Biomedical subjects
E J Hall
Publications and source records attributed to E J Hall.
The molecular biology of radiation carcinogenesis.
Major new insights into carcinogenesis have come from recent advances in cellular and molecular biology. The concept of oncogenes provides a simple explanation for how agents as diverse as radiation, chemicals or retroviruses can induce tumors that are indistinguishable one from another. Oncogenes may be activated by a point mutation, by a chromosome translocation, or by amplification. Ionizing radiations are efficient at the first two mechanisms. While oncogenes are frequently associated with leukemias and lymphomas, they are associated with only 10 to 15% of human solid cancers. The importance of the loss of suppressor genes was suggested first from studies with human-hamster hybrid cells, but has since been shown to be of importance in an increasing number of human solid tumors, from rare tumors such as retinoblastoma to more common tumors such as small cell lung cancer and colorectal cancer. The mechanism of somatic homozygosity clearly involves several steps, some of which, such as a deletion, could be readily produced by ionizing radiation. The multi-step nature of carcinogenesis can be demonstrated in the petri dish, where the transfection of multiple oncogenes is required to transform normal cells from short-term explants. It can be shown, too, in colorectal cancer in the human, where the activation of an oncogene and the loss of more than one suppressor gene may be involved in the progression from normal epithelium to a frank malignancy.
Differential sugar absorption for the assessment of canine intestinal permeability: the cellobiose/mannitol test in gluten-sensitive enteropathy of Irish setters.
Intestinal permeability was assessed in Irish setters with gluten-sensitive enteropathy by oral administration of an isotonic solution of cellobiose and mannitol, and measurement of their urinary excretion ratio. The cellobiose/mannitol ratio was increased in affected Irish setters fed a wheat-containing diet compared both with littermates reared on a cereal-free diet, with no evidence of jejunal damage, and clinically healthy Irish setters. The ratio fell following six weeks on a gluten-free diet to be comparable with control values, and subsequently increased after six weeks gluten challenge. The results indicate that the cellobiose/mannitol test may be useful for the detection of mucosal damage and for monitoring the response to therapy.
Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy.
Low dose rate interstitial brachytherapy is extremely useful for those tumors that are accessible for an implant, while the introduction of remote afterloaders has eliminated exposure to nursing personnel. Currently, such machines require an inventory of many sources which are loaded into catheters implanted in the tumor and kept in place during treatment. A significant simplification of such machines would be possible in a pulsed mode, with a single source moving under computer control through the catheters. Assuming that the treatment time and average dose rate are kept unchanged, the question addressed is to find those combinations of radiation pulse widths and frequencies that would be functionally equivalent to a continuous irradiation. The linear-quadratic formalism was used to reanalyze published low dose-rate studies on cells of human origin to obtain 36 parameter sets [alpha, beta, T1/2], where T1/2 is the half time for sublethal damage repair. These data are consistent with those for human tumors. For each parameter set, those combinations of pulse width and frequency were calculated that would yield a functionally equivalent cell survival. For a regimen of 30 Gy in 60 hr, a pulse width of 10 min with a period between pulses of 1 hr would be appropriate for all the cell lines considered. Similar results were found for other possible time/dose combinations. For late effects, a 1-hr period between 10-min pulses might produce up to a 2% increase in late-effect probability, which is probably acceptable for the small volumes irradiated in interstitial brachytherapy.
Dedication to Frank Ellis.
Explore the source record for details and available documents.
The dose-rate effect revisited: radiobiological considerations of importance in radiotherapy.
A wide range of dose-rates have been used in radiation biology and radiation therapy, extending from a few cGy per day to hundreds of Gy in a fraction of a second. The dose-rate range of importance in radiotherapy extends from about 0.1 Gy/hr to several Gy/min. In this range, the fraction of cells killed by a given dose decreases as the dose-rate is reduced, principally because of the repair of sub-lethal damage. In some cell lines, an inverse dose-rate effect is observed where, over a narrow range of dose-rates, the effectiveness of a given dose increases with decreasing dose-rate if cells move through the cycle and are arrested in G2, which is a radiosensitive phase. In recent years data have accumulated for cells of human origin. About 40 data sets have been analyzed for values of the survival curve parameters and the rate of repair of sub-lethal damage. These data have been used to address three questions of relevance to radiotherapy. (1) The proposal to use pulsed rather than continuous irradiation in interstitial brachytherapy. (2) The equivalence of high dose-rate and low dose-rate intracavitary treatments for carcinoma of the cervix. (3) An analysis of equivalent doses for a range of dose-rates in interstitial implants.
