Risks of adverse obstetric outcomes among female survivors of adolescent and young adult cancer in England (TYACSS): a population-based, retrospective cohort study.

BACKGROUND: There are limited data on the risks of obstetric complications among survivors of adolescent and young adult cancer with most previous studies only reporting risks for all types of cancers combined. The aim of this study was to quantify deficits in birth rates and risks of obstetric complications for female survivors of 17 specific types of adolescent and young adult cancer. METHODS: The Teenage and Young Adult Cancer Survivor Study (TYACSS)-a retrospective, population-based cohort of 200 945 5-year survivors of cancer diagnosed at age 15-39 years from England and Wales-was linked to the English Hospital Episode Statistics (HES) database from April 1, 1997, to March 31, 2022. The cohort included 17 different types of adolescent and young adult cancers. We ascertained 27 specific obstetric complications through HES among 96 947 women in the TYACSS cohort. Observed and expected numbers for births and obstetric complications were compared between the study cohort and the general population of England to identify survivors of adolescent and young adult cancer at a heighted risk of birth deficits and obstetric complications relative to the general population. FINDINGS: Between April 1, 1997, and March 31, 2022, 21 437 births were observed among 13 886 female survivors of adolescent and young adult cancer from England, which was lower than expected (observed-to-expected ratio: 0·68, 95% CI 0·67-0·69). Other survivors of genitourinary, cervical, and breast cancer had under 50% of expected births. Focusing on more common (observed ≥100) obstetric complications that were at least moderately in excess (observed-to-expected ratio ≥1·25), survivors of cervical cancer were at risk of malpresentation of fetus, obstructed labour, amniotic fluid and membranes disorders, premature rupture of membranes, preterm birth, placental disorders including placenta praevia, and antepartum haemorrhage. Survivors of leukaemia were at risk of preterm delivery, obstructed labour, postpartum haemorrhage, and retained placenta. Survivors of all other specific cancers had no more than two obstetric complications that exceeded an observed-to-expected ratio of 1·25 or greater. INTERPRETATION: Survivors of cervical cancer and leukaemia are at risk of several serious obstetric complications; therefore, any pregnancy should be considered high-risk and would benefit from obstetrician-led antenatal care. Despite observing deficits in birth rates across all 17 different types of adolescent and young adult cancer, we provide reassurance for almost all survivors of adolescent and young adult cancer concerning their risk of almost all obstetric complications. Our results provide evidence for the development of clinical guidelines relating to counselling and surveillance of obstetrical risk for female survivors of adolescent and young adult cancer. FUNDING: Children with Cancer UK, The Brain Tumour Charity, and Academy of Medical Sciences.

Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML.

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.

A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia.

AIMS: AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia. METHODS: Data from Phase I dose-escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model-derived area under the concentration-time curve was used to investigate the relationship between dose and exposure in adults and children. RESULTS: The plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two-compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h-1 provided similar drug exposures at the MTD as the adult population. The estimated MTD for children with leukaemia, therefore, is 30 mg kg-1  72 h-1 . CONCLUSION: For adults, GFR was a significant predictor of clearance, whilst body-weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg-1  72 h-1 children with leukaemia.

Pharmacogenetic association of MBL2 and CD95 polymorphisms with grade 3 infection following adjuvant therapy for breast cancer with doxorubicin and cyclophosphamide.

Life-threatening infection as an adverse reaction to cytotoxic therapy of cancer remains a major problem, potentially limiting efficacy. Administration of colony-stimulation factors benefits only a minority of patients, and improved stratification guidelines are needed to identify those patients likely to benefit. We investigated single nucleotide polymorphisms (SNPs) in two genes related to immune function to identify associations with severe infection following treatment of breast cancer with doxorubicin and cyclophosphamide. CD95 mediates the extrinsic apoptosis pathway in haematopoietic cells and a CD95 promoter SNP (rs2234767) has been shown to result in reduced expression of the receptor. MBL2 activates the classical complement pathway in the presence of pathogens and independently of antibodies. Numerous SNPs have been described including a promoter SNP (rs7096206) which results in decreased expression of the protein. Homozygotes for the CD95 minor allele were more likely to experience a grade 3 infection than heterozygote and homozygote wild-type patients (29%, 3% and 5%, respectively p=0.048). CD95 minor allele homozygotes also had higher basal white blood cell and neutrophil counts compared with wild-type allele carriers, which was sustained throughout therapy. There was an allele-dose association between the MBL2 SNP and grade 3 infection, with 2, 8 and 17% of wild-type homozygotes, heterozygotes and minor allele homozygotes, respectively, experiencing grade 3 infection (p=0.02). These associations demonstrate the utility of a pharmacogenetic approach to identify individuals more likely to acquire a life-threatening infection during chemotherapy. The apparent association with a CD95 SNP and a mild neutrophilia merits further investigation.

