CYP2D6 genotype predicts tamoxifen discontinuation and drug response: a secondary analysis of the KARISMA trial.

BACKGROUND: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status is associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. PATIENTS AND METHODS: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were -0.8 cm2, -4.5 cm2, -4.1 cm2, and -8.0 cm2 respectively. CONCLUSIONS: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.

Resource availability affects investment in carnivory in Drosera rotundifolia.

• Carnivory in plants is restricted to nutrient-poor and open habitats presumably because of high benefits and/or low costs of carnivory in these conditions. Carnivory is costly because the plants need specific adaptations to capture prey. Drosera rotundifolia produces sticky substances on its leaf surface to catch prey. These substances are primarily carbon-based, and their production can be expected to be lower in shade. The benefit of carnivory is in terms of the increased nutritional gain which will be low when inorganic nutrients are available in the growth medium. We expected that investment in carnivory would be lower in shade and nutrient-rich conditions. • A factorial experiment involving shading and the addition of inorganic nutrients confirmed these predictions in the carnivorous, perennial herb D. rotundifolia. • Plants growing in shade or in media with nutrients added had less sticky leaves and had reduced their investment in carnivory. • Interestingly, the observed changes in the stickiness of the leaves were in accord with the carbon/nutrient balance theory, whereas a carbon-based secondary compound, 7-methyljuglone, in the leaves did not respond to shading or nutrient addition.

Prey capture by three Pinguicula species in a subarctic environment.

The number and biomass of prey captured were estimated for Pinguicula alpina, P. villosa and P. vulgaris in a subarctic environment. Seasonal captures were estimated for one site per species for 4-5 years. Captures were related to reproductive status (reproductive/non-reproductive) and to leaf area. For one species (P. vulgaris) the catch was also compared across a range of habitats. Of the seasonal catch, 50-75% was obtained during June and less than 5% during August. For P. alpina and P. villosa the seasonal catch varied threefold or more between years (means of 89-329 µg dry matter plant-1 season-1 for P. alpina, and 11-91 µg dry matter plant-1 season-1 for P. villosa), whereas the between-year variation for P. vulgaris was small (mean c. 600 µg plant-1 season-1). Large variations were, however, observed among habitats for P. vulgaris. Captured prey may contribute a substantial amount of nutrients to the most successful individuals (up to 85% of the mean seasonal turnover), but prey capture varied greatly and during any given season many individuals obtained only marginal amounts of nutrients through carnivory. P. vulgaris trapped almost twice as much per unit leaf area and season as the other two species (224 for P. vulgaris versus 127 µg cm-2 season-1 for the other two species). Reproductive individuals of P. vulgaris trapped almost twice as much as non-reproductive individuals (after taking differences in leaf area into account). For the other two species no differences were observed between reproductive and non-reproductive individuals.

Cefaclor AF in the treatment of streptococcal pharyngitis/tonsillitis.

Two double-blind, double-dummy, randomized multicentre studies compared the safety and efficacy of 10-day regimens of cefaclor advanced formulation (cefaclor AF) (375 mg twice daily) with cefaclor (250 mg three times daily) in the treatment of proven group A beta-haemolytic streptococcal pharyngitis/tonsillitis. Of the 1,138 patients enrolled, 764 (cefaclor AF:392; cefaclor: 372) were evaluated for efficacy. All patients enrolled in the studies (570 treated with cefaclor AF and 568 treated with cefaclor) were evaluated for safety. Clinical and bacteriological evaluations were performed on treatment days 4-6, and after completion of treatment within 3-5 days and 2-3 weeks. In evaluable patients, the post-therapy clinical success and bacteriological cure rates for cefaclor AF were 96.7% and 93.6%, respectively; the rates were 98.1% and 94.1% for cefaclor. Sixteen cefaclor AF-treated patients and 14 cefaclor-treated patients withdrew early from the trial because of adverse events. There were no significant differences between treatment groups in the overall number of adverse events reported. Diarrhoea was the most frequently reported adverse event (5.6%) in cefaclor AF-treated patients, and headache/migraine was the most frequently reported adverse event (5.6%) in the cefaclor-treated patients. Cefaclor AF (375 mg twice daily) is as effective and safe as cefaclor capsules (250 mg three times daily) in the treatment of streptococcal pharyngitis/tonsillitis.

Lethal horse-riding injuries.

Riding accidents can be of a serious nature. Knowledge of risk factors is of essential value in the prevention of injuries. From the years 1969 through 1982 a series of 53 lethal riding injuries is analysed with reference to the rider, the horse, and the environment. Craniocerebral injuries dominate in this series, indicating the importance of adequately protecting helmets. Among the victims the female sex is dominating before the age of 25 and the males above this age. Older horses are less frequently involved in these accidents than younger ones. A long training period for riders under surveillance of a teacher is of outmost importance. Outdoor riding should be recommended only to experienced riders.

Late results of operation for primary hyperparathyroidism in 441 patients.

The late results of operation for primary hyperparathyroidism (HPT) were analyzed in 441 patients operated on 4 to 27 years earlier (mean follow-up time, 7.7 years). A conservative surgical approach was mainly used, attempting if possible to visualize all four parathyroid glands and extirpate only the enlarged glands. Subtotal resection was performed in patients with hyperplasia. The histopathologic diagnosis was adenoma in 77% and hyperplasia in 18%. In 5% of the patients, the histopathologic classification was uncertain. Hypercalcemia persisted after operation in 8% of all patients. This generally occurred because of an incomplete neck exploration or too limited a resection in the patients with hyperplasia. Recurrent hypercalcemia occurred in 16% of the patients operated on for hyperplasia and was noted 1 to 19 years after surgery. Recurrences were also seen in 3% of the patients with adenomas but not earlier than 9 years after the operation. These findings suggest that primary HPT may even in patients with adenomatous disease, sometimes affect all parathyroid glands. Nevertheless, it was obvious that most of the patients with adenomas would not have benefited from a more radical procedure. On the other hand, it was evidently important to obtain a correct histopathologic diagnosis intraoperatively so that patients with hyperplasia could be identified and adequatley treated.

Relationship between weight reduction and state of malabsorption after jejunoileal bypass for excessive obesity.

A 10-year follow-up study of 30 patients subjected to jejunoileal bypass surgery for obesity is reported. The technique used which resulted in a jejunoileal shunt length of 50-55 cm gave satisfactory weight reduction in 75 per cent of the patients. There were no serious complications. The weight loss occurred essentially during the first 12-18 months, the main cause being defective digestion and malabsorption. In some instances this was supported by initially reduced food consumption. A certain degree of steatorrhoea persists in most cases after 10 years and may be of importance in the maintenance of the new stable weight level.