A Novel Radiotherapeutic Approach to Treat Bulky Metastases Even From Cutaneous Squamous Cell Carcinoma: Its Rationale and a Look at the Reliability of the Linear-Quadratic Model to Explain Its Radiobiological Effects

Introduction: Metastatic cutaneous squamous cell carcinoma (cSCC) is a very rare condition. The lack of definition of an oligometastatic subgroup means that there is no consensus for its treatment, unlike the mucosal head and neck counterpart. Like the latter, the cutaneous form is able to develop bulky tumor masses. When this happens, the classic care approach is just for palliative intent due to a likely unfavorable benefit–risk balance typical of aggressive treatments. Here we proposed a novel radiotherapy (RT) technique to treat bulky metastases from cSCC in the context of an overall limited tumor burden and tried to explain its clinical outcome by the currently available mathematical radiobiological and ad hoc developed models. Methods: We treated a case of facial cSCC with three metastases: two of them by classic stereotactic RT and the other by lattice RT supported by metabolic imaging (18F-FDG PET) due to its excessively large dimensions. For the latter lesion, we compared four treatment plans with different RT techniques in order to define the best approach in terms of normal tissue complication probability (NTCP) and tumor control probability (TCP). Moreover, we developed an ad hoc mathematical radiobiological model that could fit better with the characteristics of heterogeneity of this bulky metastasis for which, indeed, a segmentation of normoxic, hypoxic, and necrotic subvolumes might have been assumed. Results: We observed a clinical complete response in all three disease sites; the bulky metastasis actually regressed more rapidly than the other two treated by stereotactic RT. For the large lesion, NTCP predictions were good for all four different plans but even significantly better for the lattice RT plan. Neither the classic TCP nor the ad hoc developed radiobiological models could be totally adequate to explain the reported outcome. This finding might support a key role of the host immune system. Conclusions: PET-guided lattice RT might be safe and effective for the treatment of bulky lesions from cSCC. There might be some need for complex mathematical radiobiological models that are able to take into account any immune system’s role in order to explain the possible mechanisms of the tumor response to radiation and the relevant key points to enhance it

Time to care: why the humanities and the social sciences belong in the science of health

Health is more than the absence of disease. It is also more than a biological phenomenon. It is inherently social, psychological, cultural, and historical. Social and personal resources are both key components and key determinants of health, as it has been recognised by major health actors for decades [1–3]. However, open questions remain as to how to build systems that reflect the complexity of health, healthy lives, disease, and sickness, and in a context that is increasingly technologized. Although we find in the literature an increasing understanding of the complexity of health [4–7], the implementation of this knowledge lags behind. Biological approaches to health and disease, as a matter of fact, dominate the development of curative and preventive interventions. We argue that an urgent change of approach is necessary. Methods and concepts from the humanities and social science must be embedded in the concepts and methods of the health sciences and of public health, if we are to promote sustainable interventions capable of engaging with the recognized complexity of health, healthy lives, disease, and sickness. This resonates with the vision expressed by UK Health Secretary and by many policy documents [8,9] from the last decades. Yet, given the difficulties associated with interdisciplinary research, integrated strategies to understand and to intervene on the complexity of health and that engage with biological, social, psychological and behavioural factors are still needed. Our vision is one of radical interdisciplinarity, integrating aspects of biological, psychological, social, and humanities approaches across areas of urgent health need. These areas include, but is not confined to, chronic conditions such as the obesity epidemic, cancer, mental health. Radical interdisciplinarity entails the practical, methodological, and conceptual integration of approaches to health, as they are developed in the health and social sciences, and in the humanities. It is the combination of cognitive resources from individuals belonging to different disciplines, who accept and respect the division of labour and the resulting epistemic dependence to tackle phenomena that would not be adequately conceptualised within any of the involved discipline alone [10]. In what follows, we describe our current understanding of these three aspects, and describe how radical interdisciplinarity would change them.Not funde

Mechanisms and Difference-Making

I argue that difference-making should be a crucial element for evaluating the quality of evidence for mechanisms, especially with respect to the robustness of mechanisms, and that it should take central stage when it comes to the general role played by mechanisms in establishing causal claims in medicine. The difference- making of mechanisms should provide additional compelling reasons to accept the gist of Russo-Williamson thesis and include mechanisms in the protocols for Evidence- Based Medicine (EBM), as the EBM+ research group has been advocatin

