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Summary The present work reports the synthesis of a series of compounds structurally related to the antiinflammatory and antihistaminic agent nimesulide (I), in which the p-nitrophenyl moiety has been replaced by pyridine (1a-c) and pyridine N-oxide (2a-c). In addition, two compounds (3a, 4a) have been synthesized in which the p-nitro group of I was substituted by a cyano and a iH-tetrazol-5-yl group, respectively. Representative 1a and 2a were also modified by replacing the methanesulfonamido group with an acetamido group (5a, 6a). The pharmacological evaluation of compounds 1-6 in comparison to I, indicates that such modifications are detrimental to the activity. Moreover 3a and 4a caused bronchoconstriction and hypotension, thus behaving as histaminic-like rather then antihistaminic agents.

OBJECTIVE: To investigate the pattern of care and outcomes for newly diagnosed glioblastoma in Italy and compare our results with the previous Italian Patterns of Care study to determine whether significant changes occurred in clinical practice during the past 10 years. METHODS: Clinical, pathological, therapeutic, and survival data regarding 1059 patients treated in 18 radiotherapy centers between 2002 and 2007 were collected and retrospectively reviewed. RESULTS:Most patients underwent both computed tomography and magnetic resonance imaging either preoperatively (62.7%) or postoperatively (35.5%). Only 123 patients (11.6%) underwent a biopsy. Radiochemotherapy with temozolomide was the most frequent adjuvant treatment (70.7%). Most patients (88.2%) received 3-dimensional conformal radiotherapy. Median survival was 9.5 months. Two- and 5-year survival rates were 24.8% and 3.9%, respectively. Multivariate analysis showed the statistical significance of age, postoperative Karnofsky Performance Status scale score, surgical extent, use of 3-dimensional conformal radiotherapy, and use of chemotherapy. Use of a more aggressive approach was associated with longer survival in elderly patients. Comparing our results with those of the subgroup of patients included in our previous study who were treated between 1997 and 2001, relevant differences were found: more frequent use of magnetic resonance imaging, surgical removal more common than biopsy, and widespread use of 3-dimensional conformal radiotherapy + temozolomide. Furthermore, a significant improvement in terms of survival was noted (P < .001). CONCLUSION: Changes in the care of glioblastoma over the past few years are documented. Prognosis of glioblastoma patients has slightly but significantly improved with a small but noteworthy number of relatively long-term survivors.

Psoas abscess following spine surgery is a rare condition that can be overlooked or delayed as a result of its vague clinical manifestations. Gone unchecked, it can lead to severe morbidity and even death. We present a 71-year-old female patient who developed bilateral psoas abscess immediately following L2 through S1 posterior instrumented fusion. The patient underwent CT-guided percutaneous drainage of the bilateral psoas abscess and blood cultures revealed methicillin-resistant Staphylococcus aureus (MRSA) sensitive to vancomycin. Following surgical re-exploration, debridement and removal of part of the instrumentation, the patient received antibiotic treatment for 12 weeks and at 1-year follow-up the patient continues asymptomatic.

Hydrogen sulphide (H(2)S) is an endogenous gaseous mediator active in the multilevel regulation of pathophysiological functions in mammalian cardiovascular tissues.This study investigated the pharmacological activity of a new H(2)S-releasing derivative of diclofenac, S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) in the isolated rabbit heart submitted to low-flow ischaemia-reperfusion damage.S-diclofenac (3, 10 and 30 microM), despite inhibiting prostacyclin generation by cardiac tissues, achieved dose-dependent normalization of coronary perfusion pressure, reducing left ventricular contracture during ischaemia and improving left ventricular developed pressure and +/-dP/dt(max) at reperfusion. Creatine kinase and lactate dehydrogenase activities in heart perfusates were significantly reduced during reperfusion. These effects were accompanied by substantial release of reduced glutathione (GSH), indicating that the H(2)S moiety may have up-regulated cysteine transport. The anti-ischaemic activities of S-diclofenac and the H(2)S-donor sodium hydro sulphide (NaHS) were partially prevented by the K(ATP) channel antagonist glibenclamide, suggesting a mechanism similar to H(2)S-induced cardioprotection in metabolic ischaemic preconditioning. Perfusion with the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine worsened the myocardial ischaemia-reperfusion damage, but this was dose-dependently prevented by S-diclofenac and NaHS, suggesting that the released H(2)S may have overcome NO deficiency.These data show that S-diclofenac had marked anti-ischaemic activity in ischaemic-reperfused rabbit hearts despite inhibition of prostaglandin generation. Increased GSH formation leading to activation of K(ATP) channels may have contributed to this beneficial effect. The pharmacological profile of S-diclofenac and its anti-inflammatory activity, with diminished gastrointestinal side effects, offer therapeutic applications in cardiovascular disease.

Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by N -nitro-L-arginine methyl ester (L-NAME) in the rat.Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg-1day-1 for four weeks, either alone or with L-NAME (35-40 mg kg-1 day-1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1alpha, thromboxane B2, 8-isoprostane-prostaglandin F2 and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia-reperfusion, and myocardial levels of guanosine 3', 5'cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings.Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2alpha and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it.In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels.

