Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986.

PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.

Influence of breathing pattern and lung inflation on impulse oscillometry measurements in horses.

The objective of this paper was to determine if changes in ventilation patterns could influence the outcome of respiratory function measurements performed with our impulse oscillometry system (IOS) in horses. In a first study, IOS tests were performed in vitro on six isolated equine lungs. Lung inflation levels were controlled by modifying depressurisation inside an artificial thorax and different ventilation patterns were imposed. In a second in vivo study, transient variations in breathing pattern were evaluated both with the IOS and a current reference technique (CRT) in five healthy mature horses after an intravenous (i.v.) injection of lobeline hydrochloride. In both studies, respiratory rate (RR, range: 7-42 breaths/min.) and tidal volume (V(T), range: 0.4-25 L) had minor or no influence on IOS parameters. The influence of lung inflation, most marked for resistance at 5 Hz (R(5 Hz)), was limited for the considered physiological range. In vivo, statistical models indicated that maximal changes in pleural pressure (Max Delta Ppl) and peak flows were the main determinants of the variability of the resistance (R(rs)) and the reactance (X(rs)) of the respiratory system. The fourfold increase in baseline Max Delta Ppl and peak flows obtained during hyperpnoea caused a significant increase in R(rs) at 5 and 10 Hz and a decrease in X(rs) at all frequencies. We conclude that IOS parameters are not influenced by tachypnoea, but will reflect alterations in respiratory mechanics caused by hyperpnoeic breathing.

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

Effect of chronic airway inflammation and exercise on pulmonary and systemic antioxidant status of healthy and heaves-affected horses.

In heaves-affected horses the relation between oxidant status, airway inflammation (AI) and pulmonary function (PF) is unknown. The oxidant status of blood and pulmonary epithelial lining fluid (PELF) of healthy (H, n = 6) and heaves-affected horses in clinical remission (REM, n = 6) and in crisis (CR, n = 7) was assessed at rest, during and after standardised exercise test by measurement of reduced and oxidised glutathione, glutathione redox ratio [GRR%]; uric acid and 8-epi-PGF2alpha. Oxidant status was related to PF parameters (mechanics of breathing and arterial blood gas tension) and Al parameters (bronchoalveolar lavage [BAL] neutrophil % and AI score). Haemolysate glutathione was significantly different between groups and was correlated with PF and AI parameters; GRR in PELF was increased during CR and was correlated with PF and AI parameters. Exercise induced an increase of plasma uric acid that was significantly higher both in REM and CR. PELF 8-epi-PGF2alpha was significantly increased in CR and correlated with PF and AI parameters. These results suggest that oxidative stress occurring in heaves is correlated with PF and AI and may be locally assessed by PELF glutathione status, uric acid and 8-epi-PGF2alpha. Systemic repercussions are reflected by assay of GSH in resting horses and by uric acid in exercising horses.

Virus neutralising antibodies against 22 bovine viral diarrhoea virus isolates in vaccinated calves.

Seven of nine colostrum deprived calves, free from bovine viral diarrhoea virus (BVDV), were vaccinated with a commercially available vaccine containing two inactivated strains of BVDV, an inactivated strain of bovine herpesvirus-1 and modified-live strains of bovine respiratory syncytial virus and para-influenza-3 virus. The two other calves were kept as controls. The virus neutralising (VN) antibodies induced by vaccination were tested against 22 antigenically diverse BVDV isolates, including reference strains and field isolates, both cytopathic and non-cytopathic, as well as genotypes I and II. The strains were isolated in Belgium, France, Germany, the United Kingdom and the USA. While there were variations in the VN titres of the individual calves against all the strains, serum from the seven animals neutralised 20 or more of the strains tested. From the results, it can be concluded that the vaccine can stimulate the production of VN antibodies capable of neutralising a wide range of European and American isolates of BVDV, including genotypes I and II.

Effect of intravenous platelet-activating factor on bovine pulmonary mast cells.

