Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: the diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial.

In 1996, the US Food and Drug Administration (FDA) enacted Rule 21 CFR section 50.24, which allows a narrow exception to the requirement for prospective informed consent from human research subjects in clinical trials investigating potentially beneficial therapies for acute, life-threatening conditions. The first clinical trial to be conducted under this rule was sponsored by Baxter Healthcare Corporation and approved by the FDA on November 21, 1996. This large, multicenter, randomized clinical trial was designed to compare the addition of diaspirin cross-linked hemoglobin (DCLHb) with standard care in the initial resuscitation of adults experiencing severe, uncompensated, traumatic hemorrhagic shock. Before the first planned interim analysis of the data, review of fatal adverse events revealed an imbalance in mortality between the 2 treatment groups. The Data Monitoring Committee (DMC) recommended suspension of patient enrollment 24 days later. Additional data collection and analyses confirmed the excess number of deaths in patients treated with DCLHb but failed to reveal the cause of these deaths. The trial was formally terminated after only 112 of the planned 850 patients had been enrolled. We review the events leading up to and the rationale behind the DMC recommendations for suspension of patient enrollment and trial termination. Although the DCLHb trial was unsuccessful in achieving its goals, the monitoring process worked well. Emergency research was facilitated by DMC oversight, and the interests of research subjects were protected by the actions of the DMC.

Basic radiobiological investigations of fast neutrons.

The radiobiological properties of a cyclotron-produced 43-MeV (p----Be) fast-neutron beam relative to gamma rays have been investigated using Chinese hamster V79 cells in culture. As expected, the relative biological effectiveness (RBE) of this neutron beam for cell killing was shown to increase as dose decreased, and the effectiveness per unit dose was slightly less compared to a 25-MeV (d----Be) neutron beam. By tracing single cells that formed microcolonies after irradiation, we found cell proliferation kinetics to be retarded to a greater extent by fast neutrons than by gamma irradiation. Following either neutron or gamma irradiation, a fraction of the irradiated cells failed to divide in the first postirradiation division and another fraction could produce as many as four generations of progeny before proliferation stopped. The properties of these cells presumed to be destined for death suggest that more than one mechanism and/or multistep process underlies the radiation-induced proliferative death. The fast-neutron beam was also found to be more effective quantitatively than gamma rays in producing DNA double-strand breaks (DSBs, measured by nondenaturing filter elution), and G1-phase chromosome fragments (measured by the premature chromosome condensation technique). However, the reverse was observed for DNA single-strand breaks (SSBs, measured by alkaline filter elution or hydroxylapatite uncoiling). Interestingly, both fast neutrons and gamma rays produced a large component of SSBs and DSBs with a fast-rejoining time constant of about 2-5 min, which appears to be independent of dose. The latter results could not resolve the possibility of lengthening the repair-time constant by increasing radiation dose within the range that is reflected by the shoulder of the survival curve, and consequently did not support the idea of repair saturation as a mechanism for the presence of the shoulder. The RBE for the hypoxanthine phosphoribosyl transferase mutation frequency per survivor at the 10% survival level was estimated to be 2.5, a value that is comparable to the RBE (2.1) for cell killing at the same survival level. Although most of the above-mentioned findings are compatible qualitatively with the relatively high-LET (linear energy transfer) nature associated with the fast-neutron beam, the significance of the action attributable to the mixture of LET could not be delineated in these experiments. Further, the biological significance of DSBs and chromosome aberration and the molecular mechanisms responsible for the repair and expression of these damaging processes remain to be elucidated.

An experimental study of the moderator assembly for a low-energy proton accelerator neutron irradiation facility for BNCT.