Since the early 1970s, increasing evidence has suggested that the consumption of moderate amounts of alcohol is inversely correlated with mortality from myocardial infarction. There is also some evidence that the protective effects of wine might be more pronounced than those of other alcoholic beverages. These observations prompted us to investigate the cardioprotective activity of Vitis vinifera seeds in experimental ischemia-reperfusion injury. An isolated rabbit heart preparation paced electrically was used to evaluate the effects of a highly purified, high molecular weight fraction of oligomeric procyanidins isolated from Vitis vinifera seeds on myocardial reperfusion injury after 40 min of low-flow (1 ml/min) ischemia. Infusion of the heart with 100 or 200 microg/ml procyanidins dose-dependently reduced left ventricular end-diastolic pressure during ischemia, decreased coronary perfusion pressure, improved cardiac mechanical performance upon reperfusion, increased the release of 6-Keto-prostaglandin F1alpha into the perfusate in both the preischemic and the reperfusion periods and suppressed rhythm irregularity. Procyanidins dose-dependently relaxed human internal mammary aortic (IMA) rings (with intact endothelium) precontracted with norepinephrine. This effect was completely abolished in IMA-rings without functional endothelium or when this vascular tissue was pretreated with nitric oxide synthase inhibitor (NG-monomethyl-L-arginine) or with guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). In conclusion, these results indicate that procyanidins could be of therapeutical potential in cardiovascular diseases. However, further investigations are required for a better definition of the mode of action of these oligomers.

Background: The initial studies on nitrosoureas were performed >30 years ago. These drugs remain the standard chemotherapy for glioblastoma. However, because the criteria used to evaluate the activity of nitrosoureas in a neuro-oncologic setting have changed, new data on their activity are needed. Methods: The authors conducted a phase II study on 40 patients with recurrent glioblastoma following surgery and standard radiotherapy. They analyzed progression-free survival at 6 months (PFS-6), time to progression (TTP), response rate, and toxicity. Patients were treated with 80 mg/m 2 carmustine on days 1 to 3, every 8 weeks for a maximum of six cycles. Results: Median TTP was 13.3 weeks (95% CI, 10.26 to 16.86 weeks), and PFS-6 was 17.5% (95% CI, 8.9 to 34.3). Response to chemotherapy, age ≤40 years, and performance status ≥90 were significant prognostic factors for TTP; however, with multivariate analysis, only response to chemotherapy was significant. The major side effects were reversible hematologic and long-lasting hepatic and pulmonary toxicity. Conclusion: The activity of this BCNU regimen is comparable with that reported in the past and with the newest therapies, such as temozolomide. However, BCNU toxicity is high and recovery is slow, thus compromising the administration of further drugs in patients with progressive disease.

Purpose To assess in a prospective trial the value of prognostic factors and the outcome of medulloblastoma in adults. Methods and materials Patients (≥18 years) with a histologic diagnosis of medulloblastoma were staged according to Chang et al. 's classification (low risk: T1, T2, T3a, M0, and no residual disease after surgery; high risk: T3b–T4, any M+ or postoperative presence of residual tumor). In low-risk patients, treatment consisted of 36 Gy to the craniospinal axis, supplemented by a local tumor dose of 18.8 Gy (total dose of 54.8 Gy). In high-risk patients, 2 cycles of “up-front chemotherapy” were delivered before the same radiation therapy, followed by maintenance chemotherapy if M1, M2, or M3 disease was present. Results Over a 12-year period, 36 evaluable patients were enrolled. Progression-free survival (PFS) at 5 years was higher in low-risk patients compared to the high-risk group: 76% ± 14% (95% confidence interval [CI] = 52%–100%) vs. 61% ± 11% (95% CI = 42%–87%). Patients with M− disease showed a significantly better outcome than M+ patients, with 75% showing PFS at 5 years vs. 45% ( p = 0.01). Conclusions The overall PFS observed is comparable to that obtained in pediatric series and suggests that a more effective therapy must be developed for high-risk patients.

Objectives: To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. Methods: Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m2/daily for 5 days every 4 weeks. Results: The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14–42%) and 8% (CI = 2–27%), respectively, with a median TTP of 11.7 weeks (CI = 9–22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7–31%). Conclusion: TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM.

Aim: The efficacy of temozolomide(TMZ) plus radiation therapy(RT) in elderly patients(EP) with glioblastoma(GBM) is unclear. We describe our experience of combining RT with concurrent TMZ in EP. Methods: Medical records of patients ≥65 years old with newly GBM, histologically confirmed and treated at Venetian Institute of Oncology – Padua, were reviewed. Concomitant TMZ was 75mg/m2/die. The adjuvant treatment consisted of TMZ 150-200mg/m2/die for six cycles. Results: We analyzed 67 consecutive patients(PTS), 35 males and 32 females; the average age was 71 (range 65-86); ECOG PS was 0-1 in 37 PTS and 2-3 in 30 PTS; complete surgery was performed in 41 PTS, partial surgery in 24 PTS. MGMT was analyzed in 46 PTS: methylated(met) MGMT in 21 PTS (46%). 36 PTS were treated with RT 40Gy in 15 fractions, 23 PTS with RT 60Gy in 30 fractions, 8 PTS with only TMZ. For all PTS, PFS and OS was 7 and 12.4 ms, respectively. PFS was 7.2 vs 6.7 ms (p = 0.5), OS was 11.9 vs 13.8 ms (p = 0.3), for PTS treated with RT 40Gy and 60Gy, respectively. PFS was 7.2 vs 4.5 ms (p = 0.04), OS was 13 vs 7.3 ms (p Conclusions: RT plus TMZ is effective and safe in EP with GBM. RT + TMZ treatment seems more effective than only TMZ. PFS and OS were not statistically different between RT 40Gy or 60Gy. RT + TMZ treatment and met MGMT were independent predictors of longer survival. In contrast, severe haematological toxicity was higher in PTS with RT + TMZ compared to TMZ alone. Disclosure: All authors have declared no conflicts of interest.

NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.

A new family of nitroderivatives of conventional non-steroidal anti-inflammatory drugs capable of releasing nitric oxide has been synthesized. Among these compounds, a nitroderivative of aspirin (NCX 4016), which displays antiplatelet and vasodilating activities, appears to have clinical potential in cardiac pathology related to coronary insufficiency.In this study the beneficial effects of NCX 4016 and aspirin were evaluated in vitro in a model of myocardial ischemia-reperfusion of the rabbit and in vivo in a model of acute myocardial infarction of the same animal species.The NCX 4016 (from 1 x 10(-5) M to 3 x 10(-4) M) caused dose-dependent cardiac protection in isolated rabbit hearts subjected to low flow ischemia-reperfusion. Inhibition of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) generation and proportional reduction of creatine kinase (CK) activity at reperfusion was observed. Aspirin (1 x 10(-4)M) markedly worsened the post-ischemic ventricular dysfunction and this event was paralleled by a 63% increase in CK activity and abolition of 6-keto-PGF1alpha formation. Perfusion of the hearts with NG-monomethyl-L-arginine (1 x 10(-5) M) worsened the ischemia-reperfusion damage in perfused hearts. This event was prevented by prior treatment with NCX 4016 (1 x 10(-4) M) but not with aspirin (1 x 10(-4) M). Ligation of the first antero-lateral branch of the left coronary artery in rabbits resulted in acute myocardial infarction with a mortality rate of 60% at 24 hours. NCX 4016 (0.5 mg/kg/min for 2 hours) significantly reduced the mortality rate by 10%, protected the rabbits against electrocardiogram derangement and almost abolished CK activity in plasma and myeloperoxidase activity in cardiac tissue. Aspirin was devoid of any protective activity.In the rabbit NCX 4016 appears to exert a relevant cardioprotection likely mediated by nitric oxide donation. These results suggest that this nitroderivative of aspirin may lead to innovative therapy in myocardial ischemia and infarction.

This study investigates the microvascular permeability changes in tracheal tissue of rats exposed to hyperbaric oxygen (HBO). Rats, following exposure to HBO or ambient air (control animals) for 1.5, 3 and 6 h, were prepared for recording of nitric oxide exhaled (FENO) in air using a chemiluminescence analyser. The level of FENO was not statistically different in the two groups. Plasma exudation, evaluated by measuring the leakage of Evans blue (EB) dye into the tracheal tissue, was significantly elevated (48, 86 and 105% at 1.5, 3 and 6 h, respectively) in HBO-treated rats. Plasma exudation in the trachea of control rats was significantly increased (42%, P0.05) by NG-nitro-L-arginine methyl ester (L-NAME), whereas it was significantly reduced (31%, P0.05) in rats exposed to HBO for 3 h. N-acetylcysteine (NAC) and flunisolide significantly prevented the increase in plasma leakage in HBO-treated rats. In contrast, indomethacin was devoid of anti-exudative activity in these experiments. Western immunoblot showed a significant increase in the level of inducible nitric oxide synthase (iNOS) protein in the tracheal homogenates of HBO-treated rats, as compared to basal levels. These results indicate that nitric oxide (NO) is involved in the maintenance of microvascular permeability in tracheal tissue of rats. The protective effect observed with the steroid seems to support this hypothesis. Furthermore, the beneficial action of NAC underlines that reactive oxygen species participate in the microvascular permeability changes observed in tracheal tissue of rats exposed to HBO.

PURPOSE: A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP). PATIENTS AND METHODS: Fifty-three patients were treated with procarbazine in repeated 30-day courses at 100 mg/m2/d plus tamoxifen 100 mg/d, with a 30-day interval between courses. Thirty-four patients had been pretreated with a first-line nitrosourea-based chemotherapy regimen (group A), and 19 patients had also been pretreated with a second-line chemotherapy regimen consisting of carboplatin and teniposide (group B). Twenty-one of the patients had also been procarbazine pretreated, whereas the remaining 32 patients were not procarbazine pretreated. RESULTS: The response was assessed in 51 patients, 28 of whom had glioblastoma multiforme (GBM) and 23 of whom had anaplastic astrocytoma (AA). There were two complete responses (CR) (4%) and 13 partial responses (PR) (25.5%). The overall response rate (CR + PR) was 29.5% (SE, 6.4; 95% confidence interval [CI], 23 to 35.8). Seventeen patients (32%) had stable disease (SE, 6.2; 95% CI, 21 to 33.6). The median TTP was 13 weeks for patients with GBM and 33 weeks for patients with AA (P = .006). The median survival time (MST) was 27 weeks for patients with GBM and 57 weeks for those with AA (P = .006). CONCLUSION: Combined PCB and tamoxifen as a second-line regimen gave a reasonably high response rate in patients with heavily pretreated high-grade gliomas. However, although it resulted in an improvement in the patients' quality of life and/or performance status, it was not followed by an increased TTP or MST.

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 microg/kg sc), given for 7 days, prevented exacerbation of the ischemia-reperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 microg/kg sc) produced similar results, whereas administration of EP 51389 (80 microg/kg sc), another GH-releasing peptide that does not bind to the heart, was ineffective. In conclusion, we demonstrate that hexarelin prevents cardiac damage after ischemia-reperfusion, and that its action is not mediated by GH but likely occurs through activation of specific cardiac receptors.

