Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma.

BACKGROUND: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. RESULTS: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. CONCLUSION: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.

Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.

PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.

A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy.

Thrombocytopenia is a complication of cancer treatment that can limit dose intensity. Interleukin-11 (IL-11) is a growth factor that increases platelet production. We conducted a multicenter, randomized, placebo-controlled trial of recombinant human IL-11 (rhIL-11) in 93 patients with cancer who had already been transfused platelets for severe thrombocytopenia resulting from chemotherapy. The patients had received platelet transfusions for nadir platelet counts of < or = 20,000/microL during the chemotherapy cycle immediately preceding study entry. Chemotherapy was continued during the study without dose reduction. Patients were randomized to receive placebo or rhIL-11 at 50 or 25 micrograms/kg subcutaneously once daily for 14 to 21 days beginning 1 day after chemotherapy. Eight of 27 (30%) evaluable patients treated with rhIL-11 at a dose of 50 micrograms/kg did not require platelet transfusions versus 1 of 27 (4%) patients who received placebo (P < .05). Five of 23 (18%) patients treated with rhIL-11 at 25 micrograms/kg avoided platelet transfusions (P = .23). Side effects were fatigue and cardiovascular symptoms, including a low incidence of atrial arrhythmias and syncope. There were no differences among treatment groups in the incidence of neutropenic fever, days of hospitalization, or number of red blood cell transfusions. This study shows that rhIL-11 treatment of a dose of 50 micrograms/kg significantly increases the likelihood that patients who have already been transfused platelets for severe chemotherapy-induced thrombocytopenia will not require platelet transfusions during a subsequent chemotherapy cycle.

Cementless total knee arthroplasty in obese patients. A comparison with a matched control group.

The heaviest 45 patients (50 knees) who underwent cementless total knee arthroplasty were compared with a matched control group of 45 total knee arthroplasty patients (50 knees) with respect to clinical and radiographic data. Surgery was performed over a 10-year period (1980-1989) and follow-up evaluation averaged 7 years (range, 2-11 years). The control group consisted of nonobese patients matched to the obese group with respect to age, sex, diagnosis, preoperative deformity, and length of follow-up evaluation. Clinical evaluation was made using the Knee Society rating scale as well as an analysis of multiple other clinical parameters. Radiographically, each patient was evaluated with long-standing anteroposterior views, lateral and patellar views, and spot fluoroscopic views of the involved knee. This evaluation included an analysis of lucencies, bead shedding, and prosthetic alignment. The final average clinical score in the obese group was 88 points with four revisions, and that for the control group was 91 points with two revisions. There were no significant differences in the combined percentage of good and excellent results between the two groups. On the basis of the results of this study, it is believed that weight as a factor by itself should not compromise the early (7-year average follow-up period) results of total knee arthroplasty.

Upper extremity physical factors affecting tennis serve velocity.

Forty tournament-level tennis players with expert serve technique volunteered to have their serve evaluated to determine relationships between anthropometric data, extremity strength, and functional serve velocity. All players underwent a complete physical examination, a video taped serve analysis, a radar measurement of serve velocity, and a series of upper extremity strength measurements. Statistical analysis was performed to determine which factors were related to serve velocity. Statistically significant relationships were found between serve velocity and several flexibility measurements including increased dominant wrist flexion (P < 0.05), increased dominant shoulder flexion (P < 0.05), and increased dominant shoulder internal rotation at 0 degrees of abduction (P < 0.05). Several strength measurements were also related to serve velocity including elbow extension torque production (P < 0.01) and the ratios of internal to external rotational torque production for both low- and high-speed measurements (P < 0.01 concentrically and P < 0.05 eccentrically). These findings relate strength and flexibility to serve velocity, suggesting that it may be possible to increase a tennis player's serve velocity through specifically directed muscular strengthening or stretching regimens. However, prospective studies must be undertaken to demonstrate these possibilities.

Identifying predictive variables for long-term weight change after participation in a weight loss program.

OBJECTIVE AND DESIGN: To determine if there was an association between weight change and 31 independent variables among obese persons 2 years after a weight loss program. Data were obtained from subjects' records and from questionnaires administered at enrollment and after a 2-year follow-up. SETTING: The 8-week weight control program was taught by registered dietitians and developed by the staff at the Sid Richardson Institute for Preventive Medicine, Houston, Tex. SUBJECTS/SAMPLES: Of the 1,460 subjects who attended at least one of eight classes, 509 subjects (123 men and 386 women) responded to the mailed follow-up questionnaire. MAIN OUTCOME MEASURES: Associations between weight change and the 31 independent variables were assessed. Heights and weights were measured by the dietitians during treatment. Two-year follow-up weights were self-reported. STATISTICAL ANALYSES PERFORMED: Analysis of variance was used for 16 of the independent variables. For the remaining variables we performed a test of the null hypothesis that the correlation coefficient was 0 based on the test of the regression coefficient between the independent and dependent variable. A stepwise regression process was used to determine the best combination of variables predictive of weight change. RESULTS: Of the 31 independent variables, 16 were significantly predictive of weight change. The adjusted R2 for the entire group of 16 variables was .379. Thus, 37.9% of the variance was explained by the joint efforts of the 16 variables. Eight variables with an adjusted R2 of .371 (accounting for 37.1% of the variance) were most important: feeling in control of eating habits, percentage over ideal body weight at enrollment, percentage of weight lost during the 8-week treatment, frequency of weight measurement, increase in physical activity, frequency of eating in response to emotions, number of pounds gained before subject resumed diet, and occupation. APPLICATION/CONCLUSION: The predictive variables for weight change may be useful to professionals who treat obese clients and may improve success rates of long-term weight loss.

