The strategies to reduce iron deficiency in blood donors randomized trial: design, enrolment and early retention.

BACKGROUND AND OBJECTIVES: Repeated blood donation produces iron deficiency. Changes in dietary iron intake do not prevent donation-induced iron deficiency. Prolonging the interdonation interval or using oral iron supplements can mitigate donation-induced iron deficiency. The most effective operational methods for reducing iron deficiency in donors are unknown. MATERIALS AND METHODS: 'Strategies To Reduce Iron Deficiency' (STRIDE) was a two-year, randomized, placebo-controlled study in blood donors. 692 donors were randomized into one of two educational groups or one of three interventional groups. Donors randomized to educational groups either received letters thanking them for donating, or, suggesting iron supplements or delayed donation if they had low ferritin. Donors randomized to interventional groups either received placebo, 19-mg or 38-mg iron pills. RESULTS: Iron deficient erythropoiesis was present in 52·7% of males and 74·6% of females at enrolment. Adverse events within 60 days of enrolment were primarily mild gastrointestinal symptoms (64%). The incidence of de-enrolment within 60 days was more common in the interventional groups than in the educational groups (P = 0·002), but not more common in those receiving iron than placebo (P = 0·68). CONCLUSION: The prevalence of iron deficient erythropoiesis in donors enrolled in the STRIDE study is comparable to previously described cohorts of regular blood donors. De-enrolment within 60 days was higher for donors receiving tablets, although no more common in donors receiving iron than placebo.

Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury.

Limb denervation leads to reorganization of the representational zones of the somatosensory cortex. Using [11C](R)-PK11195, a sensitive in vivo marker of glial cell activation, and PET, we provide first evidence that limb denervation induces a trans-synaptic increase in [11C](R)-PK11195 binding in the human thalamus but not somatosensory cortex: these brain structures appeared morphologically normal on magnetic resonance imaging (MRI). The increased thalamic signal was detectable many years after nerve injury, indicating persistent reorganization of the thalamus. This glial activation, beyond the first-order projection area of the injured neurons, may reflect continually altered afferent activity. Our findings support the view that long-term rearrangement of cortical representational maps is significantly determined within the thalamus.

Adjuvant dose-intense chemotherapy with peripheral blood stem cell support in stage II-III breast cancer with five to nine involved axillary lymph nodes.

The purpose of this study is to determine outcomes for patients with high-risk nonmetastatic breast cancer undergoing high-dose chemotherapy with peripheral blood stem cell support. Forty-three patients with stage II-III disease, five to nine positive axillary lymph nodes, and a median age of 44 years (range, 27-60 years) were enrolled in a study that included: 1) standard dose doxorubicin, 5-fluorouracil, and methotrexate adjuvant therapy; 2) cyclophosphamide, etoposide, filgrastim, and peripheral blood stem cell harvest; and 3) high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by peripheral blood stem cell infusion. All 43 patients received doxorubicin, 5-fluorouracil, and methotrexate, 42 (98%) received etoposide, and 41 (95%) received CTCb. Thirty-two patients (74%) are alive, 28 (65%) without relapse at a median of 55 months (range, 41-87 months). Two died (5%) of treatment-related causes, (subclavian catheter complication after etoposide and late radiation pneumonitis), and nine other deaths (21%) were associated with recurrent breast cancer. The probabilities of overall and event-free survival at 4 years were 0.77 and 0.67, respectively, compared with 0.82 and 0.69, respectively, for 72 similar patients with 10 or more positive axillary nodes receiving the same sequence of therapy. Thus, patients with five to nine positive axillary lymph nodes have a similar risk of failure after high-dose chemotherapy and peripheral blood stem cell support as patients with 10 or more positive axillary lymph nodes.

Mitoxantrone, 5-fluorouracil, and high dose leucovorin (NFL) versus intravenous cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in first-line chemotherapy for patients with metastatic breast carcinoma: a randomized phase II trial.

BACKGROUND: Previous Phase II studies using the combination of mitoxantrone, 5-fluorouracil, and high dose leucovorin (NFL) in the treatment of metastatic breast carcinoma have shown this regimen to be active and well tolerated. In this randomized Phase II study, the authors compared the NFL regimen with a standard CMF regimen in the first-line therapy of patients with metastatic breast carcinoma. METHODS: One hundred twenty-eight women receiving their first chemotherapy for metastatic breast carcinoma were entered into this randomized study. Sixty-four patients were treated with NFL: mitoxantrone 12 mg/m2 IV on Day 1; leucovorin 300 mg IV over 30-60 minutes on Days 1, 2, and 3, immediately preceding administration of 5-fluorouracil; and 5-fluorouracil 350 mg/m2 IV bolus on Days 1, 2, and 3. Sixty-four patients received CMF: cyclophosphamide 600 mg/m2 IV on Day 1; methotrexate 40 mg/m2 IV on Day 1; and 5-fluorouracil 600 mg/m2 IV on Day 1. Both regimens were repeated at 21-day intervals; responding patients received at least 8 courses. RESULTS: Patients treated with NFL had a higher response rate than patients treated with the CMF regimen (45% vs. 26%, respectively; P = 0.021). Median duration of response was 9 months with NFL and 6 months with CMF (P = 0.10); 11 patients had long responses (>12 months) with NFL versus 4 patients with CMF (P = 0.06). Median survival was similar for both groups. Both regimens were well tolerated, with infrequent Grade 3 or 4 toxicities. CONCLUSIONS: NFL is an active, well-tolerated regimen for the treatment of metastatic breast carcinoma; it produced a higher response rate than the CMF regimen used in this study. Although more intense CMF regimens or regimens containing doxorubicin would likely increase the response rate, they would almost certainly do so with the consequence of greater toxicity as compared with NFL. NFL is an excellent initial palliative treatment option for elderly patients or patients who have exhibited poor tolerance for other chemotherapy regimens.