1. Starting from the structure of an old 4-oxystilbene derivate with ganglioplegic activity (MG624), we synthesized two further derivates (F2 and F3) and two stereoisomers of F3 (F3A and F3B), and studied their selective effect on neuronal nicotinic acetylcholine receptor (AChR) subtypes. 2. MG 624, F3, F3A and F3B inhibited of 125I-alphaBungarotoxin (alphaBgtx) binding to neuronal chick optic lobe (COL) membranes, with nM affinity, but inhibited 125I-alphaBgtx binding to TE671 cell-expressed muscle-type AChR only at much higher concentrations. 3. We immobilized the alpha7, beta2 and beta4 containing chick neuronal nicotinic AChR subtypes using anti-subunit specific antibodies. MG 624, F3, F3A and F3B inhibited 125I-alphaBgtx binding to the alpha7-containing receptors with nM affinity, but inhibited 3H-Epi binding to beta2-containing receptors only at very high concentrations (more than 35 microM); their affinity for the beta4-containing receptors was ten times more than for the beta2-containing subtype. 4. Both MG624 and F3 compounds inhibited the ACh evoked currents in homomeric oocyte-expressed chick alpha7 receptors with an IC50 of respectively 94 and 119 nM. 5. High doses of both MG 624 and F3 depressed the contractile response to vagus nerve stimulation in guinea pig nerve-stomach preparations although at different IC50s (49.4 vs 166.2 microM) The effect of MG624 on rat nerve-hemidiaphragm preparations was 33 times less potent than that of F3 (IC50 486 vs 14.5 microM). 6. In conclusion, MG624 and F3 have a high degree of antagonist selectivity for neuronal nicotinic alphaBgtx receptors containing the alpha7 subunit.

The ability of hexarelin, a recently synthesized hexapeptide with a remarkable growth hormone (GH)-releasing activity, to reverse signs of cardiovascular dysfunction in GH-deficient animals was studied in young male rats made GH deficient by the administration of an anti-GH-releasing hormone serum (GHRH-Ab) for 20 days. Heart preparations from GHRH-Ab treated rats, subjected to low-flow ischemia and reperfusion, showed: a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion as compared to control hearts; a decreased rate of formation of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, in perfusates of both preischemic and reperfusion period; an increased vasopressor activity of angiotensin II on the coronary vasculature. The endothelium-dependent relaxing function in GH-deficient rats was also evaluated in aortic ring preparations, which showed: a decreased rate of formation of 6-keto-PGF1 alpha, an hyperreactivity to endothelin-1, a markedly reduced vasopressor response to NG-monomethyl-L-arginine (the nitric oxide synthase inhibitor) and a decreased vasodilator response to acetylcholine of precontracted aortic tissue. Hexarelin (80 micrograms/kg, s.c. twice daily), administered for 15 days to GHRH-Ab-treated rats, fully restored the somatotropic function and reversed all the signs of cardiac and endothelial dysfunction. In fact, in heart preparations from rats treated with hexarelin the trend of the ischemic damage was similar to that observed in control rats and both the rate of formation of 6-keto-PGF1 alpha and the vasopressor activity of angiotensin II were reverted to control levels. Furthermore, all the parameters of endothelial function were in the normal range. These results indicate that GH deficiency in rats is responsible for an impairment of cardiac function that is associated with a damage of the endothelium-dependent relaxing function not limited to coronary vessels but widespread in the circulation. These alterations are fully reverted by an in vivo treatment with hexarelin.

The methane combustion properties of barium hexaaluminate supported Pd catalysts are compared with those of an alumina supported one. Combustion tests over catalysts calcined at 1000°C show that hexaaluminate-supported systems posses lower activity than the alumina-supported one. Tests performed upon treatment under reaction conditions show that marked deactivation occurs to the hexaaluminate based materials. XRD characterization indicate that the lower combustion activity of barium hexaaluminate-based catalysts is associated with the lower dispersion of Pd species on these supports.

Despite the reduction in the incidence of brain metastases following prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC), the use of this modality is still controversial due to the lack of improvement in survival and the appearance of neurotoxicity in long-term survivors. Moreover, the optimum dose, fraction size, and timing are not known. From 1980 to 1988, 70 patients with limited stage SCLC underwent PCI after or during multimodality treatment of their primary tumor. Most of these patients (75.7%) received an unconventional ultrarapid high-dose course of 17 Gy in two fractions over 3 days. Long-term (range 60-138 months) survivors (n = 16) were invited to have a complete neurological evaluation including computed cranial tomography (CCT), 99mTc-HMPAO single photon emission computerized tomography (SPECT) scan, electroencephalography (EEG), magnetic resonance imaging (MRI), and neuropsychometry. Delayed neurologic complications or psychometric impairment was observed in 46% of patients. One or more abnormalities were detected by CCT in all patients, and the presence of neurologic complications seemed to correlate with periventricular and subcortical white matter changes. A strong correlation was found between CCT and SPECT periventricular white matter changes. Although the incidence of late neurologic toxicity following this rapid course of irradiation was high, clinical findings were less severe than expected, and all the patients were capable of self-care.

