Purpose Meta-[F-18]fluorobenzylguanidine ([F-18]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine... Show morePurpose Meta-[F-18]fluorobenzylguanidine ([F-18]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [F-18]mFBG PET-CT for imaging in neuroblastoma. Methods In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[I-123]iodobenzylguanidine ([I-123]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [I-123]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [F-18]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score. Results Twenty paired [I-123]mIBG and [F-18]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [F-18]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [F-18]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [I-123]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [F-18]mFBG PET-CT. Compared to [I-123]mIBG scanning, [F-18]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. Conclusion Results of this study demonstrate feasibility of [F-18]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. [F-18]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma. Show less
Inverse problems are problems where we want to estimate the values of certain parameters of a system given observations of the system. Such problems occur in several areas of science and... Show moreInverse problems are problems where we want to estimate the values of certain parameters of a system given observations of the system. Such problems occur in several areas of science and engineering. Inverse problems are often ill-posed, which means that the observations of the system do not uniquely define the parameters we seek to estimate, or that the solution is highly sensitive to small changes in the observation. In order to solve such problems, therefore, we need to make use of additional knowledge about the system at hand. One such prior information is given by the notion of sparsity. Sparsity refers to the knowledge that the solution to the inverse problem can be expressed as a combination of a few terms. The sparsity of a solution can be controlled explicitly or implicitly. An explicit way to induce sparsity is to minimize the number of non-zero terms in the solution. Implicit use of sparsity can be made, for e.g., by making adjustments to the algorithm used to arrive at the solution.In this thesis we studied various inverse problems that arise in different application areas, such as tomographic imaging and equation learning for biology, and showed how ideas of sparsity can be used in each case to design effective algorithms to solve such problems. Show less
The shipping industry is one of the strongest anthropogenic emitters of NOxNOx—a substance harmful both to human health and the environment. The rapid growth of the industry causes societal... Show moreThe shipping industry is one of the strongest anthropogenic emitters of NOxNOx—a substance harmful both to human health and the environment. The rapid growth of the industry causes societal pressure on controlling the emission levels produced by ships. All the methods currently used for ship emission monitoring are costly and require proximity to a ship, which makes global and continuous emission monitoring impossible. A promising approach is the application of remote sensing. Studies showed that some of the NO2NO2 plumes from individual ships can visually be distinguished using the TROPOspheric Monitoring Instrument on board the Copernicus Sentinel 5 Precursor (TROPOMI/S5P). To deploy a remote-sensing-based global emission monitoring system, an automated procedure for the estimation of NO2NO2 emissions from individual ships is needed. The extremely low signal-to-noise ratio of the available data, as well as the absence of the ground truth makes the task very challenging. Here, we present a methodology for the automated segmentation of NO2NO2 plumes produced by seagoing ships using supervised machine learning on TROPOMI/S5P data. We show that the proposed approach leads to more than a 20% increase in the average precision score in comparison to the methods used in previous studies and results in a high correlation of 0.834 with the theoretically derived ship emission proxy. This work is a crucial step towards the development of an automated procedure for global ship emission monitoring using remote sensing data. Show less
The Hilbert class polynomial has as roots the j-invariants of elliptic curves whose endomorphism ring is a given imaginary quadratic order. It can be used to compute elliptic curves over finite... Show moreThe Hilbert class polynomial has as roots the j-invariants of elliptic curves whose endomorphism ring is a given imaginary quadratic order. It can be used to compute elliptic curves over finite fields with a prescribed number of points. Since its coefficients are typically rather large, there has been continued interest in finding alternative modular functions whose corresponding class polynomials are smaller. Best known are Weber’s functions, which reduce the size by a factor of 72 for a positive density subset of imaginary quadratic discriminants. On the other hand, Bröker and Stevenhagen showed that no modular function will ever do better than a factor of 100.83. We introduce a generalization of class polynomials, with reduction factors that are not limited by the Bröker–Stevenhagen bound. We provide examples matching Weber’s reduction factor. For an infinite family of discriminants, their reduction factors surpass those of all previously known modular functions by a factor at least 2. Show less
