Liver development is restored by blastocyst complementation of HHEX knockout in mice and pigs.

BACKGROUND: There are over 17,000 patients in the US waiting to receive liver transplants, and these numbers are increasing dramatically. Significant effort is being made to obtain functional hepatocytes and liver tissue that can for therapeutic use in patients. Blastocyst complementation is a challenging, innovative technology that could fundamentally change the future of organ transplantation. It requires the knockout (KO) of genes essential for cell or organ development in early stage host embryos followed by injection of donor pluripotent stem cells (PSCs) into host blastocysts to generate chimeric offspring in which progeny of the donor cells populate the open niche to develop functional tissues and organs. METHODS: The HHEX gene is necessary for proper liver development. We engineered loss of HHEX gene expression in early mouse and pig embryos and performed intraspecies blastocyst complementation of HHEX KO embryos with eGFP-labeled PSCs in order to rescue the loss of liver development. RESULTS: Loss of HHEX gene expression resulted in embryonic lethality at day 10.5 in mice and produced characteristics of lethality at day 18 in pigs, with absence of liver tissue in both species. Analyses of mouse and pig HHEX KO fetuses confirmed significant loss of liver-specific gene and protein expression. Intraspecies blastocyst complementation restored liver formation and liver-specific proteins in both mouse and pig. Livers in complemented chimeric fetuses in both species were comprised of eGFP-labeled donor-derived cells and survived beyond the previously observed time of HHEX KO embryonic lethality. CONCLUSIONS: This work demonstrates that loss of liver development in the HHEX KO can be rescued via blastocyst complementation in both mice and pigs. This complementation strategy is the first step towards generating interspecies chimeras for the goal of producing human liver cells, tissues, and potentially complete organs for clinical transplantation.

Phase 2 study of anastrozole in patients with estrogen receptor/progesterone receptor positive recurrent low-grade endometrial stromal sarcomas: The PARAGON trial (ANZGOG 0903).

BACKGROUND: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48-89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2-29.8%), partial response in three (20%, 95% CI 7.1-45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2-NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5-63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. CONCLUSION: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.

IL-33 increases ST2+ Tregs and promotes metastatic tumour growth in the lungs in an amphiregulin-dependent manner.

Regulatory T cells (Tregs) facilitate primary and metastatic tumour growth through the suppression of anti-tumour immunity. Emerging evidence suggests a distinct role for Tregs in mediating tissue repair and barrier integrity in the lungs by IL-33 mediated production of the growth factor amphiregulin (AREG). Dependent on the type of cancer and local microenvironment, AREG may induce tumour cell proliferation, invasion, migration or resistance to apoptosis by signaling through the epidermal growth factor receptor (EGFR). We have found that IL-33 is dramatically increased in and around metastatic tumour foci in the lungs of mice bearing orthotopic murine mammary tumours. We observed that Tregs express significantly more of the IL-33 receptor, ST2, relative to conventional T cells, that ST2+ Tregs accumulate in the lungs of metastatic tumour-bearing mice, and that ST2+ Tregs produce significantly more AREG than ST2- Tregs. The intranasal administration of recombinant IL-33 increased the proportion of AREG producing ST2+ Tregs and enhanced the level of phosphorylated EGFR in the metastatic lungs. While recombinant AREG did not impact mammary tumour cell proliferation in vitro despite inducing a dose-dependent increase in phosphorylated EGFR, intranasal administration of AREG resulted in a ten-fold increase in pulmonary metastatic tumour burden in vivo. Further, the intranasal administration of recombinant IL-33 significantly increased metastatic tumour burden in the lungs in an amphiregulin-dependent manner. These data identify ST2+ Tregs as a microenvironmental source of AREG in the lungs of mice with orthotopic metastatic mammary tumours and highlight an important role for AREG in promoting metastatic tumour growth in the lungs.

Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activation.

