US Food and Drug Administration (FDA)‐approved diagnostic assays play an increasingly common role in managing patients to prolong lifespan while also enhancing quality of life. Diagnostic assays can ...be essential for the safe and effective use of therapeutics (companion diagnostic), or may inform on improving the benefit/risk ratio without restricting drug access (complementary diagnostic). This tutorial reviews strategic considerations for drug and assay development resulting in FDA‐approved companion or complementary diagnostic status.
To determine whether a combination of high-dose therapy and autologous stem-cell transplantation (ASCT) is superior to conventional-dose consolidation and maintenance chemotherapy as postremission ...therapy in adults with lymphoblastic lymphoma.
One hundred nineteen patients were entered onto this prospective randomized trial from 37 centers. Patients received standard remission induction therapy, and responding patients were randomized either to continue with a conventional consolidation/maintenance protocol (CC) or to receive high-dose therapy and ASCT. In some centers, patients with HLA-identical sibling donors were registered on the trial but proceeded to allogeneic bone marrow transplantation (BMT) without randomization.
Of the 119 patients entered, 111 were assessable for response to induction therapy. The overall response rate was 82% (56% complete response, 26% partial response). Of the 98 patients eligible for randomization, 65 were randomized, 31 to ASCT and 34 to CC. Reasons for failure to randomize included patient refusal (12 patients), early progression or death on induction therapy (eight patients), excessive toxicity of induction regimen (six patients), and elective allogeneic BMT (12 patients). With a median follow-up of 37 months, the actuarial 3-year relapse-free survival rate is 24% for the CC arm and 55% for the ASCT arm (hazards ratio = 0.55 in favor of the ASCT arm; 95% confidence interval CI, 0.29 to 1.04; P =.065). The corresponding figures for overall survival are 45% and 56%, respectively (hazards ratio = 0.87 in favor of the ASCT arm; 95% CI, 0.42 to 1.81; P =.71).
The use of ASCT in adults with lymphoblastic lymphoma in first remission produced a trend for improved relapse-free survival but did not improve overall survival compared with conventional-dose therapy in this small randomized trial.
University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom
The aim of this study was to examine the effect
of the metabolites H + , ADP, and
P i on the rate of cardiac
relaxation. We used ...guinea pig right ventricular trabeculae that had
been chemically skinned, allowing the myofilaments to be studied in
isolation. Laser-flash photolysis of the caged
Ca 2+ chelator diazo 2, causing a
rapid fall in intracellular Ca 2+ ,
enabled investigation of relaxation independently of the rate of
Ca 2+ diffusion. On the photolysis
of diazo 2, the trabeculae relaxed biphasically with exponential rate
constants ( k 1 and
k 2 ) of 10.07 and 4.23 s 1 , respectively,
at 12°C and 18.35 and 2.52 s 1 , respectively, at a
nominal 20°C. Increasing the concentration of both protons (pH
7.2-6.8) and MgADP (0.5-3.4 mM) slowed the two phases of the
relaxation transients. Raising the concentration of
P i from the control level of 1.36 mM to 15.2 mM increased the rate of both phases, with relaxation
becoming monoexponential at 19.4 mM
P i (with a
k of 20.31 s 1 at 12°C). Cardiac
muscle was compared with skeletal muscle under identical conditions; in
cardiac muscle 19.4 mM P i
increased the rate of relaxation, whereas in skeletal muscle this
concentration of P i slowed
relaxation. We conclude that the mechanism of relaxation differs
between cardiac and skeletal muscle. This study is a direct demonstration of the effects of ATP metabolites on cardiac myofilament processes during relaxation.
