14 days after injury the total DNA content of the aorta intima/media of rats given iloprost loaded platelets during injury was significantly reduced. Although iloprost loaded platelets can clearly inhibit excessive platelet deposition, other encapsulated agents may have greater anti-proliferative effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of heparinoids on the sclerotic reaction of rat thoracic aorta to injury: comparison between standard and low-molecular-weight heparins in vitro and in vivo.

To assess further the influence of heparinoids on arterial sclerosis, we compared the effects of standard heparin and of a low-molecular-weight (low-mol-wt) heparin (CY 216) in vitro on proliferation of cultured arterial smooth muscle cells (SMC) from rat aorta and in vivo on the sclerotic response of rat thoracic aorta to injury with a balloon catheter (SMC proliferation and deposition of elastin and collagen in the intima-media, using biochemical and histomorphologic techniques). Both heparinoids decreased replication of SMC in vitro in a similar dose-dependent manner. In vivo, heparin treatment [continuous intravenous (i.v.) administration, 60 IU/h/kg body weight (0.35 mg/h/kg)] inhibited all aspects of the aortic reaction for < or = 28 days after injury: synthesis of DNA (early peak of thymidine incorporation into DNA on D3.5); accumulation of DNA, collagen and elastin on D14 and D28; intimal thickening on D14. An equivalent treatment with CY 216 [60 antiactivated factor X (Xa) IU/h/kg (0.71 mg/h/kg)] exerted similar though less intense effects on the reaction of intima-media, as assessed biochemically, but reduced formation of neointima in a proportion nearly identical to that of heparin. In some respects, which appear to be related mainly to the fibrotic reaction of aortic media to injury, heparin tended to be a slightly more potent antisclerotic agent than CY 216 although, owing to pharmacokinetic differences, CY 216 had stronger plasma anti-Xa activity than heparin.

Effect of ramipril, an inhibitor of angiotensin converting enzyme, on the response of rat thoracic aorta to injury with a balloon catheter.

We have studied the effect of ramipril (10 mg/kg daily by gastric gavage) on the development of neointima 2 and 14 days after injury to rat aorta with a balloon catheter. In treated animals, there was no significant inhibition of the early mitotic reaction after injury (synthesis of DNA, as reflected by aortic thymidine incorporation on the second day): the mean (95% confidence interval) was 3,553 (892) in the control group vs. 2,853 disintegrations/min/micrograms of DNA (555) in the treated group, 2 p greater than 0.15. However, ramipril decreased the amount of neointima formed 14 days after injury, as characterized by (a) a highly significant decrease of the intima to intima + media areas ratio [21.1 (2.4) vs. 13.7% (2.2), 2 p less than 10(-4]); (b) a significant decrease of intima-media wet weight [35.4 (1.0) vs. 30.9 mg (0.9), 2p less than 0.005]; and (c) without any significant effect on intima-media DNA content [96.3 (7.9) vs. 91.7 micrograms (5.7), 2p greater than 0.3]. These observations suggest that angiotensin converting enzyme inhibitors may not act mainly through an inhibition of smooth muscle cell proliferation. Other effects, such as inhibition of migration, hypertrophy, and matrix synthesis, should also be considered.