Atteveld, J.E. van; Winter, D.T.C. de; Pluimakers, V.G.; Fiocco, M.; Nievelstein, R.A.J.; Hobbelink, M.G.G.; ... ; Heuvel-Eibrink, M.M. van den 2022
Lymph node micrometastases could be one of the reasons for the high recurrence rate after complete surgical resection in stage I-IIIA non-small cell lung cancer (NSCLC). The standard evaluation of... Show moreLymph node micrometastases could be one of the reasons for the high recurrence rate after complete surgical resection in stage I-IIIA non-small cell lung cancer (NSCLC). The standard evaluation of a single haematoxylin and eosin (H&E) slide of a paraffin-embedded section of a lymph node is insufficient for the detection of micrometastases, and there is a need for additional histopathological evaluation. The association of lymph node micrometastases with survival remains as yet unresolved. The aim of this systematic review and meta-analysis is to investigate if lymph node micrometastases and isolated tumour cells in patients with stage I-IIIA NSCLC, detected with multiple sectioning and/or immunohistochemistry (IHC) and/or reverse transcriptase polymerase chain reaction (RT-PCR), are associated with overall survival (OS) and disease-free survival (DFS) after surgical resection. We performed a meta-analysis of time-to-event outcomes based on 15 articles using ancillary techniques to detect micrometastases. We extracted the OS and DFS every 3-6 months after surgery, for patients with and without occult lymph node micrometastasis, from the survival curves published in each article. These data were used to reconstruct OS and DFS for 'micrometastasis' and 'no micrometastasis' groups. Based on all included studies that used IHC, serial sectioning, or RT-PCR, we found a 5-year OS of 55% (micrometastasis) vs. 75% (no micrometastasis), and a 5-year DFS of 53% (micrometastasis) vs. 75% (no micrometastasis). Patients with stage I-IIIA NSCLC with lymph node micrometastases detected by ancillary histopathological and molecular techniques have a significantly poorer OS and DFS compared to patients without lymph node micrometastases. Show less
Arici, F.; D'Andrea, F.; Hajac, P.M.; Toboslki, M. 2022
To unravel the structure of fundamental examples studied in noncommutative topology, we prove that the graph C*-algebra C*(E) of a trimmable graph E is U(1)-equivariantly iso-morphic to a pullback... Show moreTo unravel the structure of fundamental examples studied in noncommutative topology, we prove that the graph C*-algebra C*(E) of a trimmable graph E is U(1)-equivariantly iso-morphic to a pullback C *-algebra of a subgraph C *-algebra C*(E'') and the C *-algebra of func-tions on a circle tensored with another subgraph C*-algebra C*(E'). This allows us to approach the structure and K-theory of the fixed-point subalgebra C*(E)U .1/ through the (typically simpler) C *-algebras C*(E'), C*(E'') and C*(E'')U.1/. As examples of trimmable graphs, we consider one-loop extensions of the standard graphs encoding respectively the Cuntz algebra O2 and the Toeplitz algebra T . Then we analyze equivariant pullback structures of trimmable graphs yielding the C*-algebras of the Vaksman-Soibelman quantum sphere S2n+1 q and the quantum lens space L3 q(l;1, l), respectively. Show less
We discuss V.P. Belavkin's approach to the Schrodinger cat problem and show its close relation to ideas based on superselection and interaction with the environment developed by N.P. Landsman. The... Show moreWe discuss V.P. Belavkin's approach to the Schrodinger cat problem and show its close relation to ideas based on superselection and interaction with the environment developed by N.P. Landsman. The purpose of the paper is to explain these ideas in the most simple possible context, namely: discrete time and separable Hilbert spaces, in order to make them accessible to those coming from the philosophy of science and not too happy with idiosyncratic notation and terminology and sophisticated mathematical tools. Conventional elementary mathematical descriptions of quantum mechanics take "measurement" to be a primitive concept. Paradoxes arise when we choose to consider smaller or larger systems as measurement devices in their own right, by making different and apparently arbitrary choices of location of the "Heisenberg cut". Various quantum interpretations have different resolutions of the paradox. In Belavkin's approach, the classical world around us does really exist, and it evolves stochastically and dynamically in time according to probability laws following from successive applications of the Born law. It is a collapse theory. The quantum/classical distinction is determined by the arrow of time. The underlying unitary evolution of the wave-function of the universe enables the designation of a collection of beables which grows as time evolves, and which therefore can be assigned random, classical trajectories. In a slogan: the past is particles, the future is a wave. We, living in the now, are located on the cutting edge between past and future. Show less
Soeteman, M.; Kappen, T.H.; Engelen, M. van; Marcelis, M.; Kilsdon, E.; Heuvel-Eibrink, M.M. van den; ... ; Wosten-van Asperen, R.M. 2022
