Construction of a FRAX® model for the assessment of fracture probability in Canada and implications for treatment.

UNLABELLED: We describe the creation of a FRAX® model for the assessment of fracture probability in Canadian men and women, calibrated from national hip fracture and mortality data. This FRAX tool was used to examine possible thresholds for therapeutic intervention in Canada in two large complementary cohorts of women and men. OBJECTIVE: To evaluate a Canadian World Health Organization (WHO) fracture risk assessment (FRAX®) tool for computing 10-year probabilities of osteoporotic fracture. METHODS: Fracture probabilities were computed from national hip fracture data (2005) and death hazards (2004) for Canada. Probabilities took account of age, sex, clinical risk factors (CRFs), and femoral neck bone mineral density (BMD). Treatment implications were studied in two large cohorts of individuals age 50 years and older: the population-based Canadian Multicentre Osteoporosis Study (4,778 women and 1,919 men) and the clinically referred Manitoba BMD Cohort (36,730 women and 2,873 men). RESULTS: Fracture probabilities increased with age, decreasing femoral neck T-score, and number of CRFs. Among women, 10.1-11.3% would be designated high risk based upon 10-year major osteoporotic fracture probability exceeding 20%. A much larger proportion would be designated high risk based upon 10-year hip fracture probability exceeding 3% (25.7-28.0%) or osteoporotic BMD (27.1-30.9%), and relatively few from prior hip or clinical spine fracture (1.6-4.2%). One or more criteria for intervention were met by 29.2-34.0% of women excluding hip fracture probability (35.3-41.0% including hip fracture probability). Lower intervention rates were seen among CaMos (Canadian Multicentre Osteoporosis Study) men (6.8-12.9%), but in clinically referred men from the Manitoba BMD Cohort, one or more criteria for high risk were seen for 26.4% excluding hip fracture probability (42.4% including hip fracture probability). CONCLUSIONS: The FRAX tool can be used to identify intervention thresholds in Canada. The FRAX model supports a shift from a dual X-ray absorptiometry (DXA)-based intervention strategy, towards a strategy based on fracture probability for a major osteoporotic fracture.

Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial.

The purpose of this randomized study was to examine if goserelin concomitant to CMF-chemotherapy as adjuvant treatment for premenopausal breast cancer, protects the ovaries from premature failure. A total of 285 premenopausal breast cancer patients, in a randomized adjuvant trial (Zoladex in premenopausal patients (ZIPP)), were assigned to a study on ovarian function. Node positive patients were assigned to CMF-(cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in addition to endocrine therapy. All patients were randomly assigned to receive 2 years of goserelin, goserelin plus tamoxifen, tamoxifen alone or no endocrine treatment. We studied, if menses were affected in the treatment groups, up to 36 months after randomization. One year after completed CMF- and endocrine therapy, 36% of the women in the goserelin group reported menses, compared to 7% in the goserelin plus tamoxifen group, 13% in the tamoxifen group and 10% of the controls. Among women treated with goserelin, there was a statistically significant increase in the proportion of menstruating women, 1 year after completed treatment compared to at 24 months of treatment (P = 0.006), in contrast to all other treatment groups, who were unchanged or more often amenorrheic. In our study, there is some evidence of protective effect of goserelin on ovarian function in CMF treated women. This effect was not observed in the combined tamoxifen and goserelin treatment.

Sympathetic modulation of muscle spindle afferent sensitivity to stretch in rabbit jaw closing muscles.

