Rene Schmidt

Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers

Purpose: To optimize neuroblastoma treatment stratification, we aimed at developing a novel risk estimation system by integrating gene expression–based classification and established prognostic markers. Experimental Design: Gene expression profiles were generated from 709 neuroblastoma specimens using customized 4 × 44 K microarrays. Classification models were built using 75 tumors with contrasting courses of disease. Validation was performed in an independent test set (n = 634) by Kaplan–Meier estimates and Cox regression analyses. Results: The best-performing classifier predicted patient outcome with an accuracy of 0.95 (sensitivity, 0.93; specificity, 0.97) in the validation cohort. The highest potential clinical value of this predictor was observed for current low-risk patients [5-year event-free survival (EFS), 0.84 ± 0.02 vs. 0.29 ± 0.10; 5-year overall survival (OS), 0.99 ± 0.01 vs. 0.76 ± 0.11; both P < 0.001] and intermediate-risk patients (5-year EFS, 0.88 ± 0.06 vs. 0.41 ± 0.10; 5-year OS, 1.0 vs. 0.70 ± 0.09; both P < 0.001). In multivariate Cox regression models for low-risk/intermediate-risk patients, the classifier outperformed risk assessment of the current German trial NB2004 [EFS: hazard ratio (HR), 5.07; 95% confidence interval (CI), 3.20–8.02; OS: HR, 25.54; 95% CI, 8.40–77.66; both P < 0.001]. On the basis of these findings, we propose to integrate the classifier into a revised risk stratification system for low-risk/intermediate-risk patients. According to this system, we identified novel subgroups with poor outcome (5-year EFS, 0.19 ± 0.08; 5-year OS, 0.59 ± 0.1), for whom we propose intensified treatment, and with beneficial outcome (5-year EFS, 0.87 ± 0.05; 5-year OS, 1.0), who may benefit from treatment de-escalation. Conclusions: Combination of gene expression–based classification and established prognostic markers improves risk estimation of patients with low-risk/intermediate-risk neuroblastoma. We propose to implement our revised treatment stratification system in a prospective clinical trial. Clin Cancer Res; 21(8); 1904–15. ©2014 AACR. See related commentary by Attiyeh and Maris, p. 1782

Computed Tomographic Blend Sign Is Associated With Computed Tomographic Angiography Spot Sign and Predicts Secondary Neurological Deterioration After Intracerebral Hemorrhage

Background and Purpose— Significant early hematoma growth in patients with intracerebral hemorrhage is an independent predictor of poor functional outcome. Recently, the novel blend sign (BS) has been introduced as a new imaging sign for predicting hematoma growth in noncontrast computed tomography. Another parameter predicting increasing hematoma size is the well-established spot sign (SS) visible in computed tomographic angiography. We, therefore, aimed to clarify the association between established SS and novel BS and their values predicting a secondary neurological deterioration. Methods— Retrospective study inclusion criteria were (1) spontaneous intracerebral hemorrhage confirmed on noncontrast computed tomography and (2) noncontrast computed tomography and computed tomographic angiography performed on admission within 6 hours after onset of symptoms. We defined a binary outcome (secondary neurological deterioration versus no secondary deterioration). As secondary neurological deterioration, we defined (1) early hemicraniectomy under standardized criteria or (2) secondary decrease of Glasgow Coma Scale of >3 points, both within the first 48 hours after symptom onset. Results— Of 182 patients with spontaneous intracerebral hemorrhage, 37 (20.3%) presented with BS and 39 (21.4%) with SS. Of the 81 patients with secondary deterioration, 31 (38.3%) had BS and SS on admission. Multivariable logistic regression analysis identified hematoma volume (odds ratio, 1.07 per mL; P⩽0.001), intraventricular hemorrhage (odds ratio, 3.08; P=0.008), and the presence of BS (odds ratio, 11.47; P⩽0.001) as independent predictors of neurological deterioration. Conclusions— The BS, which is obtainable in noncontrast computed tomography, shows a high correlation with the computed tomographic angiography SS and is a reliable predictor of secondary neurological deterioration after spontaneous intracerebral hemorrhage.

Adaptive designs with arbitrary dependence structure

Adaptive designs were originally developed for independent and uniformly distributed p-values. There are trial settings where independence is not satisfied or where it may not be possible to check whether it is satisfied. In these cases, the test statistics and p-values of each stage may be dependent. Since the probability of a type I error for a fixed adaptive design depends on the true dependence structure between the p-values of the stages, control of the type I error rate might be endangered if the dependence structure is not taken into account adequately. In this paper, we address the problem of controlling the type I error rate in two-stage adaptive designs if any dependence structure between the test statistics of the stages is admitted (worst case scenario). For this purpose, we pursue a copula approach to adaptive designs. For two-stage adaptive designs without futility stop, we derive the probability of a type I error in the worst case, that is for the most adverse dependence structure between the p-values of the stages. Explicit analytical considerations are performed for the class of inverse normal designs. A comparison with the significance level for independent and uniformly distributed p-values is performed. For inverse normal designs without futility stop and equally weighted stages, it turns out that correcting for the worst case is too conservative as compared to a simple Bonferroni design.

A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma – A final report

Background The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. Methods Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology–Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 × 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02–7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. Findings No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. Interpretation The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of ‘duration of therapy’ and ‘age at stopping therapy’.

