Predictive biomarkers are becoming increasingly important tools in drug development and clinical research. The importance of using both guidelines for specimen acquisition and analytical methods for ...biomarker measurements that are standardized has become recognized widely as an important issue, which must be addressed in order to provide high-quality, validated assays. Herein, we review the major challenges in biomarker validation processes, including pre-analytical (sample-related), analytical, and post-analytical (data-related) aspects of assay development. Recommendations for improving biomarker assay development and method validation are proposed to facilitate the use of predictive biomarkers in clinical trials and the practice of oncology.
We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer.
Between ...April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m(2) orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later.
Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences.
The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.
Ecology Letters (2011) 14: 1–8
Matrix projection models are among the most widely used tools in plant ecology. However, the way in which plant ecologists use and interpret these models differs from ...the way in which they are presented in the broader academic literature. In contrast to calls from earlier reviews, most studies of plant populations are based on < 5 matrices and present simple metrics such as deterministic population growth rates. However, plant ecologists also cautioned against literal interpretation of model predictions. Although academic studies have emphasized testing quantitative model predictions, such forecasts are not the way in which plant ecologists find matrix models to be most useful. Improving forecasting ability would necessitate increased model complexity and longer studies. Therefore, in addition to longer term studies with better links to environmental drivers, priorities for research include critically evaluating relative/comparative uses of matrix models and asking how we can use many short‐term studies to understand long‐term population dynamics.
Uncertainty associated with ecological forecasts has long been recognized, but forecast accuracy is rarely quantified. We evaluated how well data on 82 populations of 20 species of plants spanning 3 ...continents explained and predicted plant population dynamics. We parameterized stage‐based matrix models with demographic data from individually marked plants and determined how well these models forecast population sizes observed at least 5 years into the future. Simple demographic models forecasted population dynamics poorly; only 40% of observed population sizes fell within our forecasts’ 95% confidence limits. However, these models explained population dynamics during the years in which data were collected; observed changes in population size during the data‐collection period were strongly positively correlated with population growth rate. Thus, these models are at least a sound way to quantify population status. Poor forecasts were not associated with the number of individual plants or years of data. We tested whether vital rates were density dependent and found both positive and negative density dependence. However, density dependence was not associated with forecast error. Forecast error was significantly associated with environmental differences between the data collection and forecast periods. To forecast population fates, more detailed models, such as those that project how environments are likely to change and how these changes will affect population dynamics, may be needed. Such detailed models are not always feasible. Thus, it may be wiser to make risk‐averse decisions than to expect precise forecasts from models. Habilidad de los Modelos Matriciales para Explicar el Pasado y Predecir el Futuro de las Poblaciones de Plantas
Disaster Resilience: A National Imperative Cutter, Susan L.; Ahearn, Joseph A.; Amadei, Bernard ...
Environment : science and policy for sustainable development,
03/2013, Letnik:
55, Številka:
2
Journal Article
Recenzirano
Escalating disaster losses coupled with the increasing frequency of billion-dollar disaster events, such as the recent Hurricane Sandy, highlight some of the challenges to hazards and disaster policy ...in the US. Many of these changes are transformative and long lasting and, coupled with the US' inability to act decisively to counteract climate change, portend a future where we are more vulnerable to hazards at multiple scales.
Gastrointestinal side effects are particularly common with clozapine and occur with other antipsychotics, ranging from mild constipation to fatal bowel obstruction and/or ischemia. While this ...adverse-effect spectrum has been attributed to ‘gastrointestinal hypomotility’, gastrointestinal transit times in antipsychotic-treated patients have not previously been measured, making this mechanism speculative.
Using standardized radiopaque marker (‘Metcalf’) methods we established colonic transit times of antipsychotic-treated psychiatric inpatients and compared them with population normative values. We analyzed results by antipsychotic type, antipsychotic dose equivalent, anticholinergic load, duration of treatment, gender, ethnicity, and age.
For patients not prescribed clozapine, median colonic transit time was 23h. For patients prescribed clozapine, median transit time was 104.5h, over four times longer than those on other antipsychotics or normative values (p<0.0001). Eighty percent of clozapine-treated patients had colonic hypomotility, compared with none of those prescribed other antipsychotics (olanzapine, risperidone, paliperidone aripiprazole, zuclopenthixol or haloperidol). In the clozapine group, right colon, left colon and rectosigmoid transit times were all markedly abnormal suggesting pan-colonic pathology. Hypomotility occurred irrespective of gender, age, ethnicity, or length of clozapine treatment. Transit times were positively correlated with clozapine plasma level (rho=0.451, p=0.045), but not with duration of treatment, total antipsychotic load or demographic factors.
Clozapine, unlike the other antipsychotics examined, causes marked gastrointestinal hypomotility, as previously hypothesized. Pre-emptive laxative treatment is recommended when starting clozapine.
•This study confirms that the antipsychotic clozapine has profound effects on bowel function•Median colonic transit time was 104.5h if taking clozapine, >4 times normative values or if on another antipsychotic•Right, left and rectosigmoid motility were all significantly impaired suggesting pan-colonic pathology•Colonic transit times were positively correlated with clozapine plasma level, but not other variables•This is clozapine-specific: 80% of clozapine patients and 0% of those taking other antipsychotics had abnormal GI transit•Findings may explain the clozapine-related morbidity and mortality from GI complications, such as bowel obstruction
For every thousand patients treated with clozapine, 300–600 will suffer constipation and at least four will develop serious gastrointestinal complications (including ileus, bowel obstruction, bowel ischaemia or necrosis), from which one will die. Iatrogenic mortality is higher from gastrointestinal complications than from agranulocytosis. However, the mechanism for these gastrointestinal complications has been poorly understood.