Previous reports showed that sympathetic stimulation affects the activity of muscle spindle afferents (MSAs). The aim of the present work is to study the characteristics of sympathetic modulation of MSA response to stretch: (i) on the dynamic and static components of the stretch response, and (ii) on group Ia and II MSAs to evaluate potentially different effects. In anaesthetised rabbits, the peripheral stump of the cervical sympathetic nerve (CSN) was stimulated at 10 impulses s(-1) for 45-90 s. The responses of single MSAs to trapezoidal displacement of the mandible were recorded from the mesencephalic trigeminal nucleus. The following characteristic parameters were determined from averaged trapezoidal responses: initial frequency (IF), peak frequency at the end of the ramp (PF), and static index (SI). From these, other parameters were derived: dynamic index (DI = PF - SI), dynamic difference (DD = PF - IF) and static difference (SD = SI - IF). The effects of CSN stimulation were also evaluated during changes in the state of intrafusal muscle fibre contraction induced by succinylcholine and curare. In a population of 124 MSAs, 106 units (85.4 %) were affected by sympathetic stimulation. In general, while changes in resting discharge varied among different units (Ia vs. II) and experimental conditions (curarised vs. non-curarised), ranging from enhancement to strong depression of firing, the amplitude of the response to muscle stretches consistently decreased. This was confirmed and detailed in a quantitative analysis performed on 49 muscle spindle afferents. In both the non-curarised (23 units) and curarised (26 units) condition, stimulation of the CSN reduced the response amplitude in terms of DD and SD, but hardly affected DI. The effects were equally present in both Ia and II units; they were shown to be independent from gamma drive and intrafusal muscle tone and not secondary to muscle hypoxia. Sympathetic action on the resting discharge (IF) was less consistent. In the non-curarised condition, IF decreased in most Ia units, while in II units decreases and increases occurred equally often. In the curarised condition, IF in group II units mostly increased. The results have important functional implications on the control of motor function in a state of 'high' sympathetic activity, like excessive stress, as well as in certain pathological conditions such as sympathetically maintained pain.

Graves' disease in children and adolescents. Late results of surgical treatment.

All children and adolescents with Graves' disease in the county of Uppsala (catchment area population 250,000) treated between 1970 and 1994 were evaluated in a retrospective study. The material comprised 31 patients with a mean age of 11 years (range 4-16), 29 (94%) of whom were girls, and four (13%) of the patients had Down's syndrome. Treatment was primarily conservative and surgery was considered if prolonged medical treatment failed. Lasting remission after antithyroid drug therapy (median 6.5 years; range 4.5-8 years) was noted in 6/31 patients (19%), three (10%) of whom subsequently developed hypothyroidism. Twenty-four of the remaining patients (77%) ultimately underwent subtotal (N = 20) or total thyroidectomy (N = 4) after experiencing one or more episodes of recurrent hyperthyroidism during medical treatment (median 6 years; range 0.5-11 years). After surgery one patient developed permanent hypocalcemia requiring low-dose vitamin D supplementation. During a postoperative follow-up period of 12.2 years ( median; range 1-17 years), there were two cases of recurrent thyrotoxicosis, 1 and 10 years after surgery. The results underline that gender and Down's syndrome are risk factors of juvenile Graves' disease and that the disorder often is difficult to control by long-term medical therapy. In such cases thyroid surgery offers a safe and prompt reversal of the thyrotoxicosis. A proportion of the patients may ultimately develop hypothyroidism, substantiating a need for long-term follow-up of persons afflicted with Graves' disease early in life.

Influences on the gamma-muscle spindle system from muscle afferents stimulated by KCl and lactic acid.

It is known that accumulation of contraction metabolites in muscles stimulates group III and IV afferents and induces excitation of gamma-efferents to the homonymous muscle. The aim of the present study was to investigate whether increased concentrations of lactic acid and KCl in one muscle may influence the activity in primary and secondary muscle spindle afferents (MSAs) from the chemically affected muscle and from surrounding muscles. The experiments were made on 7 cats anesthetized with alpha-chloralose. Recordings were made simultaneously from 2-8 single MSAs from the triceps surae (GS) and the posterior biceps and semitendinosus muscles (PBSt). The mean rate of firing and the depth of modulation of MSA responses to sinusoidal stretching of the receptor-bearing muscles were determined. Responses of 27 primary MSAs (11 from PBSt and 16 from GS) were recorded. On 24 of these clear-cut alterations in sinusoidal response were evoked by injection of 1 ml of KCl (50-600 mM) or 1 ml of lactic acid (20-200 mM) into the artery supply of the GS muscle. Also, all secondary MSAs recorded (4 from PBSt and 1 from GS) showed sizable effects to increased intramuscular concentrations of KCl and/or lactic acid. On both primary and secondary MSAs, from GS as well as from PBSt muscles, nearly all effects observed were compatible with activation of static fusimotor neurons. Effects on MSAs were completely abolished when the ipsilateral L7-L6 ventral roots were cut and when the GS nerve was anesthetized. Intravenous injections of KCl and lactic acid, as well as arterial injections of 0.9% NaCl, were ineffective in changing the MSA responses.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer.

