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Prostate cancer can be lethal in advanced stages, for which chemotherapy may become the only viable therapeutic option. While there is no clear clinical management strategy fitting all patients, cytotoxic chemotherapy with docetaxel is currently regarded as the gold standard. However, tumors may regain activity after treatment conclusion and become resistant to docetaxel. This situation calls for new delivery strategies and drug compounds enabling an improved therapeutic outcome. Combination of docetaxel with antiangiogenic therapy has been considered a promising strategy. Bevacizumab is the most common antiangiogenic drug, but clinical studies have not revealed a clear benefit from its combination with docetaxel. Here, we capitalize on our prior work on mathematical modeling of prostate cancer growth subjected to combined cytotoxic and antiangiogenic therapies, and propose an optimal control framework to robustly compute the drug-independent cytotoxic and antiangiogenic effects enabling an optimal therapeutic control of tumor dynamics. We describe the formulation of the optimal control problem, for which we prove the existence of at least a solution and determine the necessary first-order optimality conditions. We then present numerical algorithms based on isogeometric analysis to run a preliminary simulation study over a single cycle of combined therapy. Our results suggest that only cytotoxic chemotherapy is required to optimize therapeutic performance and we show that our framework can produce superior solutions to combined therapy with docetaxel and bevacizumab. We also illustrate how the optimal drug-naïve cytotoxic effects computed in these simulations may be successfully leveraged to guide drug production and delivery strategies by running a nonlinear least-square fit of protocols involving docetaxel and a new design drug. In the future, we believe that our optimal control framework may contribute to accelerate experimental research on chemotherapeutic drugs for advanced prostate cancer and ultimately provide a means to design and monitor its optimal delivery to patients.

In the recent paper “Well-posedness and regularity for a generalized fractional Cahn–Hilliard system” (Colli et al. in Atti Accad Naz Lincei Rend Lincei Mat Appl 30:437–478, 2019), the same authors have studied viscous and nonviscous Cahn–Hilliard systems of two operator equations in which nonlinearities of double-well type, like regular or logarithmic potentials, as well as nonsmooth potentials with indicator functions, were admitted. The operators appearing in the system equations are fractional powers $$A^{2r}$$ A 2 r and $$B^{2\sigma }$$ B 2 σ (in the spectral sense) of general linear operators A and B, which are densely defined, unbounded, selfadjoint, and monotone in the Hilbert space $$L^2(\Omega )$$ L 2 ( Ω ) , for some bounded and smooth domain $$\Omega \subset {{\mathbb {R}}}^3$$ Ω ⊂ R 3 , and have compact resolvents. Existence, uniqueness, and regularity results have been proved in the quoted paper. Here, in the case of the viscous system, we analyze the asymptotic behavior of the solution as the parameter $$\sigma $$ σ appearing in the operator $$B^{2\sigma }$$ B 2 σ decreasingly tends to zero. We prove convergence to a phase relaxation problem at the limit, and we also investigate this limiting problem, in which an additional term containing the projection of the phase variable on the kernel of B appears.

In this paper, we study a system of three evolutionary operator equations involving fractional powers of selfadjoint, monotone, unbounded, linear operators having compact resolvents. This system constitutes a generalized and relaxed version of a phase field system of Cahn-Hilliard type modelling tumor growth that has originally been proposed in Hawkins-Daarud et al. (Int. J. Numer. Math. Biomed. Eng. 28 (2012), 3-24). The original phase field system and certain relaxed versions thereof have been studied in recent papers co-authored by the present authors and E. Rocca. The model consists of a Cahn-Hilliard equation for the tumor cell fraction, coupled to a reaction-diffusion equation for a function S representing the nutrient-rich extracellular water volume fraction. Effects due to fluid motion are neglected. Motivated by the possibility that the diffusional regimes governing the evolution of the different constituents of the model may be of different (e.g., fractional) type, the present authors studied in a recent note a generalization of the systems investigated in the abovementioned works. Under rather general assumptions, well-posedness and regularity results have been shown. In particular, by writing the equation governing the evolution of the chemical potential in the form of a general variational inequality, also singular or nonsmooth contributions of logarithmic or of double obstacle type to the energy density could be admitted. In this note, we perform an asymptotic analysis of the governing system as two (small) relaxation parameters approach zero separately and simultaneously. Corresponding well-posedness and regularity results are established for the respective cases; in particular, we give a detailed discussion which assumptions on the admissible nonlinearities have to be postulated in each of the occurring cases., Comment: Key words: fractional operators, Cahn-Hilliard systems, well-posedness, regularity of solutions, tumor growth models, asymptotic analysis