Fractionated high dose-rate versus low dose-rate regimens for intracavitary brachytherapy of the cervix: equivalent regimens for combined brachytherapy and external irradiation.
The conventional treatment for carcinoma of the uterine cervix is a combination of external teletherapy and low dose-rate (LDR) intracavitary brachytherapy. Recently, however, there has been an increasing trend toward the use of high dose-rate (HDR) brachytherapy, in combination with external irradiation. The question is addressed of designing HDR treatments that will produce equivalent results to the more conventional protocols. We argue that for the unique case of radiotherapeutic treatment of carcinoma of the cervix, the criterion for producing an equivalent treatment should be based on the matching of early, not late, effects. In essence, this is because the dose to the tissues at risk for late effects is usually significantly smaller than the prescribed dose. When this effect is factored in with the different shape of dose-response curves for early and late effects, we conclude that, in the majority of cases, late effects will be no worse in a HDR regimen than a LDR regimen, provided that the corresponding doses have been matched to produce equal early effects. We provide a formalism whereby equivalent protocols can be designed for combined "external + HDR brachytherapy" regimens to match current "external + LDR brachytherapy" schedules. Using extensive basic radiobiological in vitro data derived from various cells of human origin, we provide specific examples of equivalent "external + HDR brachytherapy" regimens for 23 current "external + LDR brachytherapy" commonly-used schedules.
Fractionated regimens for stereotactic radiotherapy of recurrent tumors in the brain.
Radiosurgery (single-fraction stereotactic radiotherapy) was initially developed to treat non-malignant arteriovenous malformations, but there is growing interest in its use for the treatment of recurrent brain tumors. We suggest that there are sound reasons to expect improved results for tumor radiotherapy, in terms of late effects, if a fractionated regimen is used. At present, no published guidelines are available for choosing appropriate doses for fractionated regimens. We present two sets of guidelines, based on experimentally derived radiobiological parameters: first, we estimate gamma-ray doses which, if delivered in various numbers of fractions, should produce equivalent early effects to 70 Gy of 125I X rays delivered at low dose rate; this latter regimen is currently used in RTOG interstitial brachytherapy trials. Second, we estimate doses for multi-fractioned stereotactic radiotherapy which may be advantageous alternatives to particular doses of single-fractioned radiosurgical therapy. As the appropriate hardware is available, the use of fractionated stereotactic radiotherapy deserves serious consideration for the treatment of recurrent tumors in the brain.
Weiss lecture. The dose-rate factor in radiation biology.
The dose-rate effect has been the topic of extensive radiobiological studies and has important implications in radiation therapy and in the field of radiation protection. Three examples will be discussed: two in radiation therapy and one in protection. First, continuous low dose-rate interstitial brachytherapy may be replaced by pulsed brachytherapy, using a single source moving through the catheters of the implant. This strategy, using a modern computer-controlled afterloading device, would allow better dose optimization and result in a considerable cost saving. Radiobiological data have proved useful in defining the pulse length and pulse frequency that is equivalent to continuous low dose-rate. Second, in the intracavitary treatment of carcinoma of the cervix, a few high dose-rate (HDR) fractions on an outpatients basis can replace the low dose-rate (LDR) treatment that requires the patient to be hospitalized for several days. Radiobiological data can be used to estimate the dose levels at HDR that are equivalent to conventional LDR protocols. Third, it is usually assumed in radiation protection that doses accumulated over a period of time at low dose-rate are less effective biologically than the same dose delivered in a single acute exposure. While this may be true for X- or gamma-rays, radiobiological data indicate that neutrons delivered at low dose or in a series of fractions spread out over a period of time may produce more oncogenic transformation than a single acute exposure. This has important implications in radiation protection.
