Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

Background: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. Patients and methods: Eighty-five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan-Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation. Results: In cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P <0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12-0.44; P <0.001), PFS (HR 0.37; 95% CI 0.21-0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42-11.95; P = 0.01). In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P <0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36-0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39-0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10-15.18; P = 0.001). In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46-0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01). Conclusions: Everolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy. (C) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

On the problem of interactions in quantum theory

The structure of representations describing systems of free particles in the theory with the invariance group SO(1,4) is investigated. The property of the particles to be free means as usual that the representation describing a many-particle system is the tensor product of the corresponding single-particle representations (i.e. no interaction is introduced). It is shown that the mass operator contains only continuous spectrum in the interval $(-\infty,\infty)$ and such representations are unitarily equivalent to ones describing interactions (gravitational, electromagnetic etc.). This means that there are no bound states in the theory and the Hilbert space of the many-particle system contains a subspace of states with the following property: the action of free representation operators on these states is manifested in the form of different interactions. Possible consequences of the results are discussed.Comment: 35 pages, Late

Study of the ηπo\eta\pi^o system in the mass range up to 1200 MeV

The reaction $\pi^-p \to \eta\pi^o n$ has been studied with GAMS-2000 spectrometer in the secondary 38 GeV/c $\pi^-$-beam of the IHEP U-70 accelerator. Partial wave analysis of the reaction has been performed in the $\eta\pi^o$ mass range up to 1200 MeV. The $a_0(980)$-meson is seen as a sharp peak in S-wave. The $t$-dependence of $a_0(980)$ production cross section has been studied. Dominant production of the $a_0(980)$ at a small transfer momentum $t$ confirms the hypothesis of Achasov and Shestakov about significant contribution of the $\rho_2$ exchange ($I^GJ^{PC}=1^+2^{--}$) in the mechanism of $a_0(980)$ meson production in $t$-channel of the reaction.Comment: 4 pages, 3 figures, talk given at HADRON'9

Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P=0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P=0.07), time to PD (4.5 vs 2.2 months, P=0.13) and clinical benefit (CR+PR+SD) (58 vs 37%, P=0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC

Perioperative immunomodulation with interleukin-2 in patients with renal cell carcinoma: results of a controlled phase II trial

We conducted a non-randomised controlled phase II trial to investigate the role of preoperative administration of interleukin-2 (IL-2) in patients with renal cell carcinoma undergoing tumour nephrectomy. A total of 120 consecutive patients were allocated alternately to the two study groups: perioperative immunomodulation with IL-2 (IL-2 group; n=60) and perioperative immunomonitoring without immunomodulation (control group; n=60). Patients from the IL-2 group received four doses of 10 × 106 IU m−2 twice daily subcutaneously a week before operation followed by a daily maintenance dose of 3 × 106 IU m−2 subcutaneously until a day before the operation. Parameters of cellular and humoral immunity (leucocytes, T-cell markers CD3, CD4, and CD8, B-cell marker CD19, monocyte marker CD14, natural killer (NK) cell markers CD16, CD56, and CD57, activation markers CD6, CD25, CD28, and CD69, progenitor cell marker CD34, as well as IL-2, IL-6, IL-10, soluble IL-2 receptor, IL-1 receptor antagonist, transforming growth factor-β1, and vascular endothelial growth factor) were measured in peripheral venous blood at various intervals. Interleukin-2-related toxicity was WHO grade 1 (24%), 2 (67%), and 3 (9%). In the postoperative period, T-cell markers, activation markers, and NK cell markers decreased, and IL-6 and IL-10 increased. However, all these alterations were significantly less accentuated in patients who had been pretreated with IL-2. Median follow-up was 40 months. Tumour-specific survival in the IL-2 group and the control group was 98 vs 81% after 1 year and 86 vs 73% after 5 years (P=0.04). A similar effect was found for progression-free survival. We conclude that IL-2 can be safely administered in the perioperative period and modulates immunological parameters. However, to validate the survival data, a larger randomised phase III trial is needed

Measurement of the K+→μ+νμγK^+\rightarrow{\mu^+}{\nu_{\mu}}{\gamma} decay form factors in the OKA experiment

A precise measurement of the vector and axial-vector form factors difference $F_V-F_A$ in the $K^+\rightarrow{\mu^+}{\nu_{\mu}}{\gamma}$ decay is presented. About 95K events of $K^+\rightarrow{\mu^+}{\nu_{\mu}}{\gamma}$ are selected in the OKA experiment. The result is $F_V-F_A=0.134\pm0.021(stat)\pm0.027(syst)$. Both errors are smaller than in the previous $F_V-F_A$ measurements.Comment: 9 pages, 8 figure

Intratumoural and peripheral blood lymphocyte subsets in patients with metastatic renal cell carcinoma undergoing interleukin-2 based immunotherapy: association to objective response and survival

The aim of the present study was to analyse lymphocyte subsets in consecutive peripheral blood samples and consecutive tumour tissue core needle biopsies performed before and during interleukin-2 based immunotherapy, and to correlate the findings with objective response and survival. Twenty-six patients with metastatic renal cell carcinoma were treated with low dose s.c. interleukin-2, interferon-α and histamine. A total of 250 blood samples and 62 core needle biopsies from 23 and 19 of these patients, respectively, were analysed. After 2 weeks of treatment, a significant positive correlation between absolute number of peripheral blood lymphocytes (P=0.028), CD3 (P=0.017), CD57 (P=0.041) and objective response was demonstrated. There was no correlation between any peripheral blood leukocyte subsets and survival. Cytotoxicity of peripheral blood mononuclear cells was not correlated to objective response or survival. Within the tumour tissue at baseline, a significant positive correlation between CD4 (P=0.027), CD8 (P=0.028), CD57 (P=0.007) and objective response was demonstrated. After one month of immunotherapy, a significant positive correlation between intratumoral CD3 (P=0.026), CD8 (P=0.015), CD57 (P=0.009) and objective response was demonstrated. A significant positive correlation between intratumoral baseline CD4 (P=0.047), baseline CD57 (P=0.035), CD3 at one month (P=0.049) and survival was demonstrated. These data provide novel in vivo evidence of the possible contribution of lymphocyte subsets in the tumour reduction in responding patients during interleukin-2 based immunotherapy. Confirmation of the results requires further studies including a larger number of patients