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.

Recto-urethral fistula following brachytherapy for localized prostate cancer.

OBJECTIVE: The use of prostate brachytherapy (BT) in the management of prostate cancer is increasing. BT is often chosen because of its perceived lower toxicity when compared with other radical therapy options. Rarely however serious complications can occur. One such complication is recto-urethral fistula (RUF). We report the incidence of RUF following BT at our centre and review the potential factors in fistula development. METHOD: A prospectively collected database was used to identify cases of RUF among 1455 patients treated with prostate BT at a single UK centre with at least 2 years of follow up. This included patients treated with BT monotherapy, as well as those treated with BT combined with external beam radiotherapy and BT used as salvage as all these groups have a higher incidence of RUF. Implant dose and volume characteristics for those patients, their co-morbidities and history of endoscopic procedures were recorded. RESULTS: Recto-urethral fistula was identified in three (0.2%) patients, occurring at 19-27 months following BT. All these patients had BT monotherapy. All three patients had rectal symptoms after their BT and had been investigated with endoscopy and low rectal biopsy. Subsequent surgical management with faecal and/or urinary diversion was required. On review of patients' BT details, radiation dose and volume parameters were higher on the postprocedure CT calculations than had been suggested by the preimplant plan. No other predisposing risk factors for RUF were identified. CONCLUSION: The incidence of RUF in our population is low. RUF following BT has been associated with rectal biopsy in previous series and this is confirmed in our report. Gastrointestinal specialists should not perform biopsy of the anterior rectum in patients who have had BT unless there is a very high clinical suspicion of malignancy.

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%.

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.

Re-audit of radiotherapy waiting times 2003.

AIMS: There has been increasing concern, by clinical oncologists in the UK, about the continuing long waiting times for radiotherapy treatment. An audit of patients starting treatment in 1 week in 2003 was carried out to determine waiting times and to compare current results with those obtained from a similar audit in 1998. MATERIALS AND METHODS: All centres in the UK completed the audit, which recorded waiting-list status and treatment intent for all new treatments started in 1 week, date of booking form completion and fractionation scheme used. RESULTS: Waiting times have lengthened in most centres for all categories of patients although, for palliative treatments, there was no additional increase in median waiting time compared with the last audit. Fewer patients in all categories are being treated within the Joint Collegiate Council for Oncology (JCCO) guidelines. Single-fraction treatments are now common for palliation. Most adjuvant treatment uses one of three prescriptions. In each Strategic Health Authority (StHA), the same proportion of the total number of patients with cancer seemed to be given radiotherapy. There was no obvious simple correlation of radiographer, physicist or treatment machine numbers with waiting times. CONCLUSION: The results of this survey suggest a continuing mismatch between capacity and demand. Increased complexity of radical treatments, and possibly more patients being referred for treatment, may have been offset in part by reduced fractionation for palliation.

Retrospective detection of exposure to sulfur mustard: improvements on an assay for liquid chromatography-tandem mass spectrometry analysis of albumin-sulfur mustard adducts.

We here report on the further development of the method comprising the pronase digestion of albumin alkylated by sulfur mustard and the subsequent mass spectrometric analysis of an adducted tripeptide. This includes significant improvements in both the albumin isolation procedure and the automation of the microliquid chromatography-electrospray-tandem mass spectrometric analysis. We also report on the results of a small reference range study, in which we have established that there are no detectable interferences in sera from unexposed individuals.

Brachytherapy boost to the tumour bed in high risk patients after limited surgery for breast cancer.

The results of treatment for 174 patients at high risk of local recurrence, referred for radiotherapy after conservative surgery for early breast cancer, are evaluated. Microscopic margin involvement, extensive carcinoma in situ, and vascular/lymphatic invasion were the main risk factors for local recurrence. Whole-breast irradiation (40 Gy in 15 fractions over 3 weeks) followed with a brachytherapy boost (Ir192 wire implant or PDR Ir192) of 25 Gy was applied. Median follow-up was 80 months. The actuarial 6-year overall survival rate was 91% and the within breast recurrence-free survival was 88%. The most common risk factor among those recurring within the breast was involved surgical margins (13 out of 17). Cosmesis was reported to be good or excellent in 79% of cases. In patients at high risk for local recurrence, tumour-bed boost with brachytherapy can provide satisfactory local control after limited surgery and external radiotherapy.