Abnormal intestinal permeability could play a role in the development of gluten-sensitive enteropathy in Irish setter dogs.
Explore the source record for details and available documents.
Delayed introduction of dietary cereal may modulate the development of gluten-sensitive enteropathy in Irish setter dogs.
Explore the source record for details and available documents.
Abnormal permeability precedes the development of a gluten sensitive enteropathy in Irish setter dogs.
Intestinal permeability to 51Cr-EDTA was examined during the development of gluten sensitive enteropathy in dogs bred from affected Irish setters and reared on a normal wheat containing diet. Comparisons were made with litter mates reared on a gluten free diet and with a control group of age matched, clinically healthy Irish setters reared on the normal diet. Studies at 4, 6, 8, and 12 months of age were correlated with morphometric and biochemical examinations of peroral jejunal biopsy specimens. Permeability was increased at all ages in the group fed gluten free diet compared with control dogs, although there were no differences in villus height, intraepithelial lymphocyte density, and alkaline phosphatase activity. At four months, permeability in the normal diet group was greater than in controls, although comparable with that in the gluten free diet group. Permeability in the normal diet group increased further in conjunction with the development of partial villus atrophy and reduced alkaline phosphatase activity, and by 12 months permeability was significantly greater than in their gluten free diet litter mates and the control dogs. The findings suggest that an underlying permeability abnormality may be involved in the pathogenesis of gluten sensitive enteropathy in Irish setter dogs.
Scientific view of low-level radiation risks.
The average number of diagnostic x-ray procedures per year in the United States equals the total population and results in an annual collective effective dose equivalent of about 9 million person-rem. Possible deleterious effects include (a) genetic consequences, the risks of which can be assessed only from animal studies; (b) carcinogenesis, which can be assessed from survivors of nuclear bombings and patients exposed for medical reasons; and (c) effects on the developing embryo or fetus. For stochastic endpoints such as cancer and genetic anomalies, it is estimated that the current practice of radiology in the United States increases spontaneous frequency by less than 1%. No single procedure is likely to produce harm to the conceptus, but an accumulation of procedures in a pregnant woman could be hazardous during the sensitive period of 8-15 weeks after conception, with microcephaly and mental retardation the most likely deleterious effects. The balance of risk versus benefit in diagnostic radiology is heavily weighted toward benefit, but the risks are there, and constant efforts are needed to reduce radiation doses to the minimum necessary.
From chimney sweeps to oncogenes: the quest for the causes of cancer.
Over the past 200 years, a bewildering array of chemical, physical, and viral agents has been identified that can cause cancer, but the mechanisms involved are only now becoming clear. In the leukemias and lymphomas, it appears that the activation of cellular oncogenes is important. The genes involved are present in all normal cells and are often associated with cell growth and regulation. When activated, they act in a dominant fashion to cause a cell to express the malignant phenotype. There is increasing evidence that in solid tumors, a more important mechanism may be the loss of a suppressor gene. The classic example is retinoblastoma, in which the retinoblastoma gene has been cloned and is also found to be associated with several other common cancers including sarcomas and small cell lung cancer. It is likely to be one of a family of such genes. It may well be that the activation of one or more oncogenes or the loss of one or more suppressor genes, or both, is required for a tumor to progress from initiation through promotion to a metastasizing malignancy.
Fractionated high dose rate versus low dose rate regimens for intracavitary brachytherapy of the cervix. I. General considerations based on radiobiology.
Intracavitary brachytherapy at low dose rate (LDR), often with the addition of external-beam radiotherapy, has long been considered the treatment of choice for carcinoma of the cervix, maximizing acute damage in the treatment volume, whilst minimizing late effects. In recent years, primarily for reasons of convenience and cost, there has been a move towards treatments involving a few fractions at high dose rate (HDR). Using data from cells of human origin cultured in vitro, we make estimates of the doses that, delivered in 2-12 HDR fractions, produce tumour control and early effects equivalent to intracavitary treatments at LDR. We also show that, for situations where the normal-tissue dose responsible for late effects is significantly smaller than the tumour dose, HDR schemes may be devised which, while yielding early killing comparable with that of LDR, should not result in worse late effects. We suggest that this scenario probably applies to treatment of carcinoma of the cervix.
