Extended adjuvant temozolomide with cis-retinoic acid for adult glioblastoma.

OBJECTIVE: To determine the toxicity and effectiveness of 24 months of adjuvant temozolomide (tmz) with cis-retinoic acid (cra) for patients with glioblastoma. METHODS: This retrospective population-based review considered the charts of all patients diagnosed with glioblastoma in Manitoba and referred to a provincial cancer centre during 2002-2008. Consecutive patients came from a population-based referral centre and provincial cancer registry. All patients were treated according to the local standard of care with surgical resection followed by concurrent radiotherapy and tmz 75 mg/m(2) daily, followed by tmz 150-200 mg/m(2) for days 1-5, repeated every 28 days for up to 24 cycles, and cra 50 mg/m(2) twice daily for days 1-21, repeated every 28 days. The main outcome measures were safety, tolerability, and effectiveness of long-term tmz and cra. RESULTS: Of 247 patients diagnosed with glioblastoma in Manitoba during the study period, 116 started concurrent chemoradiotherapy, and 80 received adjuvant tmz. Of the patients who started concurrent chemoradiotherapy, 80 began adjuvant chemotherapy. Patients completed a median of 5.5 cycles of tmz and 3 cycles of cra. Grade 3 or 4 hematologic toxicity was noted in 16% of patients. Median overall survival was 15.1 months, and 26.7% of patients remained alive at 2 years. CONCLUSIONS: Extended adjuvant tmz and cra is well tolerated. However, the population-based effectiveness of this regimen is similar to the clinical trial efficacy of 6 months of adjuvant tmz. Future studies in glioblastoma should incorporate duration of adjuvant chemotherapy into the study design.

A National Cancer Institute of Canada Clinical Trials Group Study--IND.135: Phase I/II study of irinotecan (camptosar), oxaliplatin and raltitrexed (tomudex) (COT) in patients with advanced colorectal cancer.

Thirty-one patients with metastatic colorectal cancer were enrolled in this phase I/II trial of a triple combination of camptosar (C), oxaliplatin (O) and tomudex (T), all given on day one of a convenient three-week schedule. Patients received 257 cycles (1-18) in five cohorts. Toxicity was manageable and haematological toxicity was mild to moderate. Diarrhoea was the main dose-limiting toxicity; nausea and vomiting were common. Fatigue was frequent, moderate in severity and a reason for discontinuation in some patients. The recommended phase II doses were (C) 220 mg/m(2), (O) 100mg/m(2), (T) 2.75 mg/m(2). A 50% response rate in 30 evaluable patients was confirmed by an independent radiology review board; progression-free survival and overall median survival were 7.3 months and 16.6 months, respectively. Of the 16 patients treated at the recommended dose, 9 (56.3%) experienced partial response. Further evaluation in a randomized study compared to sequential doublets is warranted. Triple combinations could be relevant in curative settings for high-risk patients.

Two-site assay of bovine parathyroid hormone.

A two-site assay has been developed for bovine PTH. This technique involves reaction of the antigen with two antibody molecules with the purpose of increasing specificity. In paratice the hormone was extracted form plasma samples on to plastic tubes coated with antibody specific for PTH (1-34). Uptake was then measured using 125I-labelled antibodies specific for PTH (53-84). In this way a sensitive assay was obtained for PTH (1-84) which did not recognize molecular fragments. This technique was used in conjunction with immunoradiometric assays specific for either NH2-terminal (1-34) or CO2H-terminal (53-84) molecular fragments to study the clearance of infused PTH in the cow. Preliminary results support the hypothesis that the intact molecule is rapidly degraded in the peripheral circulation with the preferential disappearance of an NH2-terminal fragment. Studies on endogenous secretion during calcium and EDTA infusions indicated that there was little intact hormone present at the times when CO2H-terminal immunoreactivity was readily measured.

An estimate of the cost of conducting phase II trials in lung cancer.

