Dose-incidence curves for tumour control and normal tissue injury, in relation to the response of clonogenic cells

A probit analysis has been made of data from the literature on local control of tumours and injury to normal tissue as a function of dose of radiation. Fifteen series were analysed for local tumour control in man and ten series for complications. The analysis yielded values for the D50 dose (50% incidence of effect) and the probit width (K), a measure of the steepness of the dose-incidence curve. The same analyses were made of data for rodents. Broadly, K was proportional to D50 in the ratio 1:7, with no major differences between tumours and reported complications. D50 was plotted as a function of dose per fraction for four normal tissues and two tumours in rodents. D50 decreased more rapidly with increasing dose per fraction for the normal tissues than for tumours. The probit width, K, varied inversely with increasing dose per fraction for normal tissues and this contrasted with the tumour response. Thus with increasing dose per fraction, the threshold for effect decreased and the steepness of the ensuing dose-incidence curve increased, relatively more rapidly for normal tissue than for tumour. These curves of gross response have been analysed also by the double negative log method of Gilbert [23], in an attempt to estimate the number and survival characteristics of "tissue-rescuing cells". These were calculated to be less than 1 in 10(4) of the numbers of clonogenic cells measured by excision assays. The D0 values of the derived survival curves for these tissue-rescuing cells were higher than those measured by excision assays.     

Treatment acceleration in radiotherapy: the relative time factors and dose-response slopes for tumours and normal tissues.

A published collation of data for control of head and neck cancer in over 4500 patients has been subjected to direct analysis to deduce dose-response, fractionation, and time parameters. The analysis confirms the presence of a significant time factor of the order of 0.5-0.6 Gy/day, deduced previously using various assumptions and normalisation procedures. In addition, the dose-response curve was characterised by Da = 29 Gy which contributed to long "effective" doubling times being deduced for tumour clonogens in the patient population as a whole. Some late-reacting normal tissues also show significant time factors, and furthermore, their dose-response curves are in general steeper than for tumours. Hence, care should be taken in accelerating treatments to improve local control, if the treatments are truly at tolerance regarding late-appearing major complications.     

Spontaneous involution of pulmonary sequestration in children: a report of two cases and review of the literature

Background. Two cases of pulmonary sequestration which regressed spontaneously are presented. Objective. To demonstrate the value of imaging studies in the diagnosis and follow-up of some forms of congenital masses of the lung in asymptomatic patients. Material and methods. We reviewed the clinical records and imaging studies of two asymptomatic children, one newborn and the other 3 months old, with thoracic masses which demonstrated variable degrees of spontaneous involution. Results. Abdominal ultrasound performed on the newborn with a palpable mass showed a triangular echogenic mass with a large central feeding vessel arising from the aorta. The mass had disappeared on follow-up US exam performed 6 years later. CT was performed in the 3-month-old patient with a persistent retrocardiac mass. A soft-tissue density mass in the left pulmonary base with a large feeding vessel arising from the aorta was visualised on contrast-enhanced CT. Five years later, a new CT scan showed significant shrinkage of the mass and no vessel. Conclusion. Radiological techniques such as real-time US with Doppler imaging and contrast-enhanced CT may establish the diagnosis of pulmonary sequestration by demonstrating the mass and its systemic vessel, thereby eliminating the need for more aggressive imaging procedures. Partial or total disappearance of these masses represents a further example of involutive pathology and suggests that not all cases of pulmonary sequestration should be surgically treated. Received: 12 September 1997 Accepted: 18 September 1997     

Levels of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (APE1, APEX, Ref-1) are associated with the intrinsic radiosensitivity of cervical cancers.

A study was made of the relationship between the intrinsic radiosensitivity of human cervical tumours and the expression of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (HAP1). The radiosensitivity of clonogenic cells in tumour biopsies was measured as surviving fraction at 2 Gy (SF2) using a soft agar assay. HAP1 expression levels were determined after staining of formalin-fixed paraffin-embedded tumour sections with a rabbit antiserum raised against recombinant HAP1. Both measurements were obtained on pretreatment biopsy material. All 25 tumours examined showed positive staining for HAP1, but there was heterogeneity in the level of expression both within and between tumours. The average coefficients of variation for intra- and intertumour heterogeneity were 62% and 82% respectively. There was a moderate but significant positive correlation between the levels of HAP1 expression and SF2 (r = 0.60, P = 0.002). Hence, this study shows that there is some relationship between intrinsic radiosensitivity and expression of a DNA repair enzyme in cervical carcinomas. The results suggest that this type of approach may be useful in the development of rapid predictive tests of tumour radiosensitivity.     

Effects of deficiency in p53 or bcl-2 on the sensitivity of clonogenic cells in the small intestine to low dose-rate irradiation

PURPOSE: To study the role of p53 and bcl-2 in the response of the small intestine to irradiation delivered at low dose-rate. MATERIALS AND METHODS: Mice homozygous for p53 or bcl-2 deletion (-/-), their respective heterozygotes (+/-), and their wild-type littermates (+/+) including a previously used hybrid strain (B6D2F1), were irradiated to the whole-body using 60Co gamma-rays at 1 Gy h(-1). Crypt survival levels in the small intestine were measured at day 3 after the end of irradiation. RESULTS: Crypt survival levels were higher in p53 -/- mice than in the other p53 genotypes after 25-30 Gy, but not after lower or higher doses. Similar experiments with the three genotypes for bcl-2 status showed lower crypt survival after all doses used in the -/- mice, compared with the +/- and +/+ mice, which were similar in response. The marked degree of curvature in the survival curve observed for the p53 genotypes was also observed in B6D2F1 hybrid mice, was particularly striking in the p53 -/- mice, but was not seen to the same extent in the bcl-2 genotypes. The heterozygotes for p53 or for bcl-2 were nearer in response to their respective +/+ genotypes rather than the -/- genotypes. CONCLUSION: The increased crypt survival levels at some radiation dose levels in the p53 nulls contrasts with the lack of change reported previously using irradiation at high dose-rate. The decreased survival in the bcl-2 nulls is consistent with the known 'survival' function of bcl-2, although bcl-2 expression has not been detected immunohistochemically in this intestinal site. The marked degree of curvature in the dose-response curve at high dose levels for some genotypes was unexpected at this low dose-rate.