A prospective study of a series of 77 patients on adjuvant radiochemotherapy following surgery for high-grade gliomas was conducted to evaluate the risk of deep vein thrombosis and identify risk factors. We found a 20.8% risk of deep vein thrombosis at 12 months (standard error = 4.8%) and a 31.7% risk (standard error = 7.4%) at 24 months (Kaplan-Meier method). Twenty patients (26%) developed deep vein thrombosis with a maximum incidence within the first 7 months after surgery when chemotherapy was still being administered, often with corticosteroids. The risk factors identified were histology (glioblastoma versus anaplastic astrocytoma, P = 0.032, log rank test; 0.0485 L-ratio) and the presence of paresis (P = 0.010, log rank test; 0.0161 L-ratio). A borderline tendency was found for an association between the deep vein thrombosis site and the side of paresis (P = 0.103, Fisher's exact test). Four patients (5%) had massive pulmonary embolism, which was fatal in 3 (4%).

A Phase II study with a combination of BCNU and alpha-interferon (IFN) was conducted in patients with high-grade glioma recurrent after surgery and radiation treatment in order to investigate tumor control and toxicity. Twenty-one non-chemotherapy pretreated patients were administered 6 MU alpha-IFN in a 2-h infusion followed by 150 mg/m2 BCNU i.v. on day 1. Three MU alpha-IFN were subsequently administered subcutaneously on alternating days three times a week, until recycling of the whole procedure on day 42. Among 21 patients, partial remission was obtained in 7 (33%; 95% CI = 15-57) and stable disease in 6 (29%; CI = 11-52); overall Kaplan-Meier median time to progression (TTP) was 4.5 months (CI = 4-9) and the overall median survival time (MST) was 7 months (CI = 5-13). In patients who underwent surgical redebulking prior to chemotherapy, TTP and MST were 9 (CI = 7-14) and 15 months (CI = 11.0-39.0); in patients who were not operated on again before chemotherapy, these values were 4 (CI = 2-5; log rank test, p = 0.0026) and 5.5 months (CI = 4-7; log rank test, p = 0.0012) respectively. The results of this regimen in relapsing patients, especially following surgical redebulking, are encouraging; toxicity is acceptable, and further studies on combined alpha-IFN and multiple-agent chemotherapy are warranted.

Rats were exposed to hyperbaric oxygen (HBO = 100% oxygen; 2.5 atmospheres absolute pressure) for 6 h. Isovolumic left heart preparations from these animals were subjected to global low flow-ischemia (perfusion rate from 12 ml/min to 2 ml/min for 40 min) and reperfusion. Hearts from rats not exposed to HBO underwent the same ischemic-reperfusion procedure (controls). As compared to control, HBO treatment caused in ex vivo hearts a significant aggravation of cardiac ischemic picture as indicated by a marked increase in left ventricular end diastolic pressure (LVEDP) and reduced post ischemic left ventricular developed pressure (LVDP). At the end of the ischemic and reperfusion periods LVEDP values were 6.8 (p0.001) and 8 (p0.001) times higher than the corresponding control values. Moreover, LVDP and coronary perfusion pressure (CPP) values were decreased (2.8 times; p0.001) and increased (56%; p0.001), respectively, as compared to control preparations. These events were also associated with a considerable impairment of the cardiac tissue to generate 6-keto-PGF1 alpha. Treatments of rats with different doses of acetylcysteine (N-acetylcysteine, CAS 616-91-1, NAC; 0.25-0.5-1 g/kg p.o.) before HBO displayed a clear-cut and dose-related protective activity in hearts subjected to ischemia-reperfusion. Also the generating capacity of 6-keto-PGF1 alpha from these hearts were restored according to the dose of NAC employed. When aortic rings from rats exposed to HBO were considered, they showed a reduced capacity to release 6-keto-PGF1 alpha and an increased sensitivity to endothelin-1. At the same time, the relaxant activity of acetylcholine in these tissues was almost lost. Again, NAC treatment of the animals before HBO restored in a dose-dependent way the capacity of the aortic rings to generate 6-keto-PGF1 alpha. This event was paralleled by normalized responses of the preparations to endothelin-1 and acetylcholine. Taken together these results clearly indicate that acute HBO treatment of the rats markedly aggravates the ischemic-reperfusion damage in ex vivo hearts. This event is coupled with a compromised integrity of cardiac and extracardiac endothelial cell functions. The protective activity of NAC observed in this study once more emphasises its therapeutic role in increasing antioxidant defence mechanisms.

1. We have studied the role of nitric oxide (NO) in the regulation of the transcellular biosynthesis of sulphidopeptide leukotrienes (cys-LT) generated upon neutrophil-vascular wall interactions and their functional consequences, in the spontaneously beating, cell-perfused, heart of the rabbit. 2. Hearts were perfused under recirculating conditions (50 ml) with 5 x 10(6) purified human neutrophils (PMNL), and challenged with 0.5 microM A-23187 for 30 min. Coronary perfusion pressure (CPP) and left-ventricular end-diastolic pressure (LVEDP) were monitored. Cys-LT formation was measured by reversed phase high performance liquid chromatography (h.p.l.c.) and u.v. spectral analysis. Myeloperoxidase (MPO) enzyme activity, assayed in aliquots of the recirculating buffer, was used as a marker of PMNL, adhesion to the coronary endothelium. 3. Basal CPP and LVEDP values averaged 45 +/- 1.4 mmHg and 5 +/- 0.1 mmHg, respectively; A-23187 triggered an increase in CPP (134 +/- 9 mmHg, at 30 min) which was significantly attenuated by pretreatment with L-arginine, 100 microM (90 +/- 3 mmHg, at 30 min). Pretreatment with NG-monomethyl-L-arginine, 10 microM (L-NMMA), induced a marked increase in CPP (290 +/- 40 mmHg, at 20 min) and in LVEDP (47 +/- 16 mmHg), so pronounced that it caused cardiac arrest in systole in 5 out of 6 hearts and these were prevented by L-arginine, 100 microM, (CPP 115 +/- 10 mmHg, LVEDP 6 +/- 1.1 mmHg, at 30 min). 4. The increase in CPP was accompanied by the release of cys-LT in the circulating buffer, which was reduced significantly by L-arginine. Pretreatment with L-NMMA, caused a marked rise in cys-LT concentrations which was prevented by L-arginine. 5. Neither L-arginine nor L-NMMA affected directly the A-23187-induced arachidonic acid (AA) metabolism in isolated PMNL alone. 6. Pretreatment with L-NMMA caused a prompt drop in myeloperoxidase (MPO), activity, suggesting rapid adhesion of PMNL to the coronary wall; this effect was significantly blunted by L-arginine. 7. This study suggests that NO provides cardioprotection in an organ model of transcellular metabolism of cys-LT by preventing PMNL adhesion to the coronary intima.

