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Hawkes highlights the health impact of the widening deprivation gap and the stark regional differences in income.1 Deprivation is associated with increased cancer incidence and worse outcomes.2 In lung cancer, deprivation …

Marcus indicates the importance of candour in outlining the choices available to individuals.1 However, there is also the effect on wider issues of public health and the availability of treatment options from which patients can choose. Unacceptable radiotherapy waiting times have been highlighted by the Royal College of Radiologists for …

The Royal College of Radiologists welcomes the chief medical officer's editorial on reducing harm from radiotherapy.1 In the five years to April 2006, only 211 incidents of a dose greater than intended were reported under the IR(ME) regulations.2 Many of these were correctable by adjusting subsequent treatment. Patient injury is a rare event; this is …

The radiation response of the mouse kidney has been assayed after a range of X ray doses given with or without the nitroimidazole misonidazole or the aminothiol WR-2721. Sensitization and protection of the kidney were investigated by comparing the X ray dose needed to achieve a particular level of injury in the presence or absence of the drug. Two functional assays and kidney weight at sacrifice were used to obtain dose response curves. Urine output and 51Chromium EDTA excretion were used as functional assays at 25 and 49 weeks after irradiation. They demonstrated no radio-sensitization by misonidazole with 1, 2 or 5 fractions of X rays. Significant radioprotection was seen when 400 mg kg 1 WR-2721 was given before single X ray doses (PF = 1.34). Similar radioprotection was observed when renal weight at 1 year after irradiation was used as the third assay of damage. These results confirm that the kidney responds as a well-oxygenated normal tissue with only a small protection being afforded against radiation injury by WR-2721.

A commercial preparation of vitamin free acid-hydrolyzed casein (casamino acids) contains a growth factor that substitutes for nicotinic acid in nicotinamide adenine dinucleotide auxotrophs of Escherichia coli . This replacing factor was purified by a combination of ethanol extraction, descending partition chromatography, gel permeation chromatography, and crystallization. Structural analysis by mass spectrometry and infrared spectroscopy indicated that the compound has a mass of 368 daltons and contains six types of radicals. A possible structure is presented.

Serial abdominal radiographs of 10 patients who had shown fluctuation in the size of opacified pelvic lymph nodes were reviewed. All had previously been treated for Hodgkin's disease by irradiation alone. Three of the patients studies were finally diagnosed as having recurrent Hodgkin's disease, but the other seven were diagnosed as having reactive change and have remained well without evidence of relapse in the pelvis or abdomen after four years follow-up; one of these patients received quadruple chemotherapy for recurrent disease at the presenting site in the neck. The differential diagnosis of enlarging pelvic lymph nodes in irradiated Hodgkin's patients may be difficult and recurrent lymphoma should not be assumed. Radiologically, reactive change is favoured by the simultaneous enlargement of several groups of nodes, whereas recurrence is favoured by the selective increase in size of solitary or neighbouring lymph nodes. In case of doubt, cytological or histological confirmation of relapse should be sought.

Cranial irradiation is an effective prophylactic treatment for subclinical meningeal infiltration in lymphoblastic leukaemia. However, central nervous system (CNS) relapse still occurs in 6-10% of cases overall and in as many as 30% of cases with a poor prognosis in some series. These recurrences may be due in part to inadvertent underdosage of the cribriform plate, which is centrally situated between the orbits and is projected over their upper third in a lateral view. The dose to the adjacent meninges may thus be reduced by shielding of the radiosensitive lenses. This problem is exacerbated if conventional lateral fields centred on the mid-skull are used, because the eyes will not then project over one another. If the field centre is moved to the edge of the orbit, this problem of beam divergence can be overcome. Central axis beam blocking of both lenses is then possible, and in some patients the cribriform plate can be adequately irradiated. However, in most children the geometry of the orbit is such that it is necessary to add an anterior electron beam to ensure homogeneous dosage. These refinements in irradiation technique might prevent meningeal relapse with a lower whole-brain dose and, hence, fewer neuropsychological sequelae. This hypothesis could be tested in a clinical trial.