This work represents a first contribution on the problem of boundary stabilisation for the phase field system of Cahn-Hilliard type, which models the phase separation in a binary mixture. The feedback controller we design here is with actuation only on the temperature flow of the system, on one part of the boundary only. Moreover, it is of proportional type, given in an explicit form, expressed only in terms of the eigenfunctions of the Laplace operator, being easy to manipulate from the computational point of view. Furthermore, it ensures that the closed loop nonlinear system exponentially reaches the prescribed stationary solution provided that the initial datum is close enough to it.

In the recent paper “Well-posedness and regularity for a generalized fractional Cahn–Hilliard system” by the same authors, general well-posedness results have been established for a class of evolutionary systems of two equations having the structure of a viscous Cahn–Hilliard system, in which nonlinearities of double-well type occur. The operators appearing in the system equations are fractional versions in the spectral sense of general linear operators A, B having compact resolvents, which are densely defined, unbounded, selfadjoint, and monotone in a Hilbert space of functions defined in a smooth domain. In this work we complement the results given in the quoted paper by studying a distributed control problem for this evolutionary system. The main difficulty in the analysis is to establish a rigorous Frechet differentiability result for the associated control-to-state mapping. This seems only to be possible if the state stays bounded, which, in turn, makes it necessary to postulate an additional global boundedness assumption. One typical situation, in which this assumption is satisfied, arises when B is the negative Laplacian with zero Dirichlet boundary conditions and the nonlinearity is smooth with polynomial growth of at most order four. Also a case with logarithmic nonlinearity can be handled. Under the global boundedness assumption, we establish existence and first-order necessary optimality conditions for the optimal control problem in terms of a variational inequality and the associated adjoint state system.

An asymptotic analysis for a system with equation and dynamic boundary condition of Cahn-Hilliard type is carried out as the coefficient of the surface diffusion acting on the phase variable tends to 0, thus obtaining a forward-backward dynamic boundary condition at the limit. This is done in a very general setting, with nonlinear terms admitting maximal monotone graphs both in the bulk and on the boundary. The two graphs are related by a growth condition, with the boundary graph that dominates the other one. It turns out that in the limiting procedure the solution of the problem looses some regularity and the limit equation has to be properly interpreted in the sense of a subdifferential inclusion. However, the limit problem is still well-posed since a continuous dependence estimate can be proved. Moreover, in the case when the two graphs exhibit the same growth, it is shown that the solution enjoys more regularity and the boundary condition holds almost everywhere. An error estimate can also be shown, for a suitable order of the diffusion parameter., Comment: 26 pages

The assessment and the management of the risks linked to insect pests can be supported by the use of physiologically-based demographic models. These models are useful in population ecology to simulate the dynamics of stage-structured populations, by means of functions (e.g., development, mortality and fecundity rate functions) realistically representing the nonlinear individuals physiological responses to environmental forcing variables. Since density-dependent responses are important regulating factors in population dynamics, we propose a nonlinear physiologically-based Kolmogorov model describing the dynamics of a stage-structured population in which a time-dependent mortality rate is coupled with a nonlocal density-dependent term. We prove existence and uniqueness of the solution for this resulting highly nonlinear partial differential equation. Then, the equation is discretized by finite volumes in space and semi-implicit backward Euler scheme in time. The model is applied for simulating the population dynamics of the fall armyworm moth (Spodoptera frugiperda), a highly invasive pest threatening agriculture worldwide.