Comparison of Spot Sign, Blend Sign and Black Hole Sign for Outcome Prediction in Patients with Intracerebral Hemorrhage

Background and Purpose Blend sign (BS) and black hole sign (BHS) on non-contrast computed tomography (NCCT) and spot sign (SS) on CT-angiography (CTA) are indicators of early hematoma expansion in spontaneous intracerebral hemorrhage (ICH). However, their independent contributions to outcome have not been well explored. Methods In this retrospective study, inclusion criteria were: 1) spontaneous ICH and 2) NCCT and CTA performed on admission within 6 hours after onset of symptoms. Discharge outcome was dichotomized as good (modified Rankin Scale [mRS] 0-3) and poor (mRS 4-6) outcomes. The impacts of BHS, BS and SS on outcome were assessed in univariate and multivariable logistic regression models. Results Of 182 patients with spontaneous ICH, 26 (14.3%) presented with BHS, 37 (20.3%) with BS and 39 (21.4%) with SS. There was a substantial correlation between SS and BS (κ=0.701) and a moderate correlation between SS and BHS (κ=0.424). In univariable logistic regression, higher baseline hematoma volume (P<0.001), intraventricular hemorrhage (P=0.002) and the presence of BHS/BS/SS (all P<0.001) on admission CT scan were associated with poor outcome. Multivariable analysis identified intraventricular haemorrhage (odds ratio [OR] 2.22 per mL, P=0.022), baseline hematoma volume (OR 1.03 per mL, P<0.001) and SS on CTA (OR 11.43, P<0.001) as independent predictors of poor outcome, showing that SS compared to BS and BHS was more powerful to predict poor outcome. Conclusions The NCCT BHS and BS are correlated with the CTA SS and are reliable predictors of poor outcome in patients with ICH. Of the CT variables indicating early hematoma expansion, SS on CTA was the most reliable outcome predictor. However, given their correlation with SS on CTA, BS and BHS on NCCT can be useful for predicting outcome if CTA is not obtainable.

Computed Tomography Perfusion Improves Diagnostic Accuracy in Acute Posterior Circulation Stroke.

Background and Purpose: Computed tomography perfusion (CTP) has a high diagnostic value in the detection of acute ischemic stroke in the anterior circulation. However, the diagnostic value in suspected posterior circulation (PC) stroke is uncertain, and whole brain volume perfusion is not yet in widespread use. We therefore studied the additional value of whole brain volume perfusion to non-contrast CT (NCCT) and CT angiography source images (CTA-SI) for infarct detection in patients with suspected acute ischemic PC stroke. Methods: This is a retrospective review of patients with suspected stroke in the PC in a database of our stroke center (n = 3,011) who underwent NCCT, CTA and CTP within 9 h after stroke onset and CT or MRI on follow-up. Images were evaluated for signs and pc-ASPECTS locations of ischemia. Three imaging models - A (NCCT), B (NCCT + CTA-SI) and C (NCCT + CTA-SI + CTP) - were compared with regard to the misclassification rate relative to gold standard (infarction in follow-up imaging) using the McNemars test. Results: Of 3,011 stroke patients, 267 patients had a suspected stroke in the PC and 188 patients (70.4%) evidenced a PC infarct on follow-up imaging. The sensitivity of Model C (76.6%) was higher compared with that of Model A (21.3%) and Model B (43.6%). CTP detected significantly more ischemic lesions, especially in the cerebellum, posterior cerebral artery territory and thalami. Conclusions: Our findings in a large cohort of consecutive patients show that CTP detects significantly more ischemic strokes in the PC than CTA and NCCT alone.

Sample size calculation for the one-sample log-rank test.

An improved method of sample size calculation for the one-sample log-rank test is provided. The one-sample log-rank test may be the method of choice if the survival curve of a single treatment group is to be compared with that of a historic control. Such settings arise, for example, in clinical phase-II trials if the response to a new treatment is measured by a survival endpoint. Present sample size formulas for the one-sample log-rank test are based on the number of events to be observed, that is, in order to achieve approximately a desired power for allocated significance level and effect the trial is stopped as soon as a certain critical number of events are reached. We propose a new stopping criterion to be followed. Both approaches are shown to be asymptotically equivalent. For small sample size, though, a simulation study indicates that the new criterion might be preferred when planning a corresponding trial. In our simulations, the trial is usually underpowered, and the aspired significance level is not exploited if the traditional stopping criterion based on the number of events is used, whereas a trial based on the new stopping criterion maintains power with the type-I error rate still controlled.

Effect of TH2 cytokines and interferon gamma on beat frequency of human respiratory cilia

Background:In asthmatic airways secondary ciliary dyskinesia contributes to impaired mucociliary clearance. To investigate underlying mechanisms, we studied the effects of cytokines associated with asthma phenotype on the ciliary beat frequency (CBF) in a cell culture model of ciliated human respiratory epithelial cells.Methods:Nasal respiratory epithelial cells of 21 patients were used to prepare multicellular cells (spheroids) in the presence of the T helper (TH) 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13, and the TH1 cytokine interferon gamma (IFN-γ). CBF was determined by high-speed video microscopy.Results:Addition of IL-4 and IL-13 and IL-4 + IL-13 decreased the mean CBF by 17, 21, and 22%, respectively, compared with untreated controls. Addition of IL-5 and IL-9 lead to an increase in mean CBF (20 and 10%, respectively). Lower concentrations of IFN-γ (0.1 and 1 ng/ml) decreased mean CBF and higher concentrations (10 ng/ml) increased CBF by 6%. Addition of IFN-γ to IL-13 reversed the effect of IL-13 on the CBF of spheroids.Conclusion:Cytokines directly influence the ciliary function of respiratory epithelium and contribute to the impaired mucociliary clearance in asthmatic disease. Our study encourages further research to investigate IFN-γ as a treatment option in diseases with impaired mucociliary clearance like asthma.

Adaptive designs with arbitrary dependence structure based on Fisher’s combination test

Adaptive designs were originally developed for independent and uniformly distributed