The relationship between hormone receptor status and the effect of adjuvant tamoxifen in early breast cancer remains controversial. This article presents the results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no adjuvant endocrine therapy in postmenopausal patients. During 1976 to 1984, 1,407 patients were included in the study. Of these, 427 (30%) had high-risk tumors (pN + or pT greater than 30 mm) and were included in a concurrent randomized comparison of postoperative radiotherapy versus adjuvant polychemotherapy. The mean follow-up time was 61/2 years. Tamoxifen improved the recurrence-free survival (RFS) (P less than .01), but the overall survival difference in favor of the tamoxifen-allocated patients was not significant. Data on estrogen (ER) and progesterone receptor (PgR) content were available in 750 patients. Their mean follow-up time was 41/2 years. The effect of tamoxifen was significantly related to ER level (P less than .01). No benefit with tamoxifen was observed among ER-negative patients. The relation to PgR level was of borderline significance (P = .06). Multivariate analysis indicated that most of the interaction between treatment and receptor content was explained by the interaction with ER (P less than .01). The PgR status appeared to modify the effect of tamoxifen among the ER-positive patients and the greatest effect was observed among patients who were positive for both receptors. However, the additional predictive information provided by the PgR assay did not help to identify an unresponsive subgroup of patients.

Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials.

The paper summarizes up-dated results of three randomized adjuvant trials from the Stockholm Breast Cancer Group. The objective of all studies included an evaluation of the role of megavoltage radiation in the primary management of patients with early breast cancer. The first trial was started in 1971 and included 960 pre- and postmenopausal patients with operable disease. The study compared adjuvant radiotherapy with surgery alone. All patients were treated with a modified radical mastectomy. There was a sustained improvement of the recurrence-free survival with radiotherapy (p less than 0.001). Among node positive cases radiation reduced the frequency of both loco-regional recurrence (p less than 0.001) and distant metastasis (p less than 0.01). This observation indicates that distant dissemination in subgroups of patients can originate from uncontrolled local deposits of tumor cells, for instance in the regional lymph nodes. No adverse effect from radiation on long-term survival was observed. The second study was started in 1976 and compared postmastectomy radiation with adjuvant chemotherapy in pre- and postmenopausal high-risk patients. At a mean follow-up of 6 1/2 years there was no significant difference in recurrence-free survival between the two treatments. However, postmenopausal patients fared better with radiotherapy (p less than 0.01). In this subgroup, radiation was more effective than adjuvant chemotherapy in reducing both distant metastases (p less than 0.01) and loco-regional recurrences (p less than 0.001). In the third trial--which only included postmenopausal patients--2 years of adjuvant tamoxifen was compared with no adjuvant endocrine treatment. The number of treatment failures was significantly reduced with tamoxifen (p less than 0.01) but there was no significant overall survival benefit. Subset analysis indicated that tamoxifen improved the recurrence-free survival among patients treated with adjuvant chemotherapy (p less than 0.01) but only to a level close to that achieved with radiotherapy alone. Addition of tamoxifen to radiotherapy failed to further increase the recurrence-free survival.

Parathyroid autotransplantation. An investigation of parathyroid autograft function.

During a four-year period, 27 patients underwent total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm. In order to minimize the risk of persistent or recurrent hyperparathyroidism (HPT), a routine thymic resection and a wide excision of fat tissue around the parathyroids was performed to ensure excision of possible supernumerary glands or rudimentary parathyroid tissue. The indications for operation were HPT secondary to chronic renal failure in 24 patients (22 of whom had hypercalcaemia) and persistent or recurrent primary HPT in 2 cases. One further patient, who had a multiple endocrine neoplasia syndrome type I, underwent this procedure at the primary parathyroid operation. Preoperative hypercalcaemia was reversed in all patients but three during the first postoperative days, concomitantly with a fall in the parathyroid hormone (PTH) level. Fourteen patients showed marked hypocalcaemia postoperatively, necessitating calcium or vitamin D supplementation. This medication could later be discontinued in all of them. Thirteen patients, including two of those with primary HPT, never required any supplemental therapy. Survival of the grafts was documented by several observations. In all patients normal serum calcium values were being maintained without supplemental therapy at follow-up. During induced hypocalcaemia a PTH secretory response was demonstrated in all eight studied patients with a gradient between the grafted and non-grafted arm. In two patients in whom the grafts were examined histologically 19 and 28 months after the transplantation, viable parathyroid tissue was observed. In the initial part of the study excised tissue was cryopreserved. Since persistent hypocalcaemia did not occur in our patients, we have now abandoned this safety precaution. Thus, total parathyroidectomy with autotransplantation of parathyroid tissue is a valuable method for restoring long-term parathyroid function in patients with secondary HPT and uraemia. It also appears of value in selected cases of primary HPT.