AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin.

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

Greater performance impairment of black runners than white runners when running in hypoxia.

This study aimed to compare the response of performance-matched black and white runners during maximal and sub-maximal running in normoxic and hypoxic conditions. 14 well-trained runners (8 black, 6 white) performed 2 incremental maximal exercise tests and 2 fatigue resistance tests at 21% O2 (normoxia) or 14% O2 (hypoxia). Respiratory parameters, heart rate (HR), lactate concentration ([La(-)]) as well as arterial saturation (SpO2) were measured. Enzyme activities and myosin heavy chain content (MHC) were also measured. White runners reached a significantly greater peak treadmill speed and a higher HRmax than black runners in hypoxia (p<0.05). Additionally, White runners achieved a greater time to fatigue than black runners (p<0.05), with black runners displaying a greater decline in performance in hypoxia compared to normoxia (20.3% vs. 13.4%, black vs. white, respectively). However, black runners presented lower [La(-)] and higher SpO2 than white runners in hypoxia (p<0.05). Black runners had a higher proportion of MHC IIa and higher lactate dehydrogenase activity (p<0.05). The greater performance impairment observed in black runners in hypoxia suggests a greater performance sensitivity to this condition, despite the maintenance of physiological variables such as SpO2 and [La (-) ] within a smaller range than white runners.

Local recurrence of rectal cancer: a population-based cohort study of diagnosis, treatment and outcome.

AIM: Local recurrence is an important endpoint of rectal cancer treatment, but details of this form of treatment failure are less well described. The aim of this study was to acquire deeper knowledge of local recurrence regarding symptoms, diagnostic work-up, clinical management, health-care utilization and outcome. METHOD: Of 671 patients with rectal cancer, 57 were diagnosed with local recurrence within 5 years after surgery. Their records were analysed. RESULTS: At diagnosis of local recurrence 49 (86%) of 57 patients were symptomatic and 40 (70%) were diagnosed between scheduled follow-up visits. The predominant symptom was pain. Forty-five of the 57 (79%) had a palpable tumour. Most were deemed incurable at presentation and 10 (18%) were operated on with curative intent. Five years after the initial rectal cancer surgery, two patients were alive, with one free of disease. Despite the need for multiple interventions, including surgery, only four out of 40 patients were classified as being well-palliated in the terminal stage. CONCLUSION: Follow-up after rectal cancer surgery by annual clinical examination is not sufficient to detect local recurrence when it is asymptomatic. Local recurrence of rectal cancer is often associated with intractable symptoms. These patients require frequent interventions and can rarely be cured if diagnosed at an advanced stage. Strategies for early detection of local recurrence and the management thereof require improvement.

Specific muscle adaptations in type II fibers after high-intensity interval training of well-trained runners.

High-intensity interval training (HIIT) forms an important component of endurance athletes' training, but little is known on intramuscular metabolic and fiber type adaptations. This study investigated physiological and skeletal muscle adaptations in endurance runners subjected to 6 weeks HIIT. Eighteen well-trained endurance athletes were subjected to 6 weeks HIIT. Maximal and submaximal exercise tests and muscle biopsies were performed before and after training. Results indicated that peak treadmill speed (PTS) increased (21.0 ± 0.8 vs 22.1 ± 1.2 km/h, P<0.001) and plasma lactate decreased at 64% and 80% PTS (P<0.05) after HIIT. Cross-sectional area of type II fibers tended to have decreased (P=0.06). No changes were observed in maximal oxygen consumption, muscle fiber type, capillary supply, citrate synthase and 3-hydroxyacetyl CoA dehydrogenase activities. Lactate dehydrogenase (LDH) activity increased in homogenate (P<0.05) and type IIa fiber pools (9.3%, P<0.05). The change in the latter correlated with an absolute interval training speed (r=0.65; P<0.05). In conclusion, HIIT in trained endurance runners causes no adaptations in muscle oxidative capacity but increased LDH activity, especially in type IIa fibers and in relation to absolute HIIT speed.

Hyperbaric oxygen in the treatment of postoperative infections in paediatric patients with neuromuscular spine deformity.

