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ProBio is an outcome-adaptive, multiarm, multiple-assignment randomised, biomarker-driven platform trial in men with metastatic castration-resistant prostate cancer. Here we describe the amended clinical protocol, focusing on expansion of the trial to include patients with de novo metastatic hormone-sensitive prostate cancer.

Context The aim of this review is to describe the proportion of testicular germ cell tumours (tGCTs) with recurrence, and the timing and anatomical sites of relapse across different disease stages and after different treatment options. We summarise published follow-up protocols and discuss current and future developments to personalise follow-up for patients with tGCT. Evidence acquisition A systematic literature search was conducted and current guidelines and selected institutional follow-up protocols were reviewed. Evidence synthesis Of 302 publications, we screened 68 full texts and included 29 studies; 22 of these were retrospective and seven were prospective in nature, contributing data for 20 570 patients. The number of patients included per study ranged from 119 to 2483. We compared the guideline follow-up protocols of the European Society for Medical Oncology, European Association of Urology, National Comprehensive Cancer Network, and American Urological Association, as well as institutional follow-up protocols. The protocols differed in terms of the number, time points, and type of follow-up investigations. Conclusions Future research should assess how tGCT can be followed to ensure high adherence, define the role of miR-371a-3p microRNA during follow-up, and develop follow-up protocols after curative treatment in the metastatic setting. Patient summary In this review of follow-up protocols for men with testis cancer, we observed different recommendations and discuss future research areas to improve follow-up for these patients.

Context: Each year the European Association of Urology (EAU) produce a document based on the most recent evidence on the diagnosis, therapy, and follow-up of testicular cancer (TC). Objective: To represent a summarised version of the EAU guidelines on TC for 2023 with a focus on key changes in the 2023 update. Evidence acquisition: A multidisciplinary panel of TC experts, comprising urologists, medical and radiation oncologists, and pathologists, reviewed the results from a structured literature search to compile the guidelines document. Each recommendation in the guidelines was assigned a strength rating. Evidence synthesis: For the 2023 EAU guidelines on TC, a review and restructure were undertaken. The key changes incorporated in the 2023 update include: new supporting text regarding venous thromboembolism prophylaxis in males with metastatic germ cell tumours receiving chemotherapy; quality of life after treatment; an update of the histological classifications and inclusion of the World Health Organization 2022 pathological classification; inclusion of the revalidation of the 1997 International Germ Cell Cancer Collaborative Group prognostic risk factors; and a new section covering oncology treatment protocols. Conclusions: The 2023 version of the EAU guidelines on TC include the highest available scientific evidence to standardise the management of TC. Better stratification and optimisation of treatment modalities will continue to improve the high survival rates for patients with TC. Patient summary: This article presents a summary of the European Association of Urology guidelines on testicular cancer published in 2023 and includes the latest recommendations for management of this disease. The guidelines are a valuable resource that may help patients in understanding treatment recommendations.

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is similar to 99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

Background 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. Patients and methods FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. Results One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P = 0.032). Conclusions Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.

In this contribution, a novel approach for the modeling and numerical optimal control of hybrid (discrete–continuous dynamic) systems based on a disjunctive problem formulation is proposed. It is shown that a disjunctive model representation, which constitutes an alternative to mixed-integer model formulations, provides a very flexible, intuitive and effective way to formulate hybrid (discrete–continuous dynamic) optimization problems. The structure and properties of the disjunctive process models can be exploited for an efficient and robust numerical solution by applying generalized disjunctive programming techniques. The proposed modeling and optimization approach will be illustrated by means of optimal control of hybrid systems embedding linear discrete–continuous dynamic models.

This paper presents a modeling and numerical solution method for an integrated grade transition and production scheduling problem for a continuous polymerization reactor. The optimal sequence of production stages and the transitions between them is supposed to be determined for producing a given number of polymer grades at certain amounts and quality specifications in the most economical way. The production schedule has to satisfy due dates for specific orders. This operational problem is cast into a mixed-integer dynamic optimization problem. Disjunctions and logical constraints are combined with a validated differential–algebraic model describing the polymer process during the production of a specific grade as well as along a transition between two different grades. The modeling and solution approach proposed by Oldenburg et al. [Oldenburg, J., Marquardt, W., Heinz D., & Leineweber, D. B. (2003)] is tailored to this problem class to provide an efficient solution technique. An industrial example process serves as an example to illustrate the modeling and solution techniques suggested.

