Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma.

BACKGROUND: In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. PATIENTS AND METHODS: Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. RESULTS: Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. CONCLUSIONS: Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.

Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma.

BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort. RESULTS: Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus. CONCLUSIONS: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.

Investigating prostate cancer tumour-stroma interactions: clinical and biological insights from an evolutionary game.

BACKGROUND: Tumours are made up of a mixed population of different types of cells that include normal structures as well as ones associated with the malignancy, and there are multiple interactions between the malignant cells and the local microenvironment. These intercellular interactions, modulated by the microenvironment, effect tumour progression and represent a largely under-appreciated therapeutic target. We use observations of primary tumour biology from prostate cancer to extrapolate a mathematical model. Specifically, it has been observed that in prostate cancer three disparate cellular outcomes predominate: (i) the tumour remains well differentiated and clinically indolent--in this case the local stromal cells may act to restrain the growth of the cancer; (ii) early in its genesis the tumour acquires a highly malignant phenotype, growing rapidly and displacing the original stromal population (often referred to as small cell prostate cancer)--these less common aggressive tumours are relatively independent of the local microenvironment and (iii) the tumour co-opts the local stroma--taking on a classic stromagenic phenotype where interactions with the local microenvironment are critical to the cancer growth. METHODS: We present an evolutionary game theoretical construct that models the influence of tumour-stroma interactions in driving these outcomes. We consider three characteristic and distinct cellular populations: stromal cells, tumour cells that are self-reliant in terms of microenvironmental factors and tumour cells that depend on the environment for resources, but can also co-opt stroma. RESULTS: Using evolutionary game theory we explore a number of different scenarios that elucidate the impact of tumour-stromal interactions on the dynamics of prostate cancer growth and progression, and how different treatments in the metastatic setting can affect different types of tumours. CONCLUSION: The tumour microenvironment has a crucial role in selecting the traits of the tumour cells that will determine prostate cancer progression. Equally important treatments like hormone therapy affect the selection of these cancer phenotypes making it very important to understand how they impact prostate cancer's somatic evolution.

Considerations in the management of myeloma.

Multiple myeloma remains an incurable cancer. In recent years, progress in different drug classes has improved outcomes, but management has become more complicated. Areas such as prognostic classification, the increased use of high-dose chemotherapy with autologous stem-cell rescue, and a wider array of ancillary drugs must be integrated into recommendations for a consolidated treatment plan. Estimating prognosis is dependent on both clinical features and a growing list of laboratory tests. Autologous transplantation has been applied to an increasing proportion of patients, at different points in the disease process. Besides the age cut-off issue, there are still significant treatment choices to be made within the transplant technique. Newer drugs, most recently, thalidomide (Thalomid), may offer benefits independent of conventional cytotoxic drugs or steroids. Use of ancillary drugs, such as bisphosphonates, interferon, P-glycoprotein blockers, antibiotics, and growth factors, are also discussed. For the future, immunotherapy in the posttransplant setting appears promising. Ultimately, basic research must identify intracellular targets for the development of specific new-generation drugs.

Current Clinical Practice: Application of Resistance Reversal Agents in Hematologic Malignancies.

The clinical application of resistance reversal drugs for patients with hematologic malignancies is reviewed. The phenomenon of multidrug resistance versus other mechanisms are discussed. The pump-like mechanisms of P-glycoprotein, multidrug resistance associated protein, lung resistance protein and of other ATP binding cassette transporter proteins are reviewed briefly, as well as the important substrate drugs and pump-blocking compounds. The problems associated with resistance protein assays in clinical samples and the concept of prognostic versus therapeutic clinical relevance are described, within the context of selected hematologic malignancies. Toxicities and treatment outcomes of phase II and III trials of reversal agents in lymphoma, multiple myeloma, myelodysplastic syndromes, acute myeloid leukemia and blast phase of chronic myeloid leukemia are reviewed. Finally, current options for on-study management of relapsed or refractory hematologic malignancy patients are discussed.