The initial boundary value problem for a Cahn–Hilliard system subject to a dynamic boundary condition of Allen–Cahn type is treated. The vanishing of the surface diffusion on the dynamic boundary condition is the point of emphasis. By the asymptotic analysis as the diffusion coefficient tends to 0, one can expect that the solutions of the surface diffusion problem converge to the solution of the problem without the surface diffusion. This is actually the case, but the solution of the limiting problem naturally looses some regularity. Indeed, the system we investigate is rather complicate due to the presence of nonlinear terms including general maximal monotone graphs both in the bulk and on the boundary. The two graphs are related each to the other by a growth condition, with the boundary graph that dominates the other one. In general, at the asymptotic limit a weaker form of the boundary condition is obtained, but in the case when the two graphs exhibit the same growth the boundary condition still holds almost everywhere.

The paper treats the problem of optimal distributed control of a Cahn–Hilliard–Oono system in \begin{document}$ {{\mathbb{R}}}^d $\end{document}, \begin{document}$ 1\leq d\leq 3 $\end{document}, with the control located in the mass term and admitting general potentials that include both the case of a regular potential and the case of some singular potential. The first part of the paper is concerned with the dependence of the phase variable on the control variable. For this purpose, suitable regularity and continuous dependence results are shown. In particular, in the case of a logarithmic potential, we need to prove an ad hoc strict separation property, and for this reason we have to restrict ourselves to the case \begin{document}$ d = 2 $\end{document}. In the rest of the work, we study the necessary first-order optimality conditions, which are proved under suitable compatibility conditions on the initial datum of the phase variable and the time derivative of the control, at least in case of potentials having unbounded domain.

In the present contribution we study a viscous Cahn-Hilliard system where a further leading term in the expression for the chemical potential $ \mu$ is present. This term consists of a subdifferential operator $S$ in $L^2(\Omega)$ (where $\Omega$ is the domain where the evolution takes place) acting on the difference of the phase variable $\varphi$ and a given state $\varphi^* $, which is prescribed and may depend on space and time. We prove existence and continuous dependence results in case of both homogeneous Neumann and Dirichlet boundary conditions for the chemical potential $\mu$. Next, by assuming that $S=\rho\,$sign, a multiple of the sign operator, and for smoother data, we first show regularity results. Then, in the case of Dirichlet boundary conditions for $\mu$ and under suitable conditions on $\rho$ and $\Omega$, we also prove the sliding mode property, that is, that $\varphi$ is forced to join the evolution of $\varphi^* $ in some time $T^*$ lower than the given final time $T$. We point out that all our results hold true for a very general and possibly singular multi-well potential acting on $\varphi$., Comment: Key words: viscous Cahn-Hilliard equation, state-feedback control law, initial-boundary value problem, well-posedness, regularity, sliding mode property

In this paper, we consider optimal control problems for the one-dimensional Frémond model for shape memory alloys. This model is constructed in terms of basic functionals like free energy and pseudo-potential of dissipation. The state problem is expressed by a system of partial differential equations involving the balance equations for energy and momentum. We prove the existence of an optimal control that minimizes the cost functional for a nonlinear and nonsmooth state problem. Moreover, we show the necessary condition of the optimal pair by using optimal control problems for approximating systems.