The aim of this study is to evaluate possible benefits of hyperbaric oxygen (HBO) therapy in the treatment of deep postoperative infections in six high risk paediatric patients with neuromuscular spine deformity. The study involved review of medical records including radiology, office visits, and telephone contacts for six patients, referred for postoperative HBO therapy in 2003-2005. Infection control and healing without removal of implants or major revision surgery with a minimum of 2-year follow-up after index surgery were considered to represent success. All infections were resolved. Median time for wound healing, normalisation of blood tests and antibiotic weaning were 3 months. Radiological bony fusion, intact implants without any signs of radiolucent zones were seen in all cases at a mean follow-up of 54 months (37-72). Side effects of HBO treatment were minor. HBO is a safe and potentially useful adjuvance in the treatment of early deep postoperative infections in complex situations with spinal implants in high risk paediatric patients.

A new auroral phenomenon, the anti-black aurora.

Black auroras are small-scale features embedded in the diffuse background aurora, typically occurring post-substorm after magnetic midnight and with an eastward drift imposed. Black auroras show a significant reduction in optical brightness compared to the surrounding diffuse aurora, and can appear as slow-moving arcs or rapidly-moving patches and arc segments. We report, for the first time, an even more elusive small-scale optical structure that has always been observed occurring paired with [Formula: see text] 10% of black aurora patches. A patch or arc segment of enhanced luminosity, distinctly brighter than the diffuse background, which we name the anti-black aurora, may appear adjacent to the black aurora. The anti-black aurora is of similar shape and size, and always moves in parallel to the drifting black aurora, although it may suddenly switch sides for no apparent reason. The paired phenomenon always drifts with the same average speed in an easterly direction. From the first dual-wavelength (427.8 nm and 844.6 nm) optical observations of the phenomenon recorded on 12 March 2016 outside Tromsø Norway, we show that the anti-black and black auroras have a higher and lower mean energy, respectively, of the precipitating electrons compared to the diffuse background.

The non-inherited maternal HLA haplotype affects the risk for type 1 diabetes.

The aim was to test the hypothesis that the human leucocyte antigen (HLA) haplotype that is not inherited from the mother, that is, the non-inherited maternal antigen (NIMA) affects the risk for type 1 diabetes (T1D). A total of 563 children with T1D and 286 non-diabetic control children from Sweden were genotyped for DRB1, DQA1 and DQB1 alleles. The frequency of positively (DR4-DQA1*0301-B1*0302 and DR3-DQA1*0501-B1*0201), negatively (DR15-DQ A1*0102-B1*0602) or neutrally (all other) T1D associated HLA haplotypes were compared between NIMA and non-inherited paternal antigen (NIPA). All comparisons were carried out between HLA-matched patients and controls. The frequency of positively associated NIMA was higher among both DR4/X-positive healthy individuals compared wit DR4/X-positive patients (P < 0.00003) and DR3/X-positive healthy individuals compared with DR3/X-positive patients (P < 0.009). No such difference was observed for NIPA. High-risk NIMA was increased compared to NIPA among healthy DR3/X- and DR4/X-positive children (P < 0.05). There was no difference in frequency of positively associated haplotypes between patient NIMA and NIPA. The NIMA but not the NIPA affects the risk for T1D, suggesting that not only the inherited but also non-inherited maternal HLA haplotypes, perhaps through microchimerism or other mechanisms, may influence the risk for the disease.

Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism.

Streptozotocin (STZ) given intravenously destroys pancreatic beta cells and is widely used in animal models to mimic type 1 diabetes. The effects of STZ on the clinical state of health and metabolism were studied in six high health certified domestic pigs weighing 19+/-1.3 kg at the start of the experiment. A single STZ dose of 150 mg/kg of body weight successfully induced hyperglycaemia and alterations in amino acid metabolism. Within 9 h after STZ administration, the blood glucose values fell from 5.4-7.5 mmol/L to 0.8-2.2 mmol/L. Hypoglycaemia was treated with 0.5 g glucose/kg body weight. In all pigs, hyperglycaemia was produced 24 h after STZ treatment, and 3 days after STZ injection, the glucose concentration was >25 mmol/L. Mean C-peptide concentration was 0.25+/-0.16 microg/L since 2 days after STZ injection until the end of the study. The serum concentration of the branched-chain amino acids (BCAA) increased four-fold, and alanine and taurine decreased by approximately 70% and 50%, respectively, after STZ treatment. All but one pig remained brisk and the physical examination was normal except for a retarded growth rate and a reduction of the skeletal muscle. At the end of the study, the pigs were moderately emaciated. Postmortem examination confirmed muscle wasting and a reduction of abdominal and subcutaneous fat. In conclusion, STZ-induced diabetes in pigs fulfils the requirements for a good animal model for type 1 diabetes with respect to clinical signs of the disease and alterations in the carbohydrate and amino acid metabolism.