Auxotrophs of Escherichia coli defective in biosynthesis of nicotinamide adenine dinucleotide are able to proliferate in a minimal medium containing either nicotinic acid or vitamin-free acid hydrolyzed casein (casamino acids). The active component in acid-hydrolyzed casein is not nicotinic acid or nicotinamide as determined by partition chromatography, analysis for teritary and quarternary amines, and the Mueller and Fox reaction for nicotinic acid. It is not affected by proteinases. The activity of acid-hydrolyzed casein is lost by acid or alkaline hydrolysis, ashing, and charcoal filtration. The active factor has a molecular weight of less than 500 and is slightly soluble in n-butanol. It is insoluble in ether and chloroform.

The influence of overall treatment time on the radiation response of the mouse kidney was studied by varying the time over which 2 or 5 fractions of X-rays were administered. Two functional assays (urine output and 51Cr-EDTA excretion), and renal weight at sacrifice were used to obtain dose-response curves and estimate isoeffective doses. Split dose experiments showed Elkind recovery of about 5 Gy in 24 h. With a 7-day interval between fractions a transitory increase in isoeffect dose was observed in the first experiment. In the second, more extensive, experiment the recovered dose did not increase significantly even if the interval between two fractions was prolonged up to 25 days. Therefore, if slow repair occurred it was not worth more than 1 Gy because this was the limit of resolution of the assays used. As overall time was prolonged to 60 days an additional 1-2 Gy were recovered: it is difficult to explain this delayed sparing effect on the basis of a compensatory proliferative response, because the labelling indices of the likely target cells in the kidney are so low. Whatever the mechanisms involved, an increase in overall time had only a slight effect on isoeffect dose in these experiments and values for the "T" exponent were low (0.0-0.09). Recovery from sublethal injury between fractions has a much larger effect.

Tumor regrowth delay is an assay which reflects tumor cell kill but can be modified by growth rate changes resulting from damage to the stroma (tumor bed effects). If the stromal damage is modified by radiosensitizers and radioprotectors to a different degree from the tumor cells, the overall measurement of dose modifying factors may be influenced by the choice of a regrowth size for the growth delay analysis. We have studied the response of two mouse tumors; a fibrosarcoma which showed only a small TBE and a carcinoma which showed a very large TBE. Sensitizer enhancement ratios and protection factors have been obtained by assessing regrowth to a variety of endpoint sizes. The dose modifying effects on the stroms have then been determined by analyzing the regrowth rates of tumors after irradiation. The choice of endpoint size modified both the sensitizer enhancement ratio and the protection factor for both tumors. It appears that stromal damage may be the cause of the radioprotectoon observed in the carcinoma, whereas direct tumor cell radioprotection is indicated in the fibrosarcoma. Both direct tumor cell killing and cell death secondary to stromal damage will play an important role in determining the local control of irradiated tumors.

The radiosensitizing efficiency of a novel 2-nitroimidazole (Ro 03–8799) has been compared with that of misonidazole. Each compound was assessed by constructing dose response curves for regrowth delay using a range of drug doses. The concentration of each compound was measured in tumor homogenates with high performance liquid chromatography (HPLC). When compared on the basis of administered dose the new compound was no more efficient than misonidazole. Comparison on the basis of measured tumor concentrations showed that Ro 03–8799 was 3–4 times more efficient than misonidazole, but only at very high drug levels. Previous in vitro studies had shown a constant 10-fold difference in potency. In order to eliminate possible artifacts caused by the short half life in mice, repeated injections of Ro 03–8799 were used to maintain a constant tumor concentration for two hours before irradiation. No increase in effectiveness was observed with prolonged exposure. This is a charged compound whose distribution is pH dependent; gross tumor levels should therefore be interpreted with caution.

Three patients who were evaluated by computed tomography (CT) for possible recurrent tumour of the cervix are described. Two had proven carcinoma and the third had non-Hodgkin's lymphoma of the cervix. In each, soft tissue masses in the iliac fossa, close to the iliopsoas muscles, were demonstrated. The position, shape, symmetry and, in one patient, the presence of surgical clips led to the correct diagnosis that these soft tissue masses were normal ovaries which had been moved out of the true pelvis at the time of hysterectomy. Such ovarian conservation creates a potential cause of error as the ovaries can then simulate enlarged nodal masses.