OBJECTIVE: Although it is commonly assumed that clinical trials are more costly than standard therapy, there have been no previous studies of the cost of conducting phase II trials in lung cancer. We retrospectively analyzed two National Cancer Institute of Canada phase II trials in previously untreated small cell lung cancer (SCLC) to determine the costs of conducting the trials in a cancer treatment centre. Both studies were clinical trials undertaken as part of the NCIC's Investigational New Drug program: IND 69 and IND 50 evaluated docetaxel (taxotere) and gemcitabine, respectively. METHODS: data management costs in a Canadian cancer treatment centre were determined from the time estimates provided by data managers to complete various protocol related tasks. Nursing and pharmacy personnel measured the time and supplies necessary to prepare and administer the chemotherapy. Physician fees were determined from the type and number of care visits required by the clinical protocols. Laboratory tests and imaging studies were costed according to the Ontario Health Insurance Plan (OHIP) Schedule of Fees and Benefits. To estimate whether phase II trials are more costly than standard treatment, we determined the cost of four cycles of VP-16-cisplatin, a standard treatment for SCLC. RESULTS: The total cost of performing the docetaxel study was $18443 for an average cost per case of $1317 and an average cost per treatment cycle of $683. The gemcitabine study cost more, due to the fact that the drug proved to be active against SCLC and more cycles of therapy were administered to a larger number of patients. Laboratory and administration costs were also higher, because of the drug administration schedule. The total cost of this study was estimated to be $64670 and the average cost per patient entered was $2230 with an average cost per treatment cycle of $898. In comparison, the estimated cost of four cycles of VP-16-cisplatin chemotherapy was $3948 or $987 per treatment cycle. The major cost drivers in the clinical trials were laboratory and imaging tests which made up 17 and 39%, respectively, of the costs of the taxotere study, and 29 and 27%, respectively, for the gemcitabine study. Data management costs contributed 21 and 13% of the total costs, respectively. CONCLUSION: As the main cost drivers in these phase II clinical trials are laboratory and imaging tests, the cost of clinical trials could potentially be reduced by ensuring that only essential tests are required by protocol. Not surprisingly, the cost of conducting a trial of an active agent is greater than for an inactive agent, because more patients are treated and each patient receives more treatment. The implications for the per-case funding of phase II clinical trials are discussed.

Transformations of codeine to important semisynthetic opiate derivatives by Pseudomonas putida m10.

A biotransformation mixture which contained codeine and washed cells of Pseudomonas putida M10 gave rise to a number of transformation products that are of clinical importance which included hydrocodone, dihydrocodeine and 14beta-hydroxycodeine. Incubations with the same organism and codeinone gave rise to 14beta-hydroxycodeinone and 14beta-hydroxycodeine. Cell-free extracts and membrane fractions of P. putida M10 were shown to catalyse the 14beta-hydroxylation of codeinone. In addition, the potent analgesic oxycodone was shown to be produced from 14beta-hydroxycodeinone.

Pediatric all-terrain vehicle trauma: a 5-year statewide experience.

BACKGROUND/PURPOSE: This is a retrospective review of the pediatric all-terrain vehicle trauma victims who presented to the five major trauma centers serving the state of West Virginia during the 5-year period from January 1991 to December 1995. The purpose of this research is to characterize the nature of the injuries and the individuals injured to better appreciate the magnitude of the problem of ATV-related injuries in the pediatric population. METHODS: This study is a retrospective review of these 218 consecutive pediatric patients from trauma registry data and their medical records. RESULTS: Two hundred eighteen patients between the ages of 2 years and 16 years presented during the study period. Boys outnumbered girls three to one. The average Injury Severity Score (ISS) was 8.76, the average Glasgow Coma Score (GCS) was 14.4, and the average Trauma Score (TS) was 15.2. The most common injuries were orthopedic followed by head and facial injuries. The majority of the children did not wear helmets, and their injuries resulted in an average hospital length of stay of 4.3 days. Thirty-eight percent of the children required surgery. There were a total of four deaths for a mortality rate of 1.8%. The estimated total hospitalization cost for the 218 patients was $1,918,400.00. CONCLUSIONS: All-terrain vehicle-related trauma remains an ongoing safety concern facing society today. Every physician who cares for children should address this important issue when talking to children and parents about safety issues and injury prevention.

Adipose tissue capillary blood flow in relation to fatness in sheep.

Capillary blood flow rate was measured in eight fat depots in eight Blackface and eight Clun lambs using the radiolabelled microsphere technique. Adipose tissue flow ranged from 3 to 47 ml 100 g-1 min-1 depending upon depot and degree of fatness. Blood flow declined with increasing fatness suggesting that perfusion was not an important constraint on the growth of fat. Blood flow rates were also measured in the fed and 26 hour fasted states but no effect from fasting was observed.

Studies on the sympathetic nervous system: the Valsalva like manoeuvre in sheep.

The Valsalva like manoeuvre (VLM) was examined as a test of the responsiveness of the autonomic nervous system in sheep. Within individuals, imipramine pretreatment enhanced the peak blood pressure and heart rate responses to the VLM and atropine prolonged the tachycardia without influencing the peak responses. Between individuals, the peak blood pressure response was related to the degree of hypotension during raised airway pressure (r = 0.77). The degree of hypotension was, in turn, related to gut fill (r = 0.64). Differences in gut fill were ascribed as a cause of variation in the heart rate and blood pressure responses between individual sheep and between the Scottish Blackface and Southdown breeds.

Breed differences in the position of the urethral meatus of gilts.

In a strain of Pietrain the distance between the vulva and the urethral meatus is greater than that of other breeds of pig. This difference is such that it is difficult to catheterise the bladders of Pietrain gilts since the available specula are either too short in length or too wide in diameter.

The effect of passive immunization against somatostatin on marker retention time in lambs.