Background Hospitalized pediatric oncology patients are at risk of severe clinical deterioration. Yet Pediatric Early Warning System (PEWS) scores have not been prospectively validated in these... Show moreBackground Hospitalized pediatric oncology patients are at risk of severe clinical deterioration. Yet Pediatric Early Warning System (PEWS) scores have not been prospectively validated in these patients. We aimed to determine the predictive performance of the modified BedsidePEWS score for unplanned pediatric intensive care unit (PICU) admission and cardiopulmonary resuscitation (CPR) in this patient population. Methods We performed a prospective cohort study in an 80-bed pediatric oncology hospital in the Netherlands, where care has been nationally centralized. All hospitalized pediatric oncology patients aged 0-18 years were eligible for inclusion. A Cox proportional hazard model was estimated to study the association between BedsidePEWS score and unplanned PICU admissions or CPR. The predictive performance of the model was internally validated by bootstrapping. Results A total of 1137 patients were included. During the study, 103 patients experienced 127 unplanned PICU admissions and three CPRs. The hazard ratio for unplanned PICU admission or CPR was 1.65 (95% confidence interval [CI]: 1.59-1.72) for each point increase in the modified BedsidePEWS score. The discriminative ability was moderate (D-index close to 0 and a C-index of 0.83 [95% CI: 0.79-0.90]). Positive and negative predictive values of modified BedsidePEWS score at the widely used cutoff of 8, at which escalation of care is required, were 1.4% and 99.9%, respectively. Conclusion The modified BedsidePEWS score is significantly associated with requirement of PICU transfer or CPR. In pediatric oncology patients, this PEWS score may aid in clinical decision-making for timing of PICU transfer. Show less
Spini, G.; Mancini, E.; Attema, T.; Abspoel, M.; Gier, J. de; Fehr, S.O.; ... ; Sloot, P.M.A. 2022
Background HIV treatment prescription is a complex process. Clinical decision support systems (CDSS) are a category of health information technologies that can assist clinicians to choose optimal... Show moreBackground HIV treatment prescription is a complex process. Clinical decision support systems (CDSS) are a category of health information technologies that can assist clinicians to choose optimal treatments based on clinical trials and expert knowledge. The usability of some CDSSs for HIV treatment would be significantly improved by using the knowledge obtained by treating other patients. This knowledge, however, is mainly contained in patient records, whose usage is restricted due to privacy and confidentiality constraints. Methods A treatment effectiveness measure, containing valuable information for HIV treatment prescription, was defined and a method to extract this measure from patient records was developed. This method uses an advanced cryptographic technology, known as secure Multiparty Computation (henceforth referred to as MPC), to preserve the privacy of the patient records and the confidentiality of the clinicians' decisions. Findings Our solution enables to compute an effectiveness measure of an HIV treatment, the average time-to-treatment-failure, while preserving privacy. Experimental results show that our solution, although at proof-of-concept stage, has good efficiency and provides a result to a query within 24 min for a dataset of realistic size. Interpretation This paper presents a novel and efficient approach HIV clinical decision support systems, that harnesses the potential and insights acquired from treatment data, while preserving the privacy of patient records and the confidentiality of clinician decisions. Show less
Arithmetic geometry concerns the number-theoretic properties of geometric objects defined by polynomials. Mathematicians are interested in the rational solutions to these geometric objects. However... Show moreArithmetic geometry concerns the number-theoretic properties of geometric objects defined by polynomials. Mathematicians are interested in the rational solutions to these geometric objects. However, it is usually very difficult to answer questions like this.A. Beilinson and S. Bloch conjectured a very general height theory in 1980s, which was used by B. Gross and R. Schoen in their study of the Gross-Schoen cycles. The height of canonical Gross-Schoen cycles is conjectured to be non-negative. This was verified when the curve is an elliptic or hyperelliptic curve, while very few are known in the non-hyperelliptic case.During my PhD study, I study the Beilinson-Bloch height of canonical Gross-Schoen cycles on curves with an emphasis on the genus 3 case (almost all genus 3 curves are non-hyperelliptic). I studied its unboundedness and singular properties, and did explicit computation for the height of the canonical Gross-Schoen cycle of a specific plane quartic curve.The method used in my thesis should be helpful for verifications. Show less
