Randomized phase II designs.

As the use of molecularly targeted agents, which are anticipated to increase overall survival (OS)and progression-free survival (PFS) but not necessarily tumor response, has increased in oncology, there has been a corresponding increase in the recommendation and use of randomized phase II designs. Such designs reduce the potential for bias, existent in comparisons with historical controls, but also substantially increase the sample size requirements. We review the principal statistical designs for historically controlled and randomized phase II trials, along with their advantages, disadvantages, and statistical design considerations. We review the arguments for and against the use of randomization in phase II studies, the situations in which the use of historical controls is preferred, and the situations in which the use of randomized designs is preferred. We review methods used to calculate predicted OS or PFS values from historical controls, adjusted so as to be appropriate for an experimental sample with particular prognostic characteristics. We show how adjustment of the type I and type II error bounds for randomized studies can facilitate the detection of appropriate target increases in median PFS or OS with sample sizes appropriate for phase II studies. Although there continue to be differences among investigators concerning the use of randomization versus historical controls in phase II trials, there is agreement that each approach will continue to be appropriate, and the optimal approach will depend upon the circumstances of the individual trial

Optokinetic Nystagmus Suppression as an Index of the Allocation of Visual Attention

PURPOSE. To use the suppression of optokinetic nystagmus (OKN) as an objective measure of subjects' ability to distribute their visual attention to different elements-static or dynamic, simple or complex-in their visual environment. METHODS. Large-field, constant-velocity projected images, along with a stationary central fixation target were presented to 25 young participants (13 women). Images were either black O's with a few X's or red C's, blue T's, and a few red T's, with the X's and red T's as the search targets. Stationary targets at either 0°or Ϯ12.5°were either blinking squares or a rapid succession of colored shapes-blinks or green stars were the target events. Central fixation was maintained at all times. OKN gain was calculated for all tasks and analyzed in a mixed 4-way ANOVA, with the sex of the subjects as the group variable and dynamism, location, and complexity as within-subject effects. RESULTS. There was no effect of sex; all three main withinsubject effects were significant, as were the two-way interactions between them and an interaction between dynamism and sex. The most striking result was that there was little difference across static tasks but that dynamic tasks showed significantly more OKN breakthrough, particularly for the complex search presented centrally. CONCLUSIONS. In this group of normal-sighted young subjects, OKN breakthrough was sensitive to a range of stimulus characteristics. This finding allows a single outcome measure to be used across a wide range of possible tasks and may be useful in assessing the effects of age and disease. (Invest Ophthalmol Vis Sci. 2011;52:462-467

Clinical Consensus Conference: Survey on Gram-Positive Bloodstream Infections with a Focus on Staphylococcus aureus

The increased incidence over the past decade of bloodstream infections (BSIs) caused by gram-positive bacteria, particularly methicillin-resistant Staphylococcus aureus , highlights the critical need for a consistent approach to therapy. However, there is currently no international consensus on the diagnosis and management of gram-positive BSIs. The Clinical Consensus Conference on Gram-Positive Bloodstream Infections was convened as a session at the 9th International Symposium on Modern Concepts in Endocarditis and Cardiovascular Infections held in 2007. Participants discussed various aspects of the practical treatment of patients who present with gram-positive BSI, including therapeutic options for patients with BSIs of undefined origin, the selection of appropriate empirical therapy, and treatment of complicated and uncomplicated BSIs. The opinions of participants about these key issues are reflected in this articl

Phase II Study of Palbociclib (PD-0332991) in CCND1, 2, or 3 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1B

Purpose: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3. Patients and methods: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles. Results: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%). Conclusions: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification

Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH).

PURPOSE: Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols. PATIENTS AND METHODS: Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared. RESULTS: Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, \u3e 35% for urothelial cancers and \u3c 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so. CONCLUSION: We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens

Wavefront sensing and reconstruction from gradient and Laplacian data measured with a Hartmann–Shack sensor

3 pages, 2 figures.-- OCIS codes: 010.7350, 080.2720.-- PMID: 16729090 [PubMed].-- Printed version published on Jun 15, 2006.A new wavefront sensing and reconstruction technique is presented. It is possible to measure Laplacian and gradient information of a wavefront with a Hartmann-Shack setup. By simultaneously using the Laplacian and gradient data we reconstruct the wavefront by sequentially solving two partial differential equations.Peer reviewe

Wavefront sensing and reconstruction from gradient and Laplacian data measured with a Hartmann–Shack sensor

3 pages, 2 figures.-- OCIS codes: 010.7350, 080.2720.-- PMID: 16729090 [PubMed].-- Printed version published on Jun 15, 2006.A new wavefront sensing and reconstruction technique is presented. It is possible to measure Laplacian and gradient information of a wavefront with a Hartmann-Shack setup. By simultaneously using the Laplacian and gradient data we reconstruct the wavefront by sequentially solving two partial differential equations.Peer reviewe