Two cases with fatal outcome following total lung irradiation for metastatic bone sarcoma.

We report a single institution experience with total lung irradiation in 53 metastatic bone sarcoma patients in the context of two young female patients who died from treatment-induced pulmonary toxicity. A radiation dose of 19.5 Gy in 1.5 Gy daily fractions was given as two opposing fields with a conventional technique. Both patients succumbed within 3 months following radiotherapy. One patient had osteosarcoma whereas the other advanced Ewing's sarcoma; both with widespread metastases to the lungs at primary diagnosis. In retrospect, most likely high dose methotrexate lung toxicity observed in the osteosarcoma patient, and the GI-toxicity following pelvic radiotherapy in Ewing's case, both observed during the initial phase of their multimodal treatment, might indicate an increased individual radiosensitivity. In view of this, a review of our experience in 53 bone sarcoma patients (19 with Ewing's sarcoma and 34 with osteosarcoma) treated at our institution was conducted. We have not previously experienced significant toxicity following total lung irradiation. Among these, 42% (8/19) with Ewing's sarcoma and 9% (3/34) with osteosarcoma are long-term survivors and without clinically significant lung toxicity.

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer.

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=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) 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=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.

Quality of life during radiotherapy for rectal cancer.

The aim of this study was to assess symptoms and health-related quality of life (HRQL) during (neo)adjuvant radiotherapy for rectal cancer. Patients receiving pelvic radiotherapy 50 Gy for rectal cancer, were studied prospectively (n=42). The European Organization for Research and Treatment of Cancer (EORTC) questionnaires quality of life-core 30 QLQ-C30 and QLQ-CR38 and a 5-day symptom diary were completed at the start and end of radiotherapy and 4-6 weeks later. At the end of radiotherapy, mean scores of diarrhoea, fatigue and appetite loss had significantly increased (P<0.01) compared with pretreatment scores, but this was not observed for scores for nausea or pain. At the end of radiotherapy, diarrhoea, fatigue, appetite loss, physical function, social function and global quality of life (QL) were significantly worse than the population-based norms. 64% of the patients reported an increase in fatigue and 52% an increase in diarrhoea during radiotherapy. HRQL scores had returned to pre-treatment levels 4-6 weeks after radiotherapy. Thus, diarrhoea, fatigue and appetite loss increased transiently during pelvic radiotherapy.

Intra-operative irradiation (IORT) for primary advanced and recurrent rectal cancer. a need for randomised studies.

The aim of this study was to determine the impact of intra-operative irradiation (IORT) combined with pre-operative external beam irradiation (EBRT) and surgical resection in patients with locally advanced primary or recurrent rectal cancer. 64 patients with locally advanced primary cancer and 104 with recurrence had EBRT (46-50 Gy) before surgery. 80 patients received IORT (median dose 15 Gy energy 12 MeV). 80 patients had R0 resections, 47 R1 and 41 R2 resections. More R1 resections were performed in the IORT group, more R0 and R2 resections in the non-IORT group. Median follow-up was around 22 months. 146 patients were resected, 22 had exploratory laparotomy. The cumulative overall survival was similar for both the IORT and non-IORT groups. 5-year survival for primary cancers was 48% versus 28% for recurrences. No R2 resections survived 3.5 years. 5-year-survival for R0 resections was nearly 60% and around 30% for R1 resections. The survival curves of the patients given and not given IORT treatment was not statistically different when R0, R1 and R2 resections were analysed separately. IORT did not seem to influence the local recurrence rate when R0 and R1 resections were analysed separately or in a multivariate analysis. The IORT and non-IORT groups were not identical with regard to type of cancer and R-stage. Still the lack of an identifiable impact of IORT suggests that there is a need for randomised studies of the IORT effect.

[Abdominal metastases from signet cell carcinoma of the appendix vermiformis]. / Metastaser i bukhulen fra signetcellekarsinom i appendix vermiformis.

Signet cell carcinomas are often aggressive tumours. A patient with this tumour, originally located in the appendix, was diagnosed with peritoneal metastases. When she later got abdominal symptoms, computer axial tomography indicated large infiltrating tumour masses in the pelvis. However, when a laparotomy was performed, the only macroscopic tumour masses was localised to the ovaries (Krukenberg tumour). The surgical intervention gave the patient an improved quality of life, and most likely prolonged survival. We stress the importance of thinking of this possibility.

