Multicenter phase II study of trabectedin in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP). RESULTS: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase. CONCLUSIONS: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.

Short-term sertraline treatment suppresses sympathetic nervous system activity in healthy human subjects.

Increased sympathetic nervous system (SNS) activity has been associated with stress, major depression, aging, and several medical conditions. This study assessed the effect of the selective serotonin reuptake inhibitor (SSRI), sertraline, on sympathetic nervous system (SNS) activity in healthy subjects. Twelve healthy volunteers participated in a double-blind, placebo-controlled, norepinephrine (NE) kinetic study, in which the effects of sertraline on SNS activity were ascertained by determining NE plasma concentrations and NE plasma appearance rates and clearance rates in sertraline or placebo conditions. Subjects received 50 mg of sertraline or placebo for two days and then one week later underwent the same protocol with the other drug. By single compartmental analysis, plasma NE appearance rates were significantly lower in the sertraline compared to the placebo condition (0.26+/-0.10 vs 0.40+/-0.23 microg/m(2)/min; P=0.04). Our study found that the net effect of short-term SSRI treatment is an apparent suppression of SNS activity as indicated by a decreased plasma NE appearance rate in the sertraline condition. If this preliminary finding can be extended to long-term treatment of patients, this could have significant therapeutic relevance for treating depression in elderly patients or those with cardiac disease, in which elevated SNS activity may exacerbate underlying medical conditions.

Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients.

This study was conducted to determine if the accelerated telomere attrition that occurs as a consequence of allogeneic stem cell transplantation leads to measurable functional defects. Telomere lengths in mononuclear leukocytes obtained from 15 long-term allogeneic stem cell transplant recipients and their respective donors were determined by Southern hybridization and densitometric analysis. Functional assays evaluated the ability of these cells to proliferate in response to a mitogenic stimulus and to differentiate under appropriate cytokine stimulation. Lymphocyte proliferation in response to phytohemagglutinin was determined by measurement of (3)[H]thymidine uptake. The ability of circulating myeloid cells to differentiate was determined after incubation of peripheral blood mononuclear cells with IL-3 and GM-CSF. A total of 13 patients demonstrated telomeric loss, ranging from 0.1 to 3.7 kbp. Strikingly, lymphocytes from 14 of the 15 patients demonstrated a significant decrease in proliferation when compared to their respective donors (68%+/-22, P=0.001). All patients demonstrated at least a 50% decrease in the number of myeloid colony-forming units when compared to their respective donors (P<0.0001). A decreased ability of hematopoietic cells to proliferate and differentiate is phenotypically consistent with an aged immune system. This may correlate with diminished clinically relevant immune responses to infection or vaccination, as seen in the elderly.

Fasting and cognitive function.

The effects of short-term fasting (skipping breakfast) on the problem-solving performance of 9 to 11 yr old children were studied under the controlled conditions of a metabolic ward. The behavioral test battery included an assessment of IQ, the Matching Familiar Figure Test and Hagen Central Incidental Test. Glucose and insulin levels were measured in blood. All assessments were made under fasting and non-fasting conditions. Skipping breakfast was found to have adverse effects on the children's late morning problem-solving performance. These findings support observations that the timing and nutrient composition of meals have acute and demonstrable effects on behavior.

UK registry of high-risk obstetric anaesthesia: arrhythmias, cardiomyopathy, aortic stenosis, transposition of the great arteries and Marfan's syndrome.

The UK registry of high-risk obstetric anaesthesia was set up in late 1996 to collect reports of high-risk pregnancy, pool them into a central database and disseminate the results. At the time of analysis for this paper (December 31, 2001) 308 cardiorespiratory reports had been received. The five most common conditions, occurring in 125 cases (41% of the total), were arrhythmias (43 cases), cardiomyopathy (26 cases), aortic stenosis (24 cases), transposition of the great arteries (18 cases) and Marfan's syndrome (14 cases). We describe the features and management of these cases.

Viral tropism and pathology associated with viral hemorrhagic septicemia in larval and juvenile Pacific herring.

