Report on the early efficacy and tolerability of I(125) permanent prostate brachytherapy from a UK multi-institutional database.

AIMS: To report the results of I(125) prostate brachytherapy from a central, prospectively collected database of three UK institutions. MATERIALS AND METHODS: All patients treated with I(125) permanent prostate brachytherapy at the Christie Hospital, Manchester (CHM), Cookridge Hospital, Leeds (CKL) and Mount Vernon Hospital, Northwood, London (MVL) since 2003 have been prospectively registered on a detailed central database. Patient, tumour, pre- and post-implant dosimetry data have been recorded. Urinary toxicity as assessed by the International Prostate Symptom Score, catheterisation and urinary stricture rates after implant have been documented and biochemical failure determined, using both the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus and the Phoenix (nadir + 2 ng/ml) definition. RESULTS: In total, 1535 patients were registered on the database between January 2003 and October 2006, including 432 from CHM, 926 from CKL and 177 from MVL, with a median follow-up of 21 months (range 1-56). Patient and tumour characteristics were similar at all centres. Pre-implant dose indices were comparable between centres, except for the V150, with median values of 51.9, 64.3 and 69.8% at CHM, CKL and MVL, respectively. Median post-implant dose parameters were lower than pre-planned constraints by up to 33.0% at each centre for all values, except at CKL where the V200 was 23.9% higher. The International Prostate Symptom Score increased from a median of 5 at baseline to 18, 6 weeks after implant, but was not significantly different to baseline values by 12 months. Nine per cent of men required catheterisation after implant for a median duration of 53 days, but urinary stricture rates remained low at 1%. Neoadjuvant hormonal manipulation was used in 228 men (15%) for downsizing and 159 (10%) for intermediate/high-risk disease. Collated biochemical failure rates were low at this point of follow-up, with actuarial 2-year ASTRO and Phoenix biochemical failure-free survival rates of 94.4 and 94.5%, respectively, consistent with other large single centre reports. When post-implant dosimetric factors were assessed for a relationship to biochemical failure, no indices consistently predicted for improved ASTRO and Phoenix biochemical failure-free survival rates. CONCLUSIONS: This ongoing collaboration shows that with limited infrastructure (a single industry-sponsored data manager), a large multi-institutional database estimated to represent one-third of implants carried out in the UK during this time can be developed. Patient selection was similar across all centres and adhered to published guidelines. Early biochemical and toxicity outcomes confirm the efficacy and tolerability of I(125) prostate brachytherapy in a large cohort of patients. A further analysis is planned.

Effect of germination of finger millet on nutritional value of foods and effect of food supplement on nutrition and anaemia status in Tanzanian children.

Inadequate dietary intake, often combined with an infection can lead to malnutrition that often manifest as growth failure or deficiency of essentials nutrients including iron leading to iron deficiency anaemia. In an effort to investigate diet in relation to nutrition status of children, diet and dietary intake were investigated in rural Tanzania. The effect of germination of finger millet based food recipe on its nutritional value was evaluated. The food consisted of finger millet flour, kidney beans, ground peanuts and dried mangoes at predetermined proportions of 75:10:10:5 respectively. Dietary habits of young children were investigated and effects of a fortified food supplement and the cereal based recipe on nutrition status of children were investigated. The two diets were then supplemented to children for 6 months and changes on anaemia and anthropometrical indices of children were evaluated at follow up periods. To assess anaemia and iron status, haemoglobin (Hb), haematocrit (Hct), erythrocyte protoporphyrin (EP) and serum ferritin (SF); and weights and heights were measured to assess growth. A significant improvement in nutrient density was noted in processed cereals. Bioavailability of iron in cereal based diet increased from 0.75 +/- 18 to 1.25 +/- 41 mg/100 g (P = 008), viscosity was significantly raised by 12% and phytate concentration was reduced from 4.5 +/- 0.5 to 4.1 +/- 0.5 mg/g (P = 0.03). Significantly lower intake of iron was observed in schoolchildren with Hb < 11.5 g/dl) compared to those who were normal. Total iron intake was 22+/- 7 and 27 +/- 13 mg/day, respectively (P < 0.05). There was a significant correlation between iron intake and serum ferritin (r = 0.233, P < 0.05). After six months of supplementing children with the fortified beverage a significantly larger increase in haemoglobin concentration was shown in the fortified group than in the non-fortified group (a difference of 6.2 versus 3.2 g/dl respectively). Supplementing infants with the germinated cereal based food supplement showed a general improvement on Hb status and growth that was not significantly different to that in the control group (P > 0.05). In conclusion, consumption of foods with low iron bioavailability is a major cause of anaemia. Germination improves the nutritional value of foods however there is need to fortify such processed foods for infant feeding.

