Long-Term Treatment of Metastatic Colorectal Cancer with Panitumumab

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. More than 30% patients present with metastases at diagnoses and will require systemic chemotherapy. In recent years many anti-EGFR targets have been developed. Among them, panitumumab, a fully human IgG2 monoclonal antibody has shown important benefits in the treatment of this disease

An improved method for measuring muon energy using the truncated mean of dE/dx

The measurement of muon energy is critical for many analyses in large Cherenkov detectors, particularly those that involve separating extraterrestrial neutrinos from the atmospheric neutrino background. Muon energy has traditionally been determined by measuring the specific energy loss (dE/dx) along the muon's path and relating the dE/dx to the muon energy. Because high-energy muons (E_mu > 1 TeV) lose energy randomly, the spread in dE/dx values is quite large, leading to a typical energy resolution of 0.29 in log10(E_mu) for a muon observed over a 1 km path length in the IceCube detector. In this paper, we present an improved method that uses a truncated mean and other techniques to determine the muon energy. The muon track is divided into separate segments with individual dE/dx values. The elimination of segments with the highest dE/dx results in an overall dE/dx that is more closely correlated to the muon energy. This method results in an energy resolution of 0.22 in log10(E_mu), which gives a 26% improvement. This technique is applicable to any large water or ice detector and potentially to large scintillator or liquid argon detectors.Comment: 12 pages, 16 figure

All-particle cosmic ray energy spectrum measured with 26 IceTop stations

We report on a measurement of the cosmic ray energy spectrum with the IceTop air shower array, the surface component of the IceCube Neutrino Observatory at the South Pole. The data used in this analysis were taken between June and October, 2007, with 26 surface stations operational at that time, corresponding to about one third of the final array. The fiducial area used in this analysis was 0.122 km^2. The analysis investigated the energy spectrum from 1 to 100 PeV measured for three different zenith angle ranges between 0{\deg} and 46{\deg}. Because of the isotropy of cosmic rays in this energy range the spectra from all zenith angle intervals have to agree. The cosmic-ray energy spectrum was determined under different assumptions on the primary mass composition. Good agreement of spectra in the three zenith angle ranges was found for the assumption of pure proton and a simple two-component model. For zenith angles {\theta} < 30{\deg}, where the mass dependence is smallest, the knee in the cosmic ray energy spectrum was observed between 3.5 and 4.32 PeV, depending on composition assumption. Spectral indices above the knee range from -3.08 to -3.11 depending on primary mass composition assumption. Moreover, an indication of a flattening of the spectrum above 22 PeV were observed.Comment: 38 pages, 17 figure

Expression and prognostic value of FAS receptor/FAS ligand and TrailR1/TrailR2 in acute myeloid leukemia.

We studied the expressions of FR, FL, TR1, and TR2 on blasts and T cells from 71 patients with acute myeloid leukemia (AML) and correlated expression rates with the clinical course. Compared to AML-blasts we found higher co-expressions on healthy myeloid and T cells. Expression of all markers on blasts and on T cells was similar in different subtypes and acute stages of AML. Compared to the non-responders (n = 7) responders to the AML Cooperative Group-therapy (n = 22) presented with higher proportions of blasts co-expressing the four markers (FR: 32 vs 15%; FL: 15 vs 13%; TR1: 72 vs 37%; TR2: 24 vs 23%) or T cells (FR: 88 vs 71%; FL: 76 vs 56%; TR1: 96 vs 44%; TR2: 54 vs 42%). Patients with higher expression rates of TR1 on blasts (&ge; 48%) and on T cells (&ge; 67%) were characterized by a prolonged survival. In summary, our data show a variable expression of FR, FL, TR1 and TR2 on blasts or T cells in different subgroups of AML. Higher co-expression rates of FR, FL, TR1 and TR2 were characterized by a better prognosis for the patients with respect to achieve a remission and to survive. Functional analyses should be performed to find out those patients in who induced upregulation of these markers could contribute to overcome drug resistance

Antileukemic T-cell responses can be predicted by the composition of specific regulatory T-cell subpopulations.

