We have safely conducted a clinical trial of a drug not routinely used during pregnancy. Sildenafil in the escalating dose regimen 20-80 mg tid was well tolerated, with no increase in maternal or fetal morbidity or mortality but did not prolong pregnancy duration in women with preeclampsia. (ClinicalTrials.gov number, NCT 00141310).
A B S T R AC TListening to children and young people is for social workers a legal requirement, it is also believed to lead to better outcomes and is increasingly promoted in policy. The practice of listening is, however, rarely straightforward, and this is particularly the case with socially excluded groups. As a result, the voices of the marginalized are less likely to be heard. In this paper the author draws on interview data from a research study into communication between social workers and looked-after children for the light it sheds on why effective dialogue with disaffected young people can be hard to achieve. It is argued that much that appears unsuccessful in an interaction can be understood in terms of power plays, with young people resisting the adult's agenda and trying to impose their own. True listening to disaffected young people requires time, so that a trusting relationship can be developed. It also demands an acceptance that the adult agenda may be flawed and a willingness to consider alternative possibilities. This can challenge the preconceptions, not just of individual workers, but of agencies and of national policy-makers.
Purpose:To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of MG98, an antisense oligonucleotide to DNA methyltransferase 1 (DNMT1), which has been shown to reduce CpG island methylation and allow reexpression of tumor suppressor genes in vitro. Experimental Design: In this phase I, open-label study, patients with advanced solid malignancies were treated with escalating doses of MG98 administered as a continuous i.v. infusion over 7 days repeated every 14 days. Cohorts of three patients, which could be expanded to six patients, were studied. The maximum tolerated dose was defined as the highest dose at which no more than 33 % of subjects experienced dose-limiting toxicity. Pharmacokinetic and pharmacodynamic parameters of MG98 were also characterized. Results: Thirty-three patients were treated at doses of 100 to 250 mg/m 2 /d MG98. MG98 was well tolerated with mild fatigue and myalgia, dose-limiting toxicity was asymptomatic transaminitis, and the maximum tolerated dose was 200 mg/m 2 /d. One patient achieved a partial response and another prolonged disease stabilization. Plasma half-life of MG98 was short (2 hours), drug concentrations reaching a dose-dependent steady state during infusion with a volume of distribution equivalent to plasma volume. Suppression of DNMT1 expression was observed in 26 of 32 patients studied. Conclusions: MG98 was well tolerated with early evidence of clinical activity. Proof of mechanism was observed and measurement of DNMT1 expression in peripheral blood mononuclear cells may be useful in future phase II development.
The computed tomographic (CT) findings in 118 patients with the diagnosis of leiomyosarcoma were reviewed. The tumor masses visualized in these patients were often quite large; extensive necrotic or cystic change was a frequent finding. Calcification was not observed in these tumors. The liver was the most common site of metastasis in these patients, with marked necrosis of the liver lesions a common finding. Other manifestations of tumor spread included pulmonary metastases, mesenteric or omental metastases, retroperitoneal lymphadenopathy, soft-tissue metastases, bone metastases, splenic metastases, and ascites. The metastatic lesions were often centrally necrotic. Although the CT appearance of leiomyosarcoma is not specific, these findings, when present, suggest consideration of this diagnosis.
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