National survey of radiotherapy fractionation practice in 2003.

AIMS: To document UK practice in radiotherapy fractionation. METHODS: All radiotherapy centres in the UK participated in a 1-week audit from 29 September 2003. Fractionation data were collected for all patients starting external beam radiotherapy. This included 2498 patients who were prescribed 32 547 fractions. RESULTS: For the radical treatment of non-skin malignancy (n = 708), the prescribed dose ranged from a single fraction of 8 Gy for total-body irradiation to 75 Gy in 43 fractions for prostate cancer. Postoperative treatment for breast cancer was dominated by three regimens: 40 Gy in 15 fractions; 45 Gy in 20 fractions; and 50 Gy in 25 fractions. Palliative treatment was given in a single fraction to 393 patients (36%) with doses of up to 15 Gy. Three hundred and ninety patients (36%) received four to seven fractions delivering 20-25 Gy. Only 89 patients (8%) received more than 10 fractions with palliative intent but used 29% of such fractions. In the treatment of bone metastases, the most common prescriptions were 8-10 Gy in a single fraction and 20 Gy in five fractions. CONCLUSION: UK radiotherapy practice has become more uniform and moved closer to practice in North America and Europe over the past 15 years. For radical radiotherapy, 54% of prescriptions were for a fraction size of 1.8-2.0 Gy but the distribution was bi-modal and 20% of patients were prescribed fraction sizes of 2.7-3.0 Gy. Evidence-based practice now supports hypo-fractionated palliative treatment favouring single fractions for bone metastases and one or two fractions for many patients with advanced lung cancer. Two fractions are advised for some patients with brain metastasis. If these guidelines had been applied uniformly, then the number of treatments prescribed for palliation could have fallen by 36% from 5197 to 3313. This would have represented a 6% reduction in the overall radiotherapy workload. Not all patients are suitable for such hypo-fractionated treatments, but this is an area in which resource use can be improved. In the postoperative management of breast cancer, a change in practice to use 15 fractions uniformly would reduce overall radiotherapy workload by 4%. By contrast, a change to 25 fractions would increase overall workload by 7%.

Aliphatic ketones are acetylcholinesterase inhibitors but not transition state analogs.

A number of C4--C9 aliphatic ketones are acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) inhibitors, with Ki values in the 0.7--5 mM range. Comparison to analogous substrates would suggest that these ketones are transition state analogs; e.g. 2-pentanone binds to the enzyme approx. 550 times more tightly than ethylacetate. However, a number of other criteria contradict this conclusions: (1) the binding is insensitive to ketone structure: isomeric ketones, cycloalkanones, and sterically hindered ketones have similar inhibitory potencies. (2) Analogous alcohols are also good inhibitors even though they cannot form hemiketals with the enzyme. (3) Representative ketones are relatively ineffective at blocking inactivation of the enzyme by methylsulfonyl fluoride, indicating that ketones do not bind principally at the hydrolytic site. (4) A competition experiment shows that binding of tetramethylammonium chloride excludes binding of 2-pentanone, suggesting that ketones bind to the anionic rather than the hydrolytic site. Thus, observation of tight binding relative to a substrate is not a sufficient criterion to establish that an inhibitor is a transition state analog.

The mode of binding of potential transition-state analogs to acetylcholinesterase.

Phenylacetone, 4-phenyl-2-butanone, and 4-oxopentyltrimethylammonium chloride were tested as potential transition state analogs for eel acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7). Phenylacetone is a competitive inhibitor of the enzyme but not a transition state analog, since its binding constant is similar to that for the substrate phenyl acetate. 4-Phenyl-2-butanone binds 6-18 times more tightly than the inhibitors 4-phenyl-2-butanol and N-benzylacetamide and the substrate benzyl acetate and also blocks inactivation of the enzyme with methanesulfonyl fluoride. However, its binding is independent of pH in the range 5-7.5, whereas both V and V/Km for benzyl acetate hydrolysis decrease with decreasing pH in this range. These data indicate a specific but weak interaction between the ketone carbonyl and the enzyme, but probably do not justify considering this compound a transition state analog. 4-oxopentyltrimethylammonium iodide has previously been shown to bind about 125 times more strongly than the substrate acetylcholamine. It also binds about 375 times more strongly than the alcohol 4-hydroxypentyltrimethylammonium iodide. Furthermore, the ketone protects the enzyme from inactivation by methansulfony fluoride, while the corresponding quaternary ammonium alcohol accelerates this inactivation reaction. This additional information confirms that the ketone is a transition state analog.