Statistical methods that distinguish between attributes of assessment: prolongation of life versus quality of life.

The authors propose a method to generate information relevant to the decision tree that adds additional perspective to the characterization of health quality during survival. Their approach uses survival data to distinguish two attributes of utility: prolongation of life and quality of life (QOL). Health-state transition probabilities correspond to the prolongation of life and are modeled in a discrete-time transient semi-Markov process. Quality-of-life-state transition probabilities are derived from the assumptions of a simple recurrent Markov process. They reflect events within the health-state sojourn time that differentiate perceptions of pain and suffering over a short fixed time period. Outcomes for these two dimensions of utility are highly relevant to the assessment of medical technology that might prolong life at the cost of increased pain and suffering, implying a reduced QOL. The methods are demonstrated on a subset of follow-up data from the Beta-Blocker Heart Attack Trial (BHAT).

Measurement of estrogen and progesterone receptors in human breast tumors: enzyme immunoassay versus binding assay.

To determine whether we could replace our current binding assay (BA) method for measurement of estrogen receptors (ERs) and progesterone receptors (PRs) with the recently developed enzyme immunoassay (EIA) method, we compared simultaneous measurements of ERs and PRs in frozen breast tumor samples by both methods. A value of greater than or equal to 10 fmol/mg cytosol protein was defined as positive. There was agreement between the BA and EIA on whether the sample was positive or negative in 75 of 91 (82%) samples measured for ERs and in 74 of 93 (80%) for PRs. When the threshold value for a positive assay was redefined as greater than or equal to 20 fmol/mg protein, there was agreement in 85 of 91 (93%) samples for ERs and 85 of 93 (91%) for PRs. The numerical value for ERs by EIA was not consistently greater or less than ERs by BA, but the difference between the EIA and BA measurement increased as the size of the measurement increased. We did not see an excess of premenopausal patients whose ERs by BA were negative and whose ERs by EIA were positive. Although we performed a linear regression analysis and determined the Pearson correlation coefficient to compare the BA and EIA as reported by others, we show that this analysis may be misleading when the objective is to demonstrate similarities between these methods. Our study shows that the EIA can be confidently used in place of the BA. However, a threshold value for a positive EIA should be confirmed clinically in future studies.

Bronchial micronuclei as a marker of an early stage of carcinogenesis in the human tracheobronchial epithelium.

In the bronchial epithelium, smoking initiates a multistep process that first appears histologically as premalignant squamous metaplasia/dysplasia, a biological predecessor of squamous-cell lung cancer. Reflecting chromosomal damage from a carcinogenic insult, micronuclei may reveal earlier events in the carcinogenic sequence. We prospectively evaluated and correlated micronucleus count, histology (index of metaplasia) and smoking exposure in 35 consecutive subjects (9 active smokers, 10 previous smokers and 16 never-smokers) undergoing diagnostic bronchoscopy. Samples for micronuclei and histological evaluation were taken from the main carinal mucosa in each subject for site-specific comparisons. The median and mean micronucleus counts per 1,000 cells were significantly higher in active smokers than in non-smokers (subjects who had never smoked and previous smokers): median counts were 3.7 vs. 1.4, p = 0.03; mean counts were 4.7 vs. 1.9, p = 0.01. There was no significant difference, however, in micronucleus counts between subjects who had never smoked and previous smokers. Bronchial metaplasia and smoking history were not associated. Our findings suggest that micronuclei are a readily quantitated, early intermediate-endpoint marker for detecting tobacco-initiated tracheobronchial carcinogenesis.

Long-term follow-up of weight status of subjects in a behavioral weight control program.

Few studies have examined the long-term effectiveness of behavioral weight control programs. Interpretation of the results from these studies has been limited due to small sample size, use of only one sex, and the number of evaluation parameters. A 2-year follow-up study was designed to assess the effectiveness of a behavioral weight control program on 123 obese male and 386 obese female subjects. Body weights were measured by dietitians at baseline and after an 8-week treatment program. Two-year follow-up weights were self-reported from a mailed questionnaire. The subjects' mean weight at baseline was 185.6 +/- 43.4 lb (no. = 509). Their mean percent over ideal body weight at baseline was 29.7%. Following an 8-week treatment period, mean weight was 176.4 +/- 41.3 lb (no. = 509), yielding a mean weight loss of 9.2 +/- 6.4 lb. Weight change after the 8-week treatment period ranged from a loss of 37 lb to a gain of 5 lb. The 2-year follow-up study showed that mean weight of the 498 subjects was 179.8 +/- 42.9 lb, yielding a mean weight loss of 5.8 +/- 15.5 lb. Weight change ranged from a loss of 71 lb to a gain of 47 lb. After 2 years, 325 subjects (65.3%) were still below their baseline weights, 182 subjects (36.6% of the entire study group) had maintained or enhanced the weight loss achieved during treatment, and 80 subjects (16.1%) weighed at least 10% less than their baseline weight.(ABSTRACT TRUNCATED AT 250 WORDS)