The effect of platelet-activating factor (PAF) on bovine pulmonary mast cells (MCs) was investigated in calves aged 1-4 months. PAF was administered over a 5-min period at a rate of 50 ng/kg/min to six animals, which were killed approximately 10 min later. No macroscopical lesions were observed in the lung tissue of five control calves. On semi-thin toluidine-blue stained sections, MC cytoplasm showed profuse deep-blue granulation. In the lung tissues of PAF-treated calves, striking interstitial, alveolar and interlobular oedema and emphysema were observed. MC granules occurred at the periphery of the cytoplasm and MC nuclei were easily detectable. Moreover, the number of granules in the MC cytoplasm was remarkably low. A few granules with some metachromatic material were sometimes detected outside the cell limits. Ultrastructurally, the matrix pattern of the MC granules in lung tissues of control calves was either amorphous or granular. In lung tissues of the PAF-treated calves, the granular matrix pattern was pronounced, varying from fine- to coarse-grained, and the MCs were of reduced size, with many filiform processes and exocytotic vesicles. These findings indicate that pulmonary MC degranulation was induced by PAF in healthy calves.

Virus neutralizing antibodies against a panel of 18 BVDV isolates in calves vaccinated with Rispoval RS-BVD.

Seven of nine colostrum-deprived calves, free from infection with bovine virus diarrhoea virus (BVDV), were vaccinated with Rispoval RS-BVD on two occasions, 21 days apart, while the other two were kept as BVDV infection controls. The virus neutralizing (VN) serum antibodies induced by vaccination were tested for their ability to neutralize 18 European BVDV isolates, including laboratory reference strains and recent field isolates, both cytopathic and non-cytopathic biotypes as well as genotypes I and II. The strains were isolated in Belgium, France, Germany and the United Kingdom. While there were large variations in the vaccine-induced VN titres of the individual calves against all the strains, e.g. the titres against Osloss NCP, the European reference strain ranged from 1.7 to 6.7 (1:log2), serum from each animal was capable of neutralizing between nine and all 18 of the strains tested. Nevertheless, from the results of this study, it can be concluded that in colostrum-deprived BVDV seronegative calves, Rispoval RS-BVD can stimulate the production of VN antibodies capable of neutralizing a wide range of antigenically diverse European isolates of BVDV, including genotypes I and II.

Validation of impulse oscillometry in Friesian and Blue Belgian calves with respect to changes in extrathoracic upper airway resistance.

Impulse oscillometry (IOS) was compared with conventional pulmonary function techniques (using oesophageal balloon and airflow measurements). Healthy Friesian (FR) and Blue Belgian (BB) calves were examined in different conditions of extrathoracic airway resistance (physiological and vertical head position). Higher resistance values were detected in BB calves compared with FR calves with both conventional and forced oscillation techniques in both head positions. Upper airway narrowing was characterised by increasing resistance values without changes in frequency dependence. Measuring input impedance in animals using a face mask, a considerable capacitive shunt of the upper airways (including the capacitive components of the mask) has to be taken into account. Even if the absolute value of this capacitive component is constant, its influence on the measurement results increases with growing frequency and with an increase in upper airway resistance. In conclusion, (1) impulse oscillometry is sensitive to upper airway resistance changes and (2) face mask capacitance is important and has frequency dependent effects on the respiratory impedance.

Ventilatory effects of the single-breath CO2 test, compared with eructation, in cattle.

OBJECTIVE: To assess the peripheral chemoreceptor-induced ventilatory response to single tidal-breath CO2 (SB CO2) tests, compared with eructations, in 2 breeds of calves. ANIMALS: 13 conscious unsedated Holstein-Friesian and 8 Belgian White and Blue hypermuscled calves. PROCEDURE: An SB of +/- 50% CO2 in equal parts of O2 and N2 was inhaled. Ventilatory response was determined from the increase in ventilation (delta Ve) during the first 20 seconds after the test breath or eructation and from the difference in end-tidal PCO2 between the stimulus and preceding control breaths. RESULTS: Because no difference was found between the 2 breeds of calves, all data were pooled. The increase in Ve peaked during the fifth breath after the SB CO2 test on average, corresponding to a delay of 12.4 seconds. The SB CO2 responses ranged from 0.037 to 0.151 L/min.mm of Hg.m2, with a mean +/- SD of 0.082 +/- 0.032 L/min.mm of Hg.m2 for all calves. The SB CO2 tests, similar to eructations, modified the breathing pattern significantly and in the same direction, by principally shortening expiratory time and increasing mean inspiratory flow. After eructations, Ve peak increase was more important for lower difference in end-tidal PCO2 between the stimulus and preceding control breaths and took place more rapidly than after SB CO2 tests. Accordingly, eructation responses were more marked than SB CO2 responses and averaged 0.925 +/- 0.276 L/min.mm of Hg.m2. CONCLUSIONS AND CLINICAL RELEVANCE: In cattle, the pattern of breathing and ventilation under basal conditions is characterized by a cyclic variability coupled to eructation.