Crystallization and oligomeric structure of rat liver arginase.

Rat liver arginase, a manganese-metalloenzyme, has been crystallized from polyethylene glycol 8000 in N,N-bis(2-hydroxyethyl)glycine (Bicine) buffer at pH 8.5. Crystals form as either cubes or pyramids and belong to space group P3(1) (or P3(2)) with hexagonal unit cell dimensions a = b = 88.9 A, c = 114.8 A, or a = b = 88.5 A, c = 104.5 A; the variation along the c axis does not correlate with the external crystal morphology of cube or pyramid-shaped. X-ray diffraction data are measured to a limiting resolution of 2.4 A. Given the volume constraints of the unit cell it is likely that rat liver arginase is a trimer, with three 35,000 Da monomers in the asymmetric unit. This resolves a persistent ambiguity regarding the oligomeric structure of this enzyme.

A randomised study of whole-breast vs tumour-bed irradiation after local excision and axillary dissection for early breast cancer.

AIMS: Whole-breast radiotherapy (WBRT) after conservative surgery for early breast cancer is a routine standard of care. Despite this, a number of uncertainties in management still exist. Over recent years, a number of new technologies have allowed the development of partial-breast irradiation, with the intention of improving the risk-benefit relationship of routine breast radiotherapy. We report the results of a trial comparing partial- with WBRT, with prolonged follow-up. MATERIALS AND METHODS: Between 1986 and 1990, 174 women were randomised to receive conventional whole-breast radiotherapy (WBRT) (40 Gy in 15 fractions), with a tumour-bed boost or partial-breast irradiation by a variety of techniques. Recruitment was problematic, and the trial closed prematurely well before meeting its recruitment target. RESULTS: A trend was observed towards higher local recurrence and a higher locoregional recurrence rate after irradiation of the tumour bed alone. Distant recurrence and survival were the same. CONCLUSIONS: Conclusions are limited in view of the failure to complete accrual of the target of 400 participants, and in the context of the techniques of partial-breast radiotherapy used during this study, which would not compare with those in current use. Tumour-bed irradiation alone cannot currently be recommended as routine treatment outside the context of clinical trial.

Sustaining safe and acceptable bowel care in spinal cord injured patients.

This article aims to increase understanding of the bowel care needs of patients with spinal cord injury. Spinal cord injury centres provide expert bowel management for these patients but healthcare staff in general hospitals may not be familiar with the techniques required.

The irreversible inactivation of two copper-dependent monooxygenases by sulfite: peptidylglycine alpha-amidating enzyme and dopamine beta-monooxygenase.

Peptidylglycine alpha-amidating enzyme (alpha-AE) and dopamine beta-monooxygenase (D beta M), two copper-dependent monooxygenases that have catalytic and structural similarities, are irreversibly inactivated by sodium sulfite in a time- and concentration-dependent manner. Studies with alpha-AE show that the sulfite-mediated inactivation is dependent on the presence of redox active transition metals free in solution, with Cu(II) being the most effective in supporting the inactivation reaction. Sulfite inactivation of alpha-AE is specific for the monooxygenase reaction of this bifunctional enzyme and amidated peptides provide protection against the inactivation. Consequently, the sulfite-mediated inactivation of alpha-AE and D beta M most likely results from the transition metal-catalyzed oxidation of sulfite to the sulfite radical, SO3-.

New drugs and future developments in photodynamic therapy.

New photosensitizing drugs are becoming available which should improve on some of the disadvantages of haematoporphyrin derivates for photodynamic therapy (PDT). The main features are shorter duration of systemic photosensitisation, activation by longer and more penetrating light and better tumour to normal tissue drug uptake ratios. These drugs together with better understanding of in vivo light dosimetry promise to improve both results and clinical acceptability for PDT in future studies.

Interstitial brachytherapy: past-present-future.

This article summarizes and reviews the development of brachytherapy from 1930 to 1990. Its purpose is to highlight the immense contribution made to its underlying science and clinical practice by Dr. Frank Ellis, who has been personally involved with it, in theory and in practice, for that whole half-century. A remarkable achievement in itself, but so much the more when it is seen beside his contributions to other aspects of radiation in the service of man. The early use of solid sources leads on to a discussion of manual afterloading and iridium. This leads on to a quick survey of the development of dosimetry. Thereafter clinical indications are briefly discussed and some published results tabulated. Lastly, some pointers to possible future development and benefits are discussed. Mention is also made of some continuing unresolved problems where new work could help to establish the most appropriate use of brachytherapy.