The effects of passive immunization against somatostatin on retention time of marker have been investigated in sheep using Cr2O3 as a marker. The mean transit time for clearance of 50% of the marker was significantly retarded in all the anti-somatostatin-treated animals by approximately 19.0 h, as compared with control lambs given a nonspecific antiserum. The findings suggest an important role for circulating somatostatin in the regulation of the rate of flow of digesta through the gastrointestinal tract in lambs. Moreover, it enhances the claim of the immunological approach as a new technique to investigate factors controlling food utilization in farm livestock.

Improvement of meat quality in pigs by beta-adrenergic blockade.

The value of giving pigs the beta-adrenergic blocking drug carazolol preslaughter to improve meat quality was tested in a stress-resistant breed (Large White) and a stress-susceptible breed (Pietrain). Pigs averaging about 70kg liveweight were injected intramuscularly (1 mg per 100 kg liveweight) 0·5h before being transported to the slaughterhouse. The journey lasted 4 h and covered about 150 km and the pigs were slaughtered after 1 h in lairage. Treatment with carazolol reduced the incidence of PSE meat and considerably improved meat quality in the stress-susceptible Pietrain breed but had little effect in the stress-resistant Large Whites which produced good meat quality in both control and treated groups.

Energy substrate provision in vivo and the changes in muscle pH post mortem.

The effects of alpha- and of beta-adrenergic stimulation (both with and without concurrent blockade of lipolysis) on energy substrate provision in vivo, and the subsequent changes in muscle metabolism post mortem, were studied in sheep. Treatment with the alpha-agonist phenylephrine had no effect upon plasma glycerol, free fatty acids, glucose or lactate levels or on muscle metabolism post mortem. Concurrent treatment with an inhibitor of lipolysis, methyl pyrazole carboxylic acid (MPCA), caused a reduction in plasma free fatty acids and glycerol and some decrease in muscle glycogen levels at slaughter. Administration of the beta-agonist, isoproterenol, stimulated an increase in plasma levels of all the energy substrates measured and caused a marked increase in liver glycogen and a decrease in muscle glycogen at slaughter, but no dark cutting. However, when energy from fat depots was blocked by MPCA during beta-stimulation, muscle glycogen was almost exhausted at slaughter and dark cutting was found in all the carcasses. From these experiments it is concluded that dark cutting meat does not result solely from increased adrenergic stimulation, but is dependent upon the availability of energy substrates from muscle, liver and fat energy stores.

Caffeine stimulated lipolysis protects pigs against catecholamine-induced dark cutting.

High ultimate pH dark cutting meat was obtained in Pietrain pigs following overnight intravenous infusion of the ß-adrenergic agonist, isoproterenol. This effect was enhanced by simultaneous administration of the antilipolytic agent nicotinic acid and completely reversed by pretreatment of the animals with caffeine (which stimulates lipolysis). These results suggest that the availability of energy substrates from adipose tissue (free fatty acids and glycerol) is an important factor in the production of dark cutting meat. Stimulation of lipolysis in animals prior to pre-slaughter stresses (such as transport and lairing) could possibly reduce the incidence of dark cutting meat.

Anaesthesia of pigs sensitive to malignant hyperthermia.

During general anaesthesia some pigs develop a hyperthermic response which is often fatal. The syndrome is most common in pigs which are susceptible to stress and have a low proportion of body fat. On the basis of an experimental investigation in Pietrain pigs recommendations are presented for the clinical management and treatment of susceptible animals.

Thyroid activity in relation to growth rate and body composition in four breeds of sheep.

Four breeds of sheep, Hampshire, Southdown, Cheviot and Scottish Blackface, which differ in mature body size and body composition were intensively reared under an ad libitum or a restricted feeding regime. Thyroid activity was assessed at 13 weeks of age by the 131I uptake method. Slaughter at 24 weeks (ad lib) or 32 weeks (restricted) was followed by carcass dissection. The anticipated differences in body type represented by the 4 breeds was confirmed in terms of size and fatness. The Hampshires had the highest growth rate (liveweight for age) and the lowest thyroid uptake, and the breed differences in thyroid activity were shown to be independent of liveweight. Thyroid activity was positively related to growth rate in the Hampshires and negatively related to growth rate in the 3 other breeds. No association could be found however between the thyroid activity and the proportionate growth of body fat or lean. None of these conclusions were affected by a mild restriction in fed intake.

The effect of chronic neonatal guanethidine treatment on body composition in pigs.

The effect of neonatal guanethidine administration (30 mg/kg/day) during the first 32 days of life on body composition at 20 weeks of age, was assessed in two breeds of pig which were known to differ in their sympathetic responsiveness. Guanethidine administration increased the proportion of fat and decreased the proportion and absolute weight of lean in the Pietrain breed; and it had no effect in Gloucester Old Spots. Thus it can be inferred that endogenous noradrenaline is responsible for promoting leanness in a pig breed with known sympathetic overactivity.