Statistical controversies in clinical research: futility analyses in oncology-lessons on potential pitfalls from a randomized controlled trial.

BACKGROUND: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER: NCT00806819.

Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

Caputo standard α-family of maps: fractional difference vs. fractional.

In this paper, the author compares behaviors of systems which can be described by fractional differential and fractional difference equations using the fractional and fractional difference Caputo standard α-Families of maps as examples. The author shows that properties of fractional difference maps (systems with falling factorial-law memory) are similar to the properties of fractional maps (systems with power-law memory). The similarities (types of attractors, power-law convergence of trajectories, existence of cascade of bifurcations and intermittent cascade of bifurcations type trajectories, and dependence of properties on the memory parameter α) and differences in properties of falling factorial- and power-law memory maps are investigated.

Universal fractional map and cascade of bifurcations type attractors.

We modified the way in which the Universal Map is obtained in the regular dynamics to derive the Universal α-Family of Maps depending on a single parameter α>0, which is the order of the fractional derivative in the nonlinear fractional differential equation describing a system experiencing periodic kicks. We consider two particular α-families corresponding to the Standard and Logistic Maps. For fractional α<2 in the area of parameter values of the transition through the period doubling cascade of bifurcations from regular to chaotic motion in regular dynamics corresponding fractional systems demonstrate a new type of attractors--cascade of bifurcations type trajectories.

[Reducing the use of medication in the elderly; why or why not?] / Medicatie minderen bij ouderen.

Many healthcare providers agree that reduction or stopping of medication, so-called deprescribing, would be good in vulnerable people with polypharmacy. However, deprescribing is not yet widely conducted. Physicians and pharmacists experience barriers, such as lack of evidence and guidance to support this process. There is also a tendency to maintain the status quo when there are no acute problems. Patients do want fewer pills but the proposal to stop certain medication can lead to resistance or confusion. The needs and concerns from a patient's perspective are a good starting point for desprescribing. It is important to set new goals and to prioritize together which medication can be stopped. It is not only relevant to react to existing problems but also to act proactively when the potential benefits no longer outweigh the medication burden or risks. Recently, more guidance and tools to support deprescribing became available in the Netherlands.

A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. PATIENTS AND METHODS: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. RESULTS: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. CONCLUSIONS: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.

Fractional dissipative standard map.

Using kicked differential equations of motion with derivatives of noninteger orders, we obtain generalizations of the dissipative standard map. The main property of these generalized maps, which are called fractional maps, is long-term memory. The memory effect in the fractional maps means that their present state of evolution depends on all past states with special forms of weights. Already a small deviation of the order of derivative from the integer value corresponding to the regular dissipative standard map (small memory effects) leads to the qualitatively new behavior of the corresponding attractors. The fractional dissipative standard maps are used to demonstrate a new type of fractional attractors in the wide range of the fractional orders of derivatives.

Tentoxin sensitivity of chloroplasts determined by codon 83 of beta subunit of proton-ATPase.

Tentoxin is a naturally occurring phytotoxic peptide that causes seedling chlorosis and arrests growth in sensitive plants and algae. In vitro, it inhibits activity of the beta subunit of the plastid proton-adenosine triphosphatase (ATPase) from sensitive species. Plastid atpB genes from six closely related, tentoxin-sensitive or -resistant Nicotiana species differ at codon 83, according to their response to the toxin: glutamate correlated with resistance and aspartate correlated with sensitivity. The genetic relevance of this site was confirmed in Chlamydomonas reinhardtii by chloroplast transformation. The alga, normally tentoxin-resistant, was rendered tentoxin-sensitive by mutagenesis of its plastid atpB gene at codon 83. Codon 83 may represent a critical site on the beta subunit that does not compete with nucleotide binding or other catalytic activities.

Problem of transport in billiards with infinite horizon.

We consider particles transport in the Sinai billiard with infinite horizon. The simulation shows that the transport is superdiffusive in both continuous and discrete time. Also, it is shown that the moments do not converge to the Gaussian moments even in the logarithmically renormalized time scale, at least for a fairly long computational time. These results are discussed with respect to the existent rigorous theorems. Similar results are obtained for the stadium billiard.

Superdiffusion in the dissipative standard map.

We consider transport properties of the chaotic (strange) attractor along unfolded trajectories of the dissipative standard map. It is shown that the diffusion process is normal except for the cases when a control parameter is close to some special values that correspond to the ballistic mode dynamics. Diffusion near the related crises is anomalous and nonuniform in time; there are large time intervals during which the transport is normal or ballistic, or even superballistic. The anomalous superdiffusion seems to be caused by stickiness of trajectories to a nonchaotic and nowhere dense invariant Cantor set that plays a similar role as cantori in Hamiltonian chaos. We provide a numerical example of such a sticky set. Distribution function on the sticky set almost coincides with the distribution function (SRB measure) of the chaotic attractor.