Continuous, pulsed or single acute irradiation of a transplanted rodent tumour model.

BACKGROUND: Recent advances in remote afterloading pulsed mode brachytherapy have provided a much needed tool for the radiation oncologist. It has the versatility of optimised physical dose distribution along with improved staff radiation protection and patient nursing. PURPOSE: This preliminary study was designed to explore the radiobiological equivalence between conventional continuous low dose rate tumour irradiation (CLDR) and the new technique of pulsed dose irradiation (PDR). MATERIALS AND METHODS: Subcutaneous isogenic sarcomas transplanted in female John's Strain Wistar rats were irradiated locally with acute, pulsed or continuous interstitial low dose-rate exposures at 9-11 mm mean diameter. RESULTS: As expected, single acute doses (5-40 Gy) were more effective (P < 0.01) in achieving tumour growth delay (1.4 days/Gy) than CLDR exposure (4-51 Gy) over 24-48 h (0.93 days/Gy). However, PDR treatment (8 hourly fractions/day) at high dose-rate (8-48Gy) over 8-72 h was significantly (P = 0.01) more effective (1.66 days/Gy) than CLDR but not acute exposures. CONCLUSIONS: These data suggest that, clinically a significantly improved therapeutic ratio may also be achievable with pulsed high dose rate brachytherapy, and that further radiobiological studies with in-vivo tumour models are needed.

Replacement of hairpin and loop implants by optimised straight line sources.

Remote after loading is desirable for all forms of brachytherapy but is difficult in the oral cavity because the tight curvature at the top of implanted loops impedes passage of the source. For this reason we investigated differential loading of straight catheters to simulate a conventional loop or hairpin. Using a pulsed brachytherapy remote after loader the top four dwell positions of straight catheters were given two to four times the dwell time of other source positions. This raised the reference isodose to cover the surface mucosa without significantly changing either the total volume treated or the volume receiving > 150% of reference dose when compared with conventional loop implants of equivalent source length and separation. This optimised straight line implant should therefore be amenable to remote afterloading and have similar dose/volume characteristics to loops.

The response of a rodent fibrosarcoma to superficial/interstitial photochemotherapy, chemotherapy or radiotherapy.

Growth and dose-response curves were established for a subcutaneously implanted isogenic fibrosarcoma in BD9 rats after treatment with photochemotherapy (PCT), using Photofrin II or polyhaematoporphyrin with superficial or interstitial 630 nm light, cyclophosphamide or gamma-irradiation. Tumour response to PCT increased with dose up to 200 J.cm-2 for superficial light or 200 J for interstitial light but no further response occurred after higher light doses. The maximum response after interstitial treatment was significantly greater than after superficial treatment where only a small margin of normal tissue was treated. The incidence of necrosis in the overlying skin was significantly less after interstitial than superficial light suggesting a better therapeutic ratio after interstitial than superficial PCT. Tumour response increased with the diameter of the treatment field after superficial light supporting the possibility of a tumour bed effect associated with PCT. The largest tumour that could be effectively treated with a single optical fibre was 12 mm. The dose-response curves for interstitial PCT and cyclophosphamide were similar but ionizing irradiation produced increasing tumour response throughout the range of doses used (5 to 30 Gy) and the maximum response was greater after radiotherapy than after PCT or chemotherapy suggesting that in this tumour model interstitial PCT is as effective as cyclophosphamide but less effective than radiotherapy.

An alternative and more cost effective method of delivery of radiotherapy in age related macular degeneration.

AIMS/BACKGROUND: In the past 5 years there has been a dramatic increase in the use of radiotherapy to treat subfoveal neovascular membranes (NVMs) in both Europe and the USA despite the high cost. An alternative, more cost effective method of delivery using x ray simulation and bite block head fixation is described. METHOD: 15 patients were recruited with classic subfoveal NVMs. Head fixation was achieved with a customised Perspex mask for eight patients and a bite block for seven. An x ray simulator was used to check the field of irradiation. No computerised tomography (CT) was performed. All patients received a total dose of 13.3 Gy ionising radiation. Visual acuities were charted before and after treatment over a 24 month period. RESULTS: After 24 months, 5/8 (67%) in the mask group showed stable visual acuities (less than two line change on Snellen chart) compared with 3/7 (43%) in the bite block group. This difference may be attributed to a variation in the pretreatment visual acuities in the two groups. From several studies it has been estimated that 24 months after diagnosis 28% untreated individuals would have stable vision compared with 53% patients in this study. CONCLUSIONS: These results compare favourably with other studies and show that teletherapy can be safe and effective form of treatment for subfoveal NVMs. The authors have described an alternative method of head fixation and shown that CT scanning is not essential. This method of delivery is considerably less costly than that traditionally used and may allow greater numbers of patients to benefit from radiotherapy treatment.