This study was designed to evaluate MEK5 and ERK5 expression in colon cancer progression and to ascertain the relevance of MEK5/ERK5 signalling in colon cancer. Expression of MEK5 and ERK5 was evaluated in 323 human colon cancer samples. To evaluate the role of MEK5/ERK5 signalling in colon cancer, we developed a stable cell line model with differential MEK5/ERK5 activation. Impact of differential MEK5/ERK5 signalling was evaluated on cell cycle progression by flow cytometry and cell migration was evaluated by wound healing and transwell migration assays. Finally, we used an orthotopic xenograft mouse model of colon cancer to assess tumour growth and progression. Our results demonstrated that MEK5 and ERK5 are overexpressed in human adenomas (P<0.01) and adenocarcinomas (P<0.05), where increased ERK5 expression correlated with the acquisition of more invasive and metastatic potential (P<0.05). Interestingly, we observed a significant correlation between ERK5 expression and NF-κB activation in human adenocarcinomas (P<0.001). We also showed that ERK5 overactivation significantly accelerated cell cycle progression (P<0.05) and increased cell migration (P<0.01). Furthermore, cells with overactivated ERK5 displayed increased NF-κB nuclear translocation and transcriptional activity (P<0.05), together with increased expression of the mesenchymal marker vimentin (P<0.05). We further demonstrated that increased NF-κB activation was associated with increased IκB phosphorylation and degradation (P<0.05). Finally, in the mouse model, lymph node metastasis was exclusively seen in orthotopically implanted tumours with overactivated MEK5/ERK5, and not in tumours with inhibited MEK5/ERK5. Our results suggested that MEK5/ERK5/NF-κB signalling pathway is important for tumour onset, progression and metastasis, possibly representing a novel relevant therapeutic target in colon cancer treatment.

EVERSUN: a phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma.

BACKGROUND: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. RESULTS: We recruited 55 eligible participants from September 2010 to August 2012. DEMOGRAPHICS: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5-10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. CONCLUSIONS: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12609000643279.

Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations†.

BACKGROUND: Screening tools are proposed to identify those older cancer patients in need of geriatric assessment (GA) and multidisciplinary approach. We aimed to update the International Society of Geriatric Oncology (SIOG) 2005 recommendations on the use of screening tools. MATERIALS AND METHODS: SIOG composed a task group to review, interpret and discuss evidence on the use of screening tools in older cancer patients. A systematic review was carried out and discussed by an expert panel, leading to a consensus statement on their use. RESULTS: Forty-four studies reporting on the use of 17 different screening tools in older cancer patients were identified. The tools most studied in older cancer patients are G8, Flemish version of the Triage Risk Screening Tool (fTRST) and Vulnerable Elders Survey-13 (VES-13). Across all studies, the highest sensitivity was observed for: G8, fTRST, Oncogeriatric screen, Study of Osteoporotic Fractures, Eastern Cooperative Oncology Group-Performance Status, Senior Adult Oncology Program (SAOP) 2 screening and Gerhematolim. In 11 direct comparisons for detecting problems on a full GA, the G8 was more or equally sensitive than other instruments in all six comparisons, whereas results were mixed for the VES-13 in seven comparisons. In addition, different tools have demonstrated associations with outcome measures, including G8 and VES-13. CONCLUSIONS: Screening tools do not replace GA but are recommended in a busy practice in order to identify those patients in need of full GA. If abnormal, screening should be followed by GA and guided multidisciplinary interventions. Several tools are available with different performance for various parameters (including sensitivity for addressing the need for further GA). Further research should focus on the ability of screening tools to build clinical pathways and to predict different outcome parameters.

Immigrants' perceptions of the quality of their cancer care: an Australian comparative study, identifying potentially modifiable factors.

