293 research outputs found
Discussion on "Joint modeling of survival and longitudinal non-survival data" by Gould et al.
X-ray structural analysis of compensating mutations at the barnase-barstar interface
AbstractThe crystal structure of the barstar mutants (Y29P) and (Y29D, Y30W) as well as that of the complexes of barstar(Y29P) with wild-type barnase and barnase(H102K) have been determined. These barstar mutants compensate for the dramatic loss of barnase-barstar interaction energy caused by a single mutation of the barnase active site His-102 to a lysine. The latter introduces an uncompensated charge in the pocket at the surface of barstar where Lys-102 is located. The analysis of the structures suggests a mechanism for this compensation based on the solvation of the charge of Lys-102. Additional compensation occurs through the formation of a hydrogen bond
Exposure to phosphine in maritime transport: a real and important occupational risk: a report of three cases
In maritime transport, to assess the risks of insect pests spreading, fumigation is recommended by the Food and Agriculture Organisation. Fumigant mostly used for foodstuffs is the phosphine gas generated by the reaction of aluminium phosphide and moisture in the atmosphere. In this article, we first discuss phosphine toxicity to humans and then we describe three cases of occupational exposure in maritime transport of cereals. We found phosphine level higher than 20 ppm in tank atmosphere of bulk carriers and levels from 2 to 3.5 ppm in port silos and port warehouses where cereals were unloaded. Two weeks later, atmospheric measurements in a silo were still at 0.8 ppm. In this case, 3 workers described symptoms which could be linked with phosphine. Exposures to phosphine and cases in maritime transport are surely underestimated. Exposure could occur at sea, in harbour but also in port warehouses, trucks and silos or warehouses along logistic chain. All workers in the chain could be exposed. We can recommend research aiming at the development of alternative techniques using a less harmful gas for humans. At individual level, we propose that, along with the training for employees, workers potentially exposed should wear a test strip (phosphine detector strips) or a personal gas badge with appropriate maintenance
Tutorial in Joint Modeling and Prediction: A Statistical Software for Correlated Longitudinal Outcomes, Recurrent Events and a Terminal Event
Extensions in the field of joint modeling of correlated data and dynamic predictions improve the development of prognosis research. The R package frailtypack provides estimations of various joint models for longitudinal data and survival events. In particular, it fits models for recurrent events and a terminal event (frailtyPenal), models for two survival outcomes for clustered data (frailtyPenal), models for two types of recurrent events and a terminal event (multivPenal), models for a longitudinal biomarker and a terminal event (longiPenal) and models for a longitudinal biomarker, recurrent events and a terminal event (trivPenal). The estimators are obtained using a standard and penalized maximum likelihood approach, each model function allows to evaluate goodness-of-fit analyses and provides plots of baseline hazard functions. Finally, the package provides individual dynamic predictions of the terminal event and evaluation of predictive accuracy. This paper presents the theoretical models with estimation techniques, applies the methods for predictions and illustrates frailtypack functions details with examples
Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents
Trials; Anticancer agents; ChildrenEnsayos; Agentes anticancerígenos; NiñosAssajos; Agents anticancerígens; NensPURPOSE
There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders.
METHODS
After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved.
RESULTS
Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements.
CONCLUSION
An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer
Explained variation of excess hazard models.