Regulatory T cells (T-reg) are important regulators of immune responses. In acute myeloid leukemia (AML) patients before/after immunotherapy (stem cell transplantation or donor lymphocyte infusion), their suppressive role can contribute to suppress severe graft-versus-host reactions, but also to impair antileukemic reactions. As leukemia-derived dendritic cells (DCleu) are known to improve the antileukemic functionality of T cells, we evaluated the composition and development of distinct T-reg subtypes in AML patients (n = 12) compared with healthy probands (n = 5) under unstimulated conditions and during stimulation with DCleu-containing DC (DC) or blast-containing mononuclear cells (MNC) in 0- to 7-day mixed lymphocyte cultures by flow cytometry. T-cell subgroups in AML patients were correlated with antileukemic functionality before and after DC or MNC stimulation by functional fluorolysis assays. (1) AML patients&#39; T cells presented with significantly higher frequencies of T-reg subgroups in unstimulated T cells compared with healthy probands. (2) After 7 days of DC or MNC stimulation, all T-reg subtypes generally increased; significantly higher frequencies of Treg subtypes were still found in AML patients. (3) Antileukemic cytotoxicity was achieved in 36% of T cells after MNC compared with 64% after DC stimulation. Antileukemic activity after DC but not after MNC stimulation correlated with significantly lower frequencies of T-reg subtypes (CD8(+) T-reg/T-eff/em reg). Furthermore, cut-off values for T-reg subpopulations could be defined, allowing a prediction of antileukemic response. We demonstrate a crucial role of special T-reg subtypes in the mediation of antileukemic functionality. High CD8(+) T-reg, T-eff/em reg, and CD39(+) T cells correlated clearly with a reduced antileukemic activity of T cells. DC stimulation of T cells contributes to overcome impaired antileukemic T-cell reactivity. Refined analyses in the context of clinical responses to immunotherapies and graft versus host reactions are required

Profiles of activation, differentiation-markers, or &beta;-integrins on T cells contribute to predict T cells&#39; antileukemic responses after stimulation with leukemia-derived dendritic cells.

Stem cell transplantations and donor lymphocyte infusions are promising immunotherapies to cure acute myeloid leukemia (AML). Leukemia-derived dendritic cells are known to improve antileukemic functionality of T cells. We evaluated the composition and development of distinct T-cell subtypes in AML patients (n=12) compared with healthy probands (n=5) before and during stimulation with leukemia-derived dendritic cells-containing DC (DC) or blast-containing mononuclear cells (MNC) in 0-7 days mixed lymphocyte cultures (MLC) by flow cytometry. AML patients&#39; T-cell subgroups were correlated with antileukemic functionality before and after DC/MNC stimulation by functional fluorolysis assays. (1) Unstimulated T cells from AML patients presented with significantly lower proportions of activated, T+ cm, CD137+, and &beta;-integrin T cells, and significantly higher proportions of T naive and Teff compared with healthy probands. (2) After 7 days of DC or MNC stimulation, T-cell profiles were characterized by (significantly) increased proportions of activated T cells with effector function and significantly decreased proportions of &beta;-integrin+m T cells. (3) Antileukemic cytotoxicity was achieved in 40% of T cells after MNC stimulation compared with 64% after DC stimulation. Antileukemic activity after DC stimulation but not after MNC stimulation correlated with higher proportions of Tcm and Tnaive before stimulation, as well as with significantly higher proportions of activated and &beta;-integrin+T cells. Furthermore, cutoff values for defined T-cell activation/differentiation markers and &beta;-integrin+T cells could be defined, allowing a prediction of antileukemic reactivity. We could demonstrate the potential of the composition of unstimulated/DC-stimulated T cells for the lysis of AML blasts. Especially, AML patients with high numbers of Tnaive and T cm could benefit from DC stimulation; proportions of activated and &beta;-integrin+ T cells correlated with increased antileukemic functionality and could serve to predict T cells&#39; reactivity during stimulation. Refined analyses in the context of responses to immunotherapies are required. Copyright &copy; 2014 by Lippincott Williams &amp; Wilkins