This study confirms clozapine has profound effects on bowel motility, with colonic transit in clozapine-treated patients taking four times longer than normal. 80% of clozapine patients had gastrointestinal hypomotility. Self-reported constipation had low sensitivity in predicting hypomotility. Prophylactic laxative treatment is recommended in all clozapine-treated patients.
To evaluate the effects of single-nucleotide polymorphisms (SNP) in microRNA-related genes on clinical outcomes in patients with colorectal cancer (CRC) receiving first-line fluoropyrimidine-based ...chemotherapy.
Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 patients with CRC recruited at the University of Texas MD Anderson Cancer Center (Houston, TX). Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in an additional 356 patients.
In patients with stage III disease, mir608: rs4919510 was associated with increased risk for both recurrence HR, 2.72; 95% confidence interval (CI), 1.38-5.33 and death (HR, 3.53; 95%CI, 1.42-8.73). The associations were confirmed in the replication set, and the combined HRs for training and replication sets were 1.65 (95% CI, 1.13-2.41) for recurrence and 1.96 (95% CI, 1.19-3.21) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR, 3.86; 95% CI, 1.33-11.22), the replication set (HR, 3.33; 95% CI, 1.39-7.98), and combined data set (HR, 3.22; 95% CI, 1.70-6.10). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6-fold increased risk of death.
Genetic polymorphisms in the microRNA pathway may predict prognosis in patients with stage III CRC treated with fluoropyrimidine-based chemotherapy.
The potential genetic basis of aortic stenosis in older people is poorly understood. A total of 265 patients with aortic stenosis involving tricuspid aortic valves and 961 controls were genotyped for ...≤660 candidate single nucleotide polymorphisms (SNPs). After dividing the patients and controls into training and validation sets, we tested the correlation of the SNPs with the age-adjusted aortic valve area, determined by echocardiography or cardiac catheterization. A bootstrapped global p value of ≤0.005 was considered evidence of a possible significant correlation. The cases were aged 73 ± 7 years, and 72.7% were men. The median aortic valve area was 1.0 cm2 (interquartile range 0.7 to 1.5). The controls were aged 69 ± 6 years, and 69.8% were men. The minor allele frequency was 21% ± 15% (37% <0.20). Three SNPs met the criteria for significant correlation (rs2276288 MYO7A, p = 0.001; rs5194 AGTR1, p = 0.004; rs207 307 ELN, p = 0.005). Another 2 SNPs reached borderline significance (p ≤0.008). In conclusion, we report 3 SNPs to be associated with aortic stenosis involving tricuspid aortic valves in older subjects. Given the concerns regarding the problem of multiple statistical testing, validation studies are required to further assess these correlations.
Clozapine, an antipsychotic used in treatment-resistant schizophrenia, causes slow gastrointestinal transit in 50-80% of patients. Clozapine-induced gastrointestinal hypomotility is both common and ...serious, and potential complications include severe constipation, ileus, bowel obstruction and related complications, with a higher mortality rate than clozapine-related agranulocytosis. Little evidence exists on its prevention and management.
Using a well-validated radiopaque marker ('Metcalf') method, we compared colonic transit times (CTTs) of clozapine-treated inpatients not receiving laxatives with their transit times when receiving laxatives, with treatment prescribed according to the Porirua Protocol for clozapine-related constipation (docusate and senna augmented by macrogol 3350 in treatment-resistant cases).
The median age of participants was 35 years, and median clozapine dose, plasma level and duration of treatment were 575 mg/day, 506 ng/mL and 2.5 years, respectively. Overall, 14 participants (10 male) were enrolled and all completed the study. Transit times improved markedly with laxative treatment. Median colonic transit without laxatives was 110 h (95% confidence interval CI 76-144 h), over four times longer than normative values (p < 0.0001). Median CTT with laxatives was 62 h (95% CI 27-96 h), a 2-day reduction in average transit time (p = 0.009). The prevalence of gastrointestinal hypomotility decreased from 86% pre-treatment to 50% post-treatment (p = 0.061). Severe gastrointestinal hypomotility decreased from 64 to 21% (p = 0.031). Subjective reporting of constipation did not correlate well with objective hypomotility, and did not change significantly with treatment.
Treating clozapine-treated patients with docusate and senna augmented by macrogol appears effective in reducing CTTs in clozapine-induced constipation. Randomised controlled trials are the next step. Australian New Zealand Clinical Trial Registry ACTRN12616001405404 (registered retrospectively).
In October 2012, the Haitian Ministry of Health and the US CDC were notified of 25 recent dengue cases, confirmed by rapid diagnostic tests (RDTs), among non-governmental organization (NGO) workers. ...We conducted a serosurvey among NGO workers in Léogane and Port-au-Prince to determine the extent of and risk factors for dengue virus infection. Of the total 776 staff from targeted NGOs in Léogane and Port-au-Prince, 173 (22%; 52 expatriates and 121 Haitians) participated. Anti-dengue virus (DENV) IgM antibody was detected in 8 (15%) expatriates and 9 (7%) Haitians, and DENV non-structural protein 1 in one expatriate. Anti-DENV IgG antibody was detected in 162 (94%) participants (79% of expatriates; 100% of Haitians), and confirmed by microneutralization testing as DENV-specific in 17/34 (50%) expatriates and 42/42 (100%) Haitians. Of 254 pupae collected from 68 containers, 65% were Aedes aegypti; 27% were Ae. albopictus. Few NGO workers reported undertaking mosquito-avoidance action. Our findings underscore the risk of dengue in expatriate workers in Haiti and Haitians themselves.
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