BACKGROUND: Recent data show a falling cancer mortality in the general population without a similar shift in immigrant outcomes, leading to a greater cancer burden and mortality for immigrants. Our aims were to compare perceived patterns of care in immigrants and native-born cancer patients. PATIENTS AND METHODS: This was a hospital-based sample of first-generation immigrants and Australian-born Anglo patients in the first year following diagnosis. It was restricted to Chinese, Arabic, or Greek speakers. Eligible participants, recruited via 16 oncology clinics, were over 18, with cancer (any type or stage), and having commenced treatment at least 1 month previously. Five hundred and seventy-one CALD patients (comprising 145 Arabic, 248 Chinese, and 178 Greek) and a control group of 274 Anglo-Australian patients participated. RESULTS: Immigrants had difficulty communicating with the doctor (73% versus 29%) and understanding the health system (38% versus 10%). Differences were found in 'difficulty knowing who to see' (P = 0.0002), 'length of time to confirm diagnosis' (P = 0.04), wanting more choice about a specialist and hospital (P < 0.0001); being offered the opportunity to see a counselor (P < 0.0001); and actually seeing one (P < 0.0001). There were no significant self-reported differences regarding how cancer was detected, time to see a health professional, or type first seen; however, immigrants reported difficulty knowing who to see. Previous studies showed differences in patterns of care according to socioeconomic status (SES) and educational level. Despite adjusting for age, sex, education, marital status, SES, time since diagnosis, and type of cancer, we did not find significant differences. Instead, we found that understanding of the health system and confidence understanding English were important factors. CONCLUSIONS: This study confirmed that immigrants with cancer perceive an inferior quality of cancer care. We highlight potentially modifiable factors including assistance in navigating the health system, translated information, and cultural competency training for health professionals.

Patterns of chemotherapy treatment for women with invasive epithelial ovarian cancer--a population-based study.

OBJECTIVE: Ovarian cancer five-year survival is poor at <40%. In the absence of effective screening or new treatments, ensuring all women receive optimal treatment is one avenue to improve survival. There is little population-based information regarding the primary chemotherapy treatment that women with epithelial ovarian cancer receive. This information is essential to identify potential gaps in care. METHODS: Cancer registries identified all women diagnosed with invasive epithelial ovarian cancer in Australia in 2005 (n=1192). Histopathology, chemotherapy and comorbidity information was abstracted from medical records. Multivariable logistic regression was used to identify factors associated with chemotherapy commencement, regimen, and completion. RESULTS: Women >70 years (p<0.0001), those with high-grade, stage IA/IB cancers (vs. stages IC-IV, p=0.003) and those with mucinous cancers (p=0.0002) were less likely to start chemotherapy. Most treated women received platinum-based drugs (97%), but only 68% received combination carboplatin-paclitaxel and only half completed six cycles without treatment modification/delay. Approximately 19% received single-agent carboplatin: mostly those aged >70 (p<0.0001) and/or with co-morbidities (p<0.0001). Age was the strongest predictor of completing six cycles of combination therapy. CONCLUSIONS: For specific patient groups, particularly older women, there is notable variation from standard treatment. Understanding how treatment variations affect survival and determining optimal regimens for these groups are research priorities.

Early life stress, MAOA, and gene-environment interactions predict behavioral disinhibition in children.

Several, but not all, studies have shown that the monoamine oxidase A functional promoter polymorphism (MAOA-LPR) interacts with childhood adversity to predict adolescent and adult antisocial behavior. However, it is not known whether MAOA-LPR interacts with early life (pre-birth-3 years) stressors to influence behavior in prepubertal children. The Avon Longitudinal Study of Parents and Children, UK, is a community-representative cohort study of children followed from pre-birth onwards. The impact of family adversity from pre-birth to age 3 years and stressful life events from 6 months to 7 years on behavioral disinhibition was determined in 7500 girls and boys. Behavioral disinhibition measures were: mother-reported hyperactivity and conduct disturbances (Strengths and Difficulties Questionnaire) at ages 4 and 7 years. In both sexes, exposure to family adversity and stressful life events in the first 3 years of life predicted behavioral disinhibition at age 4, persisting until age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3.5 years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1.5 and 2.5 years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity. In a general population sample of prepubertal children, exposure to common stressors from pre-birth to 3 years predicted behavioral disinhibition, and MAOA-LPR- stressful life event interactions specifically predicted hyperactivity.