[EEG-Expert automated diagnostic system]. / Avtomatizirovannaia diagnosticheskaia sistema EEG-Ekspert.

The system is designed to describe and collect data of virtual analysis of electroencephalograms (EEG), as well as to make an expert conclusion on the functional status of the brain and its particular regions. The system includes three parallelly operating systems in the form of a EEC visual analysis schedule as a questionnaire. A programme provides recommendations for describing the level, pattern, and magnitude of the changes detected. Another programme automatically makes an EEC description and a conclusion on cerebral function in conformity with the signs given in the questionnaire and displays them on the screen and sends them to the print. The system may be used for practice in the in- and outpatient settings, for training and postgraduate training of young specialists, and for researches.

Comparison of upper-extremity balance tasks and force platform testing in persons with hemiparesis.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the relationship between clinically accessible functional balance tools and sophisticated force platform measures in a standing position. SUBJECTS: Twenty persons who had hemiparesis secondary to a stroke and were ambulatory (mean age = 57.9 years, SD = 13.6, range = 35-79) were evaluated during a single testing session. METHODS: Performances on self-generated upper-extremity balance tasks using the nonparetic side (Functional Reach Test [FRT], arm raise and arm reach tasks) were compared with responses to external perturbations on the Balance System (postural sway, symmetry of weight distribution). RESULTS: No relationship was found between the upper-extremity balance tests and the force platform measures of postural sway. After suppressing the effect of age by means of partial correlation coefficients, the FRT was correlated with measures of postural symmetry in parallel stance on the Balance System (r = .66-.78). The FRT was only moderately correlated with the arm raise and arm reach tasks (r = .43 and .44). CONCLUSION AND DISCUSSION: Postural sway in response to force platform perturbations may have little relation to the postural control necessary for self-generated upper-extremity balance tasks. In contrast, the FRT and the force platform measures of postural symmetry appear to be evaluating comparable standing-balance abilities in persons with hemiparesis. The modest relationship between the FRT and the arm raise and arm reach tasks limits the finding's clinical relevance.

Distance distributions from the tyrosyl to disulfide residues in the oxytocin and [Arg8]-vasopressin measured using frequency-domain fluorescence resonance energy transfer.

We have examined the fluorescence intensity decays of oxytocin and [Arg8]-vasopressin resulting from the single tyrosyl residue in each peptide, and the intensity decay of the Asu1,6-analogues in which the disulfide bridge is substituted by a CH2-CH2 bridge. Viscosity-dependent steady state and intensity decay measurements indicated that fluorescence resonance energy transfer (FRET) from tyrosyl phenol to the disulfide bridge is responsible for the decrease in fluorescence relative to the Asu-analogues. The frequency-domain phase and modulation data for the tyrosyl donor were interpreted in terms of fluorescence resonance energy transfer (FRET) to the weakly absorbing disulfide bridge and a distribution of donor-to-acceptor distances. Energy transfer efficiencies were determined from both time-resolved and steady-state measurements. Fitting the frequency-domain phase and modulation data to a Gaussian distance distribution indicated that the average inter-chromophoric distance (Rav) is similar in both compounds, Rav = 7.94 A for oxytocin and Rav = 8.00 A for vasopressin. However, the width of the distance distribution is narrower for vasopression (hw = 2.80 A) than for oxytocin (hw = 3.58 A), which is consistent with restriction of the tyrosine phenol motion due to its stacking wih the Phe3 side chain of vasopressin. Finally, the recovered distance distribution functions are compared with histograms describing the distance between the chromophores during the course of long, in vacuo, molecular dynamics runs using the computer program CHARMm and the QUANTA 3.0 parameters.

[Structural organization of medical information as illustrated by diagnosis in child neurology]. / Strukturnaia organizatsiia meditsinskoi informatsii na primere ustanovleniia diagnoza v detskoi nevrologii.

Structuration of medical information is performed on three levels: structuration of the specialist's knowledge with resultant singling out key questions--blocks required for diagnosis in the given field; structuration of signs within the space of the blocks; identification of diagnostic syndromes basing on their signs analysis adjusted to resolving diagnostic tasks. The results of the method application in neuropathology are outlined.