Clinical benefit from dose modifying agents depends upon the effectiveness of the agents and the steepness of dose response curves for the local control of human tumors by radiotherapy. We have analyzed the two prospective trials and the many retrospective analyses of clinical data from the literature to determine what dose increment is needed to increase local control from 40 to 60%. This increment ranges from 3 to greater than 35%. Thus a dose modifying factor of at least 1.03 (to greater than 1.35) will be necessary for clinical detection of the benefit of a new modality, even if 135 patients are included in each arm of a trial. Two dose levels in the new treatment arm would ensure that therapeutic advantage could be assessed, and would also generate prospective dose response information.

1 We have previously reported the clinical course of a patient poisoned with paraquat who was treated with whole lung irradiation and who survived severe pulmonary damage. 2 Four further cases are reported who were much more severely poisoned and who died despite early pulmonary irradiation. 3 There is no definite evidence that this or any other form of cytotoxic therapy can influence the course of paraquat lung. As there is no adequate laboratory model, further investigation of such therapy should be in the context of a prospective clinical trial. Treatment of only one lung would allow rapid identification of a therapeutic effect of irradiation.

Summary The influence of overall treatment time on the radiation response of the mouse kidney was studied in an experiment in which 16 fractions were administered either evenly distributed over 20, 40 or 80 days, or as a split course (8 F/3 days; 74 days rest; 8 F/3 days). Urine output and an isotope assay of glomerular filtration were used to test the mice sequentially. The data were used both to obtain dose-response curves and also to determine the latent period before a chosen level of injury was expressed functionally. Prolonging the overall time from 20 to 80 days increased the isoeffect dose by 2–5 Gy (4–9%) for the isotope assay, and by 4–9 Gy (7–18%) for the urine output assay. This additional recovery as the interval between fractions was prolonged from 1 to 5 days is consistent with slow repair and can be expressed as a small " T " exponent of 0.02–0.12. (One analysis gave a result consistent with negative repair, but the errors on this result were unusually wide.) When the radiation was given as a split course, at the rate of 2 fractions per day, with a large gap of 10.5 weeks between courses, there was no additional sparing compared with 16 fractions over 20 days. This indicates that any sparing that might have resulted from slow repair or stimulated repopulation in the gap has been counterbalanced by having less time for repair of sublethal injury when intervals of 6–12 h are used instead of 24–48 h. Clearly no great increase in the tolerance dose for mouse kidney resulted from the split course.

Two functional assays (urine output and isotope clearance) have been used to assess the response of mouse kidneys to localized irradiation. The influence of the size of each X ray dose has been investigated by using single doses and two to 16 equal fractions. The X ray dose in each treatment ranged from 16 Gy as a single dose to 3.5 Gy (×16 fractions). Three separate experiments were performed, one with and two without anesthetic for the irradiation. Sequential testing of the mice was used to determine the latent period before radiation damage became manifest. Latency was found to be dose dependent; functional defects appeared earlier after higher doses but there was a minimum period of 14–19 weeks before the onset of damage. The repair capacity of the kidney was assessed by comparing isoeffective doses from the dose-response curves. Within 24 hours a recovered dose of 5 Gy was obtained if 2 doses were used instead of one. The isoeffective dose increased with fractionation and a fraction number exponent of 0.42 was obtained. Analysis of the data using a linear quadratic model yielded a low α β ratio of 0–3.5 Gy. This is similar to values obtained for other late responding normal tissues and implies that the use of small dose fractions will spare the kidney relative to tumors and acutely reacting normal tissues. In conventional radiotherapy more effective sparing of the kidney should be achieved by using thin shielding with each fraction than by completely shielding the kidney for the latter part of the treatment course.