In the present paper, we present and solve the sliding mode control (SMC) problem for a second-order generalization of the Caginalp phase-field system. This generalization, inspired by the theories developed by Green and Naghdi on one side, and Podio-Guidugli on the other, deals with the concept of thermal displacement, i.e., a primitive with respect to the time of the temperature. Two control laws are considered: the former forces the solution to reach a sliding manifold described by a linear constraint between the temperature and the phase variable; the latter forces the phase variable to reach a prescribed distribution $\varphi^*$. We prove existence, uniqueness as well as continuous dependence of the solutions for both problems; two regularity results are also given. We also prove that, under suitable conditions, the solutions reach the sliding manifold within finite time., Comment: 26 pages. Key words: phase field system, nonlinear boundary value problems, phase transition, sliding mode control, state-feedback control law

The well-posedness of a system of partial differential equations with dynamic boundary conditions is discussed. This system is a sort of transmission problem between the dynamics in the bulk Ω and on the boundary Γ. The Poisson equation for the chemical potential and the Allen–Cahn equation for the order parameter in the bulk Ω are considered as auxiliary conditions for solving the Cahn–Hilliard equation on the boundary Γ. Recently, the well-posedness of this equation with a dynamic boundary condition, both of Cahn–Hilliard type, was discussed. Based on this result, the existence of the solution and its continuous dependence on the data are proved.

In the present contribution we consider a singular phase field system located in a smooth and bounded three-dimensional domain. The entropy balance equation is perturbed by a logarithmic nonlinearity and by the presence of an additional term involving a possibly nonlocal maximal monotone operator and arising from a class of sliding mode control problems. The second equation of the system accounts for the phase dynamics, and it is deduced from a balance law for the microscopic forces that are responsible for the phase transition process. The resulting system is highly nonlinear; the main difficulties lie in the contemporary presence of two nonlinearities, one of which under time derivative, in the entropy balance equation. Consequently, we are able to prove only the existence of solutions. To this aim, we will introduce a backward finite differences scheme and argue on this by proving uniform estimates and passing to the limit on the time step., Comment: Key words: Phase field system; maximal monotone nonlinearities; nonlocal terms; initial and boundary value problem; existence of solutions

In this paper, we study an optimal boundary control problem for a model for phase separation taking place in a spatial domain that was introduced by Podio-Guidugli in Ric. Mat. 55 (2006), pp. 105-118. The model consists of a strongly coupled system of nonlinear parabolic differential equations, in which products between the unknown functions and their time derivatives occur that are difficult to handle analytically. In contrast to the existing control literature about this PDE system, we consider here a dynamic boundary condition involving the Laplace-Beltrami operator for the order parameter of the system, which models an additional nonconserving phase transition occurring on the surface of the domain. We show the Fr\'echet differentiability of the associated control-to-state operator in appropriate Banach spaces and derive results on the existence of optimal controls and on first-order necessary optimality conditions in terms of a variational inequality and the adjoint state system., Comment: Key words: optimal control, viscous Cahn-Hilliard system, phase field model, dynamic boundary conditions, first-order necessary optimality conditions

This paper deals with an initial and boundary value problem for a system coupling equation and boundary condition both of Cahn-Hilliard type; an additional convective term with a forced velocity field, which could act as a control on the system, is also present in the equation. Either regular or singular potentials are admitted in the bulk and on the boundary. Both the viscous and pure Cahn-Hilliard cases are investigated, and a number of results is proven about existence of solutions, uniqueness, regularity, continuous dependence, uniform boundedness of solutions, strict separation property. A complete approximation of the problem, based on the regularization of maximal monotone graphs and the use of a Faedo-Galerkin scheme, is introduced and rigorously discussed., Key words: Cahn-Hilliard system, convection, dynamic boundary condition, initial-boundary value problem, well-posedness, regularity of solutions

In this paper we study a distributed control problem for a phase-field system of conserved type with a possibly singular potential. We mainly handle two cases: the case of a viscous Cahn-Hilliard type dynamics for the phase variable in case of a logarithmic-type potential with bounded domain and the case of a standard Cahn-Hilliard equation in case of a regular potential with unbounded domain, like the classical double-well potential, for example. Necessary first order conditions of optimality are derived under natural assumptions on the data., Comment: The interested reader can also see the related preprint arXiv:1410.6718 addressed to the non-conserved phase field system. The results contained in arXiv:1410.6718 can be compared with the ones proved in the present paper