Distance distributions recovered from steady-state fluorescence measurements on thirteen donor-acceptor pairs with different Förster distances.

The end-to-end distance distribution of a flexible molecule was recovered from steady-state fluorescence energy transfer measurements using the method suggested by Cantor and Pechukas (Proc. Natl. Acad. Sci. USA 68, 2099-2101, 1971). In this method, the Förster distance (R 0) is varied by attaching different donor-acceptor (D-A) pairs to the flexible linker of interest. Distance distributions are then recovered from energy transfer efficiency measurements on the set of D-A pairs with differentR 0 values. Thirteen D-A pair compounds were synthesized withR 0 values ranging from 6 to 32 Å. Each compound contained a tryptamine donor linked by an alkyl chain (∼10 carbons) to 1 of 13 acceptors. Using these compounds, we have experimentally confirmed the Cantor and Pechukas method for recovering distance distributions. The measured transfer efficiencies, as a function ofR 0, were fit to the transfer efficiencies predicted for both Gaussian and skewed Gaussian distance distributions. The data support the existence of a skewed Gaussian distribution, and we believe that this is the first experimental observation of an asymmetric distribution for a flexible molecule using fluorescence resonance energy transfer measurements. Finally, the experimentally recovered distance distribution was found to be in good agreement with the distribution predicted from the rotational isomeric state model of Flory (Statistical Mechanics of Chain Molecules, John Wiley & Sons, New York, 1969, Chaps. 1, 3, and 5) but not with the predicted distribution for a freely rotating or freely jointed chain.

[Electrophysiologic analysis of the process of recognizing target and non-target stimuli in healthy and oligophrenic children]. / Elektrofiziologicheskii analiz protsessa poznaniia tselevykh i netselevykh stimulov u detei v norme i pri oligofrenii.

In an automatized experiment, with a computer on line, amplitude-temporal parameters of evoked potentials (EPs) to purposive and non-purposive stimuli (digits), were analyzed in normal and mental retarded children. At unilateral stimuli presentation to the left or right visual half-fields EPs were recorded simultaneously in projection, TPO, parietal and central areas of the left and right hemispheres. It has been shown that in normal children, differential involvement of projection and associative structures in the analysis of sensory information takes place in both hemispheres. The amplitudes of most EP components in the range of 100-400 ms to the purposive stimuli are higher than to the non-purposive ones. Considerable similarity of EPs developing in response to ipsi- and contralateral stimulations of visual fields ("direct" and "transmitted" EP) is observed. In mental retarded children significant changes are revealed in intra- and interhemisphere organization of the process of perception of purposive and non-purposive stimuli. In the right hemisphere structures there are no differential EP reactions to the two types of stimuli. Significant, in comparison with the norm, prolongation of the latencies of most EP components is noted, especially in the structures of the left hemisphere, to the purposive stimuli. In the process of perception, changes are seen of the integration of functions of both hemispheres. The totality of disturbances of systemic brain organization at perceptive activity in mental retarded children may reflect neurophysiological mechanisms of mental deficiency.

[Electrophysiological analysis of the perceptive activities of children with normal and retarded mental development]. / Elektrofiziologicheskii analiz pertseptivnoi deiatel'nosti detei s normal'nym i zaderzhannym psikhicheskim razvitiem.

Visual EPs of the occipital, parieto-temporal-occipital, parietal and central areas of the left and right hemispheres in response to unilaterally presented stimuli (figures) were analyzed in normal and developmentally backward children. In tasks of detection and recognition of the signal, developmentally backward children manifested a lowered reactivity of associative cerebral structures, especially of the left hemisphere, during perceptive activity, and a changed, in comparison with normal, interhemispheric interaction in processing of sensory information. It is suggested that properties of brain system organization during perceptive activity reflect to a certain extent neurophysiological mechanisms of disturbance of cognitive processes in developmentally backward children.