In vivo measurement of the optical interaction coefficients of human tumours at 630 nm.

The light distribution within a treatment volume is determined by the source geometry (e.g. superficial or interstitial illumination) and the optical interaction coefficients of the irradiated tissue. We have measured the energy fluence rate at various points within tumours undergoing irradiation with 630 nm light for photodynamic therapy for several source geometries. The relative positions of source and detector fibres were determined using CT scanning techniques. The results of the measurements were then applied to solutions of the diffusion theory which allowed the determination of the absorption coefficient (sigma a = 30.5 +/- 16 m-1), the reduced scattering coefficient (sigma' s = 941 +/- 735 m-1), the effective attenuation coefficient (sigma eff = 261 +/- 49 m-1) and the build-up coefficient which relates surface irradiance to the energy fluence rate at depth (k = 1.6 +/- 0.6). Knowledge of these coefficients allows the transmission of light through tissue to be predicted and hence the optical dosimetry of subsequent treatments to be planned more effectively.

Evaluation of response following irradiation of juvenile angiofibromas.

Ten cases of angiofibroma treated by irradiation are reported. Relief of symptoms occurred by the end of treatment in eight patients. Objective regression was much slower, six having visible disease for greater than 6 months and four for at least 1 year. Only one was symptomatic. Radiological resolution lagged behind clinical improvement and was complete in only one of three asymptomatic patients evaluated by computed tomography (CT) at between 2 and 3 years after treatment. The significance of these residual masses seen on CT is unclear.

Report on the clinical effects of inadvertent radiation underdosage in 1045 patients.

Between Autumn 1982 and Winter 1991, 1045 patients received lower doses of radiation than were prescribed for the treatment of their cancers because of a miscalculation of radiation doses. This occurred as a result of the introduction of a new technique of treatment planning. An error in the application of the planning system lead to an underdosage of radiation of between 5 and 35%. In patients who received radiation alone for radical treatment a dose reduction of 20% or more resulted in a lower than expected local control rate. The effects were less marked in patients who were treated by combinations of surgery and radiation and in those with a very high rate of distant metastases. In 1991, a new computer planning system was installed and a discrepancy was discovered between the new plans and those from the previous system. Further investigation revealed that the original planning system already contained within it a correction factor for the tumour to skin distance and that systematically reapplying this correction had resulted in underdoses of radiation being delivered to patients for nearly 10 years. During the 9-year period of this dose miscalculation only 6% of patients treated in the department were treated with the isocentric technique; for many of those it formed only a part of their treatment.

Radiotherapy after conservative surgery for breast cancer: selective use of iridium-192 wire boost to tumour bed in high risk patients.

The results of treatment for 51 patients referred for radiotherapy after local excision of an 'early' breast carcinoma are reviewed. The patients were considered to be at particularly high risk of local recurrence due to the presence of one or more adverse histological features, most commonly microscopic involvement of resection margins. The patients received a course of whole-breast irradiation (40 Gy in 15 fractions over 3 weeks) but instead of following this with a routine photon or electron tumour-bed boost (15 Gy in five fractions) these patients received an iridium-192 wire implant, giving a tumour-bed boost of 25 Gy over approximately 3 days. After a median follow-up of 38 months, five patients have recurred locally within the breast, giving an actuarial breast recurrence-free survival of 87.8% at 8 years. Four patients have died of metastatic breast cancer, none of whom had uncontrolled local disease. Cosmesis was good or excellent in 76% of cases. The presence of microscopic tumour at resection margins or other adverse histological features is not, therefore, necessarily an indication for further surgery, as a good level of local control can still be achieved with radiotherapy providing a relatively high-dose tumour-bed boost is employed using an iridium-192 wire implant.

Extrapulmonary small cell cancer.

Extrapulmonary small cell cancer is rare, but it occurs in a wide variety of sites, where it has a behaviour quite different from the tumours normally found at those sites. Prognosis is generally poor, but combined modality treatment with combination chemotherapy can often achieve useful palliation and, occasionally, long term remission and cure.