One-sample log-rank tests with consideration of reference curve sampling variability

The one-sample log-rank test is the method of choice for single-arm Phase II trials with time-to-event endpoint. It allows to compare the survival of the patients to a reference survival curve that typically represents the expected survival under standard of care. The classical one-sample log-rank test, however, assumes that the reference survival curve is deterministic. This ignores that the reference curve is commonly estimated from historic data and thus prone to statistical error. Ignoring sampling variability of the reference curve results in type I error rate inflation. For that reason, a new one-sample log-rank test is proposed that explicitly accounts for the statistical error made in the process of estimating the reference survival curve. The test statistic and its distributional properties are derived using martingale techniques in the large sample limit. In particular, a sample size formula is provided. Small sample properties regarding type I and type II error rate control are studied by simulation. A case study is conducted to study the influence of several design parameters of a single-armed trial on the inflation of the type I error rate when reference curve sampling variability is ignored.Comment: 24 pages, 2 pictures, 1 supplementary fil

The Yo-Yo Intermittent Tests: A Systematic Review and Structured Compendium of Test Results

Background: Although Yo-Yo intermittent tests are frequently used in a variety of sports and research studies to determine physical fitness, no structured reference exists for comparison and rating of test results. This systematic review of the most common Yo-Yo tests aimed to provide reference values for test results by statistical aggregation of published data.Methods: A systematic literature search for articles published until August 2017 was performed in MEDLINE, Web of Science, SPORTDiscus and Google Scholar. Original reports on healthy females and males ≥16 years were eligible for the analysis. Sub-maximal test versions and the Yo-Yo Intermittent Recovery Level 1 Children's test (YYIR1C) were not included.Results: 248 studies with 9,440 participants were included in the structured analysis. The Yo-Yo test types most frequently used were the Yo-Yo Intermittent Recovery Level 1 (YYIR1, 57.7%), the Yo-Yo Intermittent Recovery Level 2 (YYIR2, 28.0%), the Yo-Yo Intermittent Endurance Level 2 (YYIE2, 11.4%), and the Yo-Yo Intermittent Endurance Level 1 (YYIE1, 2.9%) test. For each separate test, reference values (global means and percentiles) for sports at different levels and both genders were calculated.Conclusions: Our analysis provides evidence that Yo-Yo intermittent tests reference values differ with respect to the type and level of sport performed.The presented results may be used by practitioners, trainers and athletes to rate Yo-Yo intermittent test performance levels and monitor training effects

Prognostic Impact of Bcl-2 Depends on Tumor Histology and Expression of MALAT-1 lncRNA in Non–Small-Cell Lung Cancer

IntroductionApoptosis is a crucial pathway in tumor growth and metastatic development. Apoptotic proteins regulate the underlying molecular cascades and are thought to modulate the tumor response to chemotherapy and radiation. However, the prognostic value of the expression of apoptosis regulators in localized non–small-cell lung cancer (NSCLC) is still unclear.MethodsWe investigated the protein expression of apoptosis regulators Bcl-2, Bcl-xl, Mcl-1, and pp32/PHAPI, and the expression of the lncRNA MALAT-1 in tumor samples from 383 NSCLC patients (median age: 65.6 years; 77.5% male; paraffin-embedded tissue microarrays). For statistical analysis correlation tests, Log rank tests and Cox proportional hazard models were applied.ResultsTumor histology was significantly associated with the expression of Bcl-2, Bcl-xl and Mcl-1 (all p < 0.001). Among the tested apoptotic markers only Bcl-2 demonstrated prognostic impact (hazard ratio = 0.64, p = 0.012). For NSCLC patients with non-adenocarcinoma histology, Bcl-2 expression was associated with increased overall survival (p = 0.036). Besides tumor histology, prognostic impact of Bcl-2 was also found to depend on MALAT-1 lncRNA expression. Gene expression analysis of A549 adenocarcinoma cells with differential MALAT-1 lncRNA expression demonstrated an influence on the expression of Bcl-2 and its interacting proteins.ConclusionsBcl-2 expression was specifically associated with superior prognosis in localized NSCLC. An interaction of Bcl-2 with MALAT-1 lncRNA expression was revealed, which merits further investigation for risk prediction in resectable NSCLC patients

Outcome of 11 children with ependymoblastoma treated within the prospective HIT-trials between 1991 and 2006