BACKGROUND: The purpose of this study was to validate a prognostic index [surgical complete response 1 (sCR1)] in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: Data and specimens from 61 patients with normalized tumor markers and postchemotherapy viable nonteratomatous NSGCT treated in 13 institutions were collected. RESULTS: With a median follow-up of 5.4 years, the 5-year progression-free survival (PFS) rate was 65%; the 5-year overall survival (OS) rate was 72%. Favorable PFS was predicted by a complete resection

Industrial processes are usually operated in a highly dynamic environment, e.g. with time-varying market prizes, customer demand, technological development or up- and downstream processes. Due to these disturbances, the operational strategies comprising objectives and constraints are regularly adjusted to reflect a change in the environment in order to achieve or maintain optimal process performance. The related operational objectives need not only be of an economical nature, but can also include flexibility, risk or ecological objectives. In this paper, a novel methodology is presented for the modeling and dynamic predictive scheduling of operational strategies for continuous processes. Optimal control actions are computed on a moving horizon employing discrete-continuous modeling and mixed-logic dynamic optimization as introduced by Oldenburg et al. (2003). The approach is successfully demonstrated considering the operation of a wastewater treatment plant.

This paper treats the solution of nonlinear optimization problems involving discrete decision variables, also known as generalized disjunctive programming (GDP) or mixed-integer nonlinear programming (MINLP) problems, that arise in process engineering. The key idea is to eliminate the discrete decision variables by adding a set of continuous variables and constraints that represent the discrete decision space of the optimization problem. With such a reformulation, we are able to apply solution algorithms for purely continuous nonlinear optimization problems to efficiently calculate local minima of GDP or MINLP problems. In this contribution, we propose different alternatives to reformulate GDP/MINLP problems as continuous optimization problems. We furthermore investigate theoretical properties of the different reformulations with regard to their numerical solution. The proposed formulations are illustrated and analyzed on the basis of optimization problems dealing with process engineering applications involving stationary as well as dynamic process models.

A novel class of methods for solving path and end point constrained dynamic optimization problems is proposed. These methods aim at improving the performance of dynamic optimization algorithms employed in on-line applications, where the required solution time is a major concern. The presented approaches are all based on the reformulation of the dynamic model constraints into a higher order differential model representation, in which state variable derivatives are eliminated. Based upon this representation, the complete state information can be accessed analytically through explicit equations, implying that numerical integration, as required by sequential optimization techniques, is thus avoided. Since these equations depend on only a relatively few variables containing the entire dynamic system behavior, advantages over simultaneous optimization strategies can be expected as well. Three different dynamic optimization problem formulations involving higher order differential model representations are discussed, of which the first requires the dynamic system to be differentially flat. The remaining two, however, do not depend on the flatness property. By means of a set of examples, the three problem formulations are illustrated and classified according to their potential to improve the efficiency in solving dynamic optimization problems.

A novel method for solving path and endpoint constrained dynamic optimization problems is proposed. State-of-the-art direct optimization techniques approximate the continuous optimization problem to a nonlinear algebraic programming (NLP) problem either by state and control vector or by control vector parameterization only. The novel optimization approach presented here is based on the reformulation of the nonlinear dynamical system into a higher order differential representation comprising a set of algebraic equations in the state variables as well as in the control and auxiliary variables and their derivatives. Hence, the dynamic optimization problem can often be converted into a formulation in which the state variables and their derivatives are entirely eliminated. This system representation combined with a suitable parameterization strategy leads to compact NLPs which promise significant reduction of computational effort compared to established approaches. The method is illustrated with the productivity optimization of a semi-batch reactor.

Endothelins, due to their potent vasoactivity and mitogenicity, appear to play an important role in the brain, where all components of the endothelin system, peptides, receptors and converting enzyme, are expressed. To further elucidate the role of the cerebral endothelin system, astrocytes and cerebral vessels from sl/sl rats, devoid of functional endothelin B receptors, have been employed. Astrocytes from sl/sl rats display the following abnormalities as compared to wild-type (+/+) cells: (i) elevated basal extracellular endothelin-1 levels; (ii) exclusive presence of functional endothelin A receptors; (iii) increased extracellular endothelin-1 levels upon endothelin A receptor blockade; (iv) augmented basal endothelin-converting enzyme activity; (v) altered calcium response to endothelin-1. The basilar artery of sl/sl rats shows an enhanced constricting response to endothelin-1 and fails to dilate in response to endothelin-3, shifting the endothelin vasomotor balance to constriction. In conclusion, endothelin B receptors may be essential for restricting extracellular endothelin-1 levels in the brain, as well as for a balanced cerebral vasomotor action of endothelins.