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.

PURPOSE: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. EXPERIMENTAL DESIGN: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. RESULTS: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. CONCLUSIONS: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

Diagnostic Biomarkers in Women With Suspected Preeclampsia in a Prospective Multicenter Study.

OBJECTIVE: To evaluate 47 biomarkers (selected from the current medical literature), in isolation or in combination with placental growth factor (PlGF), to determine the need for delivery within 14 days, in women presenting with suspected preterm preeclampsia. METHODS: In a prospective, multicenter observational study, 47 biomarkers were measured in 423 women presenting with suspected preterm preeclampsia (in two prespecified groups: group 1 at less than 35 weeks of gestation and group 2 presenting between 35 0/7 and 36 6/7 weeks of gestation) to evaluate their ability to determine the primary endpoint: preeclampsia requiring delivery within 14 days. Using factor analysis and stepwise logistic regression, we sought one or more additional biomarkers for optimal determination of the primary endpoint. RESULTS: In women presenting at less than 35 weeks of gestation (n=286), the best performing combination of PlGF, podocalyxin, endoglin, procalcitonin (receiver operating curve [ROC] area 0.90, 95% confidence interval [CI] 0.86-0.93) was not statistically better than PlGF alone (ROC 0.87, 95% CI 0.83-0.92; P=.43) for preeclampsia requiring delivery within 14 days. Two other single markers had test performance that was not significantly different to PlGF (soluble fms-like tyrosine kinase-1 [sFlt-1] ROC 0.83, 95% CI 0.78-0.88; endoglin ROC 0.83, 95% CI 0.79-0.88). Similar findings were found in women presenting between 35 0/7 and 36 6/7 weeks of gestation (n=137): ROC for PlGF alone 0.75 (95% CI 0.67-0.83); ROC for PlGF, cystatin, pregnancy-associated plasma protein A in combination 0.81 (95% CI 0.74-0.88; P=.40). CONCLUSION: This study supports the growing body of evidence that a single angiogenesis-related biomarker (PlGF, sFlt-1, or endoglin) alone represents a useful diagnostic test for women presenting with suspected preterm preeclampsia.

A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study.

PURPOSE: A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity. EXPERIMENTAL DESIGN: AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5, and 23 mg/m(2)/d). Pharmacokinetic and PD assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies. RESULTS: Thirty-three patients were evaluable for toxicity. There were six dose-limiting toxicities and the MTD was 18.5 mg/m(2)/d. Most common drug-related toxicities were hematologic (neutropenia, anemia, and thrombocytopenia in 36.4%, 18.2%, and 21.2% of patients), which were grade ≥3 in 30.3%, 6.1%, and 3% of patients. Nonhematologic toxicities included fatigue, infections, febrile neutropenia and ALT elevation. One patient with central nervous system-primitive neuroectodermal tumor (CNS-PNET) achieved a partial response after 16 cycles and 3 cases were stable for four or more cycles. Plasma concentrations were comparable with those in adults at the same dose level, clearance was similar although half-life was shorter (4.9 ± 1.5 hours, compared with 8.4 ± 3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17 of 18 patients treated at ≥11.5 mg/m(2)/d. CONCLUSION: AT9283 was well tolerated in children and adolescents with solid tumors with manageable hematologic toxicity. Target inhibition was demonstrated. Disease stabilization was documented in intracranial and extracranial pediatric solid tumors and a phase II dose determined.

Pharmacogenetics of adjuvant breast cancer treatment with cyclophosphamide, epirubicin and 5-fluorouracil.

PURPOSE: Most adjuvant breast cancer treatment regimens include the combination of an anthracycline (epirubicin or doxorubicin) and the alkylating agent cyclophosphamide. This study sought to investigate the influence of pharmacogenetics on the pharmacokinetics and metabolism of these agents. METHODS: Blood samples were taken from patients treated with cyclophosphamide (n = 51) and epirubicin (n = 35), with or without 5-fluorouracil (5-FU). The pharmacokinetics and metabolism of the three drugs were investigated, together with pharmacogenetic investigations for cyclophosphamide and epirubicin. Cyclophosphamide and its metabolites and also epirubicin and epirubicinol were measured in plasma. DNA was extracted from whole blood and genotyping performed using RT-PCR. RESULTS: Patients with at least one variant CYP2C19*17 allele had a longer CP half-life (p = 0.007), as did homozygous variants for the CYP2B6*6 allele. There was no significant effect of GSTP1, CYP2B6*2, CYP2B6*5 or CYP2C19*2 on any pharmacokinetic parameter of CP. An NQO2 exonic SNP was associated with a higher exposure to epirubicinol relative to epirubicin (p = 0.011). Other polymorphic variants of NQO1, carbonyl reductase, UGT enzymes and transporters had no influence on epirubicin or its metabolite. CONCLUSION: Overall, pharmacogenetic factors had only a minor influence on cyclophosphamide or anthracycline-based adjuvant therapy of breast cancer.

Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study.

BACKGROUND: Hypertensive disorders of pregnancy are a major contributor to death and disability for pregnant women and their infants. The diagnosis of preeclampsia by using blood pressure and proteinuria is of limited use because they are tertiary, downstream features of the disease. Placental growth factor (PlGF) is an angiogenic factor, a secondary marker of associated placental dysfunction in preeclampsia, with known low plasma concentrations in the disease. METHODS AND RESULTS: In a prospective multicenter study, we studied the diagnostic accuracy of low plasma PlGF concentration (<5th centile for gestation, Alere Triage assay) in women presenting with suspected preeclampsia between 20 and 35 weeks' gestation (and up to 41 weeks' gestation as a secondary analysis). The outcome was delivery for confirmed preeclampsia within 14 days. Of 625 women, 346 (55%) developed confirmed preeclampsia. In 287 women enrolled before 35 weeks' gestation, PlGF <5th centile had high sensitivity (0.96; 95% confidence interval, 0.89-0.99) and negative predictive value (0.98; 0.93-0.995) for preeclampsia within 14 days; specificity was lower (0.55; 0.48-0.61). Area under the receiver operating characteristic curve for low PlGF (0.87, standard error 0.03) for predicting preeclampsia within 14 days was greater than all other commonly used tests, singly or in combination (range, 0.58-0.76), in women presenting with suspected preeclampsia (P<0.001 for all comparisons). CONCLUSIONS: In women presenting before 35 weeks' gestation with suspected preeclampsia, low PlGF has high sensitivity and negative predictive value for preeclampsia within 14 days, is better than other currently used tests, and presents an innovative adjunct to management of such women.

Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy.

OBJECTIVE: A SNP in the NQO1 gene has been implicated in the response of patients with breast cancer to anthracycline containing regimens. NQO1, and its homologue NQO2, share many substrates yet retain distinct functional differences, with NQO2 being a more permissive molecule for electron accepting substrates. We aimed to determine whether functional NQO2 variants are associated with altered response to adjuvant doxorubicin and cyclophosphamide therapy, with or without tamoxifen, in the treatment of breast cancer. METHODS: Genomic DNA samples from 227 women with early breast cancer were genotyped for NQO1 and NQO2 polymorphisms. All participants were treated with an AC adjuvant therapy regimen. The functional implications of NQO2 polymorphisms were validated in in-vitro ectopic expression models. RESULTS: The NQO1 SNP (rs1800566) was associated with a poorer outcome and a lower likelihood of having a treatment delay. Patients who had ER and PR negative disease and were wild type for both the NQO1 and an NQO2 SNP (rs1143684) had 100% 5-year overall survival compared with 88% for carriers of one minor allele and 70% for carriers of two or more minor alleles (P=0.018, log rank). Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank). MCF-7 cells were sensitized to growth inhibition by doxorubicin and 4OH tamoxifen, but not cyclophosphamide, by ectopic expression of NQO2. CONCLUSION: This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity.

Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors.

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.

A phase I and pharmacokinetic study of ixabepilone in combination with Carboplatin in patients with advanced solid malignancies.

PURPOSE: To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B). RESULTS: Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B). CONCLUSIONS: Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.

Pharmacokinetic investigation of imatinib using accelerator mass spectrometry in patients with chronic myeloid leukemia.

PURPOSE: To investigate the potential use of accelerator mass spectrometry (AMS) in the study of the clinical pharmacology of imatinib. EXPERIMENTAL DESIGN: Six patients who were receiving imatinib (400 mg/d) as part of their ongoing treatment for chronic myeloid leukemia (CML) received a dose containing a trace quantity (13.6 kBq) of (14)C-imatinib. Blood samples were collected from patients before and at various times up to 72 h after administration of the test dose and were processed to provide samples of plasma and peripheral blood lymphocytes (PBL). Samples were analyzed by AMS, with chromatographic separation of parent compound from metabolites. In addition, plasma samples were analyzed by liquid chromatography/mass spectrometry (LCMS). RESULTS: Analysis of the AMS data indicated that imatinib was rapidly absorbed and could be detected in plasma up to 72 h after administration. Imatinib was also detectable in PBL at 24 h after administration of the (14)C-labeled dose. Comparison of plasma concentrations determined by AMS with those derived by LCMS analysis gave similar average estimates of area under plasma concentration time curve (26 +/- 3 versus 27 +/- 11 microg/mL.h), but with some variation within each individual. CONCLUSIONS: Using this technique, data were obtained in a small number of patients on the pharmacokinetics of a single dose of imatinib in the context of chronic dosing, which could shed light on possible pharmacologic causes of resistance to imatinib in CML.

