Improving therapy options for patients with metastatic castrate-resistant prostate cancer

Metastatic castrate-resistant prostate cancer (mCRPC) is the second deadliest cancer in men in the Western world. Therapy options are limited, but expanding. In the current thesis, various aspects of (pre)clinical research are discussed, all sharing the ultimate aim to improve therapy options for this group of cancer patients. Both basic, translational, biomarker, clinical and epidemiological studies have been performed, focusing primarily on novel agents that have been introduced recently into clinical practice (cabazitaxel, abiraterone, radium-223), and agents that may become antitumor agents against mCRPC in the future, such as antimitotics (polo-like kinase 1 inhibitors, aurora kinase inhibitors, Eg5), histone deacetylase inhibitors, and agents that stimulate expression of the metastasis-suppressor gene NDRG1. Furthermore, minority enrollment in phase III studies with mCRPC patients is being evaluated.Voor druk van het proefschrift: afdeling Klinische Oncologie, LUMC; Bayer; Boehringer Ingelheim; Sanofi-Aventis; Amgen B.V.UBL - phd migration 201

Nuclear Eg5 (kinesin spindle protein) expression predicts docetaxel response and prostate cancer aggressiveness

Novel biomarkers predicting prostate cancer (PCa) aggressiveness and docetaxel therapy response of PCa patients are needed. In this study the correlation between nuclear Eg5-expression, PCa docetaxel response and PCa aggressiveness was assessed. Immunohistochemical staining for nuclear Eg5 was performed on 117 archival specimens from 110 PCa patients treated with docetaxel between 2004 and 2012. Samples were histologically categorized as positive/negative. Median follow-up time from diagnosis was 11.6 years. Nuclear Eg5-expression was significantly related to docetaxel response (p=0.036) in tissues acquired within three years before docetaxel initiation. Nuclear Eg5-expression was not related to Gleason-score (p=0.994). Survival of patients after docetaxel initiation did not differ based on nuclear Eg5-expression (p=0.540). Analyzing samples taken before hormonal therapy, overall survival and time to docetaxel use were significantly decreased in patients with nuclear Eg5-expressing tumors (p<0.01). Eg5-positive nuclei were found more frequently in T4-staged tumors (p=0.04), Gleason 8-10 tumors (p=0.08), and in metastasized tumors (p<0.01). Multivariate analyses indicated that nuclear Eg5-expression may be an independent parameter for tumor aggressiveness. Limitations of a retrospective analysis apply. In conclusion, nuclear Eg5-expression may be a predictive biomarker for docetaxel response in metastatic castrate-resistant PCa patients and a prognostic biomarker for hormone-naive PCa patients. Prospective validation studies are needed

Recovery of dialysis patients with COVID-19 : health outcomes 3 months after diagnosis in ERACODA

Background. Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis. Methods. We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression. Results. In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8-6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome. Conclusions. Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis

Measurements of differential production cross sections for a Z boson in association with jets in pp collisions at root s=8 TeV

Peer reviewe

Search for jet extinction in the inclusive jet-pT spectrum from proton-proton collisions at s=8 TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7  fb−1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale

Search for the associated production of the Higgs boson with a top-quark pair

A search for the standard model Higgs boson produced in association with a top-quark pair t t ¯ H (tt¯H) is presented, using data samples corresponding to integrated luminosities of up to 5.1 fb &#8722;1 and 19.7 fb &#8722;1 collected in pp collisions at center-of-mass energies of 7 TeV and 8 TeV respectively. The search is based on the following signatures of the Higgs boson decay: H &#8594; hadrons, H &#8594; photons, and H &#8594; leptons. The results are characterized by an observed t t ¯ H tt¯H signal strength relative to the standard model cross section, &#956; = &#963;/&#963; SM ,under the assumption that the Higgs boson decays as expected in the standard model. The best fit value is &#956; = 2.8 ± 1.0 for a Higgs boson mass of 125.6 GeV

Measurement of prompt Jψ\psi pair production in pp collisions at \sqrt s = 7 Tev

Production of prompt J/ &#968; meson pairs in proton-proton collisions at s s&#8730; = 7 TeV is measured with the CMS experiment at the LHC in a data sample corresponding to an integrated luminosity of about 4.7 fb &#8722;1 . The two J/ &#968; mesons are fully reconstructed via their decays into &#956; + &#956; &#8722; pairs. This observation provides for the first time access to the high-transverse-momentum region of J/ &#968; pair production where model predictions are not yet established. The total and differential cross sections are measured in a phase space defined by the individual J/ &#968; transverse momentum ( p T J/ &#968; ) and rapidity (| y J/ &#968; |): | y J/ &#968; | 6.5 GeV/ c ; 1.2 4.5 GeV/ c . The total cross section, assuming unpolarized prompt J/ &#968; pair production is 1.49 ± 0.07 (stat) ±0.13 (syst) nb. Different assumptions about the J/ &#968; polarization imply modifications to the cross section ranging from &#8722;31% to +27%

Searches for electroweak neutralino and chargino production in channels with Higgs, Z, and W bosons in pp collisions at 8 TeV

Searches for supersymmetry (SUSY) are presented based on the electroweak pair production of neutralinos and charginos, leading to decay channels with Higgs, Z, and W bosons and undetected lightest SUSY particles (LSPs). The data sample corresponds to an integrated luminosity of about 19.5 fb(-1) of proton-proton collisions at a center-of-mass energy of 8 TeV collected in 2012 with the CMS detector at the LHC. The main emphasis is neutralino pair production in which each neutralino decays either to a Higgs boson (h) and an LSP or to a Z boson and an LSP, leading to hh, hZ, and ZZ states with missing transverse energy (E-T(miss)). A second aspect is chargino-neutralino pair production, leading to hW states with E-T(miss). The decays of a Higgs boson to a bottom-quark pair, to a photon pair, and to final states with leptons are considered in conjunction with hadronic and leptonic decay modes of the Z and W bosons. No evidence is found for supersymmetric particles, and 95% confidence level upper limits are evaluated for the respective pair production cross sections and for neutralino and chargino mass values

Charged-particle nuclear modification factors in PbPb and pPb collisions at √=sNN=5.02 TeV

The spectra of charged particles produced within the pseudorapidity window |η| < 1 at √ sNN = 5.02 TeV are measured using 404 µb −1 of PbPb and 27.4 pb−1 of pp data collected by the CMS detector at the LHC in 2015. The spectra are presented over the transverse momentum ranges spanning 0.5 < pT < 400 GeV in pp and 0.7 < pT < 400 GeV in PbPb collisions. The corresponding nuclear modification factor, RAA, is measured in bins of collision centrality. The RAA in the 5% most central collisions shows a maximal suppression by a factor of 7–8 in the pT region of 6–9 GeV. This dip is followed by an increase, which continues up to the highest pT measured, and approaches unity in the vicinity of pT = 200 GeV. The RAA is compared to theoretical predictions and earlier experimental results at lower collision energies. The newly measured pp spectrum is combined with the pPb spectrum previously published by the CMS collaboration to construct the pPb nuclear modification factor, RpA, up to 120 GeV. For pT > 20 GeV, RpA exhibits weak momentum dependence and shows a moderate enhancement above unity