Effect of anorectal eversion on long-term clinical outcome of restorative proctocolectomy.

Eversion of the rectum during restorative proctocolectomy with stapled ileal pouch-anal anastomosis (IPAA) remains a controversial surgical manoeuvre because of concern that it may impair anal sphincter function and adversely affect outcome. We have reviewed the long-term results in 41 patients whose operation included formation of a 20 cm J-pouch with stapled IPAA by the technique of rectal eversion. At median follow-up of 4 years (range 1-6 years), 4 pouches (10%) had been removed (2 for pelvic sepsis, 1 for rectovaginal fistula and 1 for Crohn's disease). In 34 patients with functioning pouches in situ, median stool frequency was 5 per 24 h (range 2-10). 11 patients (33%) regularly had to evacuate their pouch at night and 4 (12%) used antidiarrhoeal medication. No patients reported major incontinence; 2 (6%) had minor leakage, and in another 2 minor leakage had now ceased. 4 patients had had episodes of pouchitis. These favourable results offer no support for the contention that rectal eversion substantially worsens the long-term results of restorative proctocolectomy.

Intraluminal stenting in the management of adhesional intestinal obstruction.

Intraluminal stenting of the small bowel has been advocated as a method of reducing the risk of recurrent adhesional obstruction in patients requiring adhesolysis. We reviewed the complications and efficacy of this technique in 25 patients undergoing surgery for relief of intestinal obstruction due to complex, extensive and dense adhesions. Five patients developed minor and three patients major complications. Three (13%) of 23 patients alive after mean follow-up of 4 years had had episodes of recurrent intestinal obstruction, but none had required reoperation. Intraluminal stenting remains of unproven efficacy. It may find a place as an adjunct to adhesolysis in patients requiring repeated operations for the relief of obstruction due to extensive and dense adhesions; but, in view of the high rate of complications, careful case selection will be necessary.

Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.

Effects of 4-hydroxytamoxifen and a novel pure antioestrogen (ICI 182780) on the clonogenic growth of human breast cancer cells in vitro.

We have investigated the effects on breast cancer cell growth of 4-hydroxytamoxifen (4OHT), a conventional antioestrogen with agonist activity, and 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5,(10)- triene-3,17 beta-diol (ICI 182780), a novel, pure antioestrogen, using established human breast cancer cell lines and cancer cells obtained directly from breast cancer patients with malignant pleural effusions who had relapsed on tamoxifen. The effects of the two agents were assessed using the Courtenay-Mills clonogenic assay, which measures the growth of single cancer cells as colonies suspended in soft agar. The standard assay was modified by the use of defined serum- and phenol red-free growth medium. The growth of oestrogen receptor (ER)-positive MCF-7 cells in the assay was oestrogen responsive. Both antioestrogens inhibited the stimulatory effects of 1 nM oestradiol, but ICI 182780 caused significantly greater inhibition than 4OHT at 0.1-1.0 microM concentrations. In the absence of oestradiol, 4OHT but not ICI 182780 caused significant stimulation of colony formation at low (0.01-1.00 nM) concentrations. Neither antioestrogen had any effects on colony formation by the ER-negative Hs578T cell line. Successful colony formation was obtained in primary cultures from six out of eight malignant effusions. Colony formation was significantly stimulated by 0.1 nM oestradiol in four cases and by 10 nM 40HT in two cases. In contrast, ICI 182780 exhibited no intrinsic stimulatory activity and significantly inhibited both oestradiol- and 4OHT-stimulated cell growth. We conclude that the agonist activity of 4OHT and other conventional antioestrogens may cause treatment failure in some patients by stimulating breast cancer cell growth. The new, pure antioestrogen ICI 182780 is a more potent oestrogen antagonist than 4OHT and exhibits no growth-stimulatory activity. This agent may therefore offer therapeutic advantages over conventional antioestrogens in patients with advanced breast cancer and may be effective after conventional agents have failed.

Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer.

We have conducted a clinical trial of a novel pure antiestrogen, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5,(1 0)-triene-3,17 beta-diol (ICI 182780), to assess its tolerance, pharmacokinetics, and short term biological effects in women with primary breast cancer. Fifty-six patients were randomized to either a control group (n = 19), in which they received no preoperative treatment, or a treatment group (n = 37), in which they received daily i.m. injections of ICI 182780 at doses of 6 mg (n = 21) or 18 mg (n = 16) for 7 days prior to primary breast surgery. Serum drug concentrations, gonadotropin levels, and sex hormone-binding globulin levels were measured during the study period by radioimmunoassay. Expression of estrogen receptors (ER), progesterone receptors, the estrogen-induced protein pS2, and the cell proliferation-related antigen Ki67 was determined immunocytochemically in pre- and poststudy tumor samples. Treatment with ICI 182780 caused no serious drug-related adverse events and had no effect on serum gonadotropin or sex hormone-binding globulin levels. Minor adverse events occurred in 5 patients receiving the 6-mg dose and 3 patients receiving the 18-mg dose. The serum concentration of ICI 182780 was dose dependent but showed variation between individuals. There was evidence of an approximately 3-fold drug accumulation over the short treatment period but steady state levels were not reached by the end of the 7 days. In patients with ER-positive tumors, treatment with ICI 182780 was associated with significant reductions in the tumor expression of ER (median ER index, 0.72 before versus 0.02 after treatment; P < 0.001), progesterone receptor (median progesterone receptor index, 0.50 before versus 0.01 after treatment; P < 0.05), and Ki67 (median Ki67 labeling index, 3.2 before versus 1.1 after treatment; P < 0.05). Treatment with ICI 182780 also resulted in a significant reduction in pS2 expression (P < 0.05) but this appeared unrelated to tumor ER status. In conclusion, ICI 182780 was well tolerated after short term administration and produced demonstrable antiestrogenic effects in human breast tumors in vivo, without showing evidence of agonist activity. These properties identify ICI 182780 as a candidate agent with which to evaluate whether a pure estrogen antagonist offers any additional benefit in the treatment of human breast cancer over conventional nonsteroidal antiestrogens, typified by tamoxifen, which exhibit variable degrees of agonist activity.

Pneumoscrotum following endoscopic sphincterotomy.

Perforation is an infrequent complication of endoscopic sphincterotomy. We report here a man who developed a pneumoscrotum following a retroperitoneal perforation of the duodenum after endoscopic sphincterotomy. The mechanism of this unusual complication is discussed.