Clinical interest in the use of more and smaller dose fractions in radical radiotherapy has been stimulated by recent reviews of experimental results with normal tissues. It has been found that if the dose per fraction is reduced (i.e., in hyperfractionation) there is sparing of late responding normal tissues relative to those which respond early. This phenomenon can be understood in terms of the shapes of the underlying dose effect relationships, which can be described using the linear quadratic equation. The ratio (alpha/beta) of the linear (alpha) and quadratic (beta) terms is a useful measure of the curviness of such dose effect curves. Low alpha/beta values (1.5 to 5 Gy) have been observed for late responding normal tissues and indicate that radiation damage should be greatly spared by the use of dose fractions smaller than the 2 Gy used in conventional radiotherapy. By contrast the high alpha/beta values (6-14 Gy) observed for acutely responding normal tissues indicate that the response is relatively linear over the dose range of clinical interest. Hence less extra sparing effect is to be expected if lower doses per fraction are administered. If tumors respond in the same way as acutely responding normal tissues then hyperfractionation might confer a therapeutic gain relative to late responding normal tissues. We have reviewed published results for experimental tumors irradiated in situ and either assayed in situ or after excision. The alpha/beta ratios were usually at least as high as those for acutely responding normal tissues, and 36/48 tumors gave values greater than 8 Gy. Low values of less than 5 Gy were obtained for only 4/48 tumors. There are considerable technical problems in interpreting these experiments, but the results do suggest that hyperfractionation might confer therapeutic gain relative to late responding normal tissues on the basis of differences in repair capability. In clinical practice more efficient reoxygenation, cell cycle redistribution and decreased overall treatment time might also confer therapeutic gain.

It has been shown that the propanolamine 2-nitroimidazole Ro 03–8799, is about an order of magnitude more efficient than misonidazole as a radiosensitizer in vitro , which is more than its electron affinity would predict. However, in vivo studies have so far shown only a minimal improvement compared to misonidazole. One reason for this could be that diffusion to the site of action in the hypoxic cell is restricted by the short half-life in the mouse and the net positive charge carried by the drug at physiological pH. Ways of maintaining a constant blood or tumor concentration over a period of 1–2 hours were investigated so that the tumor response could be assessed after this time. Initial experiments used multiple intraperitoneal or intravenous injections, for which the amount of drug required can be calculated theoretically provided sufficient pharmacokinetic data are available. Later experiments using continuous infusion of the drug were aimed at maintaining the gross tumor concentration equal to that found at the time of peak sensitization following a single administration. Results will be presented using each of these approaches. The technical feasibility and advantages of each method, together with general problems associated with interpreting any radiobiological results obtained using this approach will be discussed.

A departmental audit was conducted to assess the frequency, extent and causes of late completion of oncology clinics. Data were collected prospectively from clinical, medical, haematological and multidisciplinary oncology clinics. The data recorded included: clinic start and finish times, number of patients seen, type of consultation, number of doctors in each clinic, time spent by the doctor with the patient, and other factors that may have contributed to the late completion of clinics. A total of 848 patient consultations were recorded in 81 clinics. Of 67 clinics in which the finish time was recorded, 19 (28%) were completed on time, while 48 (72%) were late by a mean time of 49 minutes. The mean time spent by consultants with new, follow-up and chemotherapy patients was 37, 21 and 22 minutes respectively. This did not include time spent reviewing notes, dictating or ordering investigations. There was no significant difference in the time spent by specialist registrars compared with consultants, or clinical oncologists compared with medical oncologists and haematologists. The incidence of unforeseen problems such as difficult consultations, missing information, unplanned interruptions, late starts and overbooking of patients were not significantly different in those clinics that finished late compared with those that finished on time. The mean overrun of multidisciplinary clinics was longer than for non-multidisciplinary clinics (59 and 31 minutes respectively), despite a higher ratio of doctors to patients in the former (1:5.4 and 1:7 respectively). This audit showed that the main cause of late finishes in clinics in our department was the longer than anticipated time spent by doctors with patients. Consultations are taking longer because of the increasing complexity of non-surgical cancer treatments and the greater emphasis placed on patient information and informed consent. The Royal College of Radiologists (RCR) has calculated that, if a consultant oncologist sees a maximum of 315 new patients per year, the time available for each follow-up consultation would be 10 minutes. Our audit showed that follow-up consultations took an average of 21 minutes. These results suggest that the RCR recommendations for consultant expansion substantially underestimates the true number of consultants required for the treatment of cancer patients in the UK.