Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC. PATIENTS AND METHODS: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS). RESULTS: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34), outcomes appeared to favor ADP (median OS 19 versus 14 months). CONCLUSIONS: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.

Discrepancy in stoichiometry of steady-state muscle [Pi] and [PCr] induced by exercise.

Phosphorus nuclear magnetic resonance was used to quantify the relations between metabolic phosphates, intracellular pH, and work rate in forearm muscle of six adult men over a range of work rates from 1.0 to 3.5 W. Three work rates were studied in each of four sessions (either 1.0, 2.0, and 3.0 or 1.5, 2.5, and 3.5 W), with measurements made before and during each bout, thereby permitting the partition of the variance attributable to rest, work-dependent, and time-dependent metabolic functions by regression analysis. There were no time-dependent changes in either [ATP] or intracellular [H+] as assessed during the rest intervals between bouts of exercise. In contrast, the total nuclear magnetic resonance (NMR)-visible phosphorus pool (TVPP) decreased with time, with both phosphocreatine (PCr) and inorganic phosphate (Pi) contributing significantly to TVPP reduction. Muscle [ATP] was unchanged by work at all intensities. Intracellular [H+] increased moderately and proportionately to work rate. [PCr] decreased and [Pi] increased in proportion to work rate, with the work-dependent coefficient for PCr consumption approximately 1.5 times that of Pi production. Neither Pi line width nor motion artifact accounted for the decrease in TVPP, so the reduced Pi accumulation in exercise may represent its sequestering in some NMR-invisible muscle pool and/or loss to the blood. Whatever the process involved, it is proportional to work rate and persists for at least 10-15 min after exercise.

In vivo 31P-NMR in human muscle: transient patterns with exercise.

Evaluation of dynamic changes in pH and concentrations of adenosine 5'-triphosphate (ATP), phosphocreatine (PCr), and inorganic phosphate (Pi) during the transition from rest to steady-state exercise in the human has been methodologically limited. Previous work has relied on muscle biopsy of exercising subjects at different times in different exercise bouts. Chemical evaluation of metabolites has been hampered by continuing change in metabolic concentration during the biopsy procedure. Recently, Fourier-transformed 31P nuclear magnetic resonance (31P-NMR), employing surface coils, has made evaluation of phosphorus metabolites possible by noninvasive atraumatic means in human muscle. Relative concentrations of PCr, Pi, and ATP, together with pH, have been obtained with 31P-NMR from the flexor digitorum superficialis muscle on two occasions in four adult men during the transition from rest to exercise. [PCr] rapidly fell and was mirrored by a rise in [Pi]. The former temporarily exceeded the latter with the discrepancy apparently being absorbed by a transient rise in [ATP], which was itself mirrored by alteration in [H+].

Phosphocreatine kinetics in humans during exercise and recovery.

System linearity was assessed for exercise induced changes in energetics of forearm exercise. 31P-NMR spectroscopy techniques, with 12.5-s serial measurements of [PCr], [Pi], [ATP], and [H+] were employed during exercise and recovery transitions in four untrained men for moderate (1.7 W) and heavy (3.6 W) exercise. Signal averaging was applied and data were analyzed by regression analysis using a first-order exponential model. The time constants for both [PCr] and [Pi] responses to moderate exercise and recovery were not different both within and between nuclei ranging from 32 to 35 s (P > 0.05). The time constants derived from moderate exercise and recovery, when employed to construct predictive equations for heavy exercise and recovery, did not adequately describe [PCr] dynamics. Underestimation of the net hydrolysis of PCr during heavy exercise was associated with increases in [H+] as predicted by the creatine kinase equilibrium reaction (CKeq). Calculation of [ADP] by CKeq revealed steady state [ADP] was achieved during moderate exercise and during recovery for both intensities much earlier than during heavy exercise. We conclude that the metabolic system does not behave as a linear system. Therefore, the time constant and the net change in [PCr].W-1 must themselves be determined by work dependent combinations of other system variables.

Body composition analysis by bioelectrical impedance: effect of skin temperature.

Bioelectrical impedance analysis (BIA) was used to estimate body water and composition under both cool (14.4 degrees C, dry bulb) and warm (35.0 degrees C) ambient conditions in eight healthy adult men. The prediction equation provided with the commercially available instrument (RJL Systems) was used with the BIA measurements to estimate body composition. Skin temperature increased from 24.1 +/- 1.81 degrees C in the cool condition to 33.4 +/- 1.36 degrees C in the warm condition. (Mean increase was 9.3 +/- 1.75 degrees C, t = 15.05, P less than 0.01). The corresponding BIA resistances were 461 +/- 48 omega and 426 +/- 47 omega, respectively. (Mean reduction was 35.0 +/- 9.8 omega, t = 10.13, P less than 0.01). This resulted in a significant increase in predicted total body water (cool 47.4 +/- 5.5 l vs. warm 49.9 +/- 5.6 l, t = 3.88, P less than 0.01). Consequently, predicted fat mass was significantly lower in the warm than in the cool condition (8.8 +/- 3.2 kg vs. 11.0 +/- 3.7 kg; mean difference 2.23 +/- 0.69 kg, t = 9.22, P less than 0.01). These findings indicate that varying skin temperature by altering ambient temperature significantly changes resistance measurements and the estimation of total body water and percent fat by BIA. The observed changes in resistance are consistent with an apparent expansion of conductor volume in the warm environment and a reduction in the cooler condition. In this regard, the temperature-induced change in resistance could be due to alterations in cutaneous blood flow and/or compartmental distribution of body water. Thus, BIA measurements should be taken only under well-standardized ambient conditions.

Transcription of cauliflower mosaic virus integrated into plant genomes.

A full-length copy of cauliflower mosaic virus (CaMV) was introduced into the T DNA of the Agrobacterium Ti plasmid and integrated into plant genomes. Northern analysis of turnip galls revealed two transcripts derived from the integrated CaMV. A 1900-nucleotide (1.9 kb) transcript arises from the region VI area of the genome and is the same size as the region VI transcript found in CaMV-infected leaves. A larger 7.5-kb transcript initiates at or near the other known CaMV promoter, which in infected cells directs synthesis of a full-length transcript, and terminates in adjacent T-DNA sequences. Comparison of the two transcripts in galls from seven plant species showed wide variation of both the ratios of the two transcripts within one species and of their levels between species.

Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer.

BACKGROUND: The value of nephrectomy in metastatic renal-cell cancer has long been debated. Several nonrandomized studies suggest a higher rate of response to systemic therapy and longer survival in patients who have undergone nephrectomy. METHODS: We randomly assigned patients with metastatic renal-cell cancer who were acceptable candidates for nephrectomy to undergo radical nephrectomy followed by therapy with interferon alfa-2b or to receive interferon alfa-2b therapy alone. The primary end point was survival, and the secondary end point was a response of the tumor to treatment. RESULTS: The median survival of 120 eligible patients assigned to surgery followed by interferon was 11.1 months, and among the 121 eligible patients assigned to interferon alone it was 8.1 months (P=0.05). The difference in median survival between the two groups was independent of performance status, metastatic site, and the presence or absence of a measurable metastatic lesion. CONCLUSIONS: Nephrectomy followed by interferon therapy results in longer survival among patients with metastatic renal-cell cancer than does interferon therapy alone.