Microencapsulated octreotide pamoate in advanced gastrointestinal and pancreatic cancer: a phase I study.

Fourteen patients suffering from advanced colorectal (n = 7), pancreatic (n = 4) or gastric (n = 3) carcinomas received treatment with microencapsulated octreotide pamoate 90 mg i.m. every 4 weeks (n = 4), 160 mg i.m. every 4 weeks (n = 4) or 160 mg i.m. every 2 weeks (n = 6). Two patients had stable disease, one for 4 and one for 6 months. Plasma insulin-like growth factor (IGF)-I decreased by 49-53%, IGF-II by 27-37% and total IGF-binding protein (IGFBP)-3 by 16-19%, whereas IGFBP-1 increased by 35-55%. Insulin and C-peptide levels decreased by 29-38% and 41-46% respectively. A non-significant decrease in urinary GH secretion and an increase in the ratio of fragmented to intact IGFBP-3 as well as IGFBP-3 protease activity was seen. The increase in IGFBP-3 fragmentation correlated negatively with alterations in IGF-I and IGF-II (P < 0.05). We conclude that microencapsulated octreotide administered in doses up to 160 mg every 2 weeks is well tolerated and has pronounced effects on several components of the IGF system in plasma. In addition, changes in IGFBP-3 protease activity because of cancer may contribute to alterations in IGF-I and -II, indicating the importance of measuring this parameter in addition to IGFs and IGFBPs when evaluating alterations in IGF-I.

Combined modality treatment including intraoperative radiotherapy in locally advanced and recurrent rectal cancer.

BACKGROUND: Treatment of locally advanced and recurrent rectal cancer usually has a high local recurrence rate and poor survival. Promising results have been reported by combined external radiotherapy, extensive surgery and intraoperative radiotherapy (IORT). METHODS: One hundred fifteen patients with locally advanced rectal cancers fixed to the pelvic wall or locally recurrent rectal cancers underwent preoperative external radiotherapy with 46-50 Gy. Six to 8 weeks later radical pelvic surgery was attempted, and was combined with intraoperative electron beam radiotherapy (15-20 Gy) in 66 patients. The patients were followed closely to evaluate complication rate, local and distant recurrence rate and survival. RESULTS: Surgery with no macroscopic tumour remaining was obtained in 65% of the patients with no postoperative deaths. Pelvic infection was the major complication (21%). Although the observation time is short (3-60 months), the local recurrence rate seems low (22%) and survival seems promising (about 60% at 4 years) in patients with complete tumour resection, in contrast to patients with residual tumour (none living at 4 years). CONCLUSIONS: The combined modality treatment with preoperative external radiotherapy and extensive pelvic surgery with IORT is sufficiently promising to start a randomized trial on the clinical value of IORT as a boost treatment in the multidisciplinary approach to this disease.

Hypoxanthine, xanthine, and uric acid in newborn pigs during hypoxemia followed by resuscitation with room air or 100% oxygen.

OBJECTIVE: To determine if resuscitation with room air is as effective as resuscitation with an FIO2 of 1.0. DESIGN: Prospective, randomized laboratory study. SETTING: Experimental laboratory (neonatal or delivery ward). SUBJECTS: Twenty piglets, 1 to 2 wks of age. INTERVENTIONS: Piglets were randomized into two groups. Both groups underwent hypoxemia for 2 hrs and then underwent reoxygenation for 1 hr (group 1 with an FIO2 of 1.0 and group 2 with an FIO2 of 0.21). MEASUREMENTS AND MAIN RESULTS: Hypoxanthine, xanthine, uric acid, PaO2, oxygen saturation, pH, base excess or deficit, and arterial pressure. During hypoxemia (PaO2 26 to 49 torr [3.5 to 6.5 kPa]), the mean hypoxanthine concentrations increased (p < .02) from 26.1 to 115.4 mumol/L in plasma, from 20.9 to 81.7 mumol/L in cerebrospinal fluid, and from 12.9 to 21.5 mumol/L in vitreous humor. Xanthine concentrations changed in a similar way, whereas uric acid concentrations increased only in plasma. During reoxygenation, hypoxanthine concentrations increased both in cerebrospinal fluid and in the vitreous humor. Final concentrations in these two fluid areas were 81.8 and 39.4 mumol/L, respectively (p < .02). Xanthine concentrations increased similarly. In plasma, hypoxanthine and xanthine concentrations decreased during reoxygenation. The final mean concentration of hypoxanthine was 76.8 mumol/L (p < .02). No change in plasma or cerebrospinal fluid uric acid concentrations were found during reoxygenation. The other measurements varied throughout the experiment, but no differences were found between the groups. CONCLUSIONS: There were no significant differences between the two treatment groups at any stage in the experiments. In this porcine model of hypoxemia, resuscitation with room air was as effective as was resuscitation with an FIO2 of 1.0, when circulating concentrations of oxypurines were used as an end-point.