The availability of longstanding collection of detailed cancer patient information makes multivariable modelling of cancer-specific hazard of death appealing. We propose to report variation in survival explained by each variable that constitutes these models. We adapted the ranks explained (RE) measure to the relative survival data setting, ie, when competing risks of death are accounted for through life tables from the general population. RE is calculated at each event time. We introduce weights for each death reflecting its probability to be a cancer death. RE varies between -1 and +1 and can be reported at given times in the follow-up and as a time-varying measure from diagnosis onward. We present an application for patients diagnosed with colon or lung cancer in England. The RE measure shows reasonable properties and is comparable in both relative and cause-specific settings. One year after diagnosis, RE for the most complex excess hazard models reaches 0.56, 95% CI: 0.54 to 0.58 (0.58 95% CI: 0.56-0.60) and 0.69, 95% CI: 0.68 to 0.70 (0.67, 95% CI: 0.66-0.69) for lung and colon cancer men (women), respectively. Stage at diagnosis accounts for 12.4% (10.8%) of the overall variation in survival among lung cancer patients whereas it carries 61.8% (53.5%) of the survival variation in colon cancer patients. Variables other than performance status for lung cancer (10%) contribute very little to the overall explained variation. The proportion of the variation in survival explained by key prognostic factors is a crucial information toward understanding the mechanisms underpinning cancer survival. The time-varying RE provides insights into patterns of influence for strong predictors
Cost Effectiveness of Modified Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non–Small-Cell Lung Cancer Patients
IntroductionModified fractionation radiotherapy (RT), delivering multiple fractions per day or shortening the overall treatment time, improves overall survival for non -small-cell lung cancer (NSCLC) patients compared with conventional fractionation RT (CRT). However, its cost effectiveness is unknown. Therefore, we aimed to examine and compare the cost effectiveness of different modified RT schemes and CRT in the curative treatment of unresected NSCLC patients.MethodsA probabilistic Markov model was developed based on individual patient data from the meta-analysis of radiotherapy in lung cancer (N = 2000). Dutch health care costs, quality-adjusted life years (QALYs), and net monetary benefits (NMBs) were compared between two accelerated schemes (very accelerated RT [VART] and moderately accelerated RT [MART]), two hyperfractionated schemes (using an identical (HRTI) or higher (HRTH) total treatment dose than CRT) and CRT.ResultsAll modified fractionations were more effective and costlier than CRT (1.12 QALYs, €24,360). VART and MART were most effective (1.30 and 1.32 QALYs) and cost €25,746 and €26,208, respectively. HRTI and HRTH yielded less QALYs than the accelerated schemes (1.27 and 1.14 QALYs), and cost €26,199 and €29,683, respectively. MART had the highest NMB (€79,322; 95% confidence interval [CI], €35,478-€133,648) and was the most cost-effective treatment followed by VART (€78,347; 95% CI, €64,635-€92,526). CRT had an NMB of €65,125 (95% CI, €54,663-€75,537). MART had the highest probability of being cost effective (43%), followed by VART (31%), HRTI (24%), HRTH (2%), and CRT (0%).ConclusionImplementing accelerated RT is almost certainly more efficient than current practice CRT and should be recommended as standard RT for the curative treatment of unresected NSCLC patients not receiving concurrent chemo-radiotherapy
Portrait of Ependymoma Recurrence in Children: Biomarkers of Tumor Progression Identified by Dual-Color Microarray-Based Gene Expression Analysis
BACKGROUND: Children with ependymoma may experience a relapse in up to 50% of cases depending on the extent of resection. Key biological events associated with recurrence are unknown. METHODOLOGY/PRINCIPAL FINDINGS: To discover the biology behind the recurrence of ependymomas, we performed CGHarray and a dual-color gene expression microarray analysis of 17 tumors at diagnosis co-hybridized with the corresponding 27 first or subsequent relapses from the same patient. As treatment and location had only limited influence on specific gene expression changes at relapse, we established a common signature for relapse. Eighty-seven genes showed an absolute fold change ≥2 in at least 50% of relapses and were defined as the gene expression signature of ependymoma recurrence. The most frequently upregulated genes are involved in the kinetochore (ASPM, KIF11) or in neural development (CD133, Wnt and Notch pathways). Metallothionein (MT) genes were downregulated in up to 80% of the recurrences. Quantitative PCR for ASPM, KIF11 and MT3 plus immunohistochemistry for ASPM and MT3 confirmed the microarray results. Immunohistochemistry on an independent series of 24 tumor pairs at diagnosis and at relapse confirmed the decrease of MT3 expression at recurrence in 17/24 tumor pairs (p = 0.002). Conversely, ASPM expression was more frequently positive at relapse (87.5% vs 37.5%, p = 0.03). Loss or deletion of the MT genes cluster was never observed at relapse. Promoter sequencing after bisulfite treatment of DNA from primary tumors and recurrences as well as treatment of short-term ependymoma cells cultures with a demethylating agent showed that methylation was not involved in MT3 downregulation. However, in vitro treatment with a histone deacetylase inhibitor or zinc restored MT3 expression. CONCLUSIONS/SIGNIFICANCE: The most frequent molecular events associated with ependymoma recurrence were over-expression of kinetochore proteins and down-regulation of metallothioneins. Metallothionein-3 expression is epigenetically controlled and can be restored in vitro by histone deacetylase inhibitors