Stage migration in colorectal cancer related to improved lymph node assessment.

AIM: The aim of the study was to evaluate the clinical impact of improved cooperation between the treating surgeons and pathologists in a high volume surgical unit. As a measure we used the staging process with special focus on lymph node assessment. FINDINGS: Comparing two periods 5 years apart, we found a significant increase in the number of nodes examined and also an increase in the number of metastasis-positive nodes. Concurrently, we observed a trend in stage migration from stage I/II towards stage III, whilst stage IV remained unchanged. This was one factor that contributed to an increase in the number of patients treated with adjuvant chemotherapy. We also found that the number of assessed nodes had an impact on survival in stage II. The major change in practise was the implementation of a multidisciplinary team conference and the associated possibility of reciprocal feedback. CONCLUSION: Lymph node status has a key role in cancer staging and in the selection of further therapy. The quality and the standard of the assessment can be improved through multidisciplinary cooperation and it has an impact on the clinical decisions and can affect long-term survival. A correct node status should be mandatory in the evaluation of prognostic factors.

Blood concentrations of amino acids, glucose and lactate during experimental swine dysentery.

The aim of this study was to examine blood concentrations of amino acids, glucose and lactate in association with experimental swine dysentery. Ten pigs (approximately 23kg) were orally inoculated with Brachyspira hyodysenteriae. Eight animals developed muco-haemorrhagic diarrhoea with impaired general appearance, changes in white blood cell counts and increased levels of the acute phase protein Serum Amyolid A. Blood samples were taken before inoculation, during the incubation period, during clinical signs of dysentery and during recovery. Neither plasma glucose nor lactate concentrations changed during the course of swine dysentery, but the serum concentrations of gluconeogenic non-essential amino acids decreased during dysentery. This was mainly due to decreases in alanine, glutamine, serine and tyrosine. Lysine increased during dysentery and at the beginning of the recovery period, and leucine increased during recovery. Glutamine, alanine and tyrosine levels show negative correlations with the numbers of neutrophils and monocytes. In conclusion, swine dysentery altered the blood concentrations of amino acids, but not of glucose or lactate.

Chemical monitoring of Swedish coastal waters indicates common exceedances of environmental thresholds, both for individual substances as well as their mixtures.

Chemical pollution was monitored and assessed along the Swedish west coast. 62 of 172 analyzed organic chemicals were detected in the water phase of at least one of five monitored sites. A Concentration Addition based screening-level risk assessment indicates that all sites are put at risk from chemical contamination, with total risk quotients between 2 and 9. Only at one site did none of the individual chemicals exceeded its corresponding environmental threshold (PNEC, EQS). The monitoring data thus demonstrate a widespread blanket of diffuse pollution, with no clear trends among sites. Further issues critical for the environmental chemical risk assessment include the challenges to achieve sufficiently low levels of detection, especially for hormones and cypermethrin (a pyrethroid insecticide), the appropriate consideration of non-detects and the limited availability of reliable PNECs and EQS values.

Octreotide scintigraphy and Chromogranin A do not predict clinical response in patients with octreotide acetate-treated hormone-refractory prostate cancer.