muscle; heart; calcium; guinea pig; cross bridges
Summary
A systematic review of the literature was undertaken to assess what published evidence is currently available to support the increasing use of autologous stem cell transplantation (ASCT), and ...to evaluate the published data with regard to the comparative cost of high‐dose and conventional therapy. The review aimed to identify all published, randomized controlled trials (RCTs) comparing high‐dose therapy (HDT) with ASCT versus conventional chemotherapy (CC) in acute lymphoblastic leukaemia, non‐Hodgkin’s lymphoma, Hodgkin’s disease, multiple myeloma, and breast, lung, testicular and ovarian cancer. The review also aimed to identify all studies that had compared the cost of the two treatment strategies. Reports were identified by systematic searches of Cancerlit, Embase and Medline, and handsearching of several conference proceedings. Where possible, pooled odds ratios (ORs) were calculated according to the fixed‐effect model. A total of 18 randomized trials were identified in acute lymphoblastic leukaemia, non‐Hodgkin’s lymphoma, Hodgkin’s disease, multiple myeloma, and breast, lung and testicular cancer. Trials were generally small and no disease site had sufficient information to determine reliably whether high‐dose therapy with autologous transplant is more effective than CC. Five studies were identified that compared the cost of the two treatments. These found the cost of HDT to be between one and four times higher than that of CC. Further randomized trials are required. Where appropriate, these should include economic assessment and assessments of long‐term toxicity.
EMD 57033 is thought to produce its potentiating effect by increasing the apparent calcium sensitivity of myofibrils. We have investigated the effect of 10 microM EMD 57033 on relaxation speed, ...induced by flash photolysis of 2mM diazo-2 (a caged Ca2+ chelator), in skinned semitendinosus frog muscle fibres and guinea-pig trabeculae. 10 microM EMD 57033 has no effect on the relaxation speed of semitendinosus fibres. In trabeculae, EMD 57033 slightly increases the relaxation speed slightly, in contrast to ADP which produces a slowing. 1mM ADP combined with 10 microM EMD 57033 slows relaxation but not to the degree seen with ADP alone. Like ADP, EMD 57033 increases the number of cross-bridges in the force producing state, but unlike ADP does not affect the transition rates involved in relaxation.
The aim of this study was to examine the effect of the metabolites H+, ADP, and Pi on the rate of cardiac relaxation. We used guinea pig right ventricular trabecule that had been chemically skinned, ...allowing the myofilaments to be studied in isolation.
EMD 57033 is thought to produce its potentiating effect by increasing the apparent Ca2+ sensitivity of the myofilaments, possibly by altering the kinetics of actomyosin interaction. We have ...investigated the effect of 10 microM EMD 57033 upon activation speed, induced by flash photolysis of 2mM nitr-5 (caged Ca2+), in chemically skinned trabeculae from the guinea-pig at 12 degrees C. EMD 57033 increases the half time of activation from 238 +/- 18.5 msec (n = 6) to 132.1 +/- 34.0 msec (n = 8) (mean +/- s.e.m.) and suggests that this Ca2+ sensitiser has an important effect upon fapp, that is the transition from the non-force to force generating cross-bridge states.
In a fatigued muscle fibre, the concentrations of ADP, Pi and H+ are all increased and relaxation is slowed. We have used the technique of laser flash photolysis of the caged calcium-chelator, ...diazo-2, to investigate the direct effect of changes in pH (pH 6.5, 7.0, 7.5) upon tension during relaxation of single chemically skinned fibres, when the effects of the sarcoplasmic reticulum are absent. The relaxation transients were closely fitted with 2 exponentials, a fast (42.3 +/- 1.4; pH 7.0) and a slow process (12.0 +/- 0.7; pH 7.0). The fast phase of relaxation was pH sensitive; lowering pH leading to a slowing of the rate of force decline and raising pH leading to an increase of the rate. The rate of the slow phase was unaltered by changing pH over the range investigated. Thus the slowing of relaxation in fatigued muscle may be due, in part, to the direct action of protons on the myofilaments independent of any effects upon the sarcoplasmic reticulum.
In vivo, two effects of beta-adrenergic stimulation in cardiac muscle are phosphorylation of troponin I and an increase in relaxation rate. In vitro, cardiac TnI can be phosphorylated by protein ...kinase A (PKA). We have used the technique of laser flash photolysis of the calcium chelator diazo-2 to investigate the effect of phosphorylation of TnI on the relaxation rate of skinned trabeculae from the guinea-pig at 12 degrees C. The fibres were phosphorylated by PKA, and double exponential curve fits of the average relaxation transients showed no significant difference between the rate constants of the phosphorylated and control cases. We conclude that TnI phosphorylation has no effect on the rate of relaxation in skinned trabeculae from the guinea-pig following diazo-2 photolysis.
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