This dissertation focuses on developing new mathematical and statistical methods to properly represent time-varying covariates and model them within the context of time-to-event analysis. This... Show moreThis dissertation focuses on developing new mathematical and statistical methods to properly represent time-varying covariates and model them within the context of time-to-event analysis. This research topic is motivated by specific clinical questions aimed at gaining insights into personalised treatments for cardiological and oncological patients. The main purpose is to enrich the knowledge available for modelling patients’ survival with relevant features related to the time-varying processes of interest.The efforts of this work address the complexities of both (i) developing adequate dynamic characterizations of the processes under study (i.e., representation problem) and (ii) identifying and quantifying the association between time-varying processes and patient survival (i.e., time-to-event modelling problem). In both cases, the main issue is dealing with complex data sources while taking into account the nature of the processes and managing the complex trade-off between clinical interpretability and mathematical formulation.By solving the aforementioned statistical complexities, this work is not only impacting the community of researchers in mathematics and statistics. The development of these novel methodologies may represent a significant step forward in the definition of customized and flexible monitoring tools to support doctors and clinicians in their work.*********This doctoral dissertation was part of a cotutelle agreement between the Politecnico di Milano and Leiden University Show less
Kantidakis, G.; Litière, S.; Neven, A.; Vinches, M.; Judson, I.; Blay, J.Y.; ... ; Gelderblom, H. 2022
Background: Recently, we performed a meta-analysis based on a literature review for STS trials (published 2003-2018, >= 10 adult patients) to update long-standing reference values for... Show moreBackground: Recently, we performed a meta-analysis based on a literature review for STS trials (published 2003-2018, >= 10 adult patients) to update long-standing reference values for leiomyosarcomas. This work is extended for liposarcomas (LPS) and synovial sarcomas (SS).Materials and methods: Study endpoints were progression-free survival rates (PFSRs) at 3 and 6 months. Trial-specific estimates were pooled per treatment line (first-line or pre-treated) with random effects meta-analyses. The choice of the therapeutic benefit to target in future trials was guided by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Results: Information was acquired for 1030 LPS patients (25 trials; 7 first-line, 17 pre-treated, 1 both) and 348 SS patients (13 trials; 3 first-line, 10 pre-treated). For LPS, the overall pooled first-line PFSRs were 69% (95%-CI 60-77%) and 56% (95%-CI 45-67%) at 3 and 6 months, respectively. These rates were 49% (95%-CI 40-57%)/28% (95%-CI 22-34%) for >1 lines. For SS, first-line PFSRs were 74% (95%-CI 58-86%)/56% (95%-CI 31-78%) at 3 and 6 months, and pre-treated rates were 45% (95%-CI 34-57%)/25% (95%-CI 16-36%). Following ESMO-MCBS guidelines, the minimum values to target are 79% and 69% for first-line LPS (82% and 69% for SS) at 3 and 6 months. For pre-treated LPS, recommended PFSRs at 3 and 6 months suggesting drug activity are 63% and 44% (60% and 41% for SS).Conclusions: New benchmarks are proposed for advanced/metastatic LPS or SS to design future histology-specific phase II trials. More data are needed to provide definitive thresholds for the different LPS subtypes. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
We analyze an 'up-the-gradient' model for the formation of transport channels of the phytohormone auxin, through auxin-mediated polarization of the PIN1 auxin transporter. We show that this model... Show moreWe analyze an 'up-the-gradient' model for the formation of transport channels of the phytohormone auxin, through auxin-mediated polarization of the PIN1 auxin transporter. We show that this model admits a family of travelling wave solutions that is parameterized by the height of the auxin-pulse. We uncover scaling relations for the speed and width of these waves and verify these rigorous results with numerical computations. In addition, we provide explicit expressions for the leading-order wave profiles, which allows the influence of the biological parameters in the problem to be readily identified. Our proofs are based on a generalization of the scaling principle developed by Friesecke and Pego to construct pulse solutions to the classic Fermi-Pasta-Ulam-Tsingou model, which describes a one-dimensional chain of coupled nonlinear springs. Show less
In this thesis we study bistable reaction-diffusion equations on lattice domains. The power of reaction-diffusion equations is that they can successfully model various natural and social phenomena... Show moreIn this thesis we study bistable reaction-diffusion equations on lattice domains. The power of reaction-diffusion equations is that they can successfully model various natural and social phenomena with their intuitive and relatively simple (mathematical) representation. One of the main features of reaction-diffusion equations, both on discrete and continuous domains, is that they admit special solutions, so-called ‘travelling waves’, which we can describe as fixed profiles that move in a particular direction with some speed. Depending on their shape, we can roughly divide waves into three categories: pulses or solitons, periodic pulses (wave trains), and monotone wave fronts that connect two constant states. In this thesis we focus on the latter type of wave and we study their existence, propagation and long term behaviour on two type of discrete domains - infinite trees, and two-dimensional square lattices. Show less