In this pilot study, the predictive value of Octreotide scintigraphy (Octreoscan) and/or Chromogranin-A (CgA) was investigated in patients with hormone-refractory prostate cancer treated with Octreotide acetate. In total, 20 patients with progressive disease and bone metastases entered the trial. At baseline Octreoscan, CgA, PSA, alkaline phosphates (ALP) and two self-administered questionnaires (EORTC QLQ C-30 (v3) and brief pain index) were performed and a diary of the pharmaceutical was started. The treatment consisted of Octreotide (Sandostatin LAR) acetate 30 mg intramuscular injection every month. The blood samples and questionnaires were repeated every month until 3 months. Clinical responder was defined as a patient with increased global health score more than 10 units and stable or decreased pain score without an increase in analgesic. In all, 17 patients were treated per protocol, and four were assessed as clinical responders. Six patients developed a reduction in ALP (median -26%, range -5 to -78%). All patients increased in PSA. At baseline, three patients had a negative Octreoscan and the patients with positive lesions, demonstrated uptake of low intensity. At baseline the CgA was elevated above the normal range in 15 of the patients, and during treatment five patients decreased their CgA to the normal range. Neither baseline Octreoscan nor CgA could identify the clinical reponders. A minority of patients improves their health-related quality of life. The decrease and normalization of CgA levels in five patients during therapy indicates therapeutic activity but Octreoscan and CgA could not identify clinical responders.

Metabolic and signaling events mediated by cardiotonic steroid ouabain in rat skeletal muscle.

The cardiac glycoside ouabain initiates a cascade of signaling events through Na+,K+-ATPase, leading to an increase in cell growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in skeletal muscle and clarified the mechanisms of ouabain signal transduction. In rat soleus muscle 200 microM ouabain decreased basal glucose uptake without effect on insulin-stimulated glucose uptake. Ouabain increased glycogen synthesis additively to insulin and this effect was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a c-Src inhibitor (PP2). Ouabain exposure reduced glucose oxidation, and this effect was reversed in the presence of PP2. Incubation with ouabain did not affect intramuscular ATP and its metabolites; however acetyl-CoA carboxylase phosphorylation was reduced, with no effect on AMPK phosphorylation. Insulin-stimulated Akt phosphorylation was not affected by ouabain. Ouabain reduced basal and insulin-stimulated phosphorylation of PKC alpha/beta and delta isoforms, whereas phosphorylation of PKCzeta was unchanged. Ouabain exposure increased interaction of 1- and 2-subunits of Na-pump with c-Src, as assessed by co-immunoprecipitation with c-Src. Phosphorylation of ERK1/2, GSK 3 / and p90rsk activity was increased in response to ouabain, and these effects were prevented in the presence of PD98059 and PP2. In conclusion, the cardiac glycoside ouabain stimulates glycogen synthesis additively to insulin in rat skeletal muscle. This effect is mediated by activation of c-Src-, ERK1/2- p90rsk- and GSK3-dependent signaling pathway.

Mechanisms of innate resistance to thymidylate synthase inhibition after 5-fluorouracil.

Fifty-four patients with metastatic adenocarcinoma received i.v. bolus 5-fluorouracil, 500 mg/m2, prior to surgical biopsy of tumor at 20-400 min, for analysis of biochemical parameters of resistance to thymidylate synthase (TS) inhibition. The majority of patients, 37, had colon or rectal adenocarcinoma, five had breast cancer, five had gastric primary disease, four had pancreatic adenocarcinoma, and three had hepatocellular adenocarcinoma. Fluorodeoxyuridylate (FdUMP) was assayed by isotope dilution of [3H]FdUMP binding to bacterial TS; free and total TS was determined by [3H]FdUMP binding; and deoxyuridylate (dUMP) was assayed by conversion to [14C]thymidylate. Free levels of TS were lower in breast cancers, 0.08 +/- 0.06 pmol/g, than in other histologies (overall average, 1.41 +/- 2.25), associated with significantly greater percentages of TS inhibition (88.6% versus 62.0% overall). Colorectal tumors showed significantly greater FdUMP levels than other gastrointestinal malignancies, associated with somewhat lower free TS values. Plots of FdUMP levels, or (FdUMP/dUMP) x 100 values versus percentages of TS inhibition suggested minima of 75 pmol/g and 0.10, respectively, for achieving maximal enzyme inhibition. Analyses of normal tissues showed: poor TS inhibition in liver and normal colonic mucosa, related to low FdUMP levels; and very high dUMP levels in bone marrow leukocytes suggestive of reactive increases in dUMP as an important mechanism of recovery in this tissue. Among the 30 of the 37 colorectal tumors that showed suboptimal (less than 85%) inhibition of TS, 16 (53%) showed FdUMP levels less than 75 pmol/g, 8 (27%) showed relatively high dUMP levels (over 35 nmol/g), and 16 (53%) showed poor efficiency of inhibition of TS, with the major overlap between these mechanisms of resistance being high dUMP and poor binding in 6 (20%). These data provide a strong rationale for administration of leucovorin to the majority of patients receiving 5-fluorouracil, since increased intratumoral reduced folates potentially can overcome multiple mechanisms of resistance including low FdUMP, high dUMP, and high total TS levels, in addition to that caused by isolated folate deficiency.