Use of the monofrequency forced oscillation technique to measure changes in upper airway resistance in Friesian and blue Belgian calves.

Monofrequency forced oscillometry (MFO) using a sinusoidal test signal of one frequency (10 Hz) was compared with the classical pulmonary function technique (using an oesophageal balloon with airflow measurements) in two breeds of cattle which differ in their respiratory physiology, particularly to assess changes in upper airway resistance. Six healthy male Friesian calves (mean [SD] bodyweight 131 [12] kg) and six healthy male blue Belgian calves (mean [SD] bodyweight 137 [13] kg) were examined successively with their heads either in a normal position or held vertically, using a cross-over study design. In the normal position, higher resistances, a higher respiratory impedance, and lower values of the dynamic lung compliance (Cdyn) were measured in the blue Belgian than in the Friesian calves. In the vertical head position, total pulmonary resistance (RL) increased and Cdyn decreased significantly (P < 0.05). The changes in MFO-derived parameters were in accordance with the changes in classical parameters, and for both methods, the percentage changes were markedly higher in the blue Belgian calves.

Deposition in the distal parts of the bovine respiratory tract: assessment of equipment suitable for drug inhalation.

The efficiency of equipment suitable for the inhalation of drugs by calves was assessed in six animals which inhaled radioisotopically labelled particles while suffering from reversible diffuse bronchoconstriction induced experimentally with 5-hydroxytryptamine and while they were breathing normally. Respiratory rates and data from pulmonary function tests and scintiscans were recorded during both investigations. After the first investigation, a mean (se) wash-out period of 9.8 (3.2) days was allowed. Under diffuse bronchoconstriction, the respiratory rate, the oscillatory resistance and the compliance of the respiratory system reached 282.1 (22.0), 161.1 (10.8) and 68.8 (2.7) per cent of their respective baseline values. When the calves were breathing normally these parameters did not change over time. The ratios (Cp/Ct) of the counts of gamma-disintegrations in the peripheral part (Cp) of the lungs and in the total lung area (Ct) were not significantly different when comparing the results from the two investigations. The ratios of Cp/Ct in the left lungs did not differ significantly from those in the right lungs.

Physical properties of particles of ipratropium and clenbuterol generated by equipment suitable for the inhalation of drugs by calves.

When solutions of ipratropium and clenbuterol were atomised at 300 kPa and 450 kPa in equipment suitable for the inhalation of drugs by calves, the numbers, velocities and diameters of the particles produced were similar. When the pressure was increased to 600 kPa more of the particles were less than 2 microns in diameter and fewer were more than 7 microns in diameter, the fractions of the total mass of the solution generated in these size ranges were similarly increased and decreased, and the velocities of the particles were increased. At any given pressure, the numbers of particles of different sizes, and the proportions of the total mass generated, were similar for the solutions of ipratropium and clenbuterol, but a solution of saline produced more particles with a diameter less than 3 microns. Particles from the solution of ipratropium had the highest velocity and particles from the solution of clenbuterol had the lowest velocity.

Pulmonary function changes induced by three regimens of bronchodilating agents in calves with acute respiratory distress syndrome.

Two aerosolised bronchodilators, one sympathomimetic and one parasympatholytic, were tested either alone or in combination for their ability to improve the pulmonary function of double-muscled calves suffering from acute respiratory distress syndrome. In control animals treated with 0.9 per cent saline the parameters of pulmonary function and signs of clinical distress did not change significantly within the hour following the first treatment. Among the other animals, both at one hour and seven days after the first treatment, the most clinical improvement was observed in the animals treated with both bronchodilators and the least in the animals treated with clenbuterol hydrochloride. One hour after the first treatment the respiratory system compliance of the animals treated with ipratropium bromide and the arterial oxygen tension of the animals treated with both bronchodilators were significantly enhanced. After seven days the resistive parameters, the rectal temperature and the respiratory rate were also significantly improved in the animals treated with ipratropium bromide or both bronchodilators whereas only the respiratory rate and rectal temperature were significantly reduced in the animals treated with clenbuterol hydrochloride.

Ability of bronchodilators to prevent bovine experimental respiratory distress.