Socioeconomic status and its relation with breast cancer recurrence and survival in young women in the Netherlands
BACKGROUND: Associations between socioeconomic status (SES) and breast cancer survival are most pronounced in young patients. We further investigated the relation between SES, subsequent recurrent events and mortality in breast cancer patients < 40 years. Using detailed data on all recurrences that occur between date of diagnosis of the primary tumor and last observation, we provide a unique insight in the prognosis of young breast cancer patients according to SES. METHODS: All women < 40 years diagnosed with primary operated stage I-III breast cancer in 2005 were selected from the nationwide population-based Netherlands Cancer Registry. Data on all recurrences within 10 years from primary tumor diagnosis were collected directly from patient files. Recurrence patterns and absolute risks of recurrence, contralateral breast cancer (CBC) and mortality - accounting for competing risks - were analysed according to SES. Relationships between SES, recurrence patterns and excess mortality were estimated using a multivariable joint model, wherein the association between recurrent events and excess mortality (expected mortality derived from the general population) was included. RESULTS: We included 525 patients. The 10-year recurrence risk was lowest in high SES (18.1%), highest in low SES (29.8%). Death and CBC as first events were rare. In high, medium and low SES 13.2%, 15.3% and 19.1% died following a recurrence. Low SES patients had shorter median time intervals between diagnosis, first recurrence and 10-year mortality (2.6 and 2.7 years, respectively) compared to high SES (3.5 and 3.3 years, respectively). In multivariable joint modeling, high SES was significantly related to lower recurrence rates over 10-year follow-up, compared to low SES. A strong association between the recurrent event process and excess mortality was found. CONCLUSIONS: High SES is associated with lower recurrence risks, less subsequent events and better prognosis after recurrence over 10 years than low SES. Breast cancer risk factors, adjuvant treatment adherence and treatment of recurrence may possibly play a role in this association
Auditory stimuli mimicking ambient sounds drive temporal "delta-brushes" in premature infants
In the premature infant, somatosensory and visual stimuli trigger an immature electroencephalographic (EEG) pattern, "delta-brushes," in the corresponding sensory cortical areas. Whether auditory stimuli evoke delta-brushes in the premature auditory cortex has not been reported. Here, responses to auditory stimuli were studied in 46 premature infants without neurologic risk aged 31 to 38 postmenstrual weeks (PMW) during routine EEG recording. Stimuli consisted of either low-volume technogenic "clicks" near the background noise level of the neonatal care unit, or a human voice at conversational sound level. Stimuli were administrated pseudo-randomly during quiet and active sleep. In another protocol, the cortical response to a composite stimulus ("click" and voice) was manually triggered during EEG hypoactive periods of quiet sleep. Cortical responses were analyzed by event detection, power frequency analysis and stimulus locked averaging. Before 34 PMW, both voice and "click" stimuli evoked cortical responses with similar frequency-power topographic characteristics, namely a temporal negative slow-wave and rapid oscillations similar to spontaneous delta-brushes. Responses to composite stimuli also showed a maximal frequency-power increase in temporal areas before 35 PMW. From 34 PMW the topography of responses in quiet sleep was different for "click" and voice stimuli: responses to "clicks" became diffuse but responses to voice remained limited to temporal areas. After the age of 35 PMW auditory evoked delta-brushes progressively disappeared and were replaced by a low amplitude response in the same location. Our data show that auditory stimuli mimicking ambient sounds efficiently evoke delta-brushes in temporal areas in the premature infant before 35 PMW. Along with findings in other sensory modalities (visual and somatosensory), these findings suggest that sensory driven delta-brushes represent a ubiquitous feature of the human sensory cortex during fetal stages and provide a potential test of functional cortical maturation during fetal development. © 2013 Chipaux et al
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