Effect of micronutrient fortified beverage on nutritional anaemia during pregnancy.

OBJECTIVE: To evaluate the efficacy of a multiple micronutrient fortified beverage containing eleven nutrients at physiological levels in prevention of anaemia and improving iron and vitamin A status during pregnancy. DESIGN: A randomised double blind placebo controlled study. SETTING: Mpwapwa and Kongwa Districts in Dodoma Region of Tanzania. SUBJECTS: Five hundred and seventy nine pregnant women were screened for entry into the study and 439 women who met the study criteria were enrolled. INTERVENTIONS: Study participants received either a fortified (F) or non-fortified (NF) orange flavoured drinks identical in appearance, provided in two self administered servings per day for an eight week period. MAIN OUTCOME MEASURES: Comparison of haemoglobin (Hb), serum ferritin (SF) and serum retinol (SR) at baseline and follow up. RESULTS: After eight weeks of supplementation, the F group (n=129) had a significantly higher Hb increase of 0.86 g/dL compared to 0.45 g/dL in the NF group (n=130) p<0.0001. Gestational age at entry into the study, moderated the effect on Hb of the fortified drink. Women at earlier gestational age upon entry, had a higher rise in Hb than women of late gestational age (0.8 g/dL versus 0.04 g/dL rise respectively, p=0.038, n=188). The risk of being anaemic at the end of the study for those in the F group was reduced by 51% (RR=0.49, CI=0.28 to 0.85). Iron stores (by serum ferritin levels) increased by 3 microg/L in the F group (p=0.012) and a decrease of 2 microg/L in the NF group (p=0.115). The follow up ferritin concentration depended on initial ferritin level. Regardless of treatment group, serum retinol concentrations were significantly higher in mothers who had delivered. Mothers who had adequate levels at entry benefited more from the supplement than those with low levels (0.26 micromol/L versus no significant difference). CONCLUSIONS: The multiple micronutrient-fortified beverage given for eight weeks to pregnant women improved their haemoglobin, serum ferritin and retinol status. The risk for anaemia was also significantly reduced. The important predictors of Hb increase at follow up were the fortified beverage, baseline Hb, serum retinol, baseline ferritin and gestational age at entry into study. Anthropological research showed that the beverage was highly acceptable and well liked.

Micronutrient dietary supplements--a new fourth approach.

Currently the three main widely used strategies to control micronutrient deficiencies are food diversification, fortification, and consumption of medicinal supplements. In Tanzania a fourth strategy has been evaluated in school children, and is to be studied in pregnant and lactating women. The dietary supplement comes in the form of a powder used to prepare a fruit flavored drink. Children consumed for six months 25 grams per school day attended, the powder being added to 200 ml of water. The dietary supplement provides between 40 and 100 percent of the RDA of 10 micronutrients, which includes iron, vitamin A and iodine. Unlike medicinal supplements it provides the multiple vitamins and minerals in physiologic, not megadoses. In a well conducted randomized double blind placebo controlled trial, a dietary supplement in the form of a fortified powder fruit drink produced statistically significant differences not only in vitamin A and iron status, but also in the growth of young school age children.

Classical and slow-binding inhibitors of human type II arginase.

Arginases catalyze the hydrolysis of L-arginine to yield L-ornithine and urea. Recent studies indicate that arginases, both the type I and type II isozymes, participate in the regulation of nitric oxide production by modulating the availability of arginine for nitric oxide synthase. Due to the reciprocal regulation between arginase and nitric oxide synthase, arginase inhibitors have therapeutic potential in treating nitric oxide-dependent smooth muscle disorders, such as erectile dysfunction. We demonstrate the competitive inhibition of the mitochondrial human type II arginase by N(omega)-hydroxy-L-arginine, the intermediate in the reaction catalyzed by nitric oxide synthase, and its analogue N(omega)-hydroxy-nor-L-arginine, with K(i) values of 1.6 microM and 51 nM at pH 7.5, respectively. We also demonstrate the inhibition of human type II arginase by the boronic acid-based transition-state analogues 2(S)-amino-6-boronohexanoic acid (ABH) and S-(2-boronoethyl)-L-cysteine (BEC), which are known inhibitors of type I arginase. At pH 7.5, both ABH and BEC are classical, competitive inhibitors of human type II arginase with K(i) values of 0.25 and 0.31 microM, respectively. However, at pH 9.5, ABH and BEC are slow-binding inhibitors of the enzyme with K(i) values of 8.5 and 30 nM, respectively. The findings presented here indicate that the design of arginine analogues with uncharged, tetrahedral functional groups will lead to the development of more potent inhibitors of arginases at physiological pH.