The double edged sword of the immune response: mutational analysis of a murine anti-pneumococcal, anti-DNA antibody.

Anti-double-stranded (ds) DNA antibodies are not only an important diagnostic marker for SLE, but also play an important role in tissue injury. Microbial antigen may be a stimulus for the production of these antibodies. We isolated 99D.7E, an IgG2b monoclonal antibody from a nonautoimmune BALB/c mouse that is cross-reactive with both dsDNA and phosphorylcholine, the dominant hapten on the pneumococcal cell wall. While partially protective against a bacterial challenge, 99D.7E is also pathogenic to the kidney. To identify those molecular motifs that confer on anti-PC antibodies the potential for autoreactivity, we created a panel of 99D.7E mutants with single amino acid substitutions in the heavy chain, and examined the changes in antigen binding and renal deposition. Our results support the hypothesis that charge and affinity for dsDNA are not adequate predictors of the pathogenicity of anti-DNA antibodies. Differential renal damage from anti-dsDNA antibodies may be due to differences in fine specificity, rather than differential affinity for dsDNA. Importantly, high affinity IgG antibodies cross-reactive with bacterial and self antigen exist and can display pathogenic potential, suggesting that defects in peripheral regulation of B cells, activated by foreign antigen but cross-reactive with self antigen, might lead to autoimmune disorders.

Comparative Effects of CT Imaging Measurement on RECIST End Points and Tumor Growth Kinetics Modeling.

Quantitative assessments of tumor burden and modeling of longitudinal growth could improve phase II oncology trials. To identify obstacles to wider use of quantitative measures we obtained recorded linear tumor measurements from three published lung cancer trials. Model-based parameters of tumor burden change were estimated and compared with similarly sized samples from separate trials. Time-to-tumor growth (TTG) was computed from measurements recorded on case report forms and a second radiologist blinded to the form data. Response Evaluation Criteria in Solid Tumors (RECIST)-based progression-free survival (PFS) measures were perfectly concordant between the original forms data and the blinded radiologist re-evaluation (intraclass correlation coefficient = 1), but these routine interrater differences in the identification and measurement of target lesions were associated with an average 18-week delay (range, -20 to 55 weeks) in TTG (intraclass correlation coefficient = 0.32). To exploit computational metrics for improving statistical power in small clinical trials will require increased precision of tumor burden assessments.

Poly(A)-associated RNA in plants.

The RNA associated with poly(A) sequences from Euglena gracilis and Vicia faba has been isolated by binding to millipore filters and characterized by sedimentation velocity centrifugation and electrophoretic mobility. Poly(A)-associated RNA as isolated in solution was highly aggregated. When denatured, it sedimented as a broad peak with a mean value of 16-18 S. This RNA was shown to be covalently linked to poly(A) sequences which are 150-250 nucleotides long. Our size estimates for plant poly(A) and poly(A)-associated RNA are similar to those obtained for animal cells.

Twice-weekly paclitaxel and weekly carboplatin with concurrent thoracic radiation followed by carboplatin/paclitaxel consolidation for stage III non-small-cell lung cancer: a California Cancer Consortium phase II trial.

PURPOSE: Recent studies have suggested the superiority of concurrent chemoradiotherapy and the efficacy of paclitaxel/carboplatin in advanced non-small-cell lung cancer (NSCLC). In view of those results, we sought to examine the safety and efficacy of administration of radiosensitizing paclitaxel twice weekly and carboplatin weekly with concurrent thoracic radiation therapy (XRT) followed by consolidation paclitaxel and carboplatin for stage III NSCLC in a multi-institutional phase II trial. PATIENTS AND METHODS: Induction chemoradiotherapy consisted of paclitaxel 30 mg/m2 delivered intravenously (IV) for 1 hour twice weekly for 6 weeks, carboplatin at a dose based on an area under the concentration-time curve (AUC) of 1.5 mg/mL x min, given IV once weekly for 6 weeks, and concomitant XRT of 1.8 to 2.0 Gy daily for a total of 61 Gy. Patients who achieved a complete response, partial response, or stable disease received two 21-day cycles of consolidation chemotherapy consisting of paclitaxel 200 mg/m2 IV for 3 hours and carboplatin at a dose based on an AUC of 6 mg/mL x min. RESULTS: Thirty-four patients were eligible. Their median age was 62 years (range, 39 to 73 years), 59% were female, 41% were male, 94% had a performance status of 0 or 1, 38% had stage IIIA NSCLC, and 62% had stage IIIB NSCLC. Common grade III and IV toxicities during the induction chemoradiation phase included esophagitis (38%) and neutropenia (12%). The most common adverse reaction during consolidation chemotherapy was grade III neutropenia in five patients (15%). The overall response rate was 71%, which was achieved in the induction phase. The median follow-up was 20 months, the median survival was 17 months, and 2-year actuarial survival rate was 40% (95% confidence interval, 20% to 65%). CONCLUSION: This regimen is tolerable and results are promising. We recommend further evaluation of this regimen in a phase III trial.