Ependymoblastoma is a rare malignant brain tumor of early childhood. Data on clinical behavior and optimal treatment strategies are scarce. We report on 11 consecutively treated children with centrally confirmed diagnosis of CNS ependymoblastoma, registered between February 1994 and October 2006 to the prospective GPOH-HIT multicenter brain tumor trials, and treated by multimodal regimens. Median age at diagnosis was 3.5years (range, 1.8-5.6years), and the median follow-up of survivors was 5.9years (range, 2.2-12.7years). Initial stage was M0 in 9, and M0/1 (no cerebrospinal fluid examination done) in 2 patients. Gross-total tumor resection was achieved in 7 patients, incomplete resection in 4 patients. Further primary therapy included chemotherapy in all patients, craniospinal radiotherapy in 5 patients and high-dose chemotherapy in 2 patients. Tumor response to chemotherapy was observed in 1 of 4 evaluable patients. Tumor progression occurred in 7 patients after a median time of 5.0months (range, 2.5-19.2months). Five-year progression-free survival was 36.4% (±14.5%), 5-year overall survival 30.3% (±15.9%). Of 4 survivors, 3 had gross-total tumor resection, and all were treated by either craniospinal radiotherapy and/or high-dose chemotherapy with autologous blood stem cell rescue. Prognosis of children with ependymoblastoma is poor, but sustained remissions have been achieved after multimodal treatment. Considerable diagnostic discrepancies between local and central pathologists underscore the importance of central review. Further studies are needed to improve survival of children with this rare malignant central nervous system tumo

Local and systemic therapy of recurrent medulloblastomas in children and adolescents: results of the P-HIT-REZ 2005 study

SIMPLE SUMMARY: A medulloblastoma recurrence is usually associated with an unfavorable prognosis. The German P-HIT-REZ 2005 Study gathered data from patients with relapsed medulloblastomas treated in different, non-randomized therapy arms dependent on preconditions of the patients (previous treatment, comorbidities, relapse pattern), the decision of treating physicians, and the patients’/parents’ choice. A total of 93 evaluable patients with refractory or relapsed medulloblastoma were enrolled. The main aim of this study was to analyze the impact of patient and disease characteristics as well as local and systemic therapies on post-relapse progression-free (PFS) and overall survival (OS). In multivariate analysis, a short time until the first recurrence (<18 months) was the strongest predictor for a worse PFS and OS, which was mainly associated with molecular subgroup 3. Metastatic disease, at relapse, only had a significant impact on OS. Re-biopsy, at relapse, is highly recommended to investigate the histopathological and molecular genetic tumor characteristics and to exclude a secondary malignancy. ABSTRACT: Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival

Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective

Studies on the Utilization of Sugar Beet Leaves as the Rock-Horn Cockerels Green Feed

Purpose: To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. Patients and Methods: In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. Results: After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm2 was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. Conclusion: In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease

Implementing online interventions in ICare: A biostatistical perspective

The implementation of research studies is a highly complex process. All decisions with respect to the study design impact the statistical analyses and interpretation of the results. Within the ICare research project (EU H2020 Grant agreement 634757) seven research trials are conducted to generate evidence on efficacy, effectiveness and the dissemination potential of online interventions targeting eating disorders, common mental health problems and resilience. Within the project a central biometrical unit was established to manage and coordinate data collection, processing and statistical data analysis. This allows for harmonized trial planning, conduct, data management processes and analysis strategies. The purpose of this article is to describe the common concepts underlying all seven ICare trials. This includes development of (adaptive sequential) study designs, handling of missing values, general data management and processing as well as data protection aspects. Keywords: Biostatistics, Study designs, Statistical analysis, Data management and protection, Randomized controlled trial

Degradation of phosphatidylethanol counteracts the apparent phospholipase D-mediated formation in heart and other organs

Phosphatidylalcohols, such as phosphatidylethanol (PEth), are formed from phosphatidylcholine in the presence of a primary alcohol (e.g., ethanol). This 'transphosphatidylation' reaction is used as specific phospholipase D (PLD) assay. Accumulation of PEth in tissues is recognized as a reliable measure of PLD activity, as PEth is allegedly metabolically stable. The general validity of this assumption was reinvestigated in isolated rat heart, small intestine and brain slices. The half-times of 3H-PEth degradation (labelled with 3H-myristic acid and preformed by ethanol exposure for 30 min) were about 1 h in heart and small intestine, but 17 h in brain. As the formation of PEth is superimposed by simultaneous degradation, a mathematical model was established to calculate the differences between 'true' and 'apparent' PEth formation. As expected, this difference was relevant in heart and intestine, but not in brain tissue. For example, ischemia in the perfused heart for 30 min reversibly blocked PEth degradation and seemingly enhanced PEth formation; the block was reversed by ischemic preconditioning (IPC) and by pretreatment with diazoxide, an opener of mitochondrial K(ATP) channels. In conclusion, PEth degradation in heart was energy-dependent and rapid, which, when ignored, may lead to misinterpretation of PEth values with respect to PLD activity