The influence of dietary creatine supplementation on performance during repeated bouts of maximal isokinetic cycling in man.

The effect of dietary creatine (Cr) supplementation on performance during 3, 30 s bouts maximal isokinetic cycling and on plasma ammonia and blood lactate accumulation during exercise was investigated. Placebo (P) ingestion had no effect on peak power output (PPO), mean power output (MPO) and total work output during each bout of exercise. Cr ingestion (4 x 5 g.day-1 for 5 days) significantly increased PPO in exercise bout 1 (p < 0.05) and MPO and total work output in exercise bouts 1 (p < 0.05, p < 0.05, respectively) and 2 (p < 0.05, p < 0.05, respectively). Cr ingestion had no effect on any of the measures of performance during exercise bout 3. No difference was observed in peak plasma ammonia accumulation before (146 + 30 mumol.l-1) and after (122 +/- 17 mumol.l-1) P ingestion, however the corresponding concentration was lower following Cr ingestion (129 +/- 22 mumol.l-1) compared with before Cr ingestion (160 +/- 18 mumol.l-1, p < 0.05), despite subjects performing more work. No difference in peak blood lactate accumulation was observed before and after P or Cr ingestion. The results demonstrate that Cr ingestion can increase whole body exercise performance during the initial two, but not a third, successive bout of maximal exercise lasting 30 s. The lower accumulation of plasma ammonia under these conditions suggests this response is achieved by an effect on muscle ATP turnover.

Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial.

To test whether changes in folate and vitamin B12 nutrition modify the severity of potentially premalignant lesions identified by cytology in sputum samples of smokers, we conducted a randomized, controlled prospective intervention trial in smokers with bronchial squamous metaplasia. Seventy-three men with a history of 20 or more pack-years of cigarette smoking who had metaplasia on one or more sputum samples were stratified according to smoking level and randomly assigned to four months' treatment with either placebo or 10 mg of folate plus 500 micrograms of hydroxocobalamin. Direct cytological comparison of the two groups after four months showed significantly greater reduction of atypia in the supplemented group. This provides preliminary evidence that atypical bronchial squamous metaplasia may be reduced by supplementation with folate and vitamin B12. However, the significance of these findings is tempered by substantial spontaneous variation in sputum cytologies, the small study population, the short duration of the trial, and the supraphysiological doses of folate and B12 used. The results should not be construed as pointing to a potential way of preventing lung cancer in individuals who continue to smoke or as supporting self-medication with large doses of folate or B12 by smokers.

Phase I study and pharmacokinetics of weekly high-dose 13-cis-retinoic acid.

In an attempt to increase the peak plasma levels of 13-cis-retinoic acid (13-cis-RA) and its efficacy in vivo, a Phase I study and pharmacokinetics of weekly high-dose, oral 13-cis-RA was conducted in 23 cancer patients who were refractory to conventional treatments. At 200 mg/sq m, the mean peak plasma level of 13-cis-RA was 1.5 +/- 0.1 (SE) micrograms/ml; at 400 mg/sq m, the mean peak plasma level increased to 3.8 +/- 0.7 micrograms/ml. Further increases of the 13-cis-RA dose up to 1800 mg/sq m did not lead to proportional increases in either the mean peak plasma levels or area under the curve, indicating a saturable absorption phenomenon. The terminal half-life was highly variable (range, 2.8 to 101.3 h) and was not related to the dose given. A secondary peak plasma concentration was seen in five patients, suggesting enterohepatic circulation. The toxicities such as headache, cheilitis, dry skin, and dry eyes were frequent on the weekly schedule but were not dose-limiting. One patient had an elevation of the triglycerides of 2 to 5 times the upper limit of normal; five patients had an elevation of 1.1 to 2 times normal. No objective responses were observed to treatment with 13-cis-RA. Of 20 patients receiving an adequate trial of the drug, 18 showed progression of their cancer, and two had stable disease.

Time-calorie displacement diet for weight control: a prospective evaluation of its adequacy for maintaining normal nutritional status.

An unsupplemented 1000 kcal (4186 kJ) diet emphasizing large quantities of unrefined complex carbohydrates was evaluated for nutritional adequacy in a 20-week weight-control program for obese adults. Assessment of nutritional status, routinely obtained upon admission, was repeated at approximately 10-week intervals on 26 patients who were losing weight while adhering to the dietary guidelines. At least one repeat assessment was obtained on all 26 patients: 13 had follow-up assessment at 10 weeks, three at 20 weeks, and ten at both 10 and 20 weeks. Weight loss averaged 0.7 kg/wk over an average of 15 weeks with a mean energy intake of 1020 kcal (4270 kJ), 55 percent of baseline. At each follow-up assessment mean skinfold thickness fell significantly whereas muscle mass was maintained according to arm muscle circumference and creatinine-height index. Mean blood levels of retinol, beta-carotene, folate, vitamin B12, ascorbic acid, thiamin, riboflavin, pyridoxine, iron, transferrin saturation and calcium excretion remained within normal limits throughout treatment. Ascorbic acid levels rose significantly. The results indicate that the experimental diet, without supplementation, can fulfil nutritional requirements while restricting energy intake for weight reduction.