Cancer in older people: a tale of two disciplines.

Management of cancer in the elderly presents an unprecedented challenge in Australia with the proportion of the population aged over 65 years set to double over the next four decades. Despite the complex healthcare needs of the older patient with cancer, there is currently little communication or cooperation between the fields of oncology and geriatrics. Improved interdisciplinary communication would facilitate care that is framed within current oncology practice while taking account of physiological age, complex comorbidities, risk of adverse events and pharmacological interactions as well as the implications of cognitive impairment on suitability for treatment and consent. An important first step has been taken towards the development of a strategic, focused and collaborative approach to the management of cancer in older people through a national interdisciplinary workshop convened by the Clinical Oncological Society of Australia in April 2008. Engagement and commitment of both oncology and geriatric disciplines is now critical to ensure that momentum is not lost in progressing this important and growing area of healthcare.

Effects of early childhood lead exposure on academic performance and behaviour of school age children.

AIM: To determine whether early lead exposure at levels below 10 microg/dl has an impact on educational and behavioural outcomes at school. METHODS: Venous samples were taken from a subgroup of the Avon Longitudinal Study of Parents and Children (ALSPAC) attending a research clinic at 30 months of age (n = 582), and lead levels were measured by atomic absorption spectrometry. Developmental, behavioural and standardised educational outcomes (Standard Assessment Tests, SATs) were collected on these children at age 7-8 years. In the analysis, blood lead concentration was investigated both as a continuous covariate and as a categorical variable. RESULTS: 488 cases (84%) had complete data on confounders and outcomes. After adjustment for confounders and using a log dose-response model for lead concentration, blood lead levels showed significant associations with reading, writing and spelling grades on SATs, and antisocial behaviour. A doubling in lead concentration was associated with a 0.3 point (95% CI -0.5 to -0.1) decline in SATs grades. Treating lead levels categorically, with the reference group 0-2 microg/dl, no effects on outcomes were apparent at 2-5 microg/dl, but levels of 5-10 microg/dl were associated with a reduction in scores for reading (OR 0.51, p = 0.006) and writing (OR 0.49, p = 0.003). Lead levels >10 microg/dl were also associated with increased scores for antisocial behaviour (OR 2.9, p = 0.040) and hyperactivity (OR 2.82, p = 0.034). CONCLUSIONS: Exposure to lead early in childhood has effects on subsequent educational attainment, even at blood levels below 10 microg/dl. These data suggest that the threshold for clinical concern should be reduced to 5 microg/dl.

Assessing the value of atomoxetine in treating children and adolescents with ADHD in the UK.

BACKGROUND: Economic evaluation of healthcare technologies is becoming increasingly relevant, enabling decision makers to assess and compare treatments within the context of costs and outcomes. Moreover, it is increasingly important for clinicians and prescribers to have some understanding of economic evaluation. For attention-deficit/hyperactivity disorder (ADHD), economic evaluations have largely focused on pharmacotherapy, and results indicate that such treatments are cost-effective compared with other interventions. AIMS: This review provides an overview of ADHD, its consequences and pharmacotherapy; describes the principles of health economic analysis, health-related quality of life (HRQL) and a cost-effectiveness model of atomoxetine for ADHD treatment; and outlines guidance from the National Institute for Health and Clinical Excellence on ADHD pharmacotherapy. METHODS: The cost-effectiveness of atomoxetine for children with ADHD in the UK was compared with treatment alternatives using an economic model with Markov processes. The model evaluated atomoxetine in five patient subgroups according to treatment history and comorbidities precluding stimulants. Incremental cost per quality-adjusted life-year (QALY) was calculated and compared between treatment algorithms. The Markov process incorporated 18 health states, representing a range of outcomes across the treatments. Utility values were derived from a survey of 83 parents of children with ADHD, and treatment efficacy and safety were based on a review of controlled clinical trials and literature, and validated by international experts. Costs and outcomes were estimated using Monte Carlo simulation over 1-year. RESULTS: Atomoxetine was a cost-effective treatment across the whole ADHD population, with incremental cost-effectiveness ratios ranging from pound 11,500 to pound 15,900 per QALY, compared with alternative pharmacotherapies, which are within UK and rest of Europe acceptability limits. Higher utility values achieved treating ADHD with atomoxetine, compensate for the relatively higher acquisition cost compared with stimulants. CONCLUSIONS: Atomoxetine is cost-effective and may have advantages over stimulants, including benefits to HRQL and no abuse liability and is the only treatment in the UK licensed for continued treatment into adulthood in adolescents who have shown a response from treatment.