Effect of the hypoxanthine/xanthine oxidase system on dopamine outflow from rat striatal synaptosomes.

The effect of the oxygen radical generating system, hypoxanthine/xanthine oxidase (Hx/XOD), on the spontaneous and potassium-stimulated outflow of the neurotransmitter dopamine (DA) from rat striatal synaptosomes was studied. The efficacy of some radical scavengers was also tested. DA outflow was measured by incubation of [3H]-DA prelabeled synaptosomes (P2) in Krebs-Ringer buffer, containing either normal or depolarizing K+ concentrations. The reactions were terminated by filtration of the synaptosomes through Sartorius filters. Hx/XOD increased the spontaneous DA outflow in a dose and time dependent manner. The reduction found in synaptosomal DA content could be explained by disturbances of DA uptake or reuptake. The K+ stimulated outflow was not altered by the lower doses of Hx/XOD, whereas, when very high doses of Hx/XOD were used, the K+ stimulated DA outflow was decreased. High doses of Hx/XOD may deplete the synaptosomal DA releasable pool, leaving little DA available for extra-stimulated outflow by high concentrations of K+. The K(+)-stimulated outflow of DA is a less sensitive process against radical attack than the spontaneous release of DA. A protective action of catalase, but no effect of superoxide dismutase was demonstrated in these experiments.

Post-mortem concentrations of hypoxanthine in the vitreous humor--a comparison between babies with severe respiratory failure, congenital abnormalities of the heart, and victims of sudden infant death syndrome.

Post-mortem hypoxanthine concentrations in the vitreous humor of human infants were investigated. Hypoxanthine is formed from hypoxic degradation of adenosine monophosphate. The concentrations in the vitreous humor can give information about antemortem hypoxia. The post-mortem levels were corrected for the time elapsing between death and the autopsy. Four groups of infants were compared: 17 babies who died of respiratory distress syndrome (RDS), 72 infants who died of sudden infant death syndrome (SIDS), 23 children dying of congenital heart disease (both cyanotic and acyanotic), and 15 children dying acutely in accidents without any known significant time of hypoxia before death. The corrected, median hypoxanthine levels in victims of SIDS (200 mumol/L) was significantly higher (p < 0.01) than in the accident group (0 mumol/L), but no clear difference was found between the SIDS group and the RDS group (101 mumol/L), or the heart group (54 mumol/L). A number of children with "normal" hypoxanthine levels (0 to 38 mumol/L) were found in all four groups, but the numbers were significantly lower (p < 0.005) in the RDS, SIDS and heart groups than in the accident group. It is concluded that SIDS is probably not a sudden event, but may be preceded by relatively long, or repeated intermittent periods of hypoxia (of unknown etiology).

The effects of hypoxanthine, xanthine oxidase and hyperoxia on the accumulation of bilirubin and albumin in young rat brain.

Hyperoxia has been suggested as a risk factor for kernicterus. The toxicity of hyperoxia may be mediated by free radicals. We investigated the effects of free radicals, formed by the hypoxanthine/xanthine oxidase system, with and without additional hyperoxia, on the accumulation of bilirubin and albumin in rat brain. Hypoxanthine was infused for 60 min into retrograde carotid catheters in awake, young, male SPRD rats. After 30 min the infusion was briefly interrupted to inject xanthine oxidase 1 U/kg through the same catheter. Group I (controls) received 0.9% NaCl in lieu of hypoxanthine/xanthine oxidase. Groups I and II breathed room air at all times, while group III breathed 90% O2. After 60 min all groups received a bolus dose of 125I-albumin through a peripheral venous catheter, followed by bilirubin 25 mg/kg for 5 min, then bilirubin 35 mg/kg for 55 min. There were no significant differences between the groups as regards serum bilirubin, serum albumin, brain bilirubin, or brain albumin. Neither during normoxic nor hyperoxic conditions did the hypoxanthine/xanthine oxidase system increase the accumulation of bilirubin or albumin in rat brain.

