How significant is detection of ductal carcinoma in situ in a breast screening programme?

PURPOSE: To compare the histological grades of screen detected and non-screen detected ductal carcinoma in situ (DCIS) and to identify any differences that might support the contention that DCIS found by breast screening represents an over-diagnosis. The aim was also to establish whether any particular mammographic features of DCIS can be used to predict tumour grade reliably. MATERIALS AND METHODS: Biopsy proven cases of DCIS (n=153) were reviewed with respect to grade and subdivided into high, intermediate and low grades using the Van Nuys classification. A more aggressive subset of DCIS (microinvasive and interval cancers) were similarly analysed. Mammograms were reviewed with regard to abnormal features and distribution, and the appearances correlated with grade. RESULTS: Fifty-four percent (53/98) of screen detected and 62% (34/52) of non-screen detected DCIS were high grade. The rest were equally intermediate and low grade, with no statistical difference between the two groups. Eighty-four percent of the aggressive subset of tumours were high grade. Micro-calcification was present in 90% and in 10% there were soft tissue changes alone. Seventy-six percent of linear branching calcification was associated with high grade DCIS. Only 13% of high grade DCIS demonstrated punctate micro-calcification; however, 38% of cases of punctate micro-calfication were associated with high grade tumours and there was a great deal of overlap between the groups. CONCLUSION: Most cases of DCIS in both screen and non-screen detected groups were high grade. Only one in five was low grade. Analysis of the aggressive subgroup underlines the significance of high grade DCIS. Mammographic patterns are not always reliable in the prediction of tumour grade. The detection of DCIS in screening programmes is important and should not be regarded as over-diagnosis.     

Assuring quality and performance of sustained and controlled release parenterals: AAPS workshop report,co-sponsored by FDA and USP

This is a summary report of the American Association of Pharmaceutical Scientists, the Food and Drug Administration, and the United States Pharmacopoeia cosponsored workshop on Assuring Quality and Performance of Sustained and Controlled Release Parenterals. Experts from the pharmaceutical industry, the regulatory authorities, and academia participated in this workshop to review, discuss, and debate formulation, processing, and manufacture of sustained and controlled release parenterals and identify critical process parameters and their control. Areas were identified where research is needed to understand the performance of these drug delivery systems and to assist in the development of appropriate testing procedures. Recommendations were made for future workshops, meetings, and working groups in this area.     

Co-delivery of an antisense oligonucleotide and 5-fluorouracil using sustained release poly (lactide-co-glycolide) microsphere formulations for potential combination therapy in cancer

Antisense oligonucleotides (AODNs) can selectively inhibit oncogene expression by Watson-Crick hybridisation to target mRNA and are being increasingly considered for use in combination with conventional drugs for potential anticancer therapy. Combination therapy of AODNs and cytotoxic agents using biodegradable polymeric delivery systems potentially offers several advantages including site-specific or organ-directed targeting, protection from digesting enzymes, and improved pharmacokinetics/pharmacodynamics resulting from sustained delivery of the entrapped drugs. Using a model AODN targeting the epidermal growth factor receptor (that is over-expressed in several cancers including breast and brain cancer) and the commonly used cytotoxic agent, 5-fluorouracil (5-FU), we have examined the use of poly (lactide-co-glycolide) (P(LA-GA)) microsphere formulations for co-delivery of these agents. Both agents were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations and release profiles determined in vitro. Using a double emulsion method for preparing the P(LA-GA) microspheres suitable entrapment and sustained release over 35 days was observed in both types of formulation. Release of AODN and 5-FU from all formulations appeared to be biphasic. However, the release rates of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Electrophoretic mobility shift assays suggested that this might be, in part, due to an interaction of 5-FU with the oligodeoxynucleotide (ODN). Further, our data suggest that by mixing individual formulations of 5-FU and ODNs at different mass ratios allowed greater flexibility in achieving the desired release profile as well as avoiding potential drug-drug interactions. Thus, co-administration of individual P(LA-GA) microsphere formulations of AODNs and 5-FU, at appropriate mass ratios, appears worthy of further investigation for the potential co-delivery of these anti-cancer agents in vivo.     

Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension

OBJECTIVES: To assess the efficacy and safety of sildenafil citrate (Viagra) in men with erectile dysfunction and parkinsonism due either to Parkinson's disease or multiple system atrophy. METHODS: Twenty four patients with erectile disease were recruited, 12 with Parkinson's disease and 12 with multiple system atrophy, into a randomised, double blind, placebo controlled, crossover study of sildenafil citrate. The starting dose was 50 mg active or placebo medication with the opportunity for dose adjustment depending on efficacy and tolerability. The international index of erectile function questionnaire (IIEF) was used to assess treatment efficacy and a quality of life questionnaire to assess the effect of treatment on sex life and whole life. Criteria for entry included a definite neurological diagnosis and a standing systolic blood pressure of 90-180 mm Hg and diastolic blood pressure of 50-110 mm Hg, on treatment if necessary. Blood pressure was taken at randomisation (visit 2) and crossover (visit 5) lying, sitting, and standing, before and 1 hour after taking the study medication in hospital. RESULTS: Sidenafil citrate was efficacious in men with parkinsonism with a significant improvement, as demonstrated in questionnaire responses, in ability to achieve and maintain an erection and improvement in quality of sex life. In Parkinson's disease there was minimal change in blood pressure between active and placebo medication. In multiple system atrophy, six patients were studied before recruitment was stopped because three men showed a severe drop in blood pressure 1 hour after taking the active medication. Two were already known to have orthostatic hypotension and were receiving treatment with ephedrine and midodrine but the third had asymptomatic hypotension. However, the blood pressures in all three had been within the inclusion criterion for the study protocol. Despite a significant postural fall in blood pressure after sildenafil, all patients with multiple system atrophy reported a good erectile response and were reluctant to discontinue the medication. CONCLUSIONS: Sidenafil citrate (50 mg) is efficacious in the treatment of erectile dysfunction in parkinsonism due to Parkinson's disease or multiple system atrophy; however, it may unmask or exacerbate hypotension in multiple system atrophy. As Parkinson's disease may be diagnostically difficult to distinguish from multiple system atrophy, especially in the early stages, we recommend measurement of lying and standing blood pressure before prescribing sildenafil to men with parkinsonism. Furthermore, such patients should be made aware of seeking medical advice if they develop symptoms on treatment suggestive of orthostatic hypotension.     

Infantile nephrotic syndrome and congenital glaucoma

A case of infantile nephrotic syndrome (NS) with advanced membranoproliferative glomerulonephritis (MPGN), type I, and bilateral congenital glaucoma, is presented. The patient also had persistent thrombocytopenia and subclinical hypothyroidism. The parents were second-degree cousins and the affected infant had a sibling who was born with congenital glaucoma. His mother had an aunt and uncle on the maternal side who were born with congenital glaucoma. In addition, there was a history of infantile death in five family members of unknown causes (pedigree). To the best of our knowledge, the association of congenital glaucoma and infantile NS due to MPGN has not been reported previously. Received: 19 February 2001 / Revised: 30 May 2001 / Accepted: 31 May 2001     

p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy.

Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.     

Evaluation of the roll over test as predictor of gestational hypertension in African women.

Fifty-six primigravid women at 28-32 weeks gestation were studied prospectively to assess the roll over test (ROT) as a predictor of gestational hypertension in African women. Blood pressures were measured continuously in the supine and left lateral positions using an automated accutor machine. ROT was positive in only two women (3.6%). These two women later developed gestational hypertension but so did 18 others who had negative ROT. Measures that may be useful in increasing the predictive value of the ROT in these women are suggested.