Expression, purification, and characterization of human type II arginase.

Human type II arginase, which is extrahepatic and mitochondrial in location, catalyzes the hydrolysis of arginine to form ornithine and urea. While type I arginases function in the net production of urea for excretion of excess nitrogen, type II arginases are believed to function primarily in the net production of ornithine, a precursor of polyamines, glutamate, and proline. Type II arginases may also regulate nitric oxide biosynthesis by modulating arginine availability for nitric oxide synthase. Recombinant human type II arginase was expressed in Escherichia coli and purified to apparent homogeneity. The Km of arginine for type II arginase is approximately 4.8 mM at physiological pH. Type II arginase exists primarily as a trimer, although higher order oligomers were observed. Borate is a noncompetitive inhibitor of the enzyme, with a Kis of 0.32 mM and a Kii of 0.3 mM. Ornithine, a product of the reaction catalyzed by arginase and a potent inhibitor of type I arginase, is a poor inhibitor of the type II isozyme. The findings presented here indicate that isozyme-selectivity exists between type I and type II arginases for binding of substrate and products, as well as inhibitors. Therefore, inhibitors with greater isozyme-selectivity for type II arginase may be identified and utilized for the therapeutic treatment of smooth muscle disorders, such as erectile dysfunction.

Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum.

The boronic acid-based arginine analogue S-(2-boronoethyl)-L-cysteine (BEC) has been synthesized and assayed as a slow-binding competitive inhibitor of the binuclear manganese metalloenzyme arginase. Kinetic measurements indicate a K(I) value of 0.4-0.6 microM, which is in reasonable agreement with the dissociation constant of 2.22 microM measured by isothermal titration calorimetry. The X-ray crystal structure of the arginase-BEC complex has been determined at 2.3 A resolution from crystals perfectly twinned by hemihedry. The structure of the complex reveals that the boronic acid moiety undergoes nucleophilic attack by metal-bridging hydroxide ion to yield a tetrahedral boronate anion that bridges the binuclear manganese cluster, thereby mimicking the tetrahedral intermediate (and its flanking transition states) in the arginine hydrolysis reaction. Accordingly, the binding mode of BEC is consistent with the structure-based mechanism proposed for arginase as outlined in Cox et al. [Cox, J. D., Cama, E., Colleluori D. M., Pethe, S., Boucher, J. S., Mansuy, D., Ash, D. E., and Christianson, D. W. (2001) Biochemistry 40, 2689-2701.]. Since BEC does not inhibit nitric oxide synthase, BEC serves as a valuable reagent to probe the physiological relationship between arginase and nitric oxide (NO) synthase in regulating the NO-dependent smooth muscle relaxation in human penile corpus cavernosum tissue that is required for erection. Consequently, we demonstrate that arginase is present in human penile corpus cavernosum tissue, and that the arginase inhibitor BEC causes significant enhancement of NO-dependent smooth muscle relaxation in this tissue. Therefore, human penile arginase is a potential target for the treatment of sexual dysfunction in the male.

Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase.

Arginase is a binuclear Mn(2+) metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. X-ray crystal structures of arginase complexed to substrate analogues N(omega)-hydroxy-L-arginine and N(omega)-hydroxy-nor-L-arginine, as well as the products L-ornithine and urea, complete a set of structural "snapshots" along the reaction coordinate of arginase catalysis when interpreted along with the X-ray crystal structure of the arginase-transition-state analogue complex described in Kim et al. [Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, D. W., Morris, Jr., S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678-2688]. Taken together, these structures render important insight on the structural determinants of tight binding inhibitors. Furthermore, we demonstrate for the first time the structural mechanistic link between arginase and NO synthase through their respective complexes with N(omega)-hydroxy-L-arginine. That N(omega)-hydroxy-L-arginine is a catalytic intermediate for NO synthase and an inhibitor of arginase reflects the reciprocal metabolic relationship between these two critical enzymes of L-arginine catabolism.