Oncogenic transformation of C3H 10T1/2 cells by acute and protracted exposures to monoenergetic neutrons.
An in vitro assay was used to assess cell killing and induction of neoplastic transformation in C3H 10T1/2 cells exposed to X rays and a range of monoenergetic neutrons administered at various dose rates. Curves for cell survival and induction of neoplastic transformation showed nonlinearity for cells exposed to acute graded doses of X rays, while irradiation of cells with 0.05 to 1.5 Gy of 0.23-, 0.35-, 0.45-, 0.70-, 0.96-, 5.90-, and 13.7-MeV neutrons resulted in a linear response as a function of dose for both neoplastic transformation and killing. When compared to results obtained with 250-kVp X rays, all neutron energies were more effective at both cell killing and induction of neoplastic transformation. When expressed as maximum biological effectiveness (RBEM), both cell survival and induction of neoplastic transformation showed an initial increase with neutron energy (maximal at 0.35 MeV), followed by a decrease in effectiveness with further increases in energy. These responses are consistent with microdosimetric predictions in that recoil protons from neutron interaction are shifted to lower lineal energies as neutron energies increase. To examine the effects of temporal distribution of dose on neutron-induced neoplastic transformation, cells were exposed to either a single dose or five equal dose fractions spread over 8 h. As a function of dose for single or fractionated exposures to 0.5 Gy or 0.23-, 0.35-, 0.45-, 5.9-, or 13.7-MeV neutrons, neither a sparing nor an enhancing effect was seen with survival. Similarly, the frequency of induction of neoplastic transformation was independent of dose fractionation for all but 5.9-MeV neutrons. The enhancing effects of exposure to fractionated doses of 5.9-MeV neutrons were further studied by comparing exposures for a range of doses given singly, in five fractions over 8 h, or continuously for 8 h. Results reaffirm the enhancing effects of dose fractionation on the induction of oncogenic transformation for 5.9-MeV neutrons. Within the limits of the data, there is modest enhancement of neutron-induced neoplastic transformation when the exposure dose is extended from a few minutes to several hours, with the enhancement being dependent on neutron energy.
Neoplastic transformation and the inverse dose-rate effect for neutrons.
Considerable evidence has recently accumulated, both in vivo and in vitro, to suggest that neutrons at low dose rates, or in multiple fractions, have an enhanced effectiveness for inducing neoplastic transformation. A consistent pattern has emerged as to the dependence of the effect on dose, dose rate, and radiation type. A consistent model of the phenomenon as a function of dose, dose rate, and radiation type is presented. The approach, first suggested by Rossi, is that cells are extra sensitive in part of their cycle. Then an acute exposure of cycling cells to high-LET radiation results in some fraction of the sensitive cells receiving large depositions of energy--greater than required for the effect. If the exposure is protracted, a larger proportion of sensitive cells will be exposed, but to smaller numbers of energy depositions--still enough, however, to produce the effect. The model produces results consistent with all available data on enhancement of neoplastic transformation in the C3H 10T1/2 system by protraction or fractionation at medium or high LET. Implications for radiation protection and the radon problem are discussed.
Non-invasive brain stimulation reveals reorganized cortical outputs in amputees.
EMG responses to non-invasive electromagnetic brain stimulation (EMS) were recorded from arm muscles of congenital amputees. Responses were obtained with lower thresholds on the amputated than on the intact side and were evoked from a larger cortical area. Contracting muscles showed increased responses to EMS; the increase was more pronounced on the amputated side. Similar findings were obtained in one traumatic amputee who suffered an early amputation, but not in another patient with a late amputation. We conclude that in congenital amputees there is substantial reorganisation of the corticospinal system and that this may also occur in early traumatic cases.