Pharmacokinetic and endocrinological parameters of a slow-release depot preparation of the GnRH analogue ICI 118630 (zoladex) compared with a subcutaneous bolus and continuous subcutaneous infusion of the same drug in patients with prostatic cancer.

Seventeen patients with advanced prostatic cancer were treated with the gonadotrophin-releasing hormone analogue DSer (tBU)6 AzaGly 10 GnRH (ICI 118630), either as a constant SC infusion, or in the form of a monthly SC slowrelease depot formulation, in which case patients were randomised to receive one of three doses. Six of these patients also received a 250-microgram SC bolus of ICI 118630, for pharmacokinetic studies, before starting the infusion or the depot. Drug levels were measured using a double-antibody radioimmunoassay. In contrast to the SC infusion, which gave a smooth serum 118630 level profile, drug release from the depot preparation was not constant, levels varying in a predictable manner throughout each 28-day period, reaching a peak proportional to the dose of ICI 118630 received, between days 15 and 18 of each cycle. With all methods of administration there was an initial rise in LH, usually followed by a rise in testosterone, after which the SC infusion and the depot were both effective in reducing serum LH to basal levels and testosterone into the castrate range within 1 month. It is too early to make any assessment of clinical response; however, depot treatment was well tolerated: Four patients experienced an initial flare in bone pain, probably related to the initial rise in testosterone, and twelve patients experienced flushing; one patient with pre-existing hydronephrosis and hydroureter developed renal failure, possibly related to a tumour flare reaction. No patients have experienced cardiovascular side effects or local reaction.

Results of a nationwide prospective audit of stoma complications within 3 weeks of surgery.

OBJECTIVE: Actuarial analysis of stoma complications (problematic stomas) is lacking. The objectives of this audit were: to identify the incidence of stoma complications within the UK; to highlight any dissimilarity of incidence from centre to centre; to ascertain if the height of the stoma (distance of stoma lumen from the skin) at the time of fashioning is a predisposing factor to problems; and finally to initiate much needed research. METHOD: Commencing 1st January 2005, stoma care services nationwide (256) were invited to audit prospectively their next 50 enteric stomas or for a period of 1 year which ever came first. The definition of a problematic stoma being one, which needed one or more accessories to keep the patient clean and dry for a minimum period of 24 h. The incident is to have happened within 3 weeks of surgery. Factors taken into account were: type of stoma, height of stoma within 48 h of surgery; emergency or elective procedure, problem identified, BMI, gender and underlying diagnosis of the patient. The identities of the participating centres are confidential. RESULTS: Of the 256 hospital-based stoma care services within the UK, 93 (36%) participated. A total of 3970 stomas were recorded, of which 1329 (34%) were identified as problematic. Sixty-two centres reported 45-50 stomas with a range of complications 6-96%. The loop ileostomy was found to be the stoma which causes most problems. A stoma of <10 mm is a predisposing factor to complications and problems are more likely to occur following an emergency procedure. More men than women have stomas formed, but have significantly fewer problems and there is no significant difference between underlying diagnoses. CONCLUSION: The stoma height, stoma type and gender of the patient are significant risk factors identified in this audit. The BMI of patient did not affect the outcome. Patients undergoing an emergency procedure are more likely to have a problematic stoma. The significant variation of complications from centre to centre indicates surgical technique as being the key factor in stoma formation and subsequent quality of life for the patient.

Knowing how. Recovering after stoma surgery.

The postoperative period after stoma surgery involves helping patients to come to terms with their new condition. Effective management of any problems that may arise is crucial to the rehabilitative process.

Gravitationally redshifted absorption lines in the X-ray burst spectra of a neutron star.

The fundamental properties of neutron stars provide a direct test of the equation of state of cold nuclear matter, a relationship between pressure and density that is determined by the physics of the strong interactions between the particles that constitute the star. The most straightforward method of determining these properties is by measuring the gravitational redshift of spectral lines produced in the neutron star photosphere. The equation of state implies a mass-radius relation, while a measurement of the gravitational redshift at the surface of a neutron star provides a direct constraint on the mass-to-radius ratio. Here we report the discovery of significant absorption lines in the spectra of 28 bursts of the low-mass X-ray binary EXO0748-676. We identify the most significant features with the Fe XXVI and XXV n = 2-3 and O VIII n = 1-2 transitions, all with a redshift of z = 0.35, identical within small uncertainties for the respective transitions. For an astrophysically plausible range of masses (M approximately 1.3-2.0 solar masses; refs 2-5), this value is completely consistent with models of neutron stars composed of normal nuclear matter, while it excludes some models in which the neutron stars are made of more exotic matter.