Involvement of Thylakoid Overenergization in Tentoxin-Induced Chlorosis in Nicotiana spp.

The purpose of this work was to clarify the mechanism of tentoxin-induced chlorosis in Nicotiana spp. seedlings. We found that chlorosis does not correlate with the inhibition of chloroplast ATP synthesis in vivo, since it occurs at tentoxin concentrations far higher than that required for the inhibition of photophosphorylation measured in the same seedlings. However, tentoxin-induced chlorosis does correlate with in vivo overenergization of thylakoids. We show that tentoxin induces overenergization in intact plants and isolated thylakoids, probably via multiple interactions with ATP synthase. Furthermore, gramicidin D, a protonophore that relieves overenergization, also relieves chlorosis. Two lines of evidence suggest that reactive oxygen species may be involved in the process of chlorosis: ascorbate, a quencher of oxygen radicals, significantly protects against chlorosis, whereas transgenic Nicotiana spp. mutants overexpressing chloroplast superoxide dismutase are partially resistant to tentoxin-induced chlorosis. It is proposed that chlorosis in developing seedlings results from overenergization of thylakoids, which leads to the generation of oxygen radicals.

In Vivo Photomodification of Ribulose-1,5-Bisphosphate Carboxylase/Oxygenase Holoenzyme by Ultraviolet-B Radiation (Formation of a 66-Kilodalton Variant of the Large Subunit).

Increased levels of solar ultraviolet (290-320 nm) (UV-B) radiation could have profound effects on plant proteins because the aromatic amino acids in proteins absorb strongly in this spectral region. We have investigated the effects of UV-B radiation on plant proteins and have observed a novel 66-kD protein. This product was formed in vivo when Brassica napus L. plants grown for 21 d in 65 [mu]mol m-2 s-1 photosynthetically active radiation were subsequently exposed to 65 [mu]mol m-2 s-1 photosynthetically active radiation plus UV-B radiation (1.5 [mu]mol m-2 s-1). The protein appeared after 4 h of UV-B irradiation and accumulated during the next 16 h in UV-B. The 66-kD protein cross-reacted with an antiserum against the ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) holoenzyme. Analysis of soluble leaf proteins revealed that the 66-kD product had a number of isoforms corresponding closely to those of the large subunit of Rubisco (LSU). Partial proteolytic digests of the LSU and the 66-kD protein resulted in an equivalent pattern of protein fragments, leading to the conclusion that the 66-kD protein was a photomodified form of the LSU. A similar high molecular mass variant of Rubisco was observed in soluble protein extracts from leaves of tomato (Lycopersicon esculentum), tobacco (Nicotiana tabacum), and pea (Pisum sativum L.) plants treated in vivo with UV-B, suggesting that it might be a common product, at least among C3 plants. It is interesting that the 66-kD product appears to be generated after incorporation of the LSU into holoenzyme complexes. This conclusion was drawn from two lines of evidence. First, the LSU variant co-purified with holoenzyme complexes isolated by nondenaturing polyacrylamide gel electrophoresis. Second, a UV-B-specific 66-kD protein did not accumulate in a tobacco mutant that synthesizes the Rubisco subunits but does not assemble them into normal holoenzyme complexes.

RB status as a determinant of response to UCN-01 in non-small cell lung carcinoma.