Viral hemorrhagic septicemia virus (VHSV) genotype IVa causes mass mortality in wild Pacific herring, a species of economic value, in the Northeast Pacific Ocean. Young of the year herring are particularly susceptible and can be carriers of the virus. To understand its pathogenesis, tissue and cellular tropisms of VHSV in larval and juvenile Pacific herring were investigated with immunohistochemistry, transmission electron microscopy, and viral tissue titer. In larval herring, early viral tropism for epithelial tissues (6d post-exposure) was indicated by foci of epidermal thickening that contained heavy concentrations of virus. This was followed by a cellular tropism for fibroblasts within the fin bases and the dermis, but expanded to cells of the kidney, liver, pancreas, gastrointestinal tract and meninges in the brain. Among wild juvenile herring that underwent a VHS epizootic in the laboratory, the disease was characterized by acute and chronic phases of death. Fish that died during the acute phase had systemic infections in tissues including the submucosa of the gastrointestinal tract, spleen, kidney, liver, and meninges. The disease then transitioned into a chronic phase that was characterized by the appearance of neurological signs including erratic and corkscrew swimming and darkening of the dorsal skin. During the chronic phase viral persistence occurred in nervous tissues including meninges and brain parenchymal cells and in one case in peripheral nerves, while virus was mostly cleared from the other tissues. The results demonstrate the varying VHSV tropisms dependent on the timing of infection and the importance of neural tissues for the persistence and perpetuation of chronic infections in Pacific herring.

Strabismus in infants of opiate-dependent mothers.

AIM: At a follow-up clinic for infants of opiate-dependent mothers it was noted that more infants than expected developed strabismus. This study aimed to assess the prevalence of strabismus and the need for active strabismus surveillance in this population. METHODS: Consecutive infants of opiate-dependent mothers born over an 18 mo period were recalled for ophthalmological assessment by an ophthalmologist and orthoptist. Those unable to attend were surveyed by telephone using a questionnaire. RESULTS: 49 (69%) of the 71 eligible infants were recalled at a mean age of 21 mo (range 6-39); 29 had a full ophthalmological examination and the remaining 20 completed the questionnaire only. Seven (14%) of the 49 recalled infants had strabismus on examination; 4 needed glasses or patching. A further seven (14%) had a history of intermittent strabismus but declined formal examination. Another child had significant hypermetropia without strabismus. The mean age at which strabismus was observed was 8.3 mo (range birth to 19 mo). The presence of strabismus was not significantly influenced by conditions at birth, maternal drug doses, family history or need for or duration of abstinence treatment. CONCLUSION: The rate of strabismus in infants of opiate-dependent mothers was at least 10 times that in the general population. As attendance at follow-up is often poor, paediatricians should be aware of the association to encourage opportunistic assessment and ophthalmological surveillance of this population.

Left lateral vs. supine, wedged position for development of block after combined spinal-epidural anaesthesia for Caesarean section.

This prospective, randomised controlled trial compared a spinal block developing in the left lateral position (LL), after sitting a combined spinal-epidural for Caesarean section with the woman sitting -- using intrathecal hyperbaric bupivacaine and fentanyl -- with a block developing in the supine, wedged position (SW). The median (IQR) block onset times for loss of cold sensation to T4 bilaterally for LL and SW women were 15 (13-19) and 12 (10.8-14) min, respectively (p = 0.004). Unilateral blocks did not occur in the left lateral group. There were no other significant differences between groups, except the median [range] 1-min Apgar scores, which were 9 [8-10] and 9 [6-9] in the LL and SW groups, respectively (p = 0.04). In summary, the LL position is associated with a relatively slower block onset, but produces a spinal block with similar characteristics to that obtained in the SW position.

Uterine activity in induced labour.

A study was made of the characteristics of oxytocin-induced labour. Twelve patients with, and eight without membrane rupture were closely matched for factors likely to influence the character and duration of labour. In both groups uterine activity increased until a stable state was achieved loowing which there was little alteration until delviery. The duration of labour was shorten in the group with ruptured membranes as compared with intact membranes although, paradoxically, the uterineactivity tended to be greater when the membranes were intact.

The effect of membrane rupture on fetal heart rate in induced labour.

The influence of the state of the membranes on the fetal heart rate was studied in a group of twelve women whose membranes were electively ruptured for oxytocin induction of labour. The results have been compared with a group of eight women of similar gestation and parity whose membranes were kept intact. While membranes were ruptured, there was an increase in the frequency and amplitude of early decelerations thorughout labour. The significance and practical implications of the results are discussed.