Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

<p>Abstract</p> <p>Background</p> <p>Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging.</p> <p>Methods</p> <p>Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm³). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment.</p> <p>Results</p> <p>After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm³) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0.</p> <p>Conclusions</p> <p>As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.</p

Measurement of D s ^± production asymmetry in pp collisions at √s=7 and 8 TeV

The inclusive $D_s^{\pm}$ production asymmetry is measured in $pp$ collisions collected by the LHCb experiment at centre-of-mass energies of $\sqrt{s} =7$ and 8 TeV. Promptly produced $D_s^{\pm}$ mesons are used, which decay as $D_s^{\pm}\to\phi\pi^{\pm}$, with $\phi\to K^+K^-$. The measurement is performed in bins of transverse momentum, $p_{\rm T}$, and rapidity, $y$, covering the range $2.5<p_{\rm T}<25.0$ GeV$/c$ and $2.0<y<4.5$. No kinematic dependence is observed. Evidence of nonzero $D_s^{\pm}$ production asymmetry is found with a significance of 3.3 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2018-010.htm

Search for CP violation in Λb0→pK− and Λb0→pπ− decays

A search for CP violation in Λb0→pK− and Λb0→pπ− decays is presented using a sample of pp collisions collected with the LHCb detector and corresponding to an integrated luminosity of 3.0fb−1. The CP -violating asymmetries are measured to be ACPpK−=−0.020±0.013±0.019 and ACPpπ−=−0.035±0.017±0.020, and their difference ACPpK−−ACPpπ−=0.014±0.022±0.010, where the first uncertainties are statistical and the second systematic. These are the most precise measurements of such asymmetries to date

Model-independent measurement of mixing parameters in D0 → K S 0 π+π− decays

The first model-independent measurement of the charm mixing parameters in the decay D 0 → K S 0 π + π − is reported, using a sample of pp collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 1.0 fb−1 at a centre-of-mass energy of 7 TeV. The measured values are x=(−0.86±0.53±0.17)×10−2,y=(+0.03±0.46±0.13)×10−2, x=(−0.86±0.53±0.17)×10−2,y=(+0.03±0.46±0.13)×10−2, where the first uncertainties are statistical and include small contributions due to the external input for the strong phase measured by the CLEO collaboration, and the second uncertainties are systematic

Measurement of CPCP asymmetry in Bs0→Ds∓K±B_s^0 \to D_s^{\mp} K^{\pm} decays

We report the measurements of the $CP$-violating parameters in $B_s^0 \to D_s^{\mp} K^{\pm}$ decays observed in $pp$ collisions, using a data set corresponding to an integrated luminosity of $3.0\,\text{fb}^{-1}$ recorded with the LHCb detector. We measure $C_f = 0.73 \pm 0.14 \pm 0.05$, $A^{\Delta \Gamma}_f = 0.39 \pm 0.28 \pm 0.15$, $A^{\Delta \Gamma}_{\overline{f}} = 0.31 \pm 0.28 \pm 0.15$, $S_f = -0.52 \pm 0.20 \pm 0.07$, $S_{\overline{f}} = -0.49 \pm 0.20 \pm 0.07$, where the uncertainties are statistical and systematic, respectively. These parameters are used together with the world-average value of the $B_s^0$ mixing phase, $-2\beta_s$, to obtain a measurement of the CKM angle $\gamma$ from $B_s^0 \to D_s^{\mp} K^{\pm}$ decays, yielding \gamma = (128\,_{-22}^{+17})^\circ modulo $180^\circ$, where the uncertainty contains both statistical and systematic contributions. This corresponds to $3.8\,\sigma$ evidence for $CP$ violation in the interference between decay and decay after mixing.We report the measurements of the CP -violating parameters in B$_{s}^{0}$  → D$_{s}^{∓}$ K$^{±}$ decays observed in pp collisions, using a data set corresponding to an integrated luminosity of 3.0 fb$^{−1}$ recorded with the LHCb detector. We measure C$_{f}$ = 0.73 ± 0.14 ± 0.05, A$_{f}^{ΔΓ}$  = 0.39 ± 0.28 ± 0.15, ${A}_{\overline{f}}^{\varDelta \varGamma }=0.31\pm 0.28\pm 0.15$ , S$_{f}$ = −0.52 ± 0.20 ± 0.07, ${S}_{\overline{f}}=-0.49\pm 0.20\pm 0.07$ , where the uncertainties are statistical and systematic, respectively. These parameters are used together with the world-average value of the B$_{s}^{0}$ mixing phase, −2β$_{s}$ , to obtain a measurement of the CKM angle γ from B$_{s}^{0}$  → D$_{s}^{∓}$ K$^{±}$ decays, yielding γ = (128$_{− 22}^{+ 17}$ )° modulo 180°, where the uncertainty contains both statistical and systematic contributions. This corresponds to 3.8 σ evidence for CP violation in the interference between decay and decay after mixing

Measurement of the electron reconstruction efficiency at LHCb

The single electron track-reconstruction efficiency is calibrated using a sample corresponding to 1.3 fb−1 of pp collision data recorded with the LHCb detector in 2017. This measurement exploits B+→ J/ψ(e+e−)K+ decays, where one of the electrons is fully reconstructed and paired with the kaon, while the other electron is reconstructed using only the information of the vertex detector. Despite this partial reconstruction, kinematic and geometric constraints allow the B meson mass to be reconstructed and the signal to be well separated from backgrounds. This in turn allows the electron reconstruction efficiency to be measured by matching the partial track segment found in the vertex detector to tracks found by LHCb's regular reconstruction algorithms. The agreement between data and simulation is evaluated, and corrections are derived for simulated electrons in bins of kinematics. These correction factors allow LHCb to measure branching fractions involving single electrons with a systematic uncertainty below 1%

First experimental study of photon polarization in radiative B-s(0) decays

The polarization of photons produced in radiative B0s decays is studied for the first time. The data are recorded by the LHCb experiment in pp collisions corresponding to an integrated luminosity of 3  fb−1 at center-of-mass energies of 7 and 8 TeV. A time-dependent analysis of the B0s→ϕγ decay rate is conducted to determine the parameter AΔ, which is related to the ratio of right- over left-handed photon polarization amplitudes in b→sγ transitions. A value of AΔ=−0.98+0.46−0.52+0.23−0.20 is measured. This result is consistent with the standard model prediction within 2 standard deviations

Late recurrences of gastrointestinal stromal tumours (GISTs) after 5 years of follow-up.

In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection occur. However, few published data are available for duration, intensity and imaging sources of follow-up in radically excised patients with localized disease. Therefore, every single institution chooses the surveillance schedule according to its experience. The aim of this study was to describe the late recurrences of disease 5 years after the primary tumour's excision in a series of patients with recurrent GIST from our institution. We retrospectively reviewed 42 patients with "recurrent" GIST, collected since 2001. Ten patients were always followed at our institution, and 32 patients came to our attention at the time of recurrence. The analysed series were divided into two groups: patients who developed recurrence before 5 years and patients who developed recurrence 5 years after the primary tumour's excision. Among 42 patients, 36 patients developed the recurrence within 5 years of the primary tumour excision, whereas 6 patients developed the recurrence 5 years after primary tumour excision diagnosed during follow-up or casually for other reasons. All patients had distant recurrence, involving liver and peritoneum, whereas no local relapse was observed. These patients were heterogeneous in primary tumour site, risk classification and molecular analysis. Duration of the follow-up for radically excised patients with GIST remains still unsettled; however, the integration of every clinical, pathological and molecular parameter is essential to optimize the duration and intensity of the follow-up for each single patient