7-Hydroxystaurosporine (UCN-01), a protein kinase inhibitor in clinical development, demonstrates potent antineoplastic activity. To determine whether specific genetic abnormalities would modulate the response to UCN-01, a model of human non-small cell lung carcinoma (NSCLC) cell lines with differential abnormalities of p16CDKN2, RB, and p53 was used for these studies. Cell growth was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, and cell cycling was studied using flow cytometric analysis of DNA content. Changes in protein levels and phosphorylation were assessed by Western blotting. In cell lines expressing wild-type RB (A549 and Calul), UCN-01 treatment resulted in dose-dependent growth inhibition, arrest of cells in G1, and a reduction of cells in S phase. p16CDKN2-null cells showed similar growth inhibition to normal fetal lung fibroblasts. UCN-01-induced growth arrest was accompanied by induction of p21CDKN1 and a shift of Rb to the hypophosphorylated state in both p53 wild-type and mutant cell lines. In contrast, UCN-01 treatment of the RB-null cell line H596 resulted in less growth inhibition. To test the role of RB in response to UCN-01, effects of treatment were examined in two human isogenic models of RB expression: the bladder cancer cell line 5637 (RB-null) and the prostate cancer cell line DU-145 (RB-mutant). In the Rb-expressing 5637 subline (RB5), UCN-01 treatment resulted in Rb hypophosphorylation and an accumulation in G1 in contrast to the parent line. Similarly, the wild-type Rb-expressing DU-145 sublines (DU1.1 and B5) showed increased G1 arrest compared with the parent cells. We conclude that UCN-01-induced G1 arrest can occur in cells null for p53 and p16CDKN2, and that RB status influences the ability of UCN-01 to induce a G1 arrest. These data suggest that the molecular profile of cell cycle regulating genes in individual tumors may predict responsiveness and provide insight into optimal therapeutic application of this new antineoplastic agent.

Polynomial dispersion of trajectories in sticky dynamics.

Hamiltonian chaotic dynamics is, in general, not ergodic and the boundaries of the ergodic or quasiergodic area (stochastic sea, stochastic layers, stochastic webs, etc.) are sticky, i.e., trajectories can spend an arbitrarily long time in the vicinity of the boundaries with a nonexponentially small probability. Segments of trajectories imposed by the stickiness are called flights. The flights have polynomial dispersion that can lead to non-Gaussian statistics of displacements and to anomalous transport in phase space. In particular, the presence of flights influences the distribution of Poincaré recurrences. We use the distribution function of (l,t;epsilon, epsilon0) -separation of trajectories that at time instant t and trajectory length l are separated for the first time by epsilon<<1, being initially at a distance epsilon0 <

Chaos-induced intensification of wave scattering.

Sound-wave propagation in a strongly idealized model of the deep-water acoustic waveguide with a periodic range dependence is considered. It is investigated how the phenomenon of ray and wave chaos affects the sound scattering at a strong mesoscale inhomogeneity of the refractive index caused by the synoptic eddy. Methods derived in the theory of dynamical and quantum chaos are applied. When studying the properties of wave chaos we decompose the wave field into a sum of Floquet modes analogous to quantum states with fixed quasi-energies. It is demonstrated numerically that the "stable islands" from the phase portrait of the ray system reveal themselves in the coarse-grained Wigner functions of individual Floquet modes. A perturbation theory has been derived which gives an insight into the role of the mode-medium resonance in the formation of Floquet modes. It is shown that the presence of a weak internal-wave-induced perturbation giving rise to ray and wave chaos strongly increases the sensitivity of the monochromatic wave field to an appearance of the eddy. To investigate the sensitivity of the transient wave field we have considered variations of the ray travel times--arrival times of sound pulses coming to the receiver through individual ray paths--caused by the eddy. It turns out that even under conditions of ray chaos these variations are relatively predictable. This result suggests that the influence of chaotic-ray motion may be partially suppressed by using pulse signals. However, the relative predictability of travel time variations caused by a large-scale inhomogeneity is not a general property of the ray chaos. This statement is illustrated numerically by considering an inhomogeneity in the form of a perfectly reflecting bar.

Topological instability along invariant surfaces and pseudochaotic transport.

The paper describes the complex topological structure of invariant surfaces that appears in a quasi-stationary regime of the tokamak plasma, and it considers in detail anomalous transport of particles along the invariant surfaces (isosurfaces) that have topological genus greater than 1. Such dynamics is pseudochaotic; i.e. it has a zero Lyapunov exponent. Simulations discover such surfaces in confined plasmas under a fairly low ratio of pressure to the magnetic field energy (beta). The isosurfaces correspond to quasi-coherent structures called "streamers" and the streamers are connected by filaments. We study distribution of time of particle separation, Poincaré; recurrences of trajectories, and first time arrival to the system's edge. A model of a multibar-in-square billiard, introduced by Carreras et al. [Chaos 13, 1175 (2003)] is studied with renormalization group method to obtain a distribution of the first time of particles arrival to the edge as a function of the number of bars, which appears to be power-like. The characteristic exponent of this distribution is discussed with respect to its dependence on the number of filaments that connect adjacent streamers.