Goodpasture's disease is characterized by lung haemorrhage, associated with glomerulus basement membrane antibody glomerulonephritis, and circulating basement membrane antibody. Other diseases (Wegener, LES, arteritis) may have the same kidney and lung involvement. The Authors present a clinical case of rapidly progressive renal failure where renal biopsy showed an extensive extracapillary proliferative glomerulonephritis with linear deposits of antibody in the basement membrane, similar to Goodpasture's disease, with following lung involvement, but without hemoptysis and in absence of circulating antiglomerular basement membrane antibody. The Authors think it could be a case of Goodpasture's disease, even if it did not show the above-mentioned symptoms, whether out of the characteristic clinical course or the exclusion of all the other diseases. The Authors believe that the absence of circulating basement membrane antibody could be due to their sediment in the target organs and suggest a revision of the standards required for the Goodpasture's disease diagnosis.

2043 Background: the optimal management of EP with GBM remains controversial. The role of RT with TMZ for EP is unclear, and EP are often treated with RT alone, TMZ alone or palliative approaches. We describe our experience of combining RT with concurrent TMZ for treatment of EP with GBM Methods: medical records of patients ≥65 years old with newly GBM, histologically confirmed at Veneto Institute of Oncology – Padua, and treated with RT plus TMZ, were reviewed. Concomitant TMZ was 75mg/m2/die. The adjuvant treatment consisted of TMZ 150-200mg/m2/die for six cycles. Median progression-free survival(PFS) and overall survival(OS) were estimated with Kaplan-Meier method. Toxicity was scored according to CTCAE 4.0 Results: we analyzed 60 patients(PTS), 34 males and 26 females; the average age was 70 (range 65-82); ECOG PS was 0-1 in 35 PTS and 2 in 25 PTS; complete surgery was performed in 35 PTS, partial surgery in 25 PTS. 40 and 20 PTS received RT within 6 or more weeks (range 7-9) from surgery. MGMT and IDH1 were analyzed in 43 PTS: MGMT methylated in 20 PTS (46%), all PTS had wild-type IDH1. 34 PTS were treated with RT 40Gy in 15 fractions, 26 PTS with RT 60Gy in 30 fractions with no significant difference in ECOG PS, MGMT and type of surgery between the two subgroups. For all PTS, PFS and OS were 9.5 and 12.7 ms, respectively. OS was 13.7 and 12.4 ms (p=0.9) in PTS receiving RT within 6 or more weeks from surgery, respectively. 13% of PTS showed grade 3-4 haematological toxicity, 12% grade 3-4 asthenia, 3% nausea/vomiting. MGMT methylated and complete surgery was associated with a longer survival. PFS was 9 vs 10 months (p=0.4) and OS was 11.7 vs 13.7 ms (p=0.1), for PTS treated with 40Gy and 60Gy, respectively. Regarding toxicity: grade 3-4 haematological toxicity was 9% vs 23%, severe asthenia was 9% vs 15%, nausea/vomiting was 3% vs 4% of PTS receiving RT 40Gy and 60Gy, respectively. Conclusions: RT plus TMZ is effective and safe in EP with GBM and good ECOG PS. PFS and OS was not statistically different between PTS receiving RT 40Gy or 60Gy, although we showed a trend for longer OS with RT 60Gy; in contrast, severe toxicity was higher in PTS with RT 60Gy. OS was similar between PTS receiving RT within 6 or more weeks (7-9ws) from surgery.

The poor results from treatment of high grade glioma prompted us to explore new protocols involving concurrent radio-chemotherapy. Our primary objective was to evaluate the feasibility of very early postoperative chemotherapy with BCNU, concurrent radio-chemotherapy with carboplatin and teniposide, and post-radiotherapy BCNU. Our secondary objectives were to evaluate time to progression, and overall survival.We treated 24 newly diagnosed patients (pts) with BCNU 150 mg/m2 seven days after surgery. Thirty days later, we started radiotherapy, 1.8 to 2 Gy/day for 5 days a week on limited fields up to 60 Gy, and concurrent chemotherapy with carboplatin 250 mg/m2 on days 1, 22, and 43, and teniposide 50 mg/m2 on days 1, 2, 3, 22, 23, 24, 43, 44 and 45. Two cycles of 150 mg/m2 BCNU were then given at 30 and 70 days, respectively, after the end of the radio-chemotherapy course. Therapy was then suspended, but if disease progression was evident, treatment was resumed with drugs that had not been previously employed. Surgical reintervention was not routinely considered.Following radio-chemotherapy treatment in the 24 pts evaluable for response, we observed partial remissions in 8 cases (33%) and stable disease in 12 (50%). Actuarial estimates of progression free survival (PFS) were 33 weeks, with 56 wks for anaplastic astrocytoma and 31 weeks for glioblastoma. Median survival time (MST) of all pts was 58 weeks; 51 weeks for glioblastoma and was not reached for anaplastic astrocytoma. This regimen was feasible. Of 144 planned cycles, 139 were delivered, and among these only in 13 and 9 cycles the doses were reduced by 75 and 50%, respectively. We did not observe any gastrointestinal toxicity. Grade 2 hematological toxicity occurred in 25% of pts. grade 3 in 4% and neurological toxicity in 3% of the pts during BCNU delivery, probably due to a sharp increase in intracranial pressure.Early chemotherapy, concurrent chemo-radiotherapy and brief post-radio-therapy chemotherapy are feasible and well tolerated. The objective response and disease stabilization rates appear similar to previous experiences.

