Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: Overexpression of the epidermal growth factor receptor has been demonstrated in advanced prostate cancer and is associated with a poor outcome. A multi-institutional, randomized, phase II study was undertaken by the National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of two doses of oral gefitinib in patients with minimally symptomatic, hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Between July and November 2001, 40 patients with HRPC and increasing prostate-specific antigen (PSA) or progression in measurable disease who had not received prior chemotherapy were randomly assigned to 250 mg (n = 19) or 500 mg (n = 21) oral gefitinib daily continuously. The primary end points were PSA response rate and objective measurable response. Functional Assessment of Cancer Therapy Prostate Cancer Subscale (FACT-P) quality-of-life questionnaires were completed at baseline and during treatment. RESULTS: None of the patients demonstrated a PSA or objective measurable response. Five (14.3%) of 35 assessable patients had stable PSA (one patient at 250 mg and four patients at 500 mg), and five patients (14.3%) had a best response of stable disease (duration, 2.5 to 16.8 months). No significant effect on the rate of increase in PSA was seen. The most common drug-related nonhematologic toxicities observed were grade 1 to 2 diarrhea (250 mg, 65%; 500 mg, 56%), fatigue (250 mg, 29%; 500 mg, 33%), and grade 1 to 2 skin rash (250 mg, 24%; 500 mg, 39%). FACT-P scores decreased during treatment, indicating worsening of symptoms compared with baseline. CONCLUSION: Gefitinib did not result in any responses in PSA or objective measurable disease at either dose level. Gefitinib has minimal single-agent activity in HRPC.     

Characterization of supercritical fluid extracts of St. John's wort (Hypericum perforatum L.) by HPLC-MS and GC-MS.

Supercritical fluid extracts (carbon dioxide without modifiers) of St. John's Wort (Hypericum perforatum L., Clusiaceae) were analyzed by GC-MS, HPLC-DAD and HPLC-DAD-MS. Besides the dominating phloroglucinols hyperforin (36.5 +/- 1.1%) and adhyperforin (4.6 +/- 0.1%), the extracts mainly contained alkanes (predominantly nonacosane), fatty acids and wax esters. The apolar components tended to accumulate in a waxy phase resting a top of the hyperforin-enriched phase. No components of higher polarity like naphthodianthrones were found. A set of hyperforin oxidation products was detected and tentatively assigned using HPLC-MS.     

Polymorphism of glutathione conjugation of methyl bromide,ethylene oxide and dichloromethane in human blood: Influence on the induction of sister chromatid exchanges (SCE) in lymphocytes

A hitherto unknown glutathione-S-transferase in human erythrocytes displays polymorphism: three quarters of the population (conjugators) possess, whereas one quarter (non-conjugators) lack this specific activity. A standard method for the identification of conjugators and non-conjugators with the use of methyl bromide and gas chromatography (head space technique) is described. Three substrates of the polymorphic enzyme, methyl bromide, ethylene oxide and dichloromethane (methylene chloride), were incubated in vitro with individual whole blood samples of conjugators and non-conjugators. All three substances led to a marked increase of sister chromatid exchanges (SCE) in the lymphocytes of the non-conjugators but not in those of conjugators. A protective effect of the glutathione-S-transferase activity in human erythrocytes for the cytogenetic toxicity of these chemicals in vitro is thus confirmed. Since the enzyme activity is not found in erythrocytes of laboratory animals, species extrapolations for risk assessment of methyl bromide, ethylene oxide and dichloromethane should be reconsidered.     

17-Hydroxyprogesterone in premature infants as a marker of intrauterine stress

AIMS: Amniotic infection (AI) and preeclampsia (PE), which are commonly the reason for prematurity, inflict stress of different duration on immature fetuses. Whether chronic stress, as reflected by intrauterine growth retardation, influences the level of 17-OH progesterone (17-OHP), was not previously examined. METHODS: We analyzed 17-OHP and TSH levels during neonatal screenings in the first hours of life of 90 premature infants born between 25 and 33 weeks of gestation in infants with AI (n=37) or with PE (n=53). Control of acute stress parameters was derived from umbilical arterial cord blood pH and base excess (BE). RESULTS: Mean 17-OHP levels of infants born to mothers with PE were 85.7 nmol/L compared to 54.6 nmol/L (P<0.001) in AI infants. 17-OHP was even higher when intrauterine growth restriction was present (99.8 nmol/L). Antenatal steroids and mode of delivery did not significantly affect 17-OHP levels. CONCLUSIONS: Stress of relatively long duration, as in cases of PE, leads to a significant increase of 17-OHP level in preterm infants. The postnatal 17-OHP level may be considered as a measure for severity of intrauterine stress and might be used as an individualized indicator for earlier intensive care.     

High-intensity focused ultrasound for the targeted destruction of uterine tissues: experiences from a pilot study using a mobile HIFU unit

Background High intensity focused ultrasound (HIFU) is a novel method which offers the non-invasive ablation of tissues without harming overlying organs or skin. It has been introduced successfully in urology for the ablation of prostatic hyperplasia and seems to be promising in the treatment of uterine fibroids. In this study we aimed to examine the feasibility and possible side effects of HIFU treatment of uterine tissues using an experimental mobile HIFU unit with ultrasound guidance. Methods For these experiments, a 1.07 MHz ultrasound source was used which allows treatment depths between 0 and 10 cm. In 12 patients scheduled to have abdominal hysterectomy, 5–60 impulses of HIFU were applied through the intact skin upon uterine tissues directly prior to the surgical procedure. Tissue intensities lay between 3,200 and 6,300 W/cm2 and a fixed pulse length of 4 s was used. Results No side effects were encountered other than one first-degree skin burn and the treatment was well tolerated. Histology showed clearly demarcated coagulative necrosis in the targeted tissues. Treatment was concluded in less than 45 min for each patient. Conclusion Focused ultrasound is an effective method to selectively destroy tissue within the uterus and the transabdominal access route is very feasible. This study shows that a mobile ultrasound source can be used safely and effectively to destroy uterine tissues, such as fibroids, without major side effects.     

A further case with a small supernumerary marker chromosome (sSMC) derived from chromosome 1--evidence for high variability in mosaicism in different tissues of sSMC carriers

A prenatally ascertained case with a de novo small supernumerary marker chromosome (sSMC) derived from chromosome 1 is reported. Due to a fetal heart defect the parents decided in favour of an induced abortion. Postmortem, a molecular cytogenetic study on eleven formalin fixed, paraffin-embedded tissues of the fetus was performed, to further characterize the levels of mosaicism of the sSMC(1). sSMC presence varied between 13 and 62% within different tissues of sSMC carriers. This finding is something common in sSMC carriers and could explain why up to the present no clinical correlations for sSMC mosaicism and clinical outcome in the corresponding carriers could be established.