In defence of activities

In this paper, we examine what is to be said in defence of Machamer, Darden and Craver’s (MDC) controversial dualism about activities and entities (Machamer, Darden and Craver’s in Philos Sci 67:1–25, 2000). We explain why we believe the notion of an activity to be a novel, valuable one, and set about clearing away some initial objections that can lead to its being brushed aside unexamined. We argue that substantive debate about ontology can only be effective when desiderata for an ontology are explicitly articulated. We distinguish three such desiderata. The first is a more permissive descriptive ontology of science, the second a more reductive ontology prioritising understanding, and the third a more reductive ontology prioritising minimalism. We compare MDC’s entities-activities ontology to its closest rival, the entities-capacities ontology, and argue that the entities-activities ontology does better on all three desiderata

Mechanisms, Then and Now: From Metaphysics to Practice

For many old and new mechanists, Mechanism is both a metaphysical position and a thesis about scientific methodology. In this paper we discuss the relation between the metaphysics of mechanisms and the role of mechanical explanation in the practice of science, by presenting and comparing the key tenets of Old and New Mechanism. First, by focusing on the case of gravity, we show how the metaphysics of Old Mechanism constrained scientific explanation, and discuss Newton’s critique of Old Mechanism. Second, we examine the current mechanistic metaphysics, arguing that it is not warranted by the use of the concept of mechanism in scientific practice, and motivate a thin conception of mechanism (the truly minimal view), according to which mechanisms are causal pathways for a certain effect or phenomenon. Finally, we draw analogies between Newton’s critique of Old Mechanism and our thesis that the metaphysical commitments of New Mechanism are not necessary in order to illuminate scientific practice

An introduction to the Philosophy of Information

This book serves as the main reference for an undergraduate course on Philosophy of Information. The book is written to be accessible to the typical undergraduate student of Philosophy and does not require propaedeutic courses in Logic, Epistemology or Ethics. Each chapter includes a rich collection of references for the student interested in furthering her understanding of the topics reviewed in the book. The book covers all the main topics of the Philosophy of Information and it should be considered an overview and not a comprehensive, in-depth analysis of a philosophical area. As a consequence, 'The Philosophy of Information: a Simple Introduction' does not contain research material as it is not aimed at graduate students or researchers

Compare and Contrast: How to Assess the Completeness of Mechanistic Explanation

Opponents of the new mechanistic account of scientific explanation argue that the new mechanists are committed to a ‘More Details Are Better’ claim: adding details about the mechanism always improves an explanation. Due to this commitment, the mechanistic account cannot be descriptively adequate as actual scientific explanations usually leave out details about the mechanism. In reply to this objection, defenders of the new mechanistic account have highlighted that only adding relevant mechanistic details improves an explanation and that relevance is to be determined relative to the phenomenon-to-be-explained. Craver and Kaplan (B J Philos Sci 71:287–319, 2020) provide a thorough reply along these lines specifying that the phenomena at issue are contrasts. In this paper, we will discuss Craver and Kaplan’s reply. We will argue that it needs to be modified in order to avoid three problems, i.e., what we will call the Odd Ontology Problem, the Multiplication of Mechanisms Problem, and the Ontic Completeness Problem. However, even this modification is confronted with two challenges: First, it remains unclear how explanatory relevance is to be determined for contrastive explananda within the mechanistic framework. Second, it remains to be shown as to how the new mechanistic account can avoid what we will call the ‘Vertical More Details are Better’ objection. We will provide answers to both challenges

First Measurement of Hard Exclusive π- Δ++ Electroproduction Beam-Spin Asymmetries off the Proton

The polarized cross-section ratio σLT′/σ0 from hard exclusive π-Δ++ electroproduction off an unpolarized hydrogen target has been extracted based on beam-spin asymmetry measurements using a 10.2 GeV/10.6 GeV incident electron beam and the CLAS12 spectrometer at Jefferson Lab. The study, which provides the first observation of this channel in the deep-inelastic regime, focuses on very forward-pion kinematics in the valence regime, and photon virtualities ranging from 1.5 GeV2 up to 7 GeV2. The reaction provides a novel access to the d-quark content of the nucleon and to p→Δ++ transition generalized parton distributions. A comparison to existing results for hard exclusive π+n and π0p electroproduction is provided, which shows a clear impact of the excitation mechanism, encoded in transition generalized parton distributions, on the asymmetry

Extrapolating from model organisms in pharmacology

In this chapter we explore the process of extrapolating causal claims from model organisms to humans in pharmacology. We describe and compare four strategies of extrapolation: enumerative induction, comparative process tracing, phylogenetic reasoning, and robustness reasoning. We argue that evidence of mechanisms plays a crucial role in several strategies for extrapolation and in the underlying logic of extrapolation: the more directly a strategy establishes mechanistic similarities between a model and humans, the more reliable the extrapolation. We present case studies from the research on atherosclerosis and the development of statins, that illustrate these strategies and the role of mechanistic evidence in extrapolation