Perfusion of the isolated rabbit heart with 5 x 10(6) human polymorphonuclear leukocytes, under recirculating conditions (50 ml), and challenge with A-23187 (0.5 microM) caused an increase in coronary perfusion pressure (from a prechallenge value of 46 +/- 1.1 to 176.2 +/- 29.7 mm Hg, 30 min after challenge, n = 6-4), which was linearly correlated (P.006) with formation of cysteinyl leukotrienes (29.7 +/- 7.3 pmol/ml, 30 min after challenge). Pretreatment with the leukotriene synthesis inhibitor BAY X1005 (1 microM) (n = 6) resulted in significant protection against the increase in coronary perfusion pressure (76.7 +/- 12.8 mm Hg, 30 min after challenge) and in almost complete inhibition of sulfidopeptide leukotriene synthesis (3.2 +/- 1.7 pmol/ml, 30 min after challenge). In in vivo experiments, ligation of the left anterior descending coronary artery in the rabbit (n = 10) resulted in acute myocardial infarction marked by a mortality rate of 60% compared with sham-operated animals (n = 10). Intravenous treatment of the rabbits with BAY X1005 (10 mg/kg/h, for 2 h) (n = 10) markedly reduced the mortality rate (20%), protected the rabbits against the marked electrocardiogram derangement and abolished the significant increase in plasma creatine phosphokinase activity and cardiac tissue myeloperoxidase activity induced by coronary artery ligation. BAY X1005 exerts a significant cardioprotection and suggests that specific leukotriene synthesis inhibitors may lead to innovative therapy in myocardial ischemia.

In the conservative treatment of early breast cancer, great attention must be paid to define the prognostic factors correlated with the local recurrence rate. The goal is to customize surgery, radiotherapy and chemotherapy to the risk predicted in every single patient. To investigate the impact of some prognostic factors in a group of patients treated with homogeneous treatment schedules, 251 women with UICC stage I or II breast cancer were examined in the Padua Radiotherapy Department from 1988 to 1990. All patients underwent conservative surgery consisting in quadrantectomy, axillary node dissection and radiotherapy. During a median follow-up period of 49.2 months, 12 patients presented a breast relapse (4.8%). In 4 patients the relapse occurred in the same quandrant as the primary lesion, whereas a different quadrant was involved in the other 8 patients. The relapse rate in women under 60 was 5% and 4.7% in older patients, with p = 0.73. In pT1 patients, the relapse rate was 4.5% and in pT2 patients it was 7.9% (p = 0.37). No significant difference was observed between pN- and pN+ patients (4.5% vs. 6.25%, p = 0.37). In our series, none of the studied factors significantly influenced breast relapse rates. The number of patients may be too little relative to the low rate of relapses. However, an unfavorable trend was observed in the patients under 60, in pT2 or pN+ patients, or in the patients with positive or unknown surgical margins.

The exposure of ovalbumin sensitized guinea-pig to an areosol of the specific antigen causes a respiratory crisis in approximately 100 s (dispnoea time) associated with a substantial increase in blood concentration of both histamine (from 27.5 +/- 1.8 ng/ml to 1570 +/- 26 ng/ml; n = 8) and thromboxane B2 (TXB2, from 0.52 +/- 0.03 ng/ml to 18.1 +/- 0.6 ng/ml; n = 8). The aerosol treatment of the animals (20 min) with furosemide (CAS 54-31-9, frusemide, FRU), nimesulide (CAS 51803-78-2, NIM), acetylsalicylic acid (CAS 50-78-2, ASA) and indometacin (CAS 53-86-1, INDO) at the concentrations of 1-3-10 and 30 mg/ml, before ovalbumin challenge, brought about an attenuation of anaphylactic response. The rank order of potency for the prolongation of dyspnoea time was FRUNIMASAINDO. In these experiments blood evaluation performed at the peak of the dyspnoea time for histamine concentration in the treated animals indicated that whereas FRU (ED25 = 2.14 mg/ml (1.97-2.38) and NIM (ED25 = 2.74 mg/ml (2.37-3.19)) were equiactive in reducing the release of histamine, ASA and INDO were devoid of this activity. On the contrary, the results obtained with ASA and INDO indicated a greater intrinsic activity in antagonizing TXB2 formation than that shown by the log-dose response curves of NIM and FRU. In another series of experiments the interaction of FRU with the other anti-inflammatory drugs in protecting guinea-pig from immune bronchoconstriction has been evaluated using the combination of two equiactive doses. The mixture considered were FRU+NIM, FRU+INDO and FRU+ASA. The results obtained indicated that FRU interacts positively with the three non-steroidal anti-inflammatory drugs in delaying the onset of the dyspnoeic crisis in guinea-pig. However, when FRU was combined with NIM the gain obtained (209%) appeared superior to that reached when FRU was combined with ASA (180%) or INDO (126%). Taken together these results suggest that non-steroidal anti-inflammatory compounds given by aerosol may represent a valid pharmacological intervention in protecting guinea-pig from anaphylactic bronchoconstriction.

