Геофизические закономерности локализации месторождений углеводородов Баренцево-Карского региона

Background: Rising serum levels of prostate-specific antigen (PSA) after radical prostatectomy are indicative of recurrent prostate cancer. This double-blind, placebo-controlled phase II study evaluated the anti-tumour activity of the anti-epithelial cell adhesion molecule (EpCAM) antibody adecatumumab in delaying biochemical disease progression. Patients and Methods: Prostate cancer patients with increasing serum PSA levels following radical prostatectomy were randomized to low- (2 mg/kg) or high-dose adecatumumab (6 mg/kg) or placebo. The primary efficacy endpoint was the mean change from baseline in total serum PSA at week 24. Secondary endpoints included PSA response rate, prolongation of serum PSA doubling time and time to biochemical disease progression. Results: The primary and secondary endpoints of the study were not met in the predefined analyses. In a retrospective analysis of patients with baseline PSA <= 1 ng/ml and a high EpCAM expression, both the mean increase in PSA from baseline to week 24 and the PSA doubling time at week 15 were significantly improved in the high-dose adecatumumab group compared with the placebo group. Most frequent treatment-related clinical adverse events were gastrointestinal (diarrhoea and nausea) or general events (chills), showing a dose dependency but no grade 3/4 intensity in any patient. Conclusion: In men with rising PSA levels after radical prostatectomy and no evidence of clinical relapse, adecatumumab delayed disease progression in a subgroup of patients with baseline PSA levels <= 1 ng/ml and high EpCAM-expressing tumours. Copyright (C) 2010 S. Karger AG, Base

Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody

Background: Ideally, monoclonal antibodies provide selective treatment by targeting the tumour, without affecting normal tissues. Therefore, antibody imaging is of interest, preferably in early stages of drug development. However, the imaging signal consists of specific, as well as non-specific, uptake. The aim of this study was to assess specific, target-mediated uptake in normal tissues, with immuno-PET in a phase I dose escalation study, using the anti-CD44 antibody RG7356 as example. Results: Data from thirteen patients with CD44-expressing solid tumours included in an imaging sub-study of a phase I dose escalation clinical trial using the anti-CD44 antibody RG7356 was analysed. 89Zirconium-labelled RG7356 (1 mg; 37 MBq) was administered after a variable dose of unlabelled RG7356 (0 to 675 mg). Tracer uptake in normal tissues (liver, spleen, kidney, lung, bone marrow, brain and blood pool) was used to calculate the area under the time antibody concentration curve (AUC) and expressed as tissue-to-blood AUC ratios. Within the dose range of 1 to 450 mg, tissue-to-blood AUC ratios decreased from 10.6 to 0.75 ± 0.16 for the spleen, 7.5 to 0.86 ± 0.18 for the liver, 3.6 to 0.48 ± 0.13 for the bone marrow, 0.69 to 0.26 ± 0.1 for the lung and 1.29 to 0.56 ± 0.14 for the kidney, indicating dose-dependent uptake. In all patients receiving ≥ 450 mg (n = 7), tumour uptake of the antibody was observed. Conclusions: This study demonstrates how immuno-PET in a dose escalation study provides a non-invasive technique to quantify dose-dependent uptake in normal tissues, indicating specific, target-mediated uptake

First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors

Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies. Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6–35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using (89)Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens

Additional file 1: Table S1. of Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody

Specific scoring criteria for CD44 expression in patient samples. (DOCX 14 kb

Additional file 2:Â Supplementary Data. of Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody

Information on the quality control of the radiolabelled tracer. (DOCX 16 kb

Additional file 5: Figure S3. of Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody

Additional examples of focal tumour uptake of 89Zr-RG7356 at 96 h p.i.. From left to right: low dose CT, attenuation-corrected PET and fused image. (a) Tumour lesion: left side of the skull (patient 8, 450 mg cohort). (b) Tumour lesion: sacrum (patient 13, 675 mg cohort). (TIFF 6335 kb

Measurement of the flow harmonic correlations in pp, p plus Pb and low multiplicity Pb plus Pb collisions with the ATLAS detector at the LHC

Recent measurements of the correlations between flow harmonics obtained using four-particle symmetric cumulants and three-particle asymmetric cumulants with the ATLAS detector at the LHC are described. The data sets of $pp$, $p$+Pb and peripheral Pb+Pb collisions at various energies are analyzed, aiming to probe the long-range collective nature of multi-particle production in small systems. The sensitivity of the standard cumulant method to non-flow correlations is investigated by introducing the subevents method. A systematic reduction of non-flow effects is observed when using the two-subevent method. Further reduction is observed with the three-subevent method that is consistent with the results obtained with the four-subevent one. A negative correlation between $ν_2$ and $v_3$ and a positive correlation between $ν_2$ and $ν_4$, for all studied collision systems and over full multiplicity range, is observed. The correlation strength computed as symmetric cumulants normalized by the $\langle\nu_n^2\rangle$ is similar for all collision systems and weakly depends on multiplicity. These measurements provide new evidence for long-range multi-particle collectivity in small collision systems and quantify the nature of its event-by-event fluctuations