Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology

Critical Behavior of the Conductivity of Si:P at the Metal-Insulator Transition under Uniaxial Stress

We report new measurements of the electrical conductivity sigma of the canonical three-dimensional metal-insulator system Si:P under uniaxial stress S. The zero-temperature extrapolation of sigma(S,T -> 0) ~\S - S_c\^mu shows an unprecidentedly sharp onset of finite conductivity at S_c with an exponent mu = 1. The value of mu differs significantly from that of earlier stress-tuning results. Our data show dynamical sigma(S,T) scaling on both metallic and insulating sides, viz. sigma(S,T) = sigma_c(T) F(\S - S_cT^y) where sigma_c(T) is the conductivity at the critical stress S_c. We find y = 1/znu = 0.34 where nu is the correlation-length exponent and z the dynamic critical exponent.Comment: 5 pages, 4 figure

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Background: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. Patients and methods: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmaco-kinetics of S9788 were determined. Results: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. Conclusions: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase I trials of S9788 infused over six hours precluded the further clinical development of S978

Scaling of the Conductivity with Temperature and Uniaxial Stress in Si:B at the Metal-Insulator Transition

Using uniaxial stress to tune Si:B through the metal-insulator transition we find the conductivity at low temperatures shows an excellent fit to scaling with temperature and stress on both sides of the transition. The scaling functions yield the conductivity in the metallic and insulating phases, and allow a reliable determination of the temperature dependence in the critical regions on both sides of the transition

Conductivity of Metallic Si:B near the Metal-Insulator Transition: Comparison between Unstressed and Uniaxially Stressed Samples

The low-temperature dc conductivities of barely metallic samples of p-type Si:B are compared for a series of samples with different dopant concentrations, n, in the absence of stress (cubic symmetry), and for a single sample driven from the metallic into the insulating phase by uniaxial compression, S. For all values of temperature and stress, the conductivity of the stressed sample collapses onto a single universal scaling curve. The scaling fit indicates that the conductivity of si:B is proportional to the square-root of T in the critical range. Our data yield a critical conductivity exponent of 1.6, considerably larger than the value reported in earlier experiments where the transition was crossed by varying the dopant concentration. The larger exponent is based on data in a narrow range of stress near the critical value within which scaling holds. We show explicitly that the temperature dependences of the conductivity of stressed and unstressed Si:B are different, suggesting that a direct comparison of the critical behavior and critical exponents for stress- tuned and concentration-tuned transitions may not be warranted

The metal-insulator transition in Si:X: Anomalous response to a magnetic field

The zero-temperature magnetoconductivity of just-metallic Si:P scales with magnetic field, H, and dopant concentration, n, lying on a single universal curve. We note that Si:P, Si:B, and Si:As all have unusually large magnetic field crossover exponents near 2, and suggest that this anomalously weak response to a magnetic field is a common feature of uncompensated doped semiconductors.Comment: 4 pages (including figures

Minimal clinically meaningful differences for the EORTC QLQ-C30 and EORTC QLQ-BN20 scales in brain cancer patients

Background: We aimed to determine the smallest changes in health-related quality of life (HRQoL) scores in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and the Brain Cancer Module (QLQ-BN20), which could be considered as clinically meaningful in brain cancer patients. Materials and methods: World Health Organisation performance status (PS) and mini-mental state examination (MMSE) were used as clinical anchors appropriate to related subscales to determine the minimal clinically important differences (MCIDs) in HRQoL change scores (range 0-100) in the QLQ-C30 and QLQ-BN20. A threshold of 0.2 standard deviation (SD) (small effect) was used to exclude anchor-based MCID estimates considered too small to inform interpretation. Results: Based on PS, our findings support the following integer estimates of the MCID for improvement and deterioration, respectively: physical (6, 9), role (14, 12), and cognitive functioning (8, 8); global health status (7, 4*), fatigue (12, 9), and motor dysfunction (4*, 5). Anchoring with MMSE, cognitive functioning MCID estimates for improvement and deterioration were (11, 2*) and for communication deficit were (9, 7). Estimates with asterisks were <0.2 SD and were excluded from our MCID range of 5-14. Conclusion: These estimates can help clinicians evaluate changes in HRQoL over time, assess the value of a health care intervention and can be useful in determining sample sizes in designing future clinical trial

Anderson-Mott transition as a quantum glass problem

We combine a recent mapping of the Anderson-Mott metal-insulator transition on a random-field problem with scaling concepts for random-field magnets to argue that disordered electrons near an Anderson-Mott transition show glass-like behavior. We first discuss attempts to interpret experimental results in terms of a conventional scaling picture, and argue that some of the difficulties encountered point towards a glassy nature of the electrons. We then develop a general scaling theory for a quantum glass, and discuss critical properties of both thermodynamic and transport variables in terms of it. Our most important conclusions are that for a correct interpretation of experiments one must distinguish between self-averaging and non-self averaging observables, and that dynamical or temperature scaling is not of power-law type but rather activated, i.e. given by a generalized Vogel-Fulcher law. Recent mutually contradicting experimental results on Si:P are discussed in the light of this, and new experiments are proposed to test the predictions of our quantum glass scaling theory.Comment: 25pp, REVTeX, 5 ps figs, final version as publishe

Non-zero temperature transport near quantum critical points

We describe the nature of charge transport at non-zero temperatures ($T$) above the two-dimensional ($d$) superfluid-insulator quantum critical point. We argue that the transport is characterized by inelastic collisions among thermally excited carriers at a rate of order $k_B T/\hbar$. This implies that the transport at frequencies $\omega \ll k_B T/\hbar$ is in the hydrodynamic, collision-dominated (or `incoherent') regime, while $\omega \gg k_B T/\hbar$ is the collisionless (or `phase-coherent') regime. The conductivity is argued to be $e^2 / h$ times a non-trivial universal scaling function of $\hbar \omega / k_B T$, and not independent of $\hbar \omega/k_B T$, as has been previously claimed, or implicitly assumed. The experimentally measured d.c. conductivity is the hydrodynamic $\hbar \omega/k_B T \to 0$ limit of this function, and is a universal number times $e^2 / h$, even though the transport is incoherent. Previous work determined the conductivity by incorrectly assuming it was also equal to the collisionless $\hbar \omega/k_B T \to \infty$ limit of the scaling function, which actually describes phase-coherent transport with a conductivity given by a different universal number times $e^2 / h$. We provide the first computation of the universal d.c. conductivity in a disorder-free boson model, along with explicit crossover functions, using a quantum Boltzmann equation and an expansion in $\epsilon=3-d$. The case of spin transport near quantum critical points in antiferromagnets is also discussed. Similar ideas should apply to the transitions in quantum Hall systems and to metal-insulator transitions. We suggest experimental tests of our picture and speculate on a new route to self-duality at two-dimensional quantum critical points.Comment: Feedback incorporated into numerous clarifying remarks; additional appendix discusses relationship to transport in dissipative quantum mechanics and quantum Hall edge state tunnelling problems, stimulated by discussions with E. Fradki

Ventricular arrhythmia and torsade de pointe: dose limiting toxicities of the MDR-modulator S9788 in a phase I trial.

BACKGROUND: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. PATIENTS AND METHODS: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. RESULTS: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. CONCLUSIONS: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788