In anaesthetized ventilated guinea-pig, acetaldehyde (CAS 75-07-0) (40-80 mg/kg i.v.) elicits a dose-dependent increase in intratracheal pressure accompanied by an increase in circulating histamine. When acetaldehyde is injected repeatedly at 15 min intervals in capsaicin-desensitized animals, it already loses its activity at the second administration (50% reduction; p0.01); this does not happen in control animals. This phenomenon is even more marked when acetaldehyde is given at the dose of 80 mg/kg i.v., since at the third injection both the bronchoconstriction and the increase in blood histamine are almost completely reduced to baseline values. The increase in intratracheal pressure caused by acetaldehyde (20, 40, 80 mg/kg i.v.) is associated with a dose related increase in microvascular permeability and leakage of protein-bound Evans blue in lower tracheal tissue. This event and the bronchoconstrictor response caused by acetaldehyde (40 mg/kg i.v.) are 87% and 35% inhibited, respectively, (p0.01) in tachykinin-depleated animals. On the contrary, thiorphan (2 mg/kg i.v.) remarkably potentiates both the rise in intratracheal pressure (110%; p0.01) and Evans blue extravasation (215%; p0.01) induced by acetaldehyde (20 mg/kg i.v.) in normal guinea-pigs. Furthermore, treatment with CP-96,345, a selective tachykinin NK1-receptor antagonist, only prevents plasma extravasation in lower tracheal tissue (82% inhibition; p0.01) without affecting the bronchoconstriction caused by acetaldehyde (40 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibiotic susceptibility on 803 strains isolated from urine in 1990 and on 500 strains isolated in 1978 have been tested. The comparison between the results on strains of the two periods confirm the utility of urine culture for cost effective treatments.

Acetaldehyde administered intravenously at various doses (20, 40 and 80 mg/kg) elicits a dose-dependent increase in intratracheal pressure (ITP) and a proportional rise in histamine blood concentration in anaesthetized guinea-pigs. Similar effects were observed in ovalbumin-sensitized guinea-pigs upon aerosol of acetaldehyde (20 mg/ml) which has been administered at the flow rate of 0.1 ml/min for 2 min. Theophylline (CAS 58-55-9) antagonized both the increase of ITP values and the rise of histamine in the blood caused by acetaldehyde given intravenously (ED50 = 5.8 mg/kg i.v.) or by aerosol (ED50 = 4.9 mg/kg i.v.). Furthermore, in animals where combined treatment with pyrilamine (2 mg/kg i.v.) and captopril (2 mg/kg i.v.) resulted in a remarkable potentiation of the bronchoconstrictor response to acetaldehyde (20 mg/kg i.v.), the administration of theophylline (5 mg/kg i.v.) or of the substance P (SP) receptor antagonist, [D-Pro4, D-Trp7.9] SP 4-11 (10 mg/kg i.v.) reduced the augmented action of acetaldehyde on respiratory airways induced by captopril by more than 50%. Moreover, the bronchoconstriction induced by acetaldehyde (40 mg/kg i.v.) was also associated with a significant increase of extravasation of Evans blue in tracheal tissue. Both these effects of acetaldehyde were inhibited by theophylline (10 mg/kg i.v.), whereas a NK1-TK (neurokinin 1-tachykinin) receptor antagonist (412 micrograms/kg i.v.) reduced (81%; p0.001) only the vascular permeability changes caused by acetaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a case of histiocytic necrotizing lymphadenitis (NHL) (Kikuchi-Fujimoto disease) in a 23-year-old patient with fever, lymphadenopathy and leukopenia. There were no other significant findings in laboratory data and all bacterial and viral researches were negative. Fever resolved spontaneously after one month, but lymphadenopathy and leukopenia persisted. The immunophenotype of bone marrow and peripheral blood cells showed an increase of B lymphocytes (CD20+, CD21+, CD22+) and activated (CD30+) and NK cells (CD16+, CD56+). This finding persisted after six months. The authors suggest that the clinical feature of NHL is sustained by an immunological substrate.

The prognosis of patients with malignant glioma is generally poor in spite of the progress that has been made in neurosurgery and radiotherapy of these tumors.

e12514 Background: In high-grade gliomas, MC using two-dimensional measurement is the most widely used method for assessing TR to treatment on MRI. With the recent introduction of AD that affect th...

The Authors focus the great importance of the endothelium-dependent relaxation in normal and diseased human coronary arteries. The impairment or loss of this powerful dilator process, that is multifactorial and related to the stage of development of the endothelial damage seems to be, beyond all doubt, implicated with vasospasm and thrombosis. Furthermore the response of coronary smooth muscles to vasoconstrictors, particularly to serotonin, may be augmented. These vasoconstrictors may be present in larger amount at the site of the rupture of atheromatous plaque, following platelet deposition and aggregation that trigger the release of platelet-derived products such as ADP, 5-HT and eicosanoids. The recognition and the increasing knowledge on the relationship between endothelial-relaxing mechanism dysfunction and coronary heart disease is certainly leading to new hope for a more rational therapeutical intervention.