A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules.

PURPOSE: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. EXPERIMENTAL DESIGN: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. RESULTS: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of >100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase Ia and one in a patient with gastric carcinoma at 175 mg/m(2) in phase Ib. CONCLUSION: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.

Patient experiences following cardiothoracic surgery: an interview study.

BACKGROUND: Numerous studies have investigated patient outcomes of cardiac surgery, including some examining health-related quality of life. While these studies have provided some insight into patients' physical function, social abilities and perceived quality of life, studies examining the experiences of individuals recovering from cardiac surgery have received only limited investigation. AIMS: This paper presents a thematic analysis of interviews conducted with patients recovering from cardiothoracic surgery, about their memories and experiences of hospital and recovery post-hospital discharge. METHODS: Using an exploratory qualitative approach, eight participants were interviewed 6 months following their surgery. Transcripts of interviews were examined using a content analysis approach, with open coding of text and categorising of similar concepts into themes. FINDINGS: Participants reported varying degrees of pain and physical dysfunction during their recovery from surgery and some had still not returned to optimal function. Seven themes emerged from the data: impressions of ICU; comfort/discomfort; being sick/getting better; companionship/isolation; hope/hopelessness; acceptance/apprehension; and life changes. A number of the themes were constructed as a continuum, with participants often demonstrating a range of views or experiences. Many had little or no memory of their stay in the intensive care unit, although others had vivid recollections. Their impressions of hospital were mostly positive, although many experienced fear, apprehension, and mood disturbances at some time during their recovery. Most participants recalled being sick, reaching a turning point, and then getting better. Many participants reported a change in life view since their recovery from surgery. CONCLUSIONS: Attention to specific areas of patient orientation, education and support was identified to facilitate realistic expectations of recovery. In addition, some form of systematic follow-up that focuses on patient recovery in terms of both physical and psychological function is important.

Iron transport systems in Neisseria meningitidis.

Acquisition of iron and iron complexes has long been recognized as a major determinant in the pathogenesis of Neisseria meningitidis. In this review, high-affinity iron uptake systems, which allow meningococci to utilize the human host proteins transferrin, lactoferrin, hemoglobin, and haptoglobin-hemoglobin as sources of essential iron, are described. Classic features of bacterial iron transport systems, such as regulation by the iron-responsive repressor Fur and TonB-dependent transport activity, are discussed, as well as more specific features of meningococcal iron transport. Our current understanding of how N. meningitidis acquires iron from the human host and the vaccine potentials of various components of these iron transport systems are also reviewed.

Determination of anti-cancer drug actinomycin D in human plasma by liquid chromatography-mass spectrometry.

Actinomycin D is an anti-cancer drug commonly used in the treatment of paediatric malignancies such as Wilms' tumour, Ewing's sarcoma and rhabdomyosarcoma. Despite its long history of clinical use, little is known about the pharmacokinetics of actinomycin D in humans, largely due to problems in developing an analytical assay with the required sensitivity to measure relevant clinical concentrations. As actinomycin D treatment in children with cancer is associated with veno-occlusive disease (VOD), and as the dose intensity of actinomycin D treatment has been defined as a significant risk factor for the development of this potentially life-threatening hepatic toxicity, pharmacokinetic studies of actinomycin D may be beneficial in optimizing treatment with this drug. In order to investigate this issue, we developed a sensitive liquid chromatography-mass spectrometry (LC-MS) method for the determination of actinomycin D in human plasma samples. Extraction of analytical samples was carried out with acetonitrile and analysis performed on an API 2000 LC/MS/MS using an internal standard of 7-aminoactinomycin D. A limit of quantitation of 1.0 ng/ml was determined, allowing the reliable measurement of actinomycin D in plasma samples obtained from patients receiving this drug clinically. The method demonstrated good reproducibility, over the calibration curve range of 1.0-100 ng/ml, with intra- and inter-assay precision CVs of 2.7-11.3 and 2.3-7.8%, respectively. Accuracy data showed relative errors of 2.0-16.4 and 10.4-15.2% for intra-assay (n=10) and inter-assay (n=7) experiments, respectively. Initial results of actinomycin D pharmacokinetics in paediatric patients are shown.

Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma.

PURPOSE: To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated. PATIENTS AND METHODS: Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m(2) (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL.min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m(2), carboplatin AUC 6 mg/mL.min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10). RESULTS: The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m(2), carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days. CONCLUSION: The MTD was pemetrexed 500 mg/m(2) and carboplatin AUC 6 mg/mL.min. The recommended phase II dose of the combination is pemetrexed 500 mg/m(2) and carboplatin AUC 5 mg/mL.min. The combination is both active and well tolerated in MPM and deserves further exploration.