Quantitation of thymidylate synthase, dihydrofolate reductase, and DT-diaphorase gene expression in human tumors using the polymerase chain reaction.

A polymerase chain reaction (PCR)-based method was used to quantitate the expression levels of low abundance genes relevant to cancer drug activity. RNA from tumor samples as small as 20 mg was isolated and converted to cDNA using random hexamers. The 5' primers for the PCR contained a T7 polymerase promoter sequence, allowing the PCR-amplified DNA to be transcribed to RNA fragments. In each sample, the linear ranges of amplification of each cDNA of interest were established. Relative gene expressions were calculated by extrapolating the amounts of PCR products generated within the linear amplification regions of each gene to equal volumes of the cDNA solution. The method was accurate to less than a 2-fold difference in expression levels. Using beta 2-microglobulin and beta-actin gene expressions as internal reference standards and cDNA from HT-29 cells as an external linearity standard, we measured the relative expressions of thymidylate synthase, dihydrofolate reductase, and DT-diaphorase in a number of clinical tumor samples. The expressions of these genes varied from 50- to 100-fold among different tumors, although most of the values were grouped within about a 10-fold range. The amount of thymidylate synthase gene expression in tumor tissues was directly proportional to the content of thymidylate synthase protein. Those tumors with the lowest thymidylate synthase expression had the best response to both the 5-fluorouracil-leucovorin and 5-fluorouracil-cisplatin combinations.

Thymidylate synthetase inhibition in malignant tumors and normal liver of patients given intravenous 5-fluorouracil.

Single surgical biopsies of solid tumor were obtained at 20 to 240 min after drug administration in 21 patients given first-dose bolus i.v. 5-fluorouracil (5-FUra), 500 mg/sq m, and assayed for 5-fluorodeoxyuridylate (FdUMP), deoxyuridylate (dUMP), total thymidylate synthetase (TS), and non-FdUMP-bound, free enzyme. Nineteen patients had cancer of gastrointestinal origin, 13 of these colorectal, and 2 patients had breast adenocarcinoma. In 9 patients, synchronous biopsies of surgically normal liver were obtained along with samples of hepatic tumors metastatic from gastrointestinal sites. Total TS averaged 4.18 pmol/g in the malignant tissues and 2.23 pmol/g in liver. FdUMP levels in the gastrointestinal tumors were higher than in normal liver, were highest at the earliest time interval studied, 20 to 30 min, and appeared to decrease exponentially through 120 min. TS inhibition averaged 70 to 80% in gastrointestinal tumor biopsies and less than 50% in normal liver. Levels of dUMP were low and varied little with time. Those gastrointestinal tumors with higher FdUMP:dUMP ratios showed significantly greater TS inhibition. Tumors of 3 patients who benefited from 5-FUra therapy (1 patient with colonic adenocarcinoma and the 2 patients with breast adenocarcinoma) showed greater TS inhibition than did tumors of remaining patients. It is concluded that the apparent time course changes observed in FdUMP, dUMP, and TS in the grouped data are qualitatively similar to findings of murine studies in vivo and that the relationship between FdUMP:dUMP ratios and TS inhibition are consistent with established in vitro enzymic kinetics. Thus, biopsies of tumors at short time periods after 5-FUra administration may be usefully studied for biochemical parameters of TS inhibition, with the objectives of correlation of sensitivity to subsequent 5-FUra therapy and clarification of mechanisms of drug resistance.

Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group.

PURPOSE: To compare raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC). PATIENTS AND METHODS: A total of 495 patients were randomized to raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks. RESULTS: The randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the raltitrexed group. Overall objective responses were comparable (19% raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 stomatitis (2% v 16%, P < .001) and a reduced incidence of leukopenia (6% v 13%) and diarrhea (10% v 19%) occurred in the raltitrexed group (particularly at cycle 1 ). This resulted in fewer dose reductions at cycle 2 (4% raltitrexed v 28% 5-FU/LV) and early quality-of-life (QoL) benefits for raltitrexed patients. Reversible, clinically insignificant increases in transaminases were reported in 13% of raltitrexed patients. Palliative benefits of weight gain, improved performance status, and reduced disease-related symptoms were evident in both groups. CONCLUSION: Raltitrexed is confirmed as an effective option in the first-line palliative management of ACC, with comparable efficacy to and tolerability advantages (in terms of reduced incidence of stomatitis, diarrhea, and leukopenia) over 5-FU/LV. Raltitrexed has the added convenience of an every 3 weeks dosing schedule.

P-Glycoprotein inhibitor valspodar (PSC 833) increases the intracellular concentrations of daunorubicin in vivo in patients with P-glycoprotein-positive acute myeloid leukemia.

PURPOSE: The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment. PATIENTS AND METHODS: Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)-positive. dnr 100 mg/m(2) was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography. RESULTS: The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 micromol/L in Pgp-negative samples and 13.5 micromol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 micromol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P<.05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed. CONCLUSION: These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.

Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous vasopressin in non-resectable pancreas cancer.

BACKGROUND: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity. AIM: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer. PATIENTS/METHODS: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750-1500 mg/m2 and intravenous Leucovorin 100 mg/m2 for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed. RESULTS: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8-54.1+), and median survival was 8.0 months (0.8-54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4+/-2.5 and 6.1+/-5.4 mumol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment. CONCLUSION: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.

Housing-related activity in rats: effects on body weight, urinary corticosterone levels, muscle properties and performance.

The cage systems commonly used for housing laboratory rats often result in sedentary and overweight animals, as a consequence of restricted opportunities for physical activity combined with ad libitum feeding. This can have implications both for animal well-being and for the experimental outcome. Physical activity has several known positive effects on health and lifespan, and physical fitness might therefore be incorporated into the animal welfare concept. The aim of this study was to investigate if and how pen housing affects the physical activity and fitness of rats. Thirty-two juvenile male Sprague-Dawley rats were randomly assigned to two different housing systems for a 4-week period. Sixteen rats were kept individually in standard Makrolon type III cages (42x26x18 cm) furnished with black plastic tubes (singly-housed, SI). The remaining rats were kept in groups of eight, housed in large floor pens (150x210 cm), which were furnished with various objects to increase environmental complexity (pen-housed, PH). The body weight gain, and food and water intake of the rats were measured. During weeks 3 or 4, home cage behaviour, urinary cortiosterone/creatinine ratios (CO/CR), and muscle strength on an inclined plane, were measured. Enzyme activities and glycogen content were measured in tissue samples from m. triceps brachii taken after euthanization at the end of the study. There were no significant differences between groups for food and water intake, but PH rats weighed 14% less than SI rats after 4 weeks, and PH rats also had a more diverse behavioural pattern than SI rats. PH rats had significantly higher oxidative capacity (28% more citrate synthase (CS)) and greater glycogen content (28%) in their muscle samples than SI rats. The PH rats performed significantly better on the inclined plane, both in the muscle strength test (mean angle 75+/-0.5 degrees for PH rats and 69+/-0.4 degrees for SI rats) and the endurance strength test (mean time 233+/-22 s for PH rats and 73+/-14 s for SI rats). There was a negative correlation between body weight and results on the inclined plane for the PH rats. There were no significant differences between housing types with respect to CO/CR ratios. In conclusion, the large pen represents an environment that stimulates physical activity and more varied behaviour, which should be beneficial for the welfare of the animal.