This cross-over trial involving 6 Blue Belgian double-muscled calves aimed to investigate whether ipratropium bromide inhaled alone or in combination with clenbuterol hydrochloride could prevent the dramatic clinical and pulmonary disturbances that are observed during an experimentally induced bronchoconstriction. Inhaled bronchodilators significantly influenced the clinical and functional responses of bovines subjected to a 5-hydroxytryptamine perfusion. However, despite a mean (standard error) wash-out period of 11.2 (3.1) and 7.5 (0.9) d after the 1st and the 2nd one-day challenges, respectively, first-order carry-over effects (ie those remaining from the previous treatment), effects of the period during which the treatment was allocated and interaction effects did not allow a definitive interpretation of overall treatment differences.

Comparison of cardiac function in double-muscled calves and in calves with conventional muscular conformation.

During growth, central venous, right ventricular, pulmonary arterial, pulmonary capillary wedge, and systemic arterial pressures, heart rate, and cardiac output were repeatedly measured in 41 Friesian calves, considered as having conventional muscular conformation, and in 19 Belgian White and Blue double-muscled calves. A total of 123 and 70 recordings were collected in conventional and double-muscled calves, respectively. These circulatory indices were calculated: stroke volume, cardiac and stroke indices, pulmonary and systemic pulse pressures, pulmonary and systemic vascular resistance indices, and right and left ventricular work indices. Results indicated that systemic arterial and pulse pressures, as well as cardiac output, stroke volume, cardiac and stroke indices, and right and left ventricular work indices were significantly (P < or = 0.05 to 0.001) lower but, in contrast, pulmonary and systemic vascular resistance indices were significantly (P < or = 0.001) higher in double-muscled than in conventional calves. Right-sided vascular pressures and heart rate were similar in the 2 groups. These results indicated that global cardiac performance may be considerably poorer in double-muscled calves. Diminished cardiac performance of double-muscled calves appears to be related neither to relative bradycardia nor to reduced ventricular preload. The potential role of increased ventricular afterload or of reduced myocardial contractility in double-muscled cattle should be determined by direct measurements.

Technical study of some major parameters influencing the performance of an aerosol delivery equipment suitable for calves.

Aerosol delivery equipment, suitable for the treatment of bovine respiratory dysfunctions and including 2 parallelly positioned jet nebulizers, was studied in depth in order to determine the optimal working conditions in the field. Indeed, some factors might reasonably alter the performance of this equipment. Among these factors, the influences of the parallel position of jet nebulizers (in order to accommodate the breathing requirements of the cattle and achieve a rapid treatment), of the long feed pipe delivering compressed air (in order to keep the animal away from the compressor unit), and finally of the ambient temperature were studied, this equipment being essentially used during the winter season. This equipment could accommodate the breathing needs of cattle weighing up to 225 kg if a pressure of 600 kPa was developed upstream to the nebulizers. The rate of atomization was significantly reduced when working at ambient air temperatures (272.25 K < T < 274.65 K) close to those encountered in winter. This was especially true when pressure upstream to the nebulizers did not exceed 500 kPa. The immersion of the feed pipe for compressed air in hot water led to an increase in the rate of atomization without raising evaporative water losses, and reduced the drop in temperature in the nebulizer solution. Finally, the rate of atomization significantly increased when the face mask including the nebulizers was maintained so that the nebulizers were in a vertical position or at an angle not less than 60 degrees with respect to the ground.

Functional effects of a muscarinic receptor blockade during acute respiratory distress syndrome in double-muscled calves.

Eighteen Belgian white and blue double-muscled calves suffering from the acute respiratory distress syndrome were studied. Fifteen of the calves inhaled ipratropium bromide (0.6 mg) four times a day for three to four days whereas the other three control calves inhaled sterile 0.9 per cent saline. All the animals were injected with ceftiofur sodium (1 mg/kg/day) for five days, the first injection being given one hour after the first inhalation of ipratropium bromide or saline. Arterial oxygen tension, alveolar arterial oxygen difference, carbon dioxide tension and arterial pH, respiratory and heart rates, oscillatory resistance and phase angle, measured by the mono-frequency forced oscillation technique, were recorded both before and one hour and 168 hours after the first inhalation. The measurement of oscillatory resistance and phase angle made it possible to resolve the impedance of the respiratory system into its real and imaginary components. The oscillatory compliance (Cosc) was determined from the imaginary component (Im). By one hour after the first inhalation of ipratropium bromide the oscillatory resistance was already significantly reduced and Im and Cosc had significantly increased, but the other parameters showed no significant improvement. However, between one hour and 168 hours after the first inhalation all the parameters reached physiological values. The control calves did not show any change. It was concluded that the pulmonary dysfunction associated with the acute respiratory distress syndrome in these calves was at least partly due to a severe bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study of the body surface electrocardiogram in double-muscled and conventional calves.

