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MATER IALS AND METHODSuate hypoxia , but to correlate a biochemi cally measured value with th e outco me of hypoxia is difficult . Measure me nts of th e pu rine metabol ite hypoxanthine can be used as an ind icator of hypoxia (I). Du rin g tissue hypo xia, elevated hypoxanthine levels have been found in plasm a (2-5), CSF (6, 7), and urine (8).H owever, no clear definition of clinical hypoxia is available, and ma ny autho rs do not distinguish between the terms hypoxemia an d hypoxia, whic h adds to the confusio n. Our meanin g of hypoxia has previou sly been described ( I). In our study th e pigs were subjected to hypoxemia. We define hypoxe mia as deficient oxygenation of th e blood. Hypoxem ia may, however, not necessarily lead to tissue hypoxia.To further assess the usefuln ess of hypoxanthine as a biochemical marker of hypoxia, we repo rt how three degrees of hypoxemi a in young pigs in fluence the level of hypoxanthine, xanthine, and uric acid in the CSF and plasma , as well as th e pigs' urin ary excretion of hypoxan thine an d xanthine.Approval. The local hosp ital' s ethi cal com m ittee for an im al studies approved these experim ents.Animal model. T he anima l model was similar to th at previously described (9). T went y-two young pigs of eit her sex (the males had been castrated shortly after birth ) weighing 17-22 kg (mea n 18.1 kg) were used. Th ey were anes thetized with an intraperitoneal injection of sodium pentobar bital (30 mg/kg). An i.v. line was estab lished through an ear vein, an d a contin uo us infusion of Ringer acetate ( 10 mL/kg/h) was given during the experime nt. A further 100 mg of sodium pentobar bital was given i.v, if necessary every 30 min. A cuffed tu be was placed in the trachea via a tracheostom y. Art ificial ventilation was given by a ventilato r (Servo-ventilator 900B, Elema-Schenander, Stoc kholm, Sweden). Ventilation rate and tidal volume were adjusted unt il Paco, ranged between 4 and 5.3 kPa (30-40 mm Hg). No further adjustme nts of the ventilato r .were done du ring th e hypoxemic period.A midlin e supr apubic laparotomy was performed and a urinary catheter was placed in the bladder for measuring diuresis and urinary hypoxanthin e and xanthine.Polyeth ylene catheters were inserted into a fem oral artery and a fem oral vein. T he arterial cathe ter was used for taking blood samples and for measuring blood pressure continuously with a strai n gauge tra nsdu cer, Go uld recorde r 2600S (Gould In c. Recording System s, Cleveland, OH). Th e venous cath eter was used for giving Ringer acetate plu s additional sodium pentobarbital.Th e pigs were divided int o three hypoxemi c and one contro l group. Seven animals were made hypoxem ic by art ificial ventilation with 8% oxygen in nitrogen (FiO z = 0.08) (group 1). Seven

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n ¼ irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P ¼ 0.02). Overall response rates were in the range 5 -11%. Secondary end points included median survival (6.4 -9.4 months), and time to progression (2.7 -3.8 months) and treatment failure (1.7 -3.2 months). Similarly, there were no significant differences in the incidence of grade 3 -4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.41

MATERIAlS AND METHODSprolonged disease process, which ma y include lon g-standing hypo xia (2, 3). During tissue hypox ia, elevated hypo xanthine levels have been found in plasma (4)(5)(6), CSF (7,8), and urine (9). We have also measured the hypoxanthine levels in vitreous humor post-mo rtem, and documented high levels when death was preceded by resp iratory failure and hypo xem ia ( 10, II ). Re cently, we reported high levels of hypoxanthine in the vitreous humor of victims of SIDS (\2), and therefore concluded that hypoxemia precedes death in SIDS .In our present study, we report how three degrees of hypoxemia in young pigs influence the level of hyp oxanthine, xanthine, and uri c acid in the vitreous humor. Furthermore, we in vestigated the time factor in volved in hypoxanthine accumulation in the vitreo us humor during hypo xemia. We also report how hypoxanthine concentrat ion s in the vitreo us humor change during th e first 24 h post-mortem . We found this important, in asmuch as the tim e from death to sam ple collection could ha ve influenced the concentrations of hypoxanthine in the vitreous humor that we have rep ort ed from our SIDS cases.Approval. The local hospital's ethical committee for animal studies approved thes e experiments.Animal m odel. The animal model was similar to that previou sly described (13). T wenty-two young pigs of either sex (the males had been castrated short ly after birth) weighing 17-22 kg (mea n 18.1 kg) were used . They were anesthetized with an intraperitoneal injection of sod ium pentobarbital (30 mg/kg), An i.v.I ine was establi shed through an ear vein , and a continuous infusion of Ringer acetate (\ 0 mL/kg/h) was given during the experim ent. A furth er 100 mg of sodium pentobarbital was given i.v. if necessary every 30 min. A cuffed tube was placed in the trachea via a tracheostomy. Artificial ventilation was given by a ventilator (Servo-ventilator 900B , Elema-Schenander, Stockholm, Sweden). Ventilation rate and tid al volume were adjusted until arterial CO 2 ten sion ranged betwe en 4 and 5.3 kPa (30-40 mm Hg). No further adjustments of the ventilator were done during the hypo xemic period.Polyeth ylene catheters were inserted into a fem oral artery and a femoral vein. The arterial catheter was used for measuring blo od gases. The veno us catheter was used for giving Ringer acetate plus additional sodium pentobarbital.After surge ry, the pigs were left for a stabilizing period of at least I h before basal concentrations were measured, and then divided into three hypoxemic and one control group. Seven animals were made hypoxemic by artificial ventilation with 8% oxygen in nitrogen (Fi0 2 = 0.08) (group I). Seven animals were ventilated with II % oxygen (Fi0 2 = 0.11 ) (group 2). Five animals were ventilated with 14% ox ygen (Fi0 2 = 0. 14) (group 3), and

Some patients with advanced rectal cancer either primary or recurrent may benefit from simultaneous en-bloc cystectomy. The higher postoperative morbidity and mortality indicate the need for well-defined indications for this procedure and the necessity for thorough preoperative staging.

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