An accelerator-based neutron irradiation facility (ANIF), which has been proposed for BNCT, is based on a 2.5-MeV proton beam bombarding a thick lithium target. Neutrons which are emitted from the lithium target are too energetic for BNCT and must be moderated. A calculational study, which was done previously on the moderator assembly for an ANIF, shows that, with an optimized moderator assembly, an ANIF can produce a neutron flux which has quality and intensity sufficient for BNCT. In order to verify our previous calculational study, a lithium target and a non-optimized moderator assembly (a cylindrical tank of D2O) have been constructed and tested at the Ohio State University Van de Graaff proton accelerator. The neutron spectrum was measured for neutrons emerging from the moderator assembly. The measured neutron spectrum agrees reasonably well with that obtained from Monte Carlo calculations, except for neutrons with energies above 100 keV. For those neutrons, the measured spectrum is lower by a factor of two than the calculated one. In addition to the neutron spectrum measurement, the boron-10 absorbed dose was measured on the axis of the neutron field in a 20 cm x 20 cm x 20 cm water phantom, and the result agrees quite well with that obtained from calculation. This experiment confirms that the calculated optimized moderator assembly, consisting of a 22.5-cm thick, 25-cm diameter cylinder of beryllia (BeO) surrounded by a 30-cm thick jacket of alumina (Al2O3), produces an epithermal neutron flux of 3.12 x 10(7) n/cm2-s per mA of protons. For an accelerator delivering 30 mA of 2.5-MeV protons, the irradiation time for a single-session treatment can be as short as 50 minutes. The calculated ratio of absorbed neutron dose to fluence for the optimized moderator assembly is 4.9 x 10(-11) cGy-cm2/n, which is equal to that of a 5-keV neutron beam. Our experimental measurements indicate that the ratio of absorbed neutron dose to fluence may in fact be lower (better) than calculated.

Radiation oncology: salary survey results in a specialized field.

The high demand for radiation therapy technologists makes it imperative for managers to stay up-to-date on changing trends in competitive salaries. The survey conducted by the authors provides current information on salary ranges for ten positions in radiation oncology, with results reported by geographic regions.

The effects of a static magnetic field on DNA synthesis and survival of mammalian cells irradiated with fast neutrons.

The effects of a static magnetic field (0.75 T) on DNA synthesis and survival were examined with Chinese hamster V79 cells in cultures with and without fast-neutron irradiation. We found that the magnetic field applied alone for up to several hours did not cause a significant effect in either the rate of DNA synthesis or cell viability; the latter was assayed by colony formation. When cells were exposed simultaneously to the magnetic field and fast neutrons, the effects resembled those observed with neutrons alone. This was the case for both inhibition of DNA synthesis and cell killing. Cells irradiated first with neutrons followed immediately by 1 h of magnetic field exposure showed a dose-survival response curve indistinguishable from that of neutrons alone. These data suggest that the biological effect due to the magnetic field is negligible and that the presence of the magnetic field either during or subsequent to fast-neutron irradiation does not affect the neutron-induced radiation damage or its repair.

PPOs, HMOs, IPAs--understanding their concepts.

Over the past ten years, hospitals, physicians and health care administrators have been inundated with changes in health care reimbursement policies. Many administrators have dealt with changes in the way hospitals and physicians are reimbursed and, as employees, have had to make choices in their own personal health care coverage. The purpose of this paper is to examine several organizational structures that have been developed in response to reimbursement changes. We will look at the structure, and the advantages and disadvantages of PPOs, HMOs and IPAs.

Collimator evaluation for Tl-201 myocardial imaging.

Three collimators--high-resolutions, converging, and pinhole--were evaluated for Tl-201 myocardial imaging. Line spread function, sensitivity measurements, and phantom and animal studies were used. Features common to all the collimators were: a) better resolution at a closer distance with higher count density, and b) higher infarct detection rate in the tangenital projection than in the en face view relative to the lesion. Furthermore, an infarct in the epicardial location was better visualized than one in the endocardial location. In terms of resolution and sensitivity, the high-resolution collimator was found to be satisfactory in most clinical imagings, but for visualization of an infarct, its size by weight must be over 10--12 g. The pinhole collimator could resolve an infarct as small as 7 g, and use of the pinhole yielded a diagnostic accuracy of over 90%, compared with 75-80% for the high-resolution collimator. Although the low sensitivity of the pinhole collimator precludes its routine clinical use, the selected view would increase diagnostic accuracy. The converging collimator performed poorly in terms of lesion detectability, and its routine clinical use is not encouraged. The conclusion drawn here is valid in the system we have studied, but the variety of converging collimators must be evaluated further for their specific purposes.

A cyclotron target for the production of radioxenons.

A liquid cesium target has been developed which allows the production and separate identification of the neutron deficient isotopes of xenon. The present report describes irradiations utilizing 34--41 MeV protons to produce millicurie quantities of 127Xe and 129Xem. At higher energies, however, the target could be used without modification to produce xenon isotopes as light as 119.

Evaluation of nuclear-reactor-produced iodine-123.

Iodine-123 has such great potential to nuclear medicine that all possible production methods should be considered. In this report an experimental study related to 123l production at a high-intensity fast flux reactor using the reaction 124Xe(n,2n)123Xe is considered. The conclusion is that 123l could be made in small quantities and the cost would be higher than the cyclotron methods presently used.