Hypoxanthine, xanthine, and uric acid concentrations in the cerebrospinal fluid, plasma, and urine of hypoxemic pigs.

The concentrations of hypoxanthine, xanthine, and uric acid in plasma and cerebrospinal fluid (CSF), as well as the urinary output of hypoxanthine and xanthine, were measured in four groups of pigs (three groups with different degrees of hypoxemia and one control group). During hypoxemia with arterial O2 tension between 2.1 and 3.0 kPa [group 1, fractional inspired oxygen (FiO2) = 0.08], hypoxanthine increased in CSF from a mean basal value of 18.1 to 39.3 mumol/L at death (p less than 0.02), in plasma from 25.4 to 103.6 mumol/L (p less than 0.05), and in urine from 21.3 to 87.1 nmol/kg/min (p less than 0.02). Xanthine changed in a similar way: in CSF from 4.0 to 10.6 mumol/L (p less than 0.02), in plasma from 0.7 to 48.1 mumol/L (p less than 0.02), and in urine from 4.0 to 12.6 nmol/kg/min (p less than 0.05). Uric acid increased in CSF from 2.7 to 11.6 mumol/L (p less than 0.05), and in plasma from 15.4 to 125.0 mumol/L (p less than 0.02). During hypoxemia with arterial O2 tension between 3.0 and 4.0 kPa (group 2, FiO2 = 0.11), hypoxanthine increased in the CSF from 14.7 to 42.9 mumol/L (p less than 0.02). Plasma hypoxanthine increased from 20.3 to a maximum of 44.1 mumol/L (p less than 0.02), but decreased to initial values by the time of death. The urinary excretion of hypoxanthine increased from 13 to 54 nmol/kg/min (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in oxypurine concentrations in vitreous humor of pigs during hypoxemia and post-mortem.

In the vitreous humor from three hypoxemic and one control group of pigs, hypoxanthine, xanthine, and uric acid concentrations were measured. The purine concentrations were measured before the hypoxemia, at the time of death, and 24 h post-mortem. During hypoxemia with arterial O2 tension between 2.1 and 3.0 kPa [fractional inspired oxygen (FiO2) = 0.08], hypoxanthine concentrations increased from a mean basal value of 11.7 +/- 5.6 mumol/L to 16.3 +/- 2.4 mumol/L at the time of death (NS). Xanthine concentrations changed from a basal value of 0.3 +/- 0.1 mumol/L to 0.6 +/- 0.2 mumol/L (p less than 0.02), and uric acid changed from 3.4 +/- 1.1 mumol/L to 5.0 +/- 4.5 mumol/L (NS). During hypoxemia with arterial O2 tension between 3.0 and 4.0 kPa (FiO2 = 0.11), hypoxanthine increased in the vitreous humor from a mean basal value of 9.1 mumol/L to 20.3 mumol/L at the time of death (p less than 0.02). Xanthine concentrations increased from 0.3 mumol/L to 1.3 mumol/L (p less than 0.05), whereas there was no change in uric acid concentration (basal 5.0 +/- 0.8 mumol/L and final 4.5 +/- 1.0 mumol/L). During milder hypoxemia with arterial O2 tension between 4.3 and 5.6 kPa (FiO2 = 0.14), or in the control group (FiO2 = 0.21), neither of the metabolites changed significantly. The vitreous humor was not stable post-mortem, inasmuch as the mean concentration of hypoxanthine increased from 18.2 +/- 7.7 mumol/L to 121.6 +/- 57.4 mumol/L 24 h post-mortem (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of the hypoxanthine/xanthine oxidase system on striatal (3H) dopamine uptake.

The effects of hypoxanthine (HX) and xanthine oxidase (XO) on the (3H)-dopamine (DA) uptake into synaptosomes of rat striatum were examined. Preincubation with 20 mU XO and 0.25 mM HX for 10 min diminished the uptake to 55% of controls. Under these conditions no increase of TBARS as an indicator of lipid peroxidation was observed. Kinetic studies revealed that the decrease in DA uptake was related to the high-affinity transport whereas the low-affinity transport carrier remained unaffected. SOD did not influence uptake inhibition, Catalase completely restituted DA uptake at an activity of 50 U. Thus, hydrogen peroxide and the hydroxyl radical appears to be involved in the deleterious action of HX/XO. The effects of this radical generating system seems to be directed to specific sites of biological membranes.