The purpose of this work was to study electrocardiographic features of double-muscled beef cattle. Electrocardiograms were recorded on one to six occasions from each of a group of 18 conventional calves of the Friesian breed and 29 double-muscled calves of the Belgian White and Blue breed. Ages of the calves at the times of examination ranged from eight to 348 days. The Holmes semi-orthogonal lead system was used. The waves and interval durations and the tridimensional P, QRS, and T modal vector orientation and amplitude were calculated. The magnitude of the cardiac vectors was significantly lower and the ventricular waves and QT interval duration significantly shorter in the double-muscled than in the conventional calves. The P modal vector pointed significantly less downwards and the QRS modal vector pointed significantly more forwards and less up- and rightwards in the Belgian White and Blue, than in the Friesian group. Most of the observed differences might be a consequence of the bodily, and more specifically the thoracic, conformation of the former calves. However, the lower cardiac vector magnitude and shorter wave and interval durations might also reflect lower cardiac mass in the double-muscled subjects.

Induction of serotonin-S2 receptor blockade during early or late stage of acute respiratory distress syndrome in double-muscled calves: a comparative study.

Ninety-four Belgian White and Blue double-muscled calves were involved in this study which aimed to compare the efficacy of a serotonin-S2 receptor blockade at two different stages of an acute respiratory distress syndrome (ARDS), i.e. at the occurrence of first clinical signs or when another anti-inflammatory compound was clinically shown to be ineffective. Metrenperone, a 5-hydroxytryptamine (5-HT2) blocker, was injected (intramuscularly, 5 times, at 12 hourly intervals, dose rate: 0.1 mg/kg) to (1) 58 calves referred to our laboratory after a treatment (group I) which lasted from 3 to 5 days and which did not improve the clinical status of the animals and (2) 36 calves investigated as soon as first clinical signs occurred (group II). Following the severity of the ARDS, the animals from group I needed to be classified into 2 groups: group IA (moderate ARDS - n = 45) and group IB (severe ARDS - n = 13). For animals in group I, the antibacterial compound previously used was maintained and administered during 4 more days whilst the previous anti-inflammatory drug was suppressed and replaced by metrenperone administered as mentioned above. In group II, each animal was treated with ceftiofur sodium as an antibacterial agent. A clinical score and a breathing score were calculated at each step of the investigation period, i.e. before (T0) and 1 hour (T1) after the first treatment, during the interval 12H-48H (T2) which followed this treatment and 168 H (T3) after this treatment. Four clinical parameters were also taken into account separately: rectal and cutaneous temperatures, respiratory and heart rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficiency of 5-hydroxytryptamine receptor blockade as therapeutic measure during acute respiratory distress syndrome in double-muscled cattle.

During this investigation, which involved 58 Belgian White and Blue double-muscled calves affected by a naturally occurring Acute Respiratory Distress Syndrome, the clinical efficiency of a 5-HT2 receptor blockade with metrenperone (group A) was compared to the efficiency of a non-steroidal (flunixine meglumine--group B) and a steroidal (prednisolone sodium succinate--group C) antiinflammatory drug. Each animal of this trial was treated with ceftiofur sodium as antimicrobial agent. A clinical score and a breathing score were calculated at each step of the investigation period, i.e. before (T0) and 1 hour (T1), 12 hours (H), 24 H, 48H and 168 H (T3) after the first treatment, the interval 12H-48H being considered as period T2. Three clinical parameters were also taken into account separately: rectal and peripheral temperatures and heart rate. A significant improvement of the clinical score was registered at T2 in group A and at T3 in groups A and B, while this score did not significantly change in group C. In group A, the breathing score was significantly improved at T2 and T3, but not in groups B and C. Peripheral and rectal temperatures recorded at T1 were, in group A, significantly increased and decreased respectively, but not significantly changed in groups B and C. The proportions requiring change of treatment during the investigation period were significantly (P = 0.022) different in the three groups, being 5.6, 21.4 and 50.0% in groups A, B and C respectively.(ABSTRACT TRUNCATED AT 250 WORDS)