Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN).

OBJECTIVE: To compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3. DESIGN: A prospective, open, randomised multicentre trial. SETTING: 32 general hospitals located in Wales and England. POPULATION OR SAMPLE: 180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment). METHODS: After 24 weeks of treatment, complete responders were followed up at 6-monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. MAIN OUTCOME MEASURES: Time to histologically confirmed disease recurrence (any grade of VIN). RESULTS: The median length of follow up was 18.4 months. At 18 months, more participants were VIN-free in the cidofovir arm: 94% (95% CI 78.2-98.5) versus 71.6% (95% CI 52.0-84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95-12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96-12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), χ2 = 0.665, P = 0.415), with no grade 4+. CONCLUSIONS: Long-term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugs TWEETABLE ABSTRACT: Long-term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod.

The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro.

Although many estrogen receptor-positive breast cancers initially respond to antihormones, responses are commonly incomplete with resistance ultimately emerging. Delineation of signaling mechanisms underlying these phenomena would allow development of therapies to improve antihormone response and compromise resistance. This in vitro investigation in MCF-7 breast cancer cells examines whether epidermal growth factor receptor (EGFR) signaling limits antiproliferative and proapoptotic activity of antihormones and ultimately supports development of resistance. It addresses whether the anti-EGFR agent gefitinib (ZD1839/Iressa; TKI: 1 mum) combined with the antihormones 4-hydroxytamoxifen (TAM: 0.1 mum) or fulvestrant (Faslodex; 0.1 mum) enhances growth inhibition and prevents resistance. TAM significantly suppressed MCF-7 growth over wk 2-5, reducing proliferation detected by immunocytochemistry and fluorescence-activated cell sorter cell cycle analysis. A modest apoptotic increase was observed by fluorescence-activated cell sorter and fluorescence microscopy, with incomplete bcl-2 suppression. EGFR induction occurred during TAM response, as measured by immunocytochemistry and Western blotting, with EGFR-positive, highly proliferative resistant growth subsequently emerging. Although TKI alone was ineffective on growth, TAM plus TKI cotreatment exhibited superior antigrowth activity vs. TAM, with no viable cells by wk 12. Cotreatment was more effective in inhibiting proliferation, promoting apoptosis, and eliminating bcl-2. Cotreatment blocked EGFR induction, markedly depleted ERK1/2 MAPK and protein kinase B phosphorylation, and prevented emergence of EGFR-positive resistance. Faslodex plus TKI cotreatment was also a superior antitumor strategy. Thus, increased EGFR evolves during treatment with antihormones, limiting their efficacy and promoting resistance. Gefitinib addition to antihormonal therapy could prove more effective in treating estrogen receptor-positive breast cancer and may combat development of resistance.

Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex).

This paper describes the establishment of an antiestrogen-resistant MCF7 breast cancer cell subline (FASMCF) by continuous culture of the estrogen-responsive parental line in steroid-depleted, ICI 182,780 (Faslodex; 10(-7) M)-supplemented medium. After a 3-month period of growth suppression, cells began to proliferate in ICI 182,780 at rates similar to those of untreated wild-type cells. Immunocytochemistry showed these cells to have reduced estrogen receptor and an absence of progesterone receptor proteins. RT-PCR and transient transfection studies with estrogen response element-reporter constructs confirmed that ICI 182,780-suppressed estrogen response element-mediated signaling. FASMCF cells show increased dependence upon epidermal growth factor receptor (EgfR)/mitogen-activated protein kinase (MAPK)-mediated signaling. Thus, EgfR protein and messenger RNA, growth responses to transforming growth factor-alpha, and extracellular signal-regulated kinase 1/2 MAPK activation levels are all increased. Unlike wild-type cells, FASMCF cells are highly sensitive to growth inhibition by an EgfR-specific tyrosine-kinase inhibitor (TKI), ZD1839 (Iressa), and an inhibitor of the activation of MEK1 (MAPKK), PD098059. Short-term ( approximately 3 weeks) withdrawal of cells from antiestrogen had no effect on growth or phenotype, whereas longer withdrawal (>10 weeks) appeared to partially reverse the cellular phenotype with increasing estrogen receptor and decreasing EgfR levels. In subsequent studies FASMCF cells were maintained in TKI, where their growth was again suppressed and secondary TKI resistance failed to develop within the 3-month period in which initial ICI 182,780 resistance arose. Furthermore, wild-type cells similarly maintained in combination ICI 182,780 and TKI treatment conditions remained growth arrested (>6 months), with notable cell loss through both reduced rates of cellular proliferation and increased cell death.

Modulation of oestrogen action by receptor gene inhibition.

Selective oestrogen receptor downregulators (SERDs) are a class of highly effective steroidal antitumour agents that reduce cellular levels of the oestrogen receptor (ER). In this study, we compared the efficacy by which three novel molecular approaches: (1) antisense oligonucleotides; (2) antisense RNA; and (3) dominant negative mutants are able to act as SERDs. Using transient and, where appropriate, stable gene transfection experiments we found that constitutive overexpression of ER antisense RNA and a hormone-binding domain compromised dominant-negative ER mutant (DNER-1), were most effective at downregulating ER expression and/or activity in vitro.

The reform of the British National Health Service.

After a 40-year existence as a service sheltered from market influences, the reforms introduced in 1990 and coming into effect at this time profoundly alter the role of hospitals and primary care physicians. The hospitals may sell and purchase services across former boundaries; the family doctor has a host of additional duties under the new contract. The details of these arrangements and professional criticisms are described.