Lymphatic mapping and sentinel node biopsy in the management of high-risk melanoma.

We review sentinel lymph node biopsy in patients with high-risk melanoma. This method of selective lymphadenectomy provides valuable staging information about the regional lymphatics without the need of prophylactic complete lymph node dissection. Only patients with micrometastases are candidates for complete lymph node dissection. This avoids, in nearly 85% of patients, the morbidity of the more extensive procedure. In addition, sentinel lymph node-positive patients may qualify for adjuvant therapy protocols. Whether this surgical approach ultimately results in a survival advantage awaits the results of a National Cancer Institute-sponsored national multicenter trial.

A radioimmunoassay for GnRH agonist analogue in serum of patients with prostate cancer treated with D-Ser (tBu)6 AZA Gly10 GnRH.

A radioimmunoassay is described for D-Ser (tBu)6 AZA Gly10 GnRH (ICI 118630) in serum of prostate cancer patients treated chronically with this peptide to produce a medical castration. With 125I-118630 as the label, and an anti-GnRH serum, the specificity of the assay is directed to the N-terminal end of the peptide, and putative degradation products have less than 6% cross-reactivity. The assay appears specific for intact 118630 which, after subcutaneous administration of 250 micrograms, has a half-time of disappearance from the serum of 4.9 +/- 0.4 h and a volume of distribution of 13.7 +/- 0.8 litres. Continuous subcutaneous infusion of 120 micrograms 118630/d gave stable serum concentrations of between 2-3 ng/ml for up to 63 d which were very similar to values predicted from pharmacokinetic analysis of the analogue clearance rate. This contrasts with the "peak and trough' pattern of serum 118630 levels measured in two subjects after 118630 administration from a subcutaneous implant containing 3.6 mg of peptide in a biodegradable formulation. Serum 118630 levels peaked at between 6-8 ng/ml 15 d after the implant and fell to less than 1 ng/ml at 29 d, immediately before the next implant. Serum 118630 levels following a second 3.6 mg implant were almost identical with respect to absolute concentration and time to peak value as after the first implant. This assay will be of value not only for evaluation of the pharmacokinetics of GnRH analogue release from new long-acting formulations, but also for correlation of serum peptide concentrations with pituitary gonadotroph desensitization.

Phase II study of Zoladex depot in advanced prostatic cancer with special reference to criteria of response and survival.

Zoladex is a potent decapeptide analogue of luteinising hormone releasing hormone (LHRH). The drug is formulated as a 3.6 mg depot dispersed in a matrix of d,l-lactide-glycolide copolymer, which is totally biodegradable. This formula releases drug continuously for at least 28 days and reliably suppresses serum testosterone into the castrate range. The effect of the depot was studied in 29 patients with locally advanced or metastatic carcinoma of the prostate. Average age at entry was 71 years (range 52-87) and follow-up was from 13.5 to 34.5 months (median 23). Endocrine studies showed that medical castration was maintained in all cases. Three patients experienced bone pain in the first month of treatment and two others had temporary nephrostomies for worsening ureteric obstruction. Subjective improvement was seen in 23/28 cases (82%). There were no complete responses, but partial response was seen in 24/28 (85.7%) using our own criteria, 24/28 (85.7%) using the criteria recommended by the British Prostate Group (BPG) and 15/28 (53.6%) using NPCP criteria. Stable disease was seen in 3/28 patients (10.7%) by our own or BPG criteria, and in 12/28 patients (42.9%) according to NPCP criteria. Progression of disease was measurable in 21 patients (72.4%) whatever criteria were applied; 11/29 (37.9%) have died, giving a median survival of 10 months (range 2.4-26). Following these encouraging results, a multicentre randomised comparative study with stilboestrol 3 mg daily is being undertaken.

High-Resolution Spectroscopy of the X-Ray-photoionized Wind in Cygnus X-3 with the Chandra High-Energy Transmission Grating Spectrometer.

We present a preliminary analysis of the 1-10 keV spectrum of the massive X-ray binary Cygnus X-3, obtained with the high-energy transmission grating spectrometer on the Chandra X-Ray Observatory. The source reveals a richly detailed discrete emission spectrum, with clear signatures of photoionization-driven excitation. Among the spectroscopic novelties in the data are the first astrophysical detections of a number of He-like "triplets" (Si, S, Ar) with emission-line ratios characteristic of photoionization equilibrium, fully resolved narrow radiative recombination continua of Mg, Si, and S, the presence of the H-like Fe Balmer series, and a clear detection of an approximately 800 km s-1 large-scale velocity field as well as an approximately 1500 km s-1 FWHM Doppler broadening in the source. We briefly touch on the implications of these findings for the structure of the Wolf-Rayet wind.