In this paper, we consider a class of coupled systems of PDEs, denoted by (ACE)$_{\varepsilon}$ for $ \varepsilon \geq 0 $. For each $ \varepsilon \geq 0 $, the system (ACE)$_{\varepsilon}$ consists of an Allen-Cahn type equation in a bounded spacial domain $ \Omega $, and another Allen-Cahn type equation on the smooth boundary $ \Gamma := \partial \Omega $, and besides, these coupled equations are transmitted via the dynamic boundary conditions. In particular, the equation in $ \Omega $ is derived from the non-smooth energy proposed by Visintin in his monography "Models of phase transitions": hence, the diffusion in $ \Omega $ is provided by a quasilinear form with singularity. The objective of this paper is to build a mathematical method to obtain meaningful $ L^2 $-based solutions to our systems, and to see some robustness of (ACE)$_\varepsilon$ with respect to $ \varepsilon \geq 0 $. On this basis, we will prove two Main Theorems 1 and 2, which will be concerned with the well-posedness of (ACE)$_\varepsilon$ for each $ \varepsilon \geq 0 $, and the continuous dependence of solutions to (ACE)$_\varepsilon$ for the variations of $ \varepsilon \geq 0 $, respectively., Comment: Key words and phrases: quasi-linear Allen-Cahn equation, dynamic boundary conditions, non-smooth energy functional, initial-boundary value problem, well-posedness, continuous dependence

In this paper, a distributed optimal control problem is studied for a diffuse interface model of tumor growth which was proposed in [A. Hawkins-Daruud, K.G. van der Zee, J.T. Oden, Numerical simulation of a thermodynamically consistent four-species tumor growth model, Int. J. Numer. Math. Biomed. Engng. 28 (2011), 3-24]. The model consists of a Cahn-Hilliard equation for the tumor cell fraction coupled to a reaction-diffusion equation for a variable representing the nutrient-rich extracellular water volume fraction. The distributed control monitors as a right-hand side the reaction-diffusion equation and can be interpreted as a nutrient supply or a medication, while the cost function, which is of standard tracking type, is meant to keep the tumor cell fraction under control during the evolution. We show that the control-to-state operator is Frechet differentiable between appropriate Banach spaces and derive the first-order necessary optimality conditions in terms of a variational inequality involving the adjoint state variables., A revised version of the paper has been published on Nonlinearity 30 (2017), 2518-2546. Let us point out that in this arXiv:1601.04567 [math.AP] version there is something missing in assumption (H3) at page 6: the first initial value in (H6) must also satisfy a Neumann homogeneous condition at the boundary of the domain

In this paper we discuss a family of viscous Cahn-Hilliard equations with a non-smooth viscosity term. This system may be viewed as an approximation of a "forward-backward" parabolic equation. The resulting problem is highly nonlinear, coupling in the same equation two nonlinearities with the diffusion term. In particular, we prove existence of solutions for the related initial and boundary value problem. Under suitable assumptions, we also state uniqueness and continuous dependence on data., Key words and phrases: diffusion of species; Cahn-Hilliard equations; viscosity; non-smooth regularization; nonlinearities; initial-boundary value problem; existence of solutions; continuous dependence

In this paper we deal with a doubly nonlinear Cahn-Hilliard system, where both an internal constraint on the time derivative of the concentration and a potential for the concentration are introduced. The definition of the chemical potential includes two regularizations: a viscosity and a diffusive term. First of all, we prove existence and uniqueness of a bounded solution to the system using a nonstandard maximum-principle argument for time-discretizations of doubly nonlinear equations. Possibly including singular potentials, this novel result brings improvements over previous approaches to this problem. Secondly, under suitable assumptions on the data, we show the convergence of solutions to the respective limit problems once either of the two regularization parameters vanishes., Comment: Key words and phrases: Cahn-Hilliard equation, nonlinear viscosity, non-smooth regularization, nonlinearities, initial-boundary value problem, bounded solutions, asymptotics