MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide: A Pooled Analysis of Four Clinical Trials.

The methylation status of the O <sup>6</sup> -methylguanine DNA methyltransferase (MGMT) gene promoter is predictive for benefit from temozolomide in glioblastoma (GBM). A clinically optimized cutoff was sought allowing patient selection for therapy without temozolomide, while avoiding to withhold it from patients who may potentially benefit.Experimental Design: Quantitative MGMT methylation-specific PCR data were obtained for newly diagnosed patients with GBM screened or treated with standard radiotherapy and temozolomide in four randomized trials. The pooled dataset was randomly split into a training and test dataset. The unsupervised cutoff was obtained at a 50% probability to be (un)methylated. ROC analysis identified an optimal cutoff supervised by overall survival (OS). For 4,041 patients valid MGMT results were obtained, whereof 1,725 were randomized. The unsupervised cutoff in the training dataset was 1.27 (log <sub>2</sub> [1,000 × (MGMT+1)/ACTB]), separating unmethylated and methylated patients. The optimal supervised cutoff for unmethylated patients was -0.28 (AUC = 0.61), classifying "truly unmethylated" (≤-0.28) and "gray zone" patients (>-0.28, ≤1.27), the latter comprising approximately 10% of cases. In contrast, for patients with MGMT methylation (>1.27) more methylation was not related to better outcome. Both methylated and gray zone patients performed significantly better for OS than truly unmethylated patients [HR = 0.35, 95% confidence interval (CI), 0.27-0.45, P < 0.0001; HR = 0.58, 95% CI, 0.43-0.78, P < 0.001], validated in the test dataset. The MGMT assay was highly reproducible upon retesting of 218 paired samples (R <sup>2</sup> = 0.94). Low MGMT methylation (gray zone) may confer some sensitivity to temozolomide treatment, hence the lower safety margin should be considered for selecting patients with unmethylated GBM into trials omitting temozolomide

Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome.

Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. These trials failed to meet their primary endpoints.Immunohistochemistry was used to assess the levels of the target integrins of cilengitide, αvβ3 and αvβ5 integrins, of αvβ8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224).αvβ3 and αvβ5 expression correlated well in tumor and endothelial cells, but showed little association with αvβ8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide.Integrins αvβ3, αvβ5 and αvβ8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-β pathway. αvβ3 integrin expression may predict benefit from integrin inhibition in patients with glioblastoma lacking MGMT promoter methylation

Transport of charged particles by adjusting rf voltage amplitudes

We propose a planar architecture for scalable quantum information processing (QIP) that includes X-junctions through which particles can move without micromotion. This is achieved by adjusting radio frequency (rf) amplitudes to move an rf null along the legs of the junction. We provide a proof-of-principle by transporting dust particles in three dimensions via adjustable rf potentials in a 3D trap. For the proposed planar architecture, we use regularization techniques to obtain amplitude settings that guarantee smooth transport through the X-junction.Comment: 16 pages, 10 figure

Modeling Single Electron Transfer in Si:P Double Quantum Dots

Solid-state systems such as P donors in Si have considerable potential for realization of scalable quantum computation. Recent experimental work in this area has focused on implanted Si:P double quantum dots (DQDs) that represent a preliminary step towards the realization of single donor charge-based qubits. This paper focuses on the techniques involved in analyzing the charge transfer within such DQD devices and understanding the impact of fabrication parameters on this process. We show that misalignment between the buried dots and surface gates affects the charge transfer behavior and identify some of the challenges posed by reducing the size of the metallic dot to the few donor regime.Comment: 11 pages, 7 figures, submitted to Nanotechnolog

Full capacitance-matrix effects in driven Josephson-junction arrays

We study the dynamic response to external currents of periodic arrays of Josephson junctions, in a resistively capacitively shunted junction (RCSJ) model, including full capacitance-matrix effects}. We define and study three different models of the capacitance matrix $C_{\vec{r},\vec{r}'}$: Model A includes only mutual capacitances; Model B includes mutual and self capacitances, leading to exponential screening of the electrostatic fields; Model C includes a dense matrix $C_{\vec{r},\vec{r}'}$ that is constructed approximately from superposition of an exact analytic solution for the capacitance between two disks of finite radius and thickness. In the latter case the electrostatic fields decay algebraically. For comparison, we have also evaluated the full capacitance matrix using the MIT fastcap algorithm, good for small lattices, as well as a corresponding continuum effective-medium analytic evaluation of a finite voltage disk inside a zero-potential plane. In all cases the effective $C_{\vec{r},\vec{r}'}$ decays algebraically with distance, with different powers. We have then calculated current voltage characteristics for DC+AC currents for all models. We find that there are novel giant capacitive fractional steps in the I-V's for Models B and C, strongly dependent on the amount of screening involved. We find that these fractional steps are quantized in units inversely proportional to the lattice sizes and depend on the properties of $C_{\vec{r},\vec{r}'}$. We also show that the capacitive steps are not related to vortex oscillations but to localized screened phase-locking of a few rows in the lattice. The possible experimental relevance of these results is also discussed.Comment: 12 pages 18 Postscript figures, REVTEX style. Paper to appear in July 1, Vol. 58, Phys. Rev. B 1998 All PS figures include

Custom Integrated Circuits

Contains reports on six research projects.U.S. Air Force - Office of Scientific Research (Contract F49620-84-C-0004)Analog Devices, Inc.Defense Advanced Research Projects Agency (Contract N00014-80-C-0622)National Science Foundation (Grant ECS83-10941

Custom Integrated Circuits

Contains reports on nine research projects.Analog Devices, Inc.International Business Machines, Inc.Joint Services Electronics Program (Contract DAALO03-86-K-0002)U.S. Air Force - Office of Scientific Research (Grant AFOSR 86-0164)Rockwell International CorporationOKI SemiconductorU.S. Navy - Office of Naval Research (Contract N00014-81-K-0742)Charles Stark Draper LaboratoryDARPA/U.S. Navy - Office of Naval Research (Contract N00014-80-C-0622)DARPA/U.S. Navy - Office of Naval Research (Contract N00014-87-K-0825)National Science Foundation (Grant ECS-83-10941)AT&T Bell Laboratorie