Radiopathological review of small bowel carcinoid tumours.

Small bowel carcinoid tumours are endocrine tumours of the gastrointestinal tract. This pictorial essay will review the pathology, clinical features, treatment and prognosis and illustrate the radiographic, computed tomographic, sonographic, magnetic resonance and nuclear medicine appearances of small bowel carcinoid tumours.

Developmental outcomes in early compared with delayed surgery for glue ear up to age 7 years: a randomised controlled trial.

OBJECTIVES: To investigate whether early versus delayed surgery for children severely affected by otitis media with effusion (OME) results in improved performance on developmental tests up to age 7 years. DESIGN: Follow-up of a randomised controlled trial. SETTING: University of Bristol. PARTICIPANTS: One hundred and eighty-two children (mean age 35 months) with persistent OME, hearing loss and speech, language or behaviour problems who were originally eligible and randomised to either early surgery or delayed surgery after a period of watchful waiting were followed-up as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 4 1/2 and 7-8 years. MAIN OUTCOME MEASURES: Measures included behaviour, language, educational attainment tests, hearing, reading, cognition and coordination. RESULTS: Of the original randomised trial, 88 of 92 of the early surgery and 74 of 90 of the watchful waiting group were still participating in ALSPAC. Analysis was by intention to treat. At age 4 1/2 years there were significant differences in teacher assessment of language (adj OR 3.45, 95% CI: 1.42-8.39) and writing (adj OR 3.74, 95% CI: 1.51-9.27), in favour of early surgery. At age 7-8 years, there was a significant difference on teacher report of emotional problems (adj OR 4.11, 95% CI: 1.15-14.64) in favour of early surgery. There were no other significant differences. CONCLUSIONS: Early surgery for the child severely affected by OME may be associated with subtle benefits at age 4 1/2 years. This may continue to 7-8 years but the small study size makes it difficult to distinguish these effects from chance. A larger study is recommended.

The early stool patterns of young children with autistic spectrum disorder.

AIM: To investigate whether children with autistic spectrum disorder (ASD) have bowel symptoms consistent with underlying enterocolitis. METHODS: Information on children's stool patterns and gut symptoms collected by questionnaire at 4 weeks and at 6, 18, 30 and 42 months of age were available for 12,984 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Data on the 78 children identified by local health and/or education systems to have special educational provision for ASD were compared with the 12,906 remaining children in the cohort. RESULTS: Comparison of the ASD and control group during the first 3.5 years of life showed no major differences in stool colour or consistency, or in frequency of diarrhoea, constipation, bloody stools or abdominal pain. The ASD children had similar stool frequency up to 18 months, but there was a trend for ASD children to pass more stools at 30 months (OR 3.73, 95% CI 1.11 to 12.6; p = 0.004) and at 42 months (OR 6.46, 95% CI 1.83 to 22.7; p<0.001), although only three children passed more than 4 stools/day. Repeating the analysis on only those cases diagnosed as having classical childhood autism resulted in very similar findings. CONCLUSIONS: During the first 42 months of life, ASD children had a stool pattern that was very similar to that of other children, apart from a slight increase in stool frequency at 30 and 42 months. There were no symptoms to support the hypothesis that ASD children had enterocolitis.

The variation in stool patterns from 1 to 42 months: a population-based observational study.

OBJECTIVE: To document the normal stool patterns of young children. DESIGN: Prospective population-based longitudinal study. SETTING: Avon Longitudinal Study of Parents and Children (ALSPAC). SUBJECTS: 12,984 children, whose parents completed questionnaires at 4 weeks, 6, 18, 30 and 42 months on their frequency of bowel movements and the consistency and colour of their stools. RESULTS: Stool frequency declined from a mean of 3.0 times/day (3rd centile 0.6, 97th centile 5.9) at 4 weeks to 1.3 times/day (0.6, 2.7) at 42 months. Stool consistency was soft in most babies with nearly half passing liquid or curdy stool at 4 weeks. 14% of babies usually passed a hard stool at 4 weeks, rising to 30% at 42 months. Stool colour was commonly yellow at 4 weeks and had changed to brown by 6 months. Black stools were extremely unusual at all ages. CONCLUSIONS: These data on the changes with age in the stool patterns of young children will be useful for clinicians.

Renal insufficiency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations.

BACKGROUND: Elderly cancer patients commonly have renal function decline. This warrants particular caution during the administration of renally excreted cancer drugs or those with established nephrotoxicity. DESIGN: An International Society for Geriatric Oncology task force was formed to discuss treatment recommendations for this group of patients. RESULTS: Before drug therapy, the assessment and optimization of hydration status and evaluation of renal function is required. Serum creatinine alone is insufficient as a means of evaluating renal function, and creatinine clearance should at least be calculated in every patient by the abbreviated modification of diet in renal disease or Cockcroft-Gault equations. In the extremes of obesity and cachexia and at very high and low creatinine values, no single tool is really accurate. In these patients, the best estimate of glomerular filtration rate is provided by direct methods such as (51)Cr-EDTA or inulin measurement. Within each drug class, preference may be given to agents less likely to be influenced by renal clearance, which are minimally nephrotoxic, or for which appropriate methods of prevention for renal toxicity exist. Coadministration of known nephrotoxic drugs should be avoided or minimized. CONCLUSIONS: Future trials should be designed to present data in a way that allows evaluation of the contribution of renal function to toxicity and efficacy.

Effect of an estrogen receptor-alpha intron 4 polymorphism on fat mass in 11-year-old children.

CONTEXT: Polymorphisms in the ESR1 gene encoding estrogen receptor (ER)-alpha may be associated with fat mass in adults. OBJECTIVES: The objective of the study was to establish whether ESR1 polymorphisms influence fat mass in childhood. DESIGN: This was a cross-sectional analysis after genotyping of rs9340799, rs2234693, and rs7757956 ESR1 polymorphisms. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC) was a population-based prospective study. PARTICIPANTS: Participants included 3097 11-yr-old children with results for ESR1 genotyping, puberty measures, and dual-energy x-ray absorptiometry results. OUTCOMES: Relationships between ESR1 polymorphisms and indices of body composition were measured. RESULTS: The rs7757956 polymorphism was associated with fat mass (P = 0.002). Total body fat mass (adjusted for height) was reduced by 6% in children with TA/AA genotypes, and risk of being overweight (> or =85th centile of fat mass) was decreased by 20%. This genetic effect appeared to interact with puberty in girls (P = 0.05 for interaction): in those with the TT genotype, total body fat mass (adjusted for height) was 18% higher in Tanner stages 3-5 vs. stages 1-2; the equivalent difference was 7% in those with TA/AA genotypes. Furthermore, the risk of being overweight was 36% lower in girls with TA/AA genotypes in Tanner stages 3-5, but no reduction was seen in those in stages 1-2. Neither rs9340799 nor rs2234693 polymorphisms were associated with body composition measures. CONCLUSIONS: Fat mass in 11-yr-old children was related to the rs7757956 ESR1 polymorphism. This association was strongest in girls in more advanced puberty, in